Abnormal States of

Brain and Mind

Readings from the Encyclopedia ofNeuroscience

Abnormal States of Brain and Mind

Selected and with an Introduction by J. Allan Hobson

Comparative Neuroscience and Neurobiology

Selected and with an Introduction by Louis N. Irwin

Learning and Memory

Selected and with an Introduction by Richard F. Thompson

Sensory Systems 1: Vision and Visual Systems

Selected and with an Introduction by Richard Held

Sensory Systems II: Senses Other than Vision

Selected and with an Introduction by Jeremy Wolfe

Speech and Language

Selected and with an Introduction by Doreen Kimura

States of Brain and Mind

Selected and with an Introduction by J. Allan Hobson
Readings from the
Encyclopedia of Neuroscience

Abnormal States of
Brain and Mind
Selected and with an Introduction by
J. Allan Hobson

Springer Science+Business Media, LLC

Library of Congress Cataloging-in-Publication Data
Abnormal states of brain and mind.
(Readings from the Encyclopedia of neuro-
science)
Bibliography: p.
I. Neurology. 2. Psychiatry. 3. Neuro-
psychiatry. I. Hobson, J. Allan, 1933-
RC 341.A26 1989 616.8 88-7822
ISBN 978·1·4899·6770·1

© 1989 by Springer Science+ Business Media New YOrk

Originally published by Birkhii.user Boston, Inc in 1989

Copyright is not claimed for works by U.S. Government employees.

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9 87 6 54 32 1

ISBN 978-1-4899-6770-1 ISBN 978-1-4899-6768-8 (eBook)

DOI 10.1007/978-1-4899-6768-8
Series Preface

This series of books, "Readings from the Encyclopedia ofNeuroscience;' consists of collec-
tions of subject-clustered articles taken from the Encyclopedia of Neuroscience.
The Encyclopedia of Neuroscience is a reference source and compendium of more than
700 articles written by world authorities and covering all of neuroscience. We define neu-
roscience broadly as including all those fields that have as a primary goal the understand-
ing of how the brain and nervous system work to mediate/control behavior, including the
mental behavior of humans.
Those interested in specific aspects of the neurosciences, particular subject areas or
specialties, can of course browse through the alphabetically arranged articles of the Ency-
clopedia or use its index to find the topics they wish to read. However, for those readers-
students, specialists, or others-who will find it useful to have collections of subject-
clustered articles from the Encyclopedia, we issue this series of "Readings" in paperback.
Students in neuroscience, psychology, medicine, biology, the mental health professions,
and other disciplines will find that these collections provide concise summaries of cutting-
edge research in rapidly advancing fields. The nonspecialist reader will find them useful
summary statements of important neuroscience areas. Each collection was compiled, and
includes an introductory essay, by an authority in that field.

George Adelman
Editor,
Encyclopedia of Neuroscience
Contents

Series Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
Introduction
J. Allan Hobson . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XI

Addiction
Harold Kalant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Aging of the Brain
Arnold B. Scheibel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Alcoholism
Donald W. Goodwin 6
Alzheimer's Disease
Joseph T. Coyle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Amnesia
Larry R. Squire . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Amphetamines
Norman J. Uretsky. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Antidepressants
Elliott Ricketson . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Anxiety and Anxiety Disorders

David V. Sheehan and Kathy H. Sheehan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Autism
Edward M. Ornitz . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Behavior Therapy, Applied Behavior Analysis, and Behavior Modification

Leo J. Reyna . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Behavioral Medicine
Neal E. Miller . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Cocaine
Roger D. ~iss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Coma
Fred Plum and Harriet 0. Kotsoris. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Convulsive Therapy
Max Fink . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Creutzfeldt-Jakob Disease
Clarence J. Gibbs, Jr., and David M. Asher. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Deafness
Joseph E. Hawkins, Jr. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
viii Contents

Dementia
Fred Plum 39
Down Syndrome
Charles J. Epstein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Dyslexia
Albert M. Galaburda . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Eating Disorders
Domeena C. Renshaw . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Epilepsy
Massimo Avoli and Pierre Gloor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Eye Movement Dysfunctions and Mental Illness
Philip S. Holzman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Fetal Alcohol Syndrome
William J. Shoemaker . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Gilles de Ia Tourette Syndrome
Arnold J. Friedhoff . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Hallucinogenic Drugs
John R. Smythies and C. B. Ireland. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Heroin (Diacety!morphine)
Conan Kornetsky . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
Huntington's Disease (HD)
James F. Gusella . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Lithium in Psychiatric Therapy
James W. Jefferson and John H. Greist . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
Marijuana
Robert C. Petersen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Mental Illness, Genetics of
Steven Matthysse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Mental Illness, Nutrition and
John W. Crayton . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Mental Retardation
Hugo W. Moser . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
Monoamine Oxidase (MAO) Inhibitors in Psychiatric Therapy
Dennis L. Murphy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
Mood Disorders
Alan J. Gelenberg . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76

Morphine
Terrance M. Egan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Neuroleptic Drugs
Solomon H. Snyder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

Neuropharmacology
Jack R. Cooper . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
Phencyclidine
Robert C. Petersen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
 Contents ix

Phenylalanine and Mental Retardation (PKU)

William L. Nyhan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
Premenstrual Syndrome
Stephanie J. Bird . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Psychiatry, Biological
Herbert Pardes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Psychoanalysis
Charles Brenner 95
Psychopharmacology
Susan D. Iversen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
Psychosis
Gardner C. Quarton . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
Psychosurgery
Lyle W. Bivens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
Schizophrenia
Erik Stromgren 103
Sleep Disorders
Thomas Roth, Timothy Roehrs, and Frank Zorick . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
Stress, Neurochemistry of
Adrian J. Dunn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
Substance Abuse
Steven M. Mirin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
Tolerance and Physical Dependence
William R. Martin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
Introduction

The subjects of brain and mind continue to fascinate philosophers. Are they really two
entities? If so, how do we conceive of their relationship? If not, why do we persist in using
different names for them? Should we not begin, at least tentatively, to refer to a
brain-mind (or a mind-brain)? This "mind-brain problem" continues to divide clinicians.
Psychiatrists treat what they call mental illness, as if such states were not also disorders
of the brain. Neurologists diagnose brain diseases without considering subjective
experience as significant manifestations of brain function. How did this mind-body
schizophrenia arise? And can it be cured-or at least treated?
In the nineteenth century psychiatry and neurology were but one branch of medical
science, and it was called neurology. Hughlings Jackson, a distinguished neurologist, was
superintendent of the West Riding Lunatic Asylum in Yorkshire, where his observations
of patients led to his dynamic theories of the evolution and dissolution of brain and
behavior. And when William James published his Principles of Psychology in 1890 he
began with what was then known about the brain. Sigmund Freud, the founder of psy-
choanalysis and the proponent of the psychodynamic approach to mental illness, was
trained as a neurologist and worked in that capacity until his clinical interest in hyponosis
and hysteria convinced him of the need to develop a psychology that was independent of
neurology. Freud concluded that he could not build a psychological theory upon what was
known about neurons in the 1890s and proceeded to elaborate his psychoanalytic theory
as if it had no relationship to brain science. The resulting separation of neurology and
psychiatry reflected a paradoxical and unproductive resurgence of brain-mind dualism
that has plagued medicine through the first half of the twentieth century.
With the recent explosive growth of neurobiological science, we are now witnessing
renewed interest in brain-mind integration. Psychiatric research has come to look more
and more neurologic. And with the growth of behavioral and cognitive science, neurology
has a renewed interest in many of the same clinical conditions that it earlier relegated to
psychiatry. Hughlings Jackson, William James, and even the youthful Freud, would all be
pleased by this recent turn of events. Much of the groundwork for this clinical revolution
is to be found in the basic science topics covered in a companion set of selections from the
Encyclopedia of Neuroscience called States of Brain and Mind.
This clinical volume abounds with encouraging examples of cross-field fertilization.
The 50 selections cover the major categories of clinical dysfunction and the treatments
used to deal with them. Among the dysfunctions, a distinction may be usefully made
between "diseases;' -where the pathogenesis is known to be structural (and often
genetic)- and "disorders;' where the pathogenesis is either unknown or known to be func-
tional, hence situational, or environmentally determined. By this definition there are only
five diseases:
Alzheimer's Disease
Creutzfeldt-Jakob Disease
Down Syndrome
Huntington's Disease (HD)
Phenylalanine and Mental Retardation (PKU)
xii Introduction

Each of these entities is characterized by mental defects that result from a well-established
neuropathology.
Many of the conditions covered may well be diseases, but in most cases we don't yet
know enough to say. In this category we consider the following entries:

Autism
Dyslexia
Epilepsy
Gilles de la Tourette Syndrome
Mental Illness, Genetics of
Mental Illness, Nutrition and
Mental Retardation
Mood Disorders
Schizophrenia

This list contains most of the problems at the cutting edge of biological research and the
patients affected by these disorders, not surprisingly, are of interest to both neurologically
oriented psychiatrists and behavioral neurologists.
Other topics included are either the manifestations of well-known neuropathologies or
may be the nonspecific outcomes of a variety of functional causes. In this group of "symp-
toms and signs" we consider:

Amnesia
Coma
Deafness
Dementia
Eating Disorders
Eye Movement Dysfunctions and Mental Illness
Psychosis
Sleep Disorders

Some of the items listed here bridge the gap between mind and body. For example, amne-
sia and psychosis may both be entirely functional, as well as sometimes symptoms of
organic brain disease.
The following list of states is even more clearly functional and includes conditions that
are even sometimes entirely normal:

Addiction
Aging of the Brain
Alcoholism
Anxiety and Anxiety Disorders
Fetal Alcohol Syndrome
Premenstrual Syndrome
Stress, Neurochemistry of
Substance Abuse
Tolerance and Physical Dependence

The heterogeneity of all these topics and the blurred boundaries between them helps us
understand why no rigid categorical system of classification can work. And it may help
explain my emphasis on the concept of state in this volume's title. It seems quite likely that
all of the above conditions are altered states of the brain-mind. What we need, then, is a
more clearly formulated state concept, not a more loosely constructed concept of disease.
Some of the entries in this volume describe whole fields that turn out to be highly
treatment-oriented. The wide range of treatments, from psychoanalysis (the talking cure)
to psychosurgery (lobotomy, lobectomy, cingulotomy, etc.)- both of which are often
recommended for the same disorders!- is a sign of our still monumental ignorance and the
obdurate difficulty of the subject matter:
 Introduction xiii

Behavior Therapy, Applied Behavior Analysis, and Behavior Modification

Behavioral Medicine
Convulsive Therapy
Neuropharmacology
Psychiatry, Biological
Psychoanalysis
Psychopharmacology
Psychosurgery
The last-and longest-category is a pharmacopeia of the chemicals that change our
brain-minds. Some are prescribed by doctors and some are sold on the streets for recrea-
tional purposes. In either case their use is almost always problematic because of side
effects, addiction and toxicity:
Amphetamines
Antidepressants
Cocaine
Hallucinogenic Drugs
Heroin (Diacetylmorphine)
Lithium in Psychiatric Therapy
Marijuana
Monoamine Oxidase (MAO) Inhibitors in Psychiatric Therapy
Morphine
Neuroleptic Drugs
Phencyclidine
The net result is a collection of papers that is more a scientific casebook than a compre-
hensive textbook of psychiatry-neurology. Being research-oriented, this compendium
should be useful as an adjunct to the texts of both fields, and it may thus serve well as a
reader to supplement medical school or undergraduate courses. We construe it also as a
potentially valuable guide to laymen seeking recent scientific views of all-too-common
clinical problems.

J. Allan Hobson, M.D.

Professor of Psychiatry
Harvard Medical School
Addiction
Harold Kalant

Addiction (or drug dependence, as the World Health Organiza- test drug as similar to, or different from, those of the standard
tion now recommends that it be called) is a concept that was drug(s) or placebo.
originally clear in empirical terms, but became progressively The reinforcing properties of drugs can also be studied expe-
more confused by successive attempts at official definitions. rimentally. The direct method consists of fitting the animal
In North America there is a tendency to regard physical depen- with an indwelling venous catheter connected to a reservoir
dence, as revealed by a withdrawal reaction, as the cardinal of drug solution by an infusion pump which is activated when
feature of addiction, but this is putting the cart before the the animal presses a lever in the operant chamber. By appropri-
horse. The essence of addiction is drug-seeking and drug-tak- ate choice of drug concentration, and programming of the
ing behavior that has become a central element of the individu- pump, the experimenter can cause a preselected dose of drug
al's life pattern. If the frequency and amount of drug taking to be injected in response to any desired pattern of bar pressing
are sufficiently high, and the circumstances of use are appropri- by the subject (i.e., the experimenter can set up a schedule
ate, tolerance and physical dependence are likely to result, of reinforcement). The more work an animal will expend to
and social, psychiatric and medical problems of various kinds obtain a dose of drug, the more strongly reinforcing the drug
may be produced, but these are all consequences of addiction. is inferred to be. The assessment can be made more rigorous
The fundamental question is: What causes the drug-taking be- by adding aversive consequences (e.g., electric shock) of the
havior to become so strongly established as to generate these same lever pressing, and seeing how much self-inflicted pun-
consequences? ishment the animal will endure while continuing to work for
drug injection.
An indirect method consists of administering a test drug to
Dependence and reinforced behavior an animal in one distinctive environment and a placebo in
Currently, the most widely accepted behavioral analysis of another, and then seeing which environment the animal prefers
addiction is based on the tenets of operant behavioral psychol- when given a free choice. Preference for the environment
ogy. Self-administration of a drug gives rise to two types of previously paired with the drug implies that the drug is rein-
effect that are held to be essential for producing dependence: forcing; preference for the other environment, that the drug is
(I) discriminative stimuli, i.e., those distinctive internal cues aversive. The direct and indirect methods do not give iden-
by which the drug taker can recognize the drug that has been tical results. In general, however, any drug that is self-
taken, and (2} reinforcing effects (in nonoperant terms, reward- administered by experimental animals is also self-administered
ing effects), which increase the probability of repeating the by humans, but humans will take some drugs that animals
self-administration. Most drugs, even highly reinforcing ones, will not.
also have aversive (i.e., punishing) effects which tend to reduce
the probability of repeated self-administration. Presumably the Types of reinforcement. The discrepancy noted above is prob-
net balance between reinforcing and aversive effects deter- ably due to the fact that self-administration studies often ex-
mines the dependence liability. The distinction may not be plore only primary positive reinforcement resulting from a
absolute: some investigators postulate that effects which are direct pharmacologic effect on a central neuronal circuit that
usually aversive may, in some circumstances, be reinforcing is presumed to mediate reinforcement. In humans, however,
to some users. other forms of reinforcement probably play a major role. For
example, secondary positive reinforcement can occur when
Methods of study. The discriminative properties of a drug can drug taking is linked to another reinforcer such as peer group
be compared experimentally with those of other drugs, in order approval for using the drug. Negative reinforcement occurs
to determine the degree of similarity or difference. In humans when the drug taking results in alleviation of an unpleasant
this can be done in double-blind trials by giving the subjects or aversive state such as anxiety, frustration, pain, or depres-
small doses of standard drugs and placebo, and asking which sion. These types of reinforcement are more difficult to study
one the test drug most closely resembles in its subjective ef- in experimental animals, but it is possible to do so.
fects. Experimental animals are trained to obtain food rewards
by pressing the correct lever in a two-lever operant chamber. Stimulus control. One further factor is required to convert
One lever is correct when the animal is performing under the strongly reinforced drug taking into addiction. Drug taking
influence of a small dose of a standard drug, and the second does not occur in a vacuum, but in a social, physical, and
lever is correct when the animal has received a different stan- psychological context. If the same context is present often
dard drug or placebo. The animal must then perform under enough, cues derived from it become conditionally linked to
the influence of a test drug, and the percentage of total re- the drug taking, which thus becomes a conditioned response
sponses it makes on each of the two levers gives a measure to those cues. In operant conditioning terms, the cues set the
of the degree to which the animal perceives the effects of the occasion for the drug taking response. In classical conditioning
2 Harold Kalan!

terms, the cues evoke the response, which is therefore no Various hypotheses concerning the neural substrates of rein-
longer a "voluntary" action. The subject is then considered forcement and addiction have been proposed. The strongest
to be addicted. evidence at present implicates dopaminergic or noradrenergic
fibers in the ventral tegmentum, and a possible modulatory
Substitution of dependence. A useful, rapid technique for role of endogenous opioid peptides, but the evidence is too
screening new drugs that may carry dependence liability is incomplete to permit a clear picture. It was recently reported
to test their ability to substitute for another drug on which (Bozarth and Wise, 1984) that the reinforcing action of mor-
the subject (human or experimental animal) is already depen- phine is exerted in the ventral tegmentum whereas physical
dent. If an animal trained to self-administer cocaine, for exam- dependence results from action in the periventricular gray sub-
ple, continues lever pressing when a different drug replaces stance.
cocaine, the new drug is presumably reinforcing and potentially
addictive. If a subject with physical dependence on morphine
fails to show a withdrawal reaction when a new drug replaces Individual predisposition
the morphine, the new drug is taken to have morphine-like Innumerable attempts to define an "addiction-prone personal-
actions and risks. However, physical dependence can be pro- ity" have been unsuccessful. However, there is good evidence
duced by passive exposure (i.e., without self-administration), for a genetic predisposition to alcoholism in the sons of alco-
and substitution of physical dependence is therefore a less holic fathers. It is not known whether the inherited trait is a
valid measure of addictive properties. greater drug sensitivity of the primary reinforcement mecha-
nism, or a feature such as an affective disorder that increases
Significance of tolerance and physical dependence the likelihood of secondary or negative reinforcement by alco-
hol. There is as yet no strong evidence concerning similar
Chronic ingestion of a drug, with sufficient frequency and genetic factors in addiction to other drugs. Nonhereditary psy-
amount, gives rise to adaptive changes in neuronal biochemis- chological or experimental factors probably also modify the
try and physiology which, augmented by behavioral factors magnitude of reinforcing effects of a drug in different individu-
including learning and classical conditioning, offset the action als.
of the drug and thus give rise to tolerance. When the drug is
withdrawn, these changes are maladaptive, giving rise to the
withdrawal reaction. The underlying neuronal changes vary Socioeconomic and cultural factors
by drug and include altered release of various neurotransmit-
ters, changes in binding properties of drug receptors, increases Epidemiological studies indicate that average values for daily
in activity of adenylate cyclase, (Na + + K +)-adenosine trip- consumption of alcohol by individuals within a population
hosphatase and other membrane-bound enzymes, and changes are distributed along a unimodal curve that shows no recogniz-
in lipid composition of plasma membranes. It is not yet known able discontinuity between alcoholics and social drinkers. Pre-
which of these are actually mechanisms of tolerance and which liminary data suggest similar distributions for consumption
are simply manifestations of it. of other potentially addictive drugs, including illicit ones.
The importance to addiction is that tolerance and physical Changes in mean per capita consumption by the whole popula-
dependence can increase the preponderance of reinforcing over tion, in response to economic, legal, and other factors, are
aversive effects of the drug. Tolerance to the aversive effects accompanied by corresponding shifts in the entire distribution-
of drugs appears to be much greater than to the reinforcing of-consumption curve. In one experiment, alcoholics and
or discriminative effects. Physical dependence can give rise nonalcoholics showed the same proportional change in alcohol
to a new source of negative reinforcement as users learn to intake in response to price change, even though their absolute
treat their withdrawal symptoms by taking more drugs. Thus, intake levels were very different. Such effects are also superim-
tolerance and physical dependence can increase the strength posed on cultural factors which give rise to differences in
of the addiction. per capita intake in different societies. Thus, it appears that
socioeconomic and cultural factors may affect the probability
of trying a drug and experiencing its reinforcing effects, but
Drugs and mechanisms of reinforcement they do not explain why one individual becomes addicted while
Drugs can be ranked in a hierarchy of intrinsic (primary) rein- another does not.
forcing efficacy. In experimental animals, cocaine and amphet-
amine-like drugs appear to be strongest, followed by heroin and
other potent tJ.-agonist opioids. Anxiolytics, rapidly acting bar- Further reading
biturates, and other sedatives are moderately effective, but Bozarth MA, Wise RA (1984): Anatomically distinct opiate receptor
ethanol is only weakly and inconsistently so. Cannabis and fields mediate reward and physical dependence. Science 224:516-
hallucinogens are aversive rather than reinforcing in animal 517
models; their use by humans implies an important role of Fishman J, ed. ( 1978): The Bases of Addiction. Berlin: Dahlem Kon-
secondary or negative reinforcement. ferenzen
Moore MH, Gerstein DR, eds. (1981): Alcohol and Public Policy:
The route of administration is very important. Operant condi-
Beyond the Shadow of Prohibition. Washington DC: National Acad-
tioning requires a close temporal relation between the drug-
emy Press
taking behavior and the onset of reinforcing effects. Therefore Smith JE, Lane JD. eds. (1983): The Neurobiology of Opiate Reward
intravenous injection, resulting in almost immediate onset, Processes. Amsterdam: Elsevier
has the highest addictive risk; inhalation or smoking is almost Woolverton WL, Schuster CR (1983): Behavioral and pharmacologi-
as rapid and effective; oral ingestion of the same drug, with cal aspects of opioid dependence: mixed agonist-antagonists. Phar-
a long absorption delay, is the least effective. macal Rev 35:33-52
Aging of the Brain
Arnold B. Scheibel

The processes of maturation and aging of the brain are becom- tions, may permanently alter the structure of the cell. These
ing increasingly relevant and active research areas as the aver- ideas are still in an early stage of development and exemplify
age longevity of the population increases. In 1900, about 4% the questions that surround the processes of aging in general,
of the population of the United States exceeded the age of and of the nervous system in particular.
65. In 1980, the figure approximated 12%, and it is predicted
that by the year 2000, more than 15% of the population (at
Structural changes
least 35 million people) will be 65 years of age or older.
Although remarkably little is known about the aging process, A number of changes, both gross and microscopic, have been
it is increasingly clear that senility and aging are not synony- reported in the brains of the aged, although variation is the
mous. One of the major thrusts of recent neural research has rule rather than the exception. The brain itself is often some-
been to separate the phenomenon of normal, vigorous aging what reduced in size and weight, especially beyond the eighth
from a broad range of disease patterns that alter the structure decade of life. Ten to fifteen percent decrements are frequently
and function of the brain and the cognitive and psychosocial quoted, although interindividual differences are large. Some
behavior of the individual. aged brains show mild to moderate gyral atrophy and sulcal
widening, but this is not the rule. The surrounding meninges
are frequently more opaque and milky in appearance than those
Possible causal factors
of the young brain, and may be adherent to underlying cortex.
Experience indicates that all living things have finite lives, Isolated deposits of calcium are found in and around the
whether they be the ephemeral summer of the butterfly, a Pacchionian granulations near the vertex of the hemisphere.
thousand days for the rat, the reported hundred-year-long lives The ventricular system may show alterations in silhouette,
of large tortoises, or the multi-thousand-year histories of giant and computed axial tomography (CT) and nuclear magnetic
redwoods and bristle cone pines. The concept of genetic pro- resonance (NMR) scans may show enlarged ventricular shad-
gramming of the aging process seemed to receive support from ows and evidence of cortical atrophy. Such phenomena are
Hayflick's studies of the late 1950s and early 1960s in which noted with increasing regularity in patients over age 80.
young, actively dividing connective tissue cells raised in vitro Microscopically, a group of well-known stigmata are seen
appeared limited to a certain maximum number of mitotic in routine Nissl or reduced silver-stained preparations. Their
divisions (50), after which degenerative changes invariably incidence varies rather widely among individuals, although
set in. In retrospect, these classic experiments now seem less there is a general tendency toward increased frequency with
convincing due to the methodological errors involved, and, age. Neuronal cell bodies gradually accumulate masses of re-
although the concept of genetic control remains intuitively fractile granules with high lipid content, known as lipofuscins.
appealing, the case is considered far from proven. A presently The significance of these so-called aging pigments is not clear,
favored alternative theory operating either independently, or and they have been found as early as the I Oth year of life in
more likely in tandem with the proposed genetic constraint, cells of the inferior olive. The present consensus is that they
envisages the possibility of progressive damage to the cell represent the remains of lysosomal and mitrochondrial mem-
from external or internal factors, resulting in a cumulative branes that have accumulated, due perhaps to gradual failure
pattern of dysfunctions. For example, toxic factors within the of mechanisms for turnover and reutilization. As such, they
environment (i.e., chemical carcinogens and background radia- do not necessarily constitute a direct threat to the neuron except
tion of terrestrial or galactic origin) may slowly affect the to the extent that they preempt increasing amounts of cyto-
cell DNA content and protein-synthesizing machinery, leading plasmic space previously used for synthesis of glycoproteins,
to errors in synthesis with resultant progressive changes in lipoproteins, neurotransmitters, etc. One interesting and oppos-
cell structure and function. This summation of many small ing view maintains that the appreciable content of myoglobin
developing errors in the synthetic and enzymatic machinery and respiratory enzymes allows lipofuscin granules to serve
of the cell is conceived as mounting to a point beyond which a positive role in providing energy to neurons under conditions
conditions for cell life become impossible (error-catastrophe of low oxygen tension. Coarser vacuolization of the cytoplasm,
theory). Obviously, this putative process might complement usually concentrated in the area of development of the apical
and potentiate a set of existing genetic instructions also directed dendrite shaft in cortical pyramidal cells, is known as granulo-
toward the cell's eventual demise. vacuolar degeneration of Simchowitz and is of equally un-
However, normal oxidative metabolic activity of the cell known etiology.
may itself result in cumulative damage. Of particular interest The neurofibrillary tangle is a structural alteration of neu-
is the development of a family of free radicals of oxygen ronal cytoplasm that may involve soma, dendrites, and axon.
(e.g., singlet oxygen, hydrogen peroxide, superoxide, and hy- Initially recognized by Alzheimer and Simchowitz as one of
droxyl radicals) that, through cross-linkage or cleavage reac- two defining microcriteria of individuals dying with dementia,
4 Arnold B. Shiebel

it is also found in very small numbers in the normal aged. to dementing syndromes such as Alzheimer's disease where
Electron microscope study reveals that the tangle consists of more than half of the complement of locus ceruleus cells may
paired helical filaments about 22 nm in width which braid disappear.
loosely around each other with a characteristic series of partial Carefully controlled studies indicate that in the rat the only
twists, each 80 nm from the next. Of uncertain origin, these significant cerebral cell losses occur during the first I 00 days
paired filaments do not seem directly derivative of the neuro- of life in what might be considered a period of adaptation
filaments and microtubules they replace. However, there is and fine tuning to the environment. After this, there is no
some evidence for cross-reaction between antibodies to tubulin further discernible neuronal loss, even at 900 days of age
(substrate for microtubules) and neurofibrillary tangles, but when the rats are beginning to die of natural causes.
not to neurofilaments. The import of the neurofibrillary tangles Although the weight of evidence from both animal and hu-
to the neuron remains uncertain, but it has been suggested man studies now increasingly points to negligible neuronal
that their development impedes intracellular axonal and den- loss during the normal, uncomplicated aging process, a large
dritic transport. number of cells appear to undergo changes in the dendritic
Accompanying these characteristically intracellular altera- (and axonal) extensions of the soma. Many neurons show
tions is the development of small foci of destruction in the progressive restriction and atrophy of their more peripheral
surrounding neuropil, the senile plaque of Alzheimer. These dendrite branches and, especially in cortical pyramidal cells,
are classically described as containing central cores of Congo among the basilar shafts. Accompanying this is irregular loss
Red-positive, amyloid-like material, surrounded by radial of dendrite spines and frequent beaded swellings along the
aurae of degenerating dendritic and axonal tissue. They consti- remaining dendritic branches. These changes can be related
tute the second component of the two major histopathological in general terms to progressive loss of protein-synthesizing
criteria of dementia and, like neurofibrillary tangles, are pres- capabilities due, perhaps in part, to increasing incursions upon
ent in more restricted number in the brains of most aged indi- cytoplasmic space by lipofuscin deposits and neurofibrillary
viduals. The density of senile plaques has been said to correlate tangles. However, it has also been shown that the potential
positively with the degree of cognitive impairment in dementia, for neuronal growth is not lost during aging. Accompanying
although these data have recently been subject to question. the progressive destruction of some dendritic systems, it ap-
Intensive biochemical and immunocytological analyses of pears that other neurons grow further dendritic extensions,
these structures are presently under way. Now known to consist thereby increasing their available synaptic areas (Fig. 1). The
of an amyloid type-B core, rich in immunoglobulin G (IgG), concept of two types of neuronal response to aging, one involv-
it has been suggested that this primarily represents an antigen- ing dendritic retraction and one reactive dendritic expansion,
antibody complex, perhaps resulting from globulin leakage brings with it a number of exciting implications for providing
through a failing blood brain barrier with subsequent attack more effective and fulfilling lives for the elderly.
upon neurons, erroneously identified as foreign antigens. In- During the first half of this century, brain aging and dementia
deed the high incidence of perivascular locations for plaques
and the report from several laboratories of high titers of anti-
brain antibodies in old mice support this interpretation. On
the other hand, data have also been presented identifying these
areas as degenerating cholinergic presynaptic terminals. This
interpretation has attracted a good deal of recent interest be-
cause of the developing age- and dementia-related deficit in
cholinergic neurons in the basal forebrain (especially the nu-
cleus basalis of Meynert). However, the size and structure of
senile plaques do not particularly support this idea.
All the histopathological changes so far described appear
most intensively in the limbic system, especially the entorhinal
cortex and hippocampus. They are also found widely through-
out the rest of the central nervous system, however, including
cerebral neocortex, diencephalon, brain stem, and spinal cord.
Since interindividual variation is the rule in the aged brain,
these descriptions represent a distillation and summary rather
than the expected picture of the brain of each aged individual.
The problem of neuronal loss has been a hotly debated one
and is still not settled. The few quantitative studies dating
from the late 1950s and 1960s suggested neuron loss of up
to 30% in the normal aging cerebral neocortex. More detailed
recent investigations based on larger numbers of cases indicate
that these levels of neuronal loss, in normal aging at least,
may have been excessive, based as they were on the study
of a few areas in a limited number of brains. More broadly
sampled data suggest a pattern of modest loss of neurons,
primarily large cortical cells, with compensatory dendritic
growth in adjacent neurons. The cholinergic cell masses of Figure 1. Two possible patterns of age-related alterations in cortical pyra-
the basal forebrain and the noradrenergic cells of the locus midal cells. The normal mature neuron (A) may show regressive dendritic
ceruleus undergo undoubted change during the aging process, changes characterized by loss of basilar dendritic branches and eventual
but even here, declining function may be more an expression loss of the entire dendritic tree (D, E, F). Other neurons (B, C) may
of waning metabolic vigor and decreased axodendritic dimen- show progressive increase in dendritic branching. Drawing based on Golgi
sions than of massive neuronal loss. This is in sharp contrast impregnations.
 Aging of the Brain 5

were usually associated with visible changes in the major arte- Catecholaminergic systems also show moderate to marked
ries of the central nervous system. Cerebral arteriosclerosis alteration in the aged brain. Levels of both dopamine and
was considered a necessary accompaniment and, in fact, virtu- norepiniphrine synthesis decrease, as do the numbers of ad-
ally synonymous with aging and senility. Careful studies dur- renergic and dopaminergic receptors. Marked attenuation of
ing the 1950s showed the inaccuracy of such concepts, and norepinephrine synthesis in the hypothalamus may, in tum,
today, large-vessel disease is seldom considered to contribute be responsible, at least in part, for decrease in the synthesis
significantly to the picture of general brain aging. Recent inves- of certain hypothalamic hormones.
tigations with positron emission tomography (PET) scanning Significant cell loss has been reported in the locus ceruleus,
methods and xenon clearance techniques have again called the single most important source of brain parenchymal norepi-
attention to the adequacy of blood flow and oxygen and glucose nephrine. The substantia nigra, a major source of dopamine,
metabolism in the aging brain. The scanning electron micro- also undergoes histological alterations that include microvascu-
scope and immunohistochemical studies have, coincidentally, lar changes and neuronal loss. The serotonin-rich systems of
focused interest on the microcirculation (capillary bed) of the the raphe seem, on the other hand, to be somewhat less vulner-
brain and on the plexus of neural fibers that normally innervate able. Resultant maintenance of minimally disturbed titers of
their walls. Subtle changes in this delicate but all-pervasive serotonin in a setting of falling catecholaminergic levels may
system may prove to have significant impact on the maintained conceivably be related to a high incidence of disturbed sleep
vigor or decline of brain structure and function. patterns and depression in the aged.
A broad range of age-related neuroendocrine changes are
known to exist. Although such alterations are documented
Biochemical and metabolic changes
by innumerable anecdotal observations, regional study of the
It is becoming clear that the aging process entails a broad mechanisms involved is in its early phases. For instance, the
range of biochemical and metabolic changes. Among these, importance of the ovary as a pacing factor in the aging female
alterations in neurotransmitter content and activity figure prom- rat is receiving documentation in many laboratories. At an
inently. As many as 90% of neurons are cholinergic, synthesiz- equally obvious level, the high likelihood of occurrence of
ing, transporting, and releasing, or else being synaptically benign prostatic hypertrophy and prostatic cancer in the aging
dependent upon, acetylcholine. Cholinergic systems are highly male is being related in meaningful fashion to age-related alter-
energy dependent, and age-related decreases in several impor- ations in testosterone metabolism that may lead to unbalanced
tant glycolytic enzymes have been reported. A link might thus growth stimulation. In a more global sense, the entire aging
conceivably be postulated between altered glycolytic energy process can apparently be slowed by early restriction of nutri-
mechanisms and cognitive function. tional input, which seems to delay pubescence and maturation.
The most important concentration of acetylcholine-rich neu- Finally, increasing imbalance among the various neurotrans-
rons is found in the basal forebrain area, in and around the mitters, and in particular among those that are aminergic,
nucleus basalis of Meynert and ventral pallidum. Most studies appears to exert progressive impact upon the hypothalamus,
indicate mild to moderate age-related cell loss in these areas. pituitary, and pineal gland, leading to cascades of dysfunction
Associated with (although not entirely dependent upon) this that manifest themselves at every level of organization.
loss are decreases in acetylcholine content in various portions Although the picture presented appears to emphasize regres-
of the brain, lower levels of the synthesizing enzyme, choline sive elements, a much more positive picture of the normal
acetyltransferase, and decreased numbers of acetylcholine re- aging brain can now be painted. Accumulated experience can
ceptor binding sites. The relevance of these alterations to cog- more than make up for age-related loss in the speed of cerebral
nitive changes in the elderly, such as impairment of recent processing or of memory recall. Experimental evidence conclu-
memory function, are not entirely clear. Of uncertain import, sively demonstrates the continued plasticity of even the very
also, is the apparent loss of fluidity of the cytoplasmic mem- old brain. Continual environmental enrichment and challenge
brane of the cell as the lipoprotein structure changes, a possible appear to enhance cognitive power in the aged. Under condi-
result of progressive diminution of choline content. Age-related tions of optimally maintained health, increasing numbers of
increases in membrane microviscosity may bring with them individuals in their 70s and 80s and beyond continue to hold
a significant train of sequelae including, initially, a higher responsible positions, or otherwise distinguish themselves in
capacity for receptor binding followed by enhanced rates of the arts and in certain of the sciences. In every case, the
receptor loss with eventual overall reduction in receptor bind- touchstone appears to be activity, involvement, and purpose!
ing affinity. Mechanisms responsible for these changes remain
uncertain,· but it has been postulated that increased microvis-
cosity of the cell membrane leads first to increased exposure Further reading
of those receptors out of the plane of the membrane, after
which the uncovered receptors are progressively sloughed off Finch C, Hayfiick L, eds (1977): Handbook of the Biology of Aging.
into the surrounding medium. This suggests that membrane- New York: Van Nostrand-Reinhold
Stein DO, ed (1980): The Psychobiology of Aging: Problems and
bound proteins such as receptors are maintained in dynamic Perspectives. New York: Elsevier, North Holland
equilibrium by the extent of fluidity of the surrounding mem- Diamond MC, Connor JR (1981): A search for the potential of the
brane lipids. Attempts to forestall or modify age-related losses aging cortex. In: Brain Neurotransmitters and Receptors in Aging
in membrane fluidity through administration of active lipid and Age Related Disorders, Enna SJ, Samorajski T, Beer B, eds
fractions are presently under investigation. Aging, 17:43-58. New York: Raven Press
Alcoholism
Donald W. Goodwin

Alcoholism refers to excessive consumption of alcoholic bever- have unknowingly harmed someone or behaved imprudently
ages resulting in persistent social, psychological, and medical while intoxicated. The amnesia is anterograde: remote and
problems. Prevalence rates differ from country to country, immediate memory are intact, but there is a specific short-
and the true prevalence is not known. In the United States term memory deficit, a situation that permits complicated acts
and northern European countries, it is estimated that 3-5% which may appear normal to a casual observer.
of men and 0.1-1% of women can be described as alcoholic In addition to psychological symptoms, alcoholics com-
at some time in their lives. "Alcohol dependence" is synony- monly have social and medical problems from drinking. Alco-
mous with alcoholism. "Problem drinking" and "alcohol holics have a high rate of marital separation and divorce. They
abuse" are other terms which overlap with alcoholism, al- often have work troubles, including frequent absenteeism and
though they usually include larger numbers of individuals job loss. They also have a high frequency of accidents-in
whose problems from- alcohol are less severe and persistent. the home, on the job, and in cars. Of the more than 30,000
highway fatalities each year in the United States, about half
involve a driver who has been drinking, usually an alcoholic.
Clinical picture
Nearly half of convicted felons are alcoholic and about half
Alcoholism is a behavioral disorder. The specific behavior of police activities in large cities are associated with alcohol-
that causes problems is the consumption of large quantities related offenses.
of alcohol on repeated occasions. The motivation underlying Medical problems fall into three categories: (I) acute effects
this behavior often is obscure. When asked why they drink of heavy drinking; (2) chronic effects; and (3) withdrawal ef-
excessively, alcoholics occasionally attribute their drinking to fects. Rapid consumption of large amounts of alcohol can
a particular mood, such as depression or anxiety, or to situa- cause death by depressing the respiratory center in the medulla.
tional problems. They sometimes describe an overpowering Acute hemorrhagic pancreatitis occasionally occurs from a sin-
need to drink, variously described as a craving or compulsion. gle heavy drinking episode. Nearly every organ system can
Just as often, however, alcoholics are unable to give a plausible be affected. Gastritis and diarrhea are common. The most
explanation for their excessive drinking. serious effect of alcohol on the gastrointestinal tract is liver
Like other drug dependencies, alcoholism is accompanied damage. A single large dose of alcohol reversibly increases
by a preoccupation with obtaining the drug in quantities suffi- the fat content of the liver. The connection between this and
cient to produce intoxification over long periods. Early in the cirrhosis, however, is unclear. Most patients with portal (Laen-
course of alcoholism the patient may deny this preoccupation. nec's) cirrhosis, in Western countries, are excessive drinkers,
As part of this denial or rationalization, alcoholics tend to but less than 10% of alcoholics develop cirrhosis.
spend their time with other heavy drinkers. As problems from Alcohol damages the nervous system by causing vitamin
drinking become more serious, alcoholics may drink alone, deficiencies. Whether alcohol itself is a neurotoxin is less cer-
sneak drinks, hide the bottles, and take other measures to tain. Peripheral neuropathy, the most common neurological
conceal the seriousness of the condition. This is accompanied complication, apparently results from multiple vitamin B defi-
by feelings of remorse which in turn may produce more drink- ciencies and usually is reversible with adequate nutrition. Re-
ing. Remorse may be particularly intense in the morning, when trobulbar neuropathy may lead to amblyopia (sometimes called
the alcoholic has not had a drink for a number of hours. This tobacco-alcohol amblyopia), also usually reversible with vita-
may provoke morning drinking. min therapy.
Prolonged drinking, even if initially guilt and anxiety reliev- Other neurological complications include anterior lobe cere-
ing, also produces anxiety and depression. The full range of bellar degenerative disease and the Wernicke-Korsakoff syn-
symptoms associated with depression and anxiety neurosis- drome. The latter results from thiamine deficiency. The acute
insomnia, low mood, irritability, and anxiety attacks--occurs. Wernicke stage consists of ocular disturbances (nystagmus of
Alcohol temporarily relieves these symptoms, resulting in a sixth nerve palsy), ataxia, and confusion. It usually clears in
vicious cycle of drinking-depression-drinking which ultimately a few days but may progress to a chronic brain syndrome
may result in an alcohol withdrawal syndrome. Often the pa- (Korsakoff psychosis). Short-term memory loss (anterograde
tient tries to stop drinking and may succeed for several days amnesia) is the most characteristic feature of Korsakoff's psy-
or weeks, only to relapse. chosis. The Wernicke-Korsakoff syndrome is associated with
Repeated relapses lead to feelings of despair and hopeless- necrotic lesions of the mammillary bodies, thalamus, and other
ness. By the time the patient consults a physician, he has brain stem areas. Thiamine corrects early Wernicke signs rap-
often hit "bottom." His problems have become so numerous idly and may prevent development of an irreversible Korsakoff
that he feels nothing can be done about them. He now acknowl- dementia.
edges his alcoholism, but feels powerless to change. Other medical complications of alcoholism include cardio-
Blackouts, amnesia for events that occur while drinking, myopathy, thrombocytopenia, anemia, and myopathy.
are particularly distressful, since these drinkers may fear they The term alcohol withdrawal syndrome is preferable to delir-
 Alcoholism 7

ium tremens (DTs). The latter refers to a specific manifestation suggest genetic factors. Monozygotic twins are more often
of the syndrome. The most common withdrawal symptom is concordant for alcoholism than dizygotic twins. A family his-
tremulousness, which usually occurs a few hours after cessa- tory of alcoholism constitutes the strongest risk factor for the
tion of drinking and may begin while the person is still drinking development of alcoholism. About 20% of sons and 5% of
("relative abstinence"). Transitory hallucinations also may daughters become alcoholic compared to rates of alcoholism
occur. If so, they usually begin 12 to 24 hours after drinking in the general population of 5% in men and I% in women.
stops. Grand mal convulsions ("rum fits") occur occasionally, Many alcoholics do not have alcoholism in the family, and
sometimes as long as two or three days after drinking stops. there has been a recent trend toward separating alcoholics
As a rule, alcoholics experiencing convulsions do not have into familial and nonfamilial types. The familial type appar-
epilepsy; they have normal electroencephalograms when not ently has a younger age of onset and a more severe course.
drinking and experience convulsions only during withdrawal. Other studies compare children of alcoholics with children of
Delirium tremens is infrequent, usually occurring in alcoholics nonalcoholics. Members of the former group more often have
who are medically ill. A severe memory disturbance is required brain abnormalities and a history of childhood hyperactivity.
for the diagnosis. Delirium tremens usually begins two or Alcoholism is unevenly distributed among national and eth-
three days after drinking stops and subsides within one to nic groups. Ireland, the Soviet Union, and the Baltic nations
five days, or when the patient recovers from the medical illness. have a high rate, and countries along the Mediterranean Basin
Suicide is an important complication of alcoholism. About a low rate, except for France (which has the world's highest
one-quarter of suicides are alcoholic, mainly men over age cirrhosis rate). There may be a correlation between parental
35. attitudes toward drinking and subsequent alcoholism. Ethnic
groups which condone drinking in moderation but condemn
drunkenness appear to have a low rate of alcoholism (e.g.,
Natural history Jews). Childhood behavior problems weakly predict future
alcoholism.
The natural history of alcoholism is somewhat different in
men and women. In men the onset usually is in the late teens No personality type is associated with alcoholism, except
or twenties. The course is insidious. The first hospitalization the antisocial personality. The latter group has a high rate of
usually occurs in the late thirties or forties. Symptoms of alco- alcoholism. Prospective studies have been of little hope in
holism in men rarely occur for the first time after age 45. predicting who will become alcoholic. Prealcoholic teenagers,
Alcoholism has a higher spontaneous remission rate in men if anything, appear more stable and self-confident than their
than is often recognized. The incidence of first admissions to peers. An unstable family life apparently does not increase
psychiatric hospitals for alcoholism drops markedly in the sixth the risk of alcoholism unless the instability is produced by
and seventh decades of life. Although the mortality rate among an alcoholic parent, in which case the increased risk of alcohol-
alcoholics is two to three times that of nonalcoholics, this is ism in the children may be a function of genetic factors.
probably insufficient to account for the apparent decrease in Millions of individuals are "protected" from becoming alco-
problem drinking in middle and late middle life. The course holic because of a profound intolerance for alcohol. Orientals
of the disorder is more variable in women. The illness often are particularly susceptible to adverse physiological effects
begins later in life, and spontaneous remission appears to be from small amounts of alcohol, which may explain the low
less frequent. rate of alcoholism in the Orient. More Caucasian women than
Treatment for alcoholism is generally considered to be unsat- men are physiologically intolerant of alcohol. The Orientals'
isfactory. Approaches include psychotherapy (individual and intolerance appears related to atypical forms of alcohol dehy-
group), behavioral therapy, aversive therapy (using emetics), drogenase and aldehyde dehydrogenase which favor an accu-
and pharmacotherapy (antidepressant drugs, anxiolytic drugs, mulation of acetaldehyde, producing effects similar to those
lithium, and disulfiram). There is little or no evidence that occurring in alcohol-disulfiram reactions.
any of these treatments alters the natural history of the illness,
that is, produces improvement rates superior to those which
occur without treatment. The value of treatment, however, Neurochemical theories
remains an open question. There have been very few controlled Two lines of research have emerged which eventually may
studies with patients randomly assigned to treatment versus help explain tolerance, physical dependence, and alcohol-in-
no-treatment groups. Some studies of disulfiram and lithium duced euphoria. One involves biological membranes. Chronic
indicate modest effectiveness; others do not. (Disulfiram deters consumption of alcohol induces an adaptation of membrane
drinking by causing deleterious effects combined with alcohol; phospholipid composition, causing increased membrane rigid-
lithium is a treatment for mania.) There is no evidence that ity (decreased fluidity). The increased rigidity impairs normal
prolonged hospitalization produces a better outcome than short-
membrane function and may contribute to tolerance. In the
term outpatient treatment.
restored presence of moderate concentrations of alcohol the
membrane becomes sufficiently fluid to resemble normal mem-
branes, and this may partly explain physical dependence. The
Etiology
evidence for these changes, however, is inconsistent and fur-
About 70% of adults in most Western countries drink alcohol. ther research is needed before the link between the physical
Of these, about one in ten are addicted, i.e., drink large and functional effects of ethanol can be understood.
amounts on repeated occasions with adverse consequences. Another promising line of research began with the observa-
It is not known why a small minority of drinkers become tion in 1970 that biogenic amines and their aldehyde metabo-
alcoholic while most are relatively unharmed. The develop- lites form condensation products with acetaldehyde, the first
ment of alcoholism, however, is influenced by three factors metabolite of alcohol. These products structurally resemble
which may have causal importance: (I) genetic factors; (2) opiate alkaloids, leading to speculation that addiction to alcohol
ethnicity; and (3) childhood behavior problems. and opiates might have a final common biochemical pathway.
Alcoholism runs in families, and does so even when the The condensation products are formed in minute quantities
children of alcoholics are separated from their parents and but bind to certain opiate receptors and otherwise behave in
raised by nonalcoholic adoptive parents. Twin studies further some ways like opiates. Naloxone, an opiate antagonist, par-
8 Donald W. Goodwin

tially blocks some effects of alcohol (e.g., incoordination) basis for variations in alcohol ingestion by animals and hu-
and has been reported anecdotally to reverse alcohol-induced mans.
coma. Also, injection of the products generically called tetra-
hydroisoquinolines (or TIQs) into rat and monkey brains has
resulted in excessive consumption of alcohol by these animals, Further reading
which persisted long after the substances had been injected.
Vaillant G (1983): The Natural History of Alcoholism. Cambridge:
Finally, TIQs have been found in cerebral spinal fluid (CSF) Harvard University Press
of alcoholics and nonalcoholics after drinking alcohol, with Goodwin D ( 1981 ): Alcoholism: The Facts. Oxford: Oxford University
higher quantities in the cerebrospinal fluid of alcoholics. Press
TIQ research also suffers from many inconsistencies but Pattison EM, Kaufman E, eds (1982): Encyclopedic Handbook of
has stimulated research directed at finding a neurochemical Alcoholism. New York: Gardner Press
Alzheimer's Disease
Joseph T. Coyle

Alzheimer's disease (AD) and senile dementia of the Alzheim- Neurofibrillary tangles represent the accumulation of highly
er's type, a distinction based primarily on age of onset, appear cross-linked protein fibrils within neuronal cell bodies. The
to be a similar, if not the same, disease process. It is now neurofibrillary tangles are remarkably resistant to conditions
apparent that AD accounts for 40% to 60% of all cases of that readily solubolize most proteins. Whether neurofibrillary
dementia with onset in adulthood and is two to threefold more tangles represent proteins unique to AD remains uncertain,
frequent than multi-infarct dementia. It is estimated that 3- although recent studies have revealed imrnunocross-reactivity
5% of individuals over the age of 65 suffer from AD, and between a component of the neurofibrillary tangles and neurofi-
current costs for nursing home care in the United States for brils. Neurofibrillary tangles are concentrated in cortical, hip-
patients afflicted with AD exceed $10 billion per year. pocampal, and limbic neurons but are also found in neuronal
perikarya within the reticular core. Granulovacuolar degenera-
tion represents the accumulation of silver-staining vacuoles
Clinical manifestations that distend neuronal cell bodies, especially the hippocampal
The most frequent initial symptom of AD is deterioration in pyramidal cells.
recent memory with relative preservation of remote memory. It is unclear whether neuronal cell loss occurs in the cerebral
However, with progression, a global deterioration in memory cortex in AD and, if so, to what extent. In part, this uncertainty
occurs, resulting in loss of recognition of even family mem- derives from the fact that normal aging is associated with
bers. Next to the memory deficits, aphasias (impairments in cortical atrophy and neuronal cell loss. Recent studies using
verbal expression) are a frequent symptom in the early stages cell counting techniques have not revealed striking reductions
of AD; this progresses to difficulties in reading and in written in cell number in cortex when AD patients are compared to
language, and as the dementia progresses, neologisms, non- age-matched controls; however, in some cortical regions, sig-
sense words, and echolalia appear. Apraxia, the inability to nificant reductions in the number of the largest cells, presum-
perform complex routine motor acts, also occurs, resulting ably neurons, have been noted. These studies, which are based
in confusion on how to use familiar objects such as dinnerware, on Nissl stain techniques, cannot address the structural integrity
tools, and writing instruments. Deterioration in this realm of neurons, and limited results from Golgi analysis suggest a
leaves the individual incapable of performing the most basic marked disruption in neuronal cell structure with a high inci-
activities of daily living such as dressing and feeding. Notably, dence of irregular, misshapen neurons with a ballooned appear-
impairments in the level of consciousness do not occur until ance in AD.
the end stages, and the disorder is not associated with focal,
motor, or sensory neurological symptoms such as paralysis
Synaptic neurochemical pathology
or anesthesia, although primitive reflexes may emerge. Ulti-
mately, the AD patient, from 5 to 15 years after the onset of A consistent finding in postmortem analysis of brains from
symptoms, is left bedridden and mute, usually dying from individuals who have died with pathologically confirmed AD
intervening infections. is a striking reduction in presynaptic markers for cholinergic
neurons, including choline acetyltransferase and acetylcho-
linesterase, in the cerebral cortex, hippocampal formation, and
Neurohistopathology
the limbic system. In analysis of biopsies of cortex in AD,
Unequivocal diagnosis of AD requires the histopathologic dem- the high-affinity uptake process for choline and the ability to
onstration of the characteristic stigmata of the disorder in the synthesize acetylcholine has been found to be similarly re-
brain. These alterations include neuritic plaques, neurofibril- duced. The predominant source of cholinergic innervation to
lary tangles, and granulovacuolar degeneration. Neuritic these structures is derived from neuronal perikarya located in
plaques are composed of extracellular deposit in the neuropil the basal forebrain magnocellular complex, including the nu-
of amyloid, which consists of beta pleated sheets of protein cleus basalis of Meynert, the diagonal band of Broca, and
that exhibit birefringence under polarized illumination. The the medial septal nucleus. Histopathologic studies have gener-
source of amyloid protein is unknown. Surrounding the amy- ally indicated that there is significant loss of these cholinergic
loid core, especially in "immature plaques," are dystrophic perikarya or that they are shrunken in appearance in AD. The
neurites, visible with silver stains, that often have clublike critical role of cholinergic forebrain projections in the patho-
terminations resembling growth cones. Neuritic plaques, which physiology of AD has been further supported by the findings
also occur at a density one magnitude lower in the normal that the severity of reduction of cholinergic markers correlates
human aged brain, are found predominantly in the cortex, significantly with the degree of cognitive impairments in pa-
hippocampus, and limbic regions in AD. The density of neuri- tients before death and that the dystrophic neurites in the neu-
tic plaques in cerebral cortex correlates significantly with the ritic plaques, an essential pathologic feature of AD, stain for
degree of cognitive impairments seen in patients before death. acetylcholinesterase and choline acetyltransferase, two markers
10 Joseph T. Coyle

for cortical cholinergic terminals. However, the severity of Etiology of AD

cortical and hippocampal cholinergic deficits does not appear
to correspond closely with the cell loss in the basal forebrain Approximately 15-20% of probands affected with AD have
cholinergic .nuclei. Thus, there is reason to believe that the a clear family history for the disorder, compatible with an
proximate cause of the cortical cholinergic deficits is not due autosomal dominant pattern of inheritance. Recent studies sug-
to an anterograde degeneration but rather reflects a retrograde gest tha~ the genetic predisposition for the disorder may be
~nderestlmated due to death of family members before they
degeneration of the cholinergic projections, with perikaryal
destruction as a terminal event. hve through the risk period. Using restricted criteria for the
The forebrain cholinergic projections are not the only com- clinical diagnosis, J. Breitner and M. Folstein have found a
ponents of the reticular core that are affected in AD. Variable 50% risk for AD in siblings of probands with AD. The role
reductions in presynaptic markers for the noradrenergic neu- of genetic factors is further strengthened by the observation
rons have also been noted, and histological studies of the that individuals with Down's syndrome, trisomy 21, invariably
nucleus locus ceruleus indicate that major neuronal loss occurs develop the histopathology and synaptic neurochemical deficits
primarily in pa~ients_ with earlier age of onset of AD. Similarly, of AD if they live into their fourth decade.
vanable reductiOns m the presynaptic markers for serotonergic Genetic predisposition to AD does not preclude environmen-
neurons in cortex and hippocampus have also been observed tal factors in the etiology. There is little evidence, at present,
in AD. Two neuropeptides-substance P and somatostatin- that aluminum is a toxic agent responsible for AD since brains
~re reduced in concentration in the cortex and hippocampus
of AD patients do not exhibit elevated levels of aluminum.
mAD. Whether these deficits reflect a degeneration of neurons Nevertheless, aluminum appears to be concentrated in neurons
containing these neuropeptides or an alteration in their synthe- that exhibit neurofibrillary tangles. The possible role of infec-
SIS or degradation is unknown.
tious agents has received increasing interest with evidence
Markers for a variety of neurons located within the cerebral that slow vi~ses or atypical infectious agents known as prions
cortex and hippocampus have also been assessed. Notably, are responsible for the progressive neurodegenerative disor-
muscarinic acetylcholine receptors, which are presumably con- ders, Jakob-Creutzfeldt dementia and kuru in humans, and
centrated on the cortical neurons receiving cholinergic input, scrapie in sh_eep. Notably, genetic factors determine the latency
are not reduced in AD. Furthermore, presynaptic markers for and expression of scrapie in experimental animals, a finding
GABAergic (gamma-aminobutyric-acidergic) neurons,. which that underlines the potenti<!l interaction between hereditary pre-
are known to be local circuit neurons within the cortex and disposition and infectious agents in AD.
hippocampus, are unaffected or mildly .reduced. In addition,
the concentrations of vasoactive intestinal peptide, cholecys- Treatment
tokinin, and enkaphalin, neuropeptides localized in neurons
At present, there is no treatment that forestalls the inexorable
!ntrinsic to the cerebral cortex, also remain in the normal range
progression of AD. Effective management is based upon struc-
mAD. Thus, the synaptic neurochemical studies point to rather
turing the environment to compensate for the cognitive limita-
selective alterations in the integrity of components of the reticu-
tions of the affected individual. Neuroleptics can often be help-
lar core projections to the telencephalon, especially the choli-
ful in treating secondary psychotic symptoms that complicate
nergic neurons, in contrast to general sparing of markers for
neurons known to be localized to neurons intrinsic to the cere- the disorder. Current research indicates that drugs that potenti-
ate central cholinergic neurotransmission, such as the acetyl-
bral cortex and hippocampal formation.
cholinesterase inhibtor physostigmine, may reduce memory
An important role played by the cortical and hippocampal
deficits in AD. The general utility of such pharmacologic
cholinergic deficits in the pathophysiology of AD has been
strategies in clinical management of AD remains to be deter-
further supported by behavioral and psychopharmacologic
studies. Administration of the muscarinic acetylcholine recep- mined.
tor antagonist scopolamine to young healthy adults reproduces
many aspects of the cognitive impairments seen in the aged. Further reading
In particular, impairments of recent memory with relative pres- Katzman R, Terry RD, Bick KL, eds (1978): Alzheimer's Disease:
ervation of verbal performance in cognitive tests are noted. Senile Dementia and Related Disorders. New York: Raven Press
In experimental animals, lesions of the basal forebrain cho- Coyle JT, Price DL, DeLong MR (1983): Alzheimer's disease: A
linergic projections either to the hippocampal formation or to disorder of cortical cholinergic innervation. Science 219: 1184-1190
the cortex result in selective impairments in recent or working Katzman RD, ed (1983): Biological Aspects of Alzheimer's Disease.
memory with preservation of long-term memory. Cold Spring Harbor Laboratory
Amnesia
Larry R. Squire

Amnesia refers to difficulty in learning new information or of amnesia. In some cases of amnesia, this retrograde aspect
in remembering the past. These impairments can have a func- of memory loss is temporally limited, affecting memories from
tional origin, but more commonly they result from neurological the recent but not the remote past. In addition, within the
injury or disease. Functional amnesia is a psychiatric disorder. affected time period, the amnesia can be temporally graded,
The amnesia in this case is presumed to result from conflict so that very recent memories are most affected and less recent
and repression, and its presentation varies from individual to memories are less affected. This point has been established
individual. Typically, a patient is admitted to the hospital in most clearly for the amnesias associated with head injury,
a confused or frightened state. Memory for the past has been electroconvulsive therapy, and certain well-studied patients
lost, especially personal, autobiographical memory. Often, the with bilateral lesions involving the medial temporal lobe. In
patient cannot produce his or her own name. Yet, the ability other cases of amnesia, for example, Korsakoff's syndrome,
to learn new material is almost always intact. After the disorder retrograde amnesia can be extensive and cover the majority
clears, usually within a week, the lost memories return except of past life. The extensiveness and severity of this remote
for the events of the day or two just prior to hospital admission. memory loss does not appear to be related to the severity of
Rarely, the disorder lasts longer, and sizable pieces of the anterograde amnesia, which raises the possibility that it is
past remain unavailable. caused by different lesions from those that cause the antero-
grade amnesia.
Characteristics
Brain injury or disease produces a different, more consistent Etiology
pattern of memory impairment. The characteristics of amnesia Amnesia can occur for a number of reasons, e.g. , after tempo-
are determined by the facts of normal brain function. Neurolog- ral lobe surgery, chronic alcohol abuse, encephalitis, head
ical disorders of memory impairment commonly occur in the injury, electroconvulsive therapy, anoxia, and rupture and re-
context of more global dementing disorders, which affect mem- pair of an anterior communicating artery aneurysm. The mem-
ory together with language, attention, visuospatial disorders, ory disorder appears to depend on disruption of normal function
and general intellectual capacity. Amnesia can also occur as
in one of two areas of the brain: the medial aspects of the
a strikingly cin;:umscribed impairment in the absence of other temporal lobe and the diencephalic midline. When the damage
cognitive deficits. Patients with this disorder have intact intelli- is bilateral, amnesia is said to be global. It affects verbal and
gence test scores, intact language and social skills, and an nonverbal material, regardless of the sensory modality through
intact memory for a great deal of information from the remote which learning occurs. When damage is unilateral, the amnesic
past, especially childhood. In addition, immediate memory
disorder is material-specific rather than global. In the case of
is intact. That is, amnesic patients have a normal ability to left-sided damage, the deficit is for verbal material. Memory
repeat back a string of six or seven digits. In fact, they can for nonverbal material (for example, for faces and spatial lay-
hold a small amount of information in mind for several min- outs) is affected in the case of right-sided damage.
utes, provided the material can be rehearsed. In much the
same way, a person with normal memory functions might
hold a telephone number in mind for a few minutes until it Spared learning and memory abilities
can be written down. For this reason, amnesic patients can
carry on a conversation and often appear quite normal to casual Although amnesia can be severely disabling, the deficit does
observation. The difficulty arises when information must be not affect all kinds of learning and memory. First, amnesia
recalled after a distraction-filled interval, or when recall is spares many kinds of skill learning. Motor skills, perceptuomo-
attempted directly after the presentation of an amount of infor- tor skills, and certain cognitive skills can be acquired at a
mation that exceeds immediate memory capacity (for example, normal rate. In one study, amnesic patients learned to read
9 or 10 digits). In this situation, normal subjects will usually mirror-reversed words at a normal rate and then retained the
recall more items than amnesic patients. Furthermore, if the skill for months, despite the fact that when they had finished
items are repeated a number of times, normal subjects quickly they could not remember the words that they had read and in
become proficient, but amnesic patients may never learn the some cases could not remember that they had ever practiced
whole list. the mirror-reading skill on a previous occasion.
A second example of spared memory ability is priming-
the facilitation of performance by recent exposure to stimulus
Retrograde amnesia
material. To illustrate priming, suppose that normal subjects
Amnesia affects not only the ability to learn new material, are shown a short word list, which includes the words motel
but also the ability to recall material learned prior to the onset and absent. When they are then shown the fragments mot--
12 Larry R. Squire

and abs-- -, with instructions to form the first word that comes Hippocampus
to mind, they have a strong tendency (about 50%) to produce
the words that were recently presented. (The probability is Occasionally, useful information about the neuroanatomy of
only about I 0% that subjects will produce these words if they amnesia comes from well-studied cases of human amnesia,
were not presented recently.) Amnesic patients exhibit this where extensive neuropsychological and neuropathological
effect to the same extent as normal subjects. Moreover, in data are available. Case R.B. became amnesic in 1978 follow-
both amnesic patients and normal subjects, this effect declines ing an ischemic episode that occurred as a complication of
gradually after word presentation and disappears in a few cardiac by-pass surgery. When he died in 1983, thorough anal-
hours. Priming effects in both amnesic patients and normal ysis of his brain revealed a bilateral lesion confined to the
subjects are modality bound, in that the effects are strongest CAl field of hippocampus. The lesion extended the: full rostral-
when words are presented in the same sensory modality as caudallength of the hippocampus, involving an estimated 4.63
word fragments, and significantly diminished (although not million pyramidal cells. There was no other clinically signifi-
eliminated) when words and fragments are in different modali- cant lesion. This case shows that a lesion limited to the hippo-
ties. campus is sufficient to cause amnesia. This level of impairment
The preservation of skills and priming in amnesia shows can be exacerbated by additional damage. For example, the
that these forms of learning and memory do not depend on well-known surgical patient H.M., who appears to be as se-
the medial temporal and diencephalic structures damaged in verely amnesic as any other thoroughly studied case, has bilat-
amnesia. These findings have raised the possibility that multi- eral damage to parahippocampal gyrus, entorhinal cortex, and
ple forms of memory exist. The kind of memory that is affected amygdala, in addition to hippocampal damage.
in amnesia is explicit and accessible as conscious memory.
For this reason, it has sometimes been termed declarative mem-
ory. It can be declared, or brought to mind, as a proposition
Amnesia as a window on normal memory functions
or as an image. In declarative learning, new facts or events
are added to memory, or associations are formed between The analysis of memory disorders in neurological patients,
already available but unrelated items. The kind of memory and in animal models of amnesia, continue.s to provide useful
that is preserved in amnesia has been termed procedural. It information about how the brain accomplishes learning and
is implicit, expressible only in performance. The knowledge memory. Amnesia appears to result from damage to a brain
is embedded in the procedures that are engaged when learning system that performs a particular function, or computation,
occurs. In priming, a preexisting representation is temporarily when learning occurs. This neural system must work in concert
facilitated. Newly formed representations can also be primed with the distributed sites in neocortex and elsewhere that are
in some cases. In skill learning, preexisting procedures are believed to be the loci of memory storage. When sufficient
combined to form long-lasting cognitive operations. time has passed after learning, the distributed si'tes~that consti-
tute memory for an event are able to support an enduring
representation in memory on their own, without the participa-
Animal models
tion of this neural system. Retrieval can then be accomplished
Animal models of human amnesia have been established in in the absence of the neural system damaged in amnesia. Better
the monkey. They could probably be achieved in any mammal understanding of this neural system, and its component parts
and possibly in other vertebrates, such as birds. Monkeys with and connections, should also illuminate neurobiological studies
bilateral medial temporal lesions exhibit a profound impairment that are conducted at more elemental levels of analysis by
on the kinds of tasks of new learning ability that human am- establishing a clearer connection between neurobiological data
nesic patients fail. The same animals succeed at tasks of motor and functional questions about the organization of memory
skill learning. They also do well at learning pattern discrimina- in the brain.
tions, which share with motor skills the factors of incremental
learning and repetition over many trials. Monkeys with bilat-
eral medial thalamic lesions also exhibit an amnesic disorder.
Lesions of the mammillary nuclei produce a small, negligible Further reading
impairment. Damage to other regions such as ventromedial
frontal cortex and basal forebrain, which have strong anatomi- Mishkin M (1982): A memory system in the monkey. Phil Trans R
cal links to the medial temporal region and medial thalamus, Soc Lond B. 298:85-95
also appears to produce memory impairment. Further work Schacter DL (1985): Multiple fonns of memory in humans and ani-
mals. In: Memory Systems of the Brain. Weinberger N, McGaugh
is needed to quantify each kind of impairment, in order to J, Lynch G, eds. New York: Guilford
compare the effects of each lesion and to determine what quali- Squire LR (1987) Memory and Brain. New York: Oxford
tative differences might exist in the memory impairment associ- Zola-Morgan S, Squire LR (1985): Complementary approaches to
ated with each lesion. In addition, further work is needed to the study of memory: human amnesia and animal models. In: Mem-
determine which lesions are required to produce a stable mem- ory Systems of the Brain, Weinberger N, McGaugh J, Lynch G,
ory impairment that can last for years. eds: New York: Guilford
Amphetamines
Norman J. Uretsky

The amphetamines are a group of central nervous system mission at synapses derived from neurons of the medial fore-
(CNS) stimulants, which produce most of their biological ef- brain bundle. Since animals will lever press in order to electri-
fects by enhancing neurotransmission at catecholaminergic cally stimulate the medial forebrain bundle, it has been postu-
synapses in the peripheral and central nervous systems. The lated that neurons of this tract are part of a reward system in
term amphetamines usually includes dextroamphetamine, le- the brain, which functions in the regulation of mood and moti-
voamphetamine, racemic amphetamine, and methamphet- vation.
amine. Amphetamine (a-methylphenethylamine) is the proto- Amphetamines can suppress appetite. This anorexic action
type drug of this class and exists in 2 stereoisomeric forms. appears in part to be due to a direct action on neurons on the
The dextroisomer, d-amphetamine, is about 3 times more po- lateral hypothalamus or feeding center. A variety of more
tent as a CNS stimulant than the levo form, !-amphetamine. "selective" anorexic phenethylamine analogs of amphetamine
In contrast, the latter compound has more potent cardiovascular have been developed that possess relatively less central stimu-
effects. Methamphetamine (N-methyl a-methylphenethyl- lant properties. Recently, a high-affinity, saturable, and ste-
amine) is a more potent CNS stimulant than d-amphetamine. reospecific binding site for d-amphetamine has been demon-
There are several other chemical analogs of amphetamine that strated in membrane preparations from rodent hypothalamus.
produce similar biological effects. These include methylpheni- The potencies of the various structural analogs of amphetamine
date, pipradrol, and a variety of compounds that are presently in inhibiting 3 H-d-amphetamine binding correlate well with
marketed for their appetite suppressant effects. their potencies in producing anorexia, suggesting that these
By enhancing noradrenergic neurotransmission, amphet- binding sites mediate the appetite suppressant effects. Clini-
amine causes the stimulation of organs innervated by postgan- cally, however, these analogs still exhibit the same side effects
glionic sympathetic neurons, resulting in a variety of effects as amphetamines, and tolerance develops rapidly to their ano-
that mimic the activation of the sympathetic nervous system. rexic effects. Therefore these drugs are unlikely to be useful
Since the therapeutic effects of amphetamine and its structural in a long-term weight reduction program.
analogs are related to their actions in the central nervous sys- Although amphetamine is a central stimulant, it has been
tem, these autonomic effects would tend to limit the therapeutic found to be useful in the treatment of hyperactive children
usefulness of these drugs. diagnosed as having attention deficit disorders. In this condi-
Amphetamines, which are lipid soluble in the free-base tion, the paradoxical "calming" effect produced by amphet-
form, readily cross the blood brain barrier and produce a variety amines may be a result of an improvement in their ability to
of behavioral changes in humans and animals. A characteristic concentrate. A, paradoxical beneficial effect of amphetamine
feature of their CNS stimulant action is an arousal or alerting has also been demonstrated in petit mal epilepsy.
response, which may account for their ability to reduce fatigue High doses of amphetamines or repeated administration of
and to enhance physical and mental performance. Amphet- these drugs produce a reversible toxic psychosis, characterized
amines also reduce rapid eye movement sleep, which together by paranoid behavior that closely resembles schizophrenia.
with the arousal response may explain their effectiveness in There may be auditory and tactile hallucinations; the latter
the treatment of narcolepsy. Amphetamine stimulates locomo- has been described as the sensation of insects or snakes crawl-
tor activity, an effect which appears to be mediated in rodents ing underneath the skin. Since evidence has been accumulating
through the enhancement of dopaminergic neurotransmission that antipsychotic drugs produce their therapeutic effects by
in the nucleus accumbens. At higher doses, amphetamine eli- blocking dopaminergic receptors, and since amphetamine en-
cits a compulsive stereotyped behavioral response which has hances dopaminergic neurotransmission, it is likely that the
been primarily related to an enhancement of dopaminergic paranoid psychosis induced by amphetamines is mediated
neurotransmission in the corpus striatum. The behavioral char- through their ability to enhance dopaminergic neurotransmis-
acteristics of this response depend on the species being studied. sion.
For example, rats injected with high doses of amphetamine Recent studies have shown that the repeated administration
display repetitive sniffing, licking, and gnawing behavior, of high doses of amphetamine can produce neurotoxic effects
while humans engage in compulsive repetitive manipulatory in the brains of several animal species. Thus, amphetamines
tasks that appear to serve no useful purpose. in high doses produce a long-lasting reduction in brain tyrosine
Another characteristic effect of amphetamines, which under- hydroxylase and tryptophan hydroxylase activities and in cate-
lies their abuse potential, is an elevation of mood or euphoria, cholamine transport, suggesting damage to catecholamine- and
which is associated with an enhanced feeling of energy and serotonin-containing neurons. These biochemical changes have
self-confidence. After intravenous administration, this effect been supported by morphological evidence of nerve degenera-
has been described as extremely intense and pleasurable. The tion. At present, the behavioral consequences of these neuro-
euphoria produced by amphetamine has been related to the toxic effects of amphetamines are unclear.
enhancement of noradrenergic and dopaminergic neurotrans- Tolerance develops to almost all the effects of amphetamines
14 Norman J. Uretsky

except the toxic psychosis which becomes progressively more nism behind the amphetamine-induced release of dopamine
intense with continuous drug administration or the intake of and norepinephrine is still unclear. Recent studies have sug-
high doses. After abrupt withdrawal following the chronic gested that amphetamine, by binding to the bidirectional cate-
intake of amphetamine, the user will experience an intense cholamine uptake carrier, might increase the concc!ntration of
fatigue, depression, feelings of hunger, and a strong desire this carrier on the inside of the membrane, thereby accelerating
to continue taking the drug. At present, it is not clear whether the carrier-mediated efflux of catecholamines.
these symptoms constitute an abstinence syndrome. In contrast to the amphetamines, the CNS stimUtlant effects
Almost all the effects of amphetamines are thought to be of some of its structural analogs (for example, methylphendi-
due to their actions on noradrenergic and dopaminergic neu- ate) are markedly antagonized by the prior administration of
rons, although at high doses actions on serotonergic neurons reserpine but are relatively unaffected by u:-methyl-p-tyrosine.
may also play a role. Amphetamine, which structurally resem- Since the CNS stimulant effects of both the amphetamines
bles norepinephrine and dopamine, can cause the release of and its analogs are antagonized by dopamine receptor blocking
these catecholamines from presynaptic nerve terminals, thus agents, it is thought that the structural analogs may act differ-
increasing their concentration in the synaptic cleft. In addition, ently on dopaminergic neurons to enhance dopaminergic neuro-
amphetamine inhibits the specific carrier-mediated uptake pro- transmission. One explanation is that the amphetamine analogs
cess for these amines. Since reuptake of catecholamines into act mainly by blocking the reuptake of dopamine released
the presynaptic nerve terminal appears to be the major mecha- from a granular (reserpine-depletable) pool and have a much
nism for terminating their synaptic action, the inhibition of weaker direct releasing action from the reserpine-insensitive
reuptake of the released catecholamines by amphetamines cytoplasmic dopamine pool.
should further increase their concentration and activity in the
synaptic cleft. Based on studies with reserpine, which depletes
Further reading
dopaminergic storage sites (but does not block the behavioral
effects of amphetamine), and u:-methyl-p-tyrosine, which in- Ridley RM (1983): Psychostimulants. In: Psychopharmacology. Part
hibits dopamine synthesis (and blocks the behavioral effects I: Preclinical Psychopharmacology, Grahame-Smith 00, Cowan
of amphetamine), the dopamine released by amphetamine plays PJ, eds. Amsterdam, Oxford, Princeton: Excerpta Medica
a major role in its CNS actions, and appears to be mainly Iversen LL, Iversen SD, Snyder SH, eds. (1978): Handbook of Psy-
chopharmacology (Stimulants) JJ, New York: Plenum Press
derived from a small reserpine-insensitive cytoplasmic pool Kalant OJ (1973): The Amphetamines: Toxicity and Addiction, 2nd
which is continually replenished by new synthesis. Amphet- ed, Toronto, Buffalo: University of Toronto Press
amine, which can stimulate dopamine synthesis, may prevent McMillen BA ( 1983): CNS stimulants: two distinct mechanisms of
the newly synthesized dopamine pool from being depleted as action for amphetamine-like drugs. Trends Pharmacol Sci 4:429-
a result of the enhanced dopamine release. The precise mecha- 432
Antidepressants
Elliott Richelson

Antidepressants are drugs which are effective for treating de- it was observed that it caused euphoria and elation in some
pression, a serious psychiatric disorder that afflicts about 5% patients treated for tuberculosis and that it reversed the apparent
of the adult population in the United States. These drugs, sedation caused by reserpine in laboratory animals. This result
which are also less commonly called psychoanaleptics, thymo- with the reserpine-treated animal (usually mouse or rat) eventu-
leptics, or mood-elevating drugs, are represented by a diverse ally led to its use as a model for the depressed human (perh:.ps
group of chemical stmctures (see Fig. I) whose mechanism in part because of the psychomotor retardation seen in many
of therapeutic action is currently unknown. However, there depressed patients). Thus, the reversal of reserpine's effects
are many hypotheses about how they work, and in general, by drugs became a screening test for new antidepressants.
these theories involve biogenic amine neurotransmitters, espe- Some justification for the use of this model is found in the
cially norepinephrine and serotonin. fact that reserpine causes depression in a small percentage
Of the many types of antidepressants, one of the first discov- (about 10%) of patients who are being treated with this drug
ered and the most widely used types is the tricyclics type, for hypertension. In general, however, biological research in
so named because of the three fused rings in their structures. psychiatry is hindered by the lack of good models of human
This class has been further subdivided according to the type mental disease.
of amine on the side chain of these compounds into tertiary Monoamine oxidase inhibitors are much less frequently used
amines (for example, imipramine and amitriptyline) and sec- than other types of antidepressants because of the "cheese
ondary amines (for example, desipramine and protriptyline). reaction," a marked and potentially fatal increase in blood
The prototype of this class of compounds, imipramine (Fig. pressure that can occur when a patient being treated with one
I), was initially synthesized for use as an antihistamine (H 1) of these drugs ingests foods high in tyramine (such as aged
but was discovered to have antidepressant properties as the cheese). The excess tyramine, unable to be degraded by
result of astute clinical observations on depressed schizo- monoamine oxidase, displaces neuronal stores of catechol-
phrenic patients. After chlorpromazine was shown to be effec- amines which ultimately increase blood pressure. Conse-
tive as an antipsychotic drug in the early 1950s, researchers quently, patients taking monoamine oxidase inhibitors are re-
sought other drugs to treat psychosis and selected imipramine quired to be on a tyramine-free diet and must also avoid the
for a trial because of its close structural similarity to chlorpro- use of certain sympathomimetic stimulants, which are often
mazine. Though imipramine was ineffective as an antipsy- found in over-the-counter cold remedies.
chotic drug, it made depressed schizophrenic patients less de- Sympathomimetic stimulants such as amphetamine and
pressed. This finding led to clinical trials with imipramine methylphenidate are not considered antidepressants although
which proved its efficacy as an antidepressant. they are used by some clinicians in special cases. In addition,
Another class of antidepressants, the monoamine oxidase lithium ion, administered as a· salt, has not been established
inhibitors, was introduced also in the 1950s as a result of as an effective antidepressant, although it has unquestioned
observations in both the clinic and the laboratory. The first efficacy in the treatment of mania and the prevention of manic-
compound of this group to be tested and proved effective as depressive illness. Likewise, amino acids such as L-tryptophan
an antidepressant was iproniazid, an antituberculous drug, after and L-dopa have not been generally proved to have antidepres-
sant effects.

Classification of antidepressants
Cl

og~HCH3 In earlier years antidepressants were classified as either tricy-

clics or monoamine oxidase inhibitors. This method of classifi-
NH cation, however, mixes structural and functional criteria, and
I
CH3·C- CH3
I
ideally it would be better to classify these drugs on the basis
CH 3 of either structure or function. Unfortunately, the newer, so-
BUPROPION FLUOXETINE called second-generation antidepressants (such as bupropion,

/"\ -0"
Cl

O
ftuoxetine, and trazodone) (Fig. 1) have diverse structures and
N, .-CH 2 CH 2 CH 2 -N N no apparent common neuropharmacologic effect, so that it is
:;; N \__/ -
difficult to arrive at a satisfying classification that encompasses
~0 all antidepressants. One temporary approach is to classify these
drugs on the basis of the total number of rings in the structure.
For this purpose such terms as bicyclic, tricyclic, or tetracyclic
IMIPRAMINE TRAZODONE
can be used, in order to describe a structure with 2, 3, or 4
Figure I. Chemical structures of some antidepressants. fused rings. The term heterocyclic, which describes a com-
16 Elliott Richelson

pound with a ring containing at least one atom different from rinic acetylcholine, a 1- and aradrenergic, dopamine D 2 , and
carbon, is not useful since to classify the antidepressants as serotoninergic (S 1 and S2 ) receptors. In general, their most
heterocyclic and nonheterocyclic subdivides the tricyclic type potent effect is at the histamine H 1 receptor, and some antide-
(for example, imipramine is heterocyclic but amitriptyline is pressants (especially the tricyclic antidepressant doxepin) have
not). such high affinity for this receptor that they are among the
most potent histamine H 1 antagonists available. This finding
has led to their use outside psychiatry for the treatment of
Pharmacologic effects of antidepressants: Focus on the
allergic and certain dermatological problems.
synapse
Acute receptor antagonism by antidepressants is probably
It is well established that antidepressants affect the synaptic not related to the mood elevating effects of these drugs but
functions of neurotransmitters by various mechanisms. Neuro- underlies various adverse effects. For example, muscarinic
transmitters are small molecules that neurons use to communi- receptor blockade can cause dry mouth and constipation; and
cate with one another; synapses are structures by which nerve histamine H 1 receptor antagonism can cause sedation and drow-
terminals abut onto other neurons. Neurotransmitters are usu- siness. However, for some depressed patients who are also
ally amino acids or their derivatives and are released from agitated, sedation is a desirable effect of the antidepressant.
the nerve terminal to diffuse into the synaptic cleft to interact These drugs vary greatly in their potential to cause these and
with specific receptors on the outside surface of the target other adverse effects, and it is possible to predict the likelihood
cells. These receptors can be located both postsynaptically that a particular antidepressant will cause a specific side effect
and presynaptically (autoreceptors). In addition, some of the from the knowledge of its affinity (from in vitro studies) for
released neurotransmitter is recovered by the nerve ending (a the particular receptor involved. Since the second-generation
process called uptake or reuptake), thereby preventing the neu- drugs in general tend to have lower affinities for receptors,
rotransmitter from overstimulating a receptor. Rapid degrada- they are less likely to cause the adverse effects commonly
tion of the neurotransmitter can also reduce the level of the seen with the older antidepressants.
molecule in the synaptic cleft. The mood-elevating effect of antidepressants does not be-
Not long after the discovery of tricyclic antidepressants, come apparent until at least I 0 days to several weeks after
researchers demonstrated that these drugs acutely blocked up- treatment has started, whereas the pharmacologic effects dis-
take by the nerve ending of both norepinephrine and serotonin. cussed above are apparent within hours after administration
It was considered, then, that the therapeutic effect of the antide- of drug. Thus, researchers have sought to find biological ac-
pressant was due to increased levels of released neurotransmit- tions of antidepressants which are evident only after chronic
ter in the synaptic cleft. The inhibition of uptake by tricyclic drug administration. One such long-term effect is the decreased
antidepressants is one of the cornerstones of the so-called bio- sensitivity (desensitization) of certain brain neurotransmitter
genic amine hypothesis of affective illness, which (in the sim- receptors which in most cases leads to a reduction (down-
plest terms) states that a deficiency of certain biogenic amines regulation) in numbers of receptors. Down-regulation of recep-
(for example, norepinephrine) at functionally important syn- tors in rat brain has been demonstrated to occur with chronic
apses causes depression, while an excess causes mania. Other administration of many different types of antidepressants as
data in support of this hypothesis are that monoamine oxidase well as with chronic electroshock. The receptors most consis-
inhibitors increase brain levels of catecholamines and serotonin tently affected are those for the catecholamines. Serotonin re-
by preventing their degradation; whereas reserpine, which as ceptors may also be reduced with chronic antidepressant ad-
noted above can cause depression in some patients on this ministration to rats. In addition, serotoninergic innervation
drug for hypertension, depletes brain levels of these molecules. may play a permissive role in catecholamine receptor desensiti-
Earlier data indicated that tertiary amine tricyclic antidepres- zation, since the reduced sensitivity of catecholaminergic re-
sants were potent blockers of serotonin uptake but weak block- ceptors caused by antidepressants does not occur when seroto-
ers of norepinephrine uptake, whereas the converse appeared nin-containing neurons are destroyed.
to be true for the secondary amine compounds. These data Problems with the desensitization hypothesis of antidepres-
led to the hypothesis that there are serotonin- and norepineph- sant action exist because some of the newer antidepressants
rine-deficient depressions. Despite decades of research, clinical such as bupropion, ftuoxetine, and trazodone (Fig. 1) do not
data to support this theory have not been conclusive. In addi- appear to cause desensitization. In addition, the antipsychotic
tion, more recent data on uptake blockade by tricyclic and chlorpromazine causes desensitization but has little or no effi-
other antidepressants in vitro show that most of these com- cacy as an antidepressant.
pounds (including tertiary amine tricyclic antidepressants) are It is clear that we must focus on synaptic function in order
more potent at blocking uptake of norepinephrine than at block- to discern the mechanisms underlying the therapeutic effect
ing uptake of serotonin, and some of the newer antidepressants of antidepressants. However, since the particular neurotrans-
are very weak at uptake blockade. These data do not support mitter system involved in affective behavior remains undis-
the hypothesis subdividing antidepressant action at serotonin- covered, further research is required before the sites of
ergic and noradrenergic systems. therapeutic action of antidepressants are known and their
More recent research on other acute pharmacologic effects mechanisms of action understood.
of antidepressants has concentrated on their ability to block
receptors. Drugs that block receptors (antagonists) cause their
effects by preventing access of the neurotransmitter to its recep- Further reading
tor. How tightly a drug binds to a receptor (the "affinity") Enna SJ, Malick JB, Richelson E, eds (1981): Antidepressants:
can be determined by a variety of techniques. The higher the Neurochemicals, Behavioral and Clinical Perspectives. New
affinity, the greater the effect of the drug, either desirable or York: Raven Press
undesirable. Antidepressants are antagonists of several differ- Richelson E (1982): Pharmacology of antidepressants in use in the
ent types of receptors including histamine (H 1 and H 2 ), musca- United States. J Clin Psychiatry 43(11) Sec 2:4
Anxiety and Anxiety Disorders
David V. Sheehan and Kathy H. Sheehan

Definition bias is associated with attacks of symptoms that are more

profoundly disruptive and disabling to the patient. These in-
Phenomenologically, anxiety may refer to an emotion, a feel-
clude sudden bursts of tachycardia, lightheadedness, dizzy
ing, a symptom, or a cluster of cognitive and somatic, symp-
spells, imbalance, difficulty getting a breath, chest pain or
toms. Etiologically, it may describe reactions to danger, stress,
discomfort, choking or smothering sensation, hot flashes, nau-
or conflict, the results of trauma or frightening memories,
sea, or a feeling that the surroundings are strange, unreal,
the toxic withdrawal reactions to many drugs and illnesses, a
detached, or unfamiliar. There is frequently a severe mental
habit (a persistent pattern of maladaptive behavior acquired
panic with a sense of loss of control or imminent doom and
by learning), or the symptomatic expression of a genetically
a flight response. While this is occurring the victim cannot
inherited metabolic disease. The prevailing opinion in psychia-
identify any immediate obvious justifiable precipitant for the
try views anxiety as a cluster of symptoms that impairs normal
attack. The suddenness of the surge of symptoms and their
functioning.
occurrence without warning or clear-cut precipitation sets this
disorder apart from response to stress anxiety.
Classification Typically, the natural history of panic disorder progresses
through several stages. It often begins with sudden attacks of
Many classification systems of anxiety disorders have been one or two symptoms without cognitive anxiety. It then pro-
suggested. The most widely used classification of anxiety dis- gresses to sudden attacks with many symptoms and a feeling
orders is that of the Diagnostic and Statistical Manual of Men- of mental panic. At a loss to identify psychological precipi-
tal Disorders, third edition (DSM III), of the American Psychi- tants, patients may believe they have a medical disease and
atric Association, published in 1980. For practical purposes, cannot be reassured. Next the severe attacks become associated
four types of anxiety are identified in most anxiety classifica- with specit}c situations (where the severe attacks occurred),
tions: and limited phobic avoidance to these situations starts. As
1. An adjustment or response to immediate stress/danger or the attacks persist there is progression to extensive phobic
conflict anxiety (adjustment disorder with anxious mood). avoidance (including social phobias and agoraphobia) and in-
2. An isolated anxiety that is bound to a stimulus, is out of creasing depression.
proportion to the reality of the situation, and leads to stimu-
lus avoidance (phobic anxiety/simple phobia). Epidemiology
3. An anxiety that is primarily autonomous-unattached to
any apparent stimulus at least some of the time (panic disor- Anxiety and phobic disorders are the most prevalent of all
der/endogenous anxiety). psychiatric disorders. A large multicentered epidemiological
4. Anxiety that is secondary to other medical or psychiatric catchment area study, using precise and conservative diagnos-
disorders or drugs. tic criteria, found the lifetime prevalence of anxiety and phobic
disorders at 8.3% of the population over 18 years. Seven per-
Whether each of these groups is homogeneous or is made up cent of the adult population over 18 suffer from a phobic
of several subgroups is a matter of debate. disorder alone. With the current adult population of the United
States at 240 million, it is estimated that 19.9 million have
suffered from an anxiety/phobic disorder and 16.8 million from
Clinical description
a phobic disorder during their lifetime. Among women it
Response to stress or conflict anxiety is characterized by symp- ranked as the number one psychiatric disorder in all age groups.
toms in direct and immediate relation to the stress. The symp- Within a six-month period, 77% of those with an anxiety
toms include dry mouth, increased heart rate and perspiration, and phobic disorder visit a health or mental health care facility
tremor of hands, fluttery stomach, increased muscle tension, to seek medical or psychiatric evaluations. Another National
and cognitive fear/anxiety. When the stress is removed the Institute of Mental Health study found that II% of the general
symptoms usually remit. population are using antianxiety medications and over 70 mil-
In conditioned or simple phobic anxiety the symptoms are lion prescriptions for tranquilizers are written annually.
similar, but there is crescendo anxiety on exposure to a stimulus Response to stress anxiety and simple phobias may start at
and it is out of proportion to the reality of the situation and any age. In contrast, the anxiety disorder associated with unex-
continues to lead to avoidance behavior. Often there is general- pected anxiety attacks (panic disorder) and multiple phobias
ization of the anxiety from the core stimulus. (e.g., agoraphobia) has an unusual age of onset with a peak
The pathological anxiety that is associated with unexpected/ age of onset in the 20s. It rarely begins before the age of 14
unprovoked anxiety attacks (panic disorder) and multiple pho- or after 40.
18 David V. Sheehan and Kathy H. Sheehan

Response to stress anxiety and simple phobias is more evenly sion or breathing 5-7% C0 2 may lead to a rapid fall in pH
distributed between men and women-with just over 60% be- at the ventral medullary center with the production of panic
ing women. Among those with unexpected anxiety attacks attacks in susceptible patients.
and multiple phobias 75-80% are women; 73-92% are symp- The evidence directly identifying a physical defect in patients
tomatic when reevaluated up to 20 years after the initial diag- with unexpected anxiety attacks is still at an early stage of
nosis. investigation. One recent study gave an 0.5 M solution of
sodium lactate to victims of panic disorder and normal controls.
Etiology Most of the panic patients had anxiety attacks after approxi-
mately 12 minutes of the infusion, but normal persons did
Simple phobias and response to stress without unexpected anxi- not. During their panic attacks, there was a significant right/
ety attacks are believed to be acquired traumatically or by left shift in the blood flow in one small area of the brain-
conditioning. This can happen to any normal person suitably the parahippocampal region--on positron emission tomogra-
exposed. phy (PET) scan. This did not occur in normal controls. For
Multiple phobias with unexpected anxiety attacks are be- the first time this showed that panic attacks in these patients
lieved to result from a metabolic disease to which there is a could be seen with this imaging technology. Although the
genetic vulnerability. In this class of phobias there appears central defect appears to be a neurochemical one it has not
to be an interaction of three causative forces: (I) the biological yet been precisely identified.
core; (2) conditioning that arises as a complication of this As a result of having unexpected, unprovoked attacks of
biological core; and (3) environmental stress. In any one indi- anxiety, patients begin to fear and avoid the situations they
vidual each of these may operate to varying degrees. The associate with their severe attacks. That is, these biologically
prevailing view is that the biological force is the largest con- based attacks condition them to become phobic. The more
tributor and that environmental stress may even be absent. intense the attacks and the longer they continue, the more
Evidence from several family studies shows that approxi- phobias the patient acquires. Eventually many patients become
mately 15--41% of first-degree relatives of affected individuals housebound and disabled by the extensive phobic avoidance.
have the condition. When both parents are affected, the pooled Stress appears to be a nonspecific aggravator of almost all
prevalence is 40%. There is an increased concordance in identi- medical illnesses. Stress will magnify panic disorder and exten-
cal, as compared to nonidentical, twins. This suggests that sive phobic avoidance when it is present. However, the view
genetic factors override environmental influences. Several bio- that all those with extreme phobias and pathological anxiety
logical models of the anxiety disorder associated with unex- have some stress or conflict in their lives seems incorrect.
pected/unprovoked anxiety attacks have been suggested. There Some do. Frequently however, their stresses do not differ sub-
are three theories (not necessarily mutually exclusive) about stantially from anyone else's.
the biological core of this disorder that show promise. Each
is backed by a body of scientific data and each probably repre-
sents a different part of the total and still incomplete picture. Complications
The first biological model, called the locus coeruleus model,
Until recently, it was widely believed that anxiety disorders
posits that anxiety attacks arise due to arousal of the locus
were not associated with any medical complications beyond
coeruleus. This small nucleus in the pons of vertebrate brain
the immediate subjective discomfort of the symptoms. How-
stem contains at least 50% of all neurons in the central nervous
ever, recent evidence suggests that panic disorder has an excess
system using norepinephrine as a neurotransmitter. It has nu-
mortality when compared to matched normal controls. This
merous projections to many areas of the brain. Electrical or
excess mortality comes from two sources-suicide and, partic-
drug (yohimbine) stimulation of the locus coeruleus tends to
ularly in men, cardiovascular death. Although those with panic
produce anxiety attacks and a fear response. Anxiety and fear-
disorder are generally not seen as depressed, over a lifetime
like responses are blocked by locus coeruleus lesions or abla-
they appear to be as likely to kill themselves as those with
tion.
depressive illness. They are at greater risk to develop hyperten-
The second biological model is the gamma-aminobutyric
sion. Approximately 34% have an associated mitral valve pro-
acid (GABA)-benzodiazepine model. It suggests that the
lapse, and approximately 20% have a history of alcohol or
GABA-benzodiazepine receptor is malfunctioning in pathologi-
substance abuse-usually in an attempt to control their symp-
cal anxiety. This may be due to a deficiency in the quality
toms.
or quantity of the inhibitory neurotransmitter, in the receptor
sensitivity to the neurotransmitter, or in the quality or quantity
of the receptors or their adjacent ion channels. Benzodiaze-
Treatment
pines, which calm anxiety, and beta carbolines and caffeine,
which precipitate anxiety, are believed to act at this site. Stress or conflict anxiety is a response to justifiable life events.
The redox hypothesis suggests that panic disorder may result The treatment of choice is psychotherapy that is supportive
from a pathological oversensitivity of central chemoreceptors and oriented to resolution of the conflict.
in the ventral medullary center to C0 2 or lactate or from a Simple phobias without unexpected anxiety attacks are con-
lability in the first steps of the ventilation arousal cascade ditioned rather than biologically based. The treatment of choice
which those chemoreceptors activate. Lactic acid is the end is behavior therapy, particularly exposure. Medications are
product of the anaerobic metabolism of carbohydrates and is rarely necessary.
derived solely by the reduction of pyruvate to lactate. The Multiple phobias with expected anxiety attacks usually re-
process requires oxidation of the CO factor NADH (nicotin- quire a combination of several treatments. About 15% of cases
amide adenine dinucleotide, reduced). The NADH/NAD ratio have a spontaneous remission-that is, the symptoms of the
is the redox state of the site where the reaction is taking place, disorder clear up for no particular reason. These 15% often
usually within the mitochondria. Rises in the lactate/pyruvate ascribe their cures to whatever positive treatment they are
ratio with concomitant falls in chemoreceptor intraneuronal engaged in at the moment. However, the majority of the vic-
pH is hypothesized as the trigger. Experimentally, lactate infu- tims of this illness, if they are to get full relief of symptoms,
 Anxiety and Anxiety Disorders 19

require an antipanic medicine, often additional exposure to Step 4. Because this is a long-term relapsing disorder in
behavior therapy, and sometimes psychotherapy. There are the majority of cases, these patients require long-term monitor-
four major steps in treatment of panic anxiety with pho- ing to ensure that they do not relapse and become disabled
bias. again. Because they have often acquired much incorrect infor-
Step 1. Control the metabolic core of the disorder with one mation about their condition, it is important to correct this
of the following classes of antipanic medications: (a) tricyclic with proper patient education about the disorder and its treat-
antidepressants, (b) monoamine oxidase (MAO) inhibitors, (c) ment. Correct information is one of the best insurances against
alprazolam and clonazepam, or (d) trazodone. Each of these future relapse and disability.
has advantages and disadvantages. Most have disruptive side
effects. They require considerable skill to use correctly and
to full advantage. They should block the core unexpected anxi- Further reading
ety attacks and help lessen the phobic anxiety.
Step 2. Extinguish any remaining phobic avoidance with Tuma AH, Maser JD, eds (1985): Aruiety and Aruiety Disorders.
exposure behavior therapy. Sometimes patients can do this New Jersey: Lawrence Erlbaum Associates
on their own without the assistance of a behavioral psycholo- Sheehan DV (1983): The Aruiety Disease. New York: C Scribners
gist. Sons; rev paperback ed Bantam Books, 1986.
Klein DF, Rabuin JG eds (1981): Aruiety: New Research and Chang-
Step 3. If psychological or social problems complicate recov- ing Concepts. New York: Raven Press
ery, then additional psychotherapy may be necessary to help
resolve remaining difficulties.
Autism
Edward M. Ornitz

Autism is a severe pervasive developmental disorder of behav- The uniqueness of this syndrome suggests one underlying
ior which is not accompanied by demonstrable neurological pathophysiological mechanism. However, multiple etiologies,
signs, consistent neuropathology, metabolic disorder, or ge- which could activate or replicate such a mechanism, are sug-
netic markers. Four in 10,000 children are afflicted and about gested by the association with autism of many prenatal, perina-
80% of those afflicted are mentally retarded. The onset is tal, and neonatal conditions which putatively are likely to insult
usually within the first 30 months of life. Most patients remain fetal or neonatal brain function. In particular, congenital ru-
severely disabled and require custodial care throughout their bella, toxemia, neonatal anoxia, and infantile spasms have
lives. There is no specific treatment; management is primarily been implicated. Such conditions account for about one-quarter
behavior modification carried out in special educational or of all cases. In the remaining cases, potential etiologic factors
residential programs, and through parent training. Longevity have not been identified, although there is some evidence from
is within the normal range. family studies suggesting a subgroup with a genetic compo-
The behavioral syndrome is unique, consisting of specific nent. There is a paucity of pathologic studies, and the few
disturbances of social relating and communication, language, autistic brains that have been examined have failed to reveal
and cognition, response to objects, sensory modulation, and consistent neuropathology. Biochemical investigations have
motility. The complete syndrome is usually observed, or de- not revealed any consistent neuromodulator or neurotransmitter
scribed retrospectively by the parents, before 5 years of age. abnormalities, although elevated blood serotonin in about 25%
During later childhood and adolescence, the clinical picture of cases remains an unexplained finding.
may change, such that some patients continue to appear primar- The symptomatology of autism, particularly the disturbance
ily autistic and others more retarded; a higher functioning mi- of sensory modulation, and some neurophysiological studies
nority develop schizoid personality disorders. Although origi- suggest that this syndrome is, in the absence of consistent
nally described as the earliest manifestation of schizophrenia, neuropathology, a true neurophysiological disease, and that
most authorities consider autism and schizophrenia to be phe- the hypothesized pathoneurophysiological mechanism is at the
nomenologically as well as genetically distinct syndromes. interface between sensory processing and information process-
However, recent developmental studies show that some high- ing. Neurophysiological and clinical studies of this mechanism
functioning verbal autistics develop a characteristic schizo- have taken two general directions, one stressing the distur-
phrenic thought disorder. Behavioral analyses point to common bances of hmguage and cognition and the other stressing the
elements in the responses to sensory input of young autistic disturbances of sensory modulation and motility.
children and older schizophrenics, suggesting a common dys- Neurophysiological studies of cortical events are relevant
function of sensory modulation and subsequent information to the autistic disturbances of language and communication,
processing. The disturbances of relating to people and objects and to an underlying postulated specific cognitive disorder,
include emotional remoteness, lack of eye contact, indifference presumably of cortical origin. This research has included elec-
to being held, stereotypic ordering and arranging of toys with- troencephalographic (EEG), radiological, including computer-
out regard to their function, intolerance of change in surround- ized axial tomography (CAT), and event-related potential stud-
ings and routines, and the absence of imaginative play. The ies. Both hemispheric lateralization and nonlateralizing
disturbances of communication and language include the ab- phenomena have been studied. The possibility of dysfunction
sence of both verbal and nonverbal communicative intent, se- of hemispheric Jateralization has been considered because of
vere delays in the acquisition of language, and deviant forms the language disorder in autism. The severe delays and devi-
of language, such as delayed echolalia and pronoun reversal. ances in language development suggest pathophysiological cor-
The disturbance of sensory modulation involves all sensory tical mechanisms, although the mesencephalic and tecta! por-
modalities, and the faulty modulation is manifest as both under- tions of the reticular core within the brain stem have been
and overreactivity to sensory stimuli. The latter is often associ- implicated in the autistic failure to perceive prosodic speech
ated with a tendency to seek out and induce sensory input, features which are essential for social communication. Gener-
e.g., visual scrutiny of spinning objects. Some of the motility ally, inadequate modulation of sensory input during subcortical
disturbances, e.g., hand flapping, may provide such input processing would compromise its value as information during
through proprioceptive and kinesthetic channels. The distur- cortical processing. Although this hypothesis suggests that ab-
bances of sensory modulation and motility occur predomi- normal cortical processing is a secondary consequence, the
nantly, though not exclusively, in 2- to 4-year-old autistic possibility of cortical dysfunction in autism has stimulated
children. Before the age of 5 years, the disturbances of sensory investigation. Specific pathophysiology of the temporal lobes
modulation and motility are observed with almost the same and dysfunction of mesolimbic cortex and associated neostria-
frequencies as the disturbances of relating to people and ob- ta! structures have been postulated. Some quantitative EEG
jects. studies, both during wakefulness, without and with tasks, and
 Autism 21

sleep, suggest abnormal patterns of cerebral lateralization. of neurons. Brain stem auditory evoked responses are re-
These findings are not consistently supported by dichotic listen- sponses of a subset of neurons within the brain stem. It has
ing studies or CAT scans. CAT scans have shown abnormal been proposed that those autistics who do have prolonged
structural configurations in only about one-quarter of autistic brain stem transmission times may have brain stem neuropa-
subjects, suggesting a subgroup in which the autism is associ- thology which replicates or activates the system dysfunction
ated with a structural brain abnormality. Impaired information reflected by the vestibular and autonomic abnormalities.
processing is suggested by reports of small P300 waves in In an attempt to integrate the clinical and experimental evi-
the evoked EEG response to target stimuli. Other event-related dence for both cortical and subcortical neurophysiological dys-
potential studies have failed to demonstrate cortical abnormali- function, it has been proposed that the disturbances of sensory
ties. modulation and motility reflect the pathophysiological mecha-
Neurophysiological studies of subcortical events are relevant nism and that the other abnormal behaviors can be understood
to the autistic disturbances of sensory modulation and motility. as consequences of distorted sensory input. This suggests a
These investigations have included autonomic, vestibular, and neurophysiological dysfunction involving a cascading series
brain stem auditory evoked response studies. The autonomic of interacting neuronal loops in the brain stem and dien-
response studies have focused on the regulation of cardiovascu- cephalon which subserve modulation of sensory input. Some
lar and respiratory responses mediated by the vagus nerve of the same systems modulate motor output in response to
and originating at its source within the brain stem. It has sensory input. The rostral projections from these structures
been proposed that the increased heart rate variability of autistic include those to the hippocampus, limbic cortex, neostriatum,
children may reflect reticular formation responses to insignifi- and parietal cortex. Parietal structures influence the direction
cant stimuli. Also, increased heart rate variability is greatest of attention to stimuli of emotional significance, integrating
during autistic stereotypic behavior, linking dysmodulation of sensory input from association cortex and thalamic centers
autonomic responsivity to the motility disturbances. Failure with limbic and reticular input. Output is to regions involved
to habituate respiratory responses and enhancement of vascular with motor responses to emotionally significant stimuli. Autis-
responses to visual stimuli, indicating incapacity to reduce tic children suffer from distortions of directed attention and
stimulus novelty and therefore sensory overload, link the ab- fail to sustain motor responses such as eye contact to socially
normal autonomic responses to the disturbances of sensory relevant stimuli. Their emotional, cognitive, and language defi-
modulation. Peripheral blood flow and heart rate are also ele- cits suggest failure of emotional surveillance, a function at-
vated. The increased reactivity of autonomic responses may tributed to dorsal parietofrontal structures. Brain stem and dien-
reflect the inability to gate or filter trivial sensory stimuli, cephalic centers project rostrally to telencephalic structures
thereby compromising appropriate selective attention. The ves- and these, in tum, modify brain stem and diencephalic func-
tibular response studies have demonstrated abnormal visual- tion. In this model, hypotheses of rostrally and caudally di-
vestibular interactions, prolonged time constants, and reduced rected sequences of pathoneurophysiological dysfunction in
secondary nystagmus. Abnormalities of vestibular adaptation autism merge, so that autism can be explained in terms of
and the influence of excessive reverberation in multisynaptic dysfunction of brain stem and related diencephalic behavioral
brain stem pathways on vestibular function have been proposed systems and their elaboration and refinement by selected higher
to account for these findings. Both the vestibular and auto- neural structures.
nomic responses distinguish autistic from control populations.
Brain stem auditory evoked response studies, on the other Further reading
hand, have not consistently supported the brain stem hypothe-
sis; prolonged brain stem transmission times are found only Ornitz EM (1983): The functional neuroanatomy of infantile autism.
in a minority of autistic children. The vestibular and autonomic Inti J Neurosci 19:85-124
Ornitz EM (1985): Neurophysiology of infantile autism. J Am Acad
responses probably involve widespread interconnecting neu-
Child Psychiat 24:251-262
ronal fields within the brain stem. The mechanism underlying Rutter M, Schopler E, eds. (1978): Autism: A Reappraisal of Concepts
the autistic behavioral syndrome is likely to involve a system and Treatment. New York: Plenum Press
dysfunction rather than a pathologic change in a specific group
Behavior Therapy, Applied Behavior Analysis,
and Behavior Modification
Leo J. Reyna

Behavior Therapy, Applied Behavior Analysis, and Behavior conditioning, analysis focused on how new behaviors take
Modification refer to a relatively recent, interrelated group of form as a result of the different classes of environmental effects
procedures for clinical assessment, intervention, and preven- that followed emitted behaviors.
tion. They are employed to relieve behavioral, emotional, and Today, just as in the area of basic research on learning in
cognitive distress and disabilities, and to enhance the individu- which a total account of behavior increasingly includes analysis
al's functional repertoires. The first journals, Behavior Re- of respondents and operants, so too clinical behavioral inter-
search and Therapy, Journal of Applied Behavior Analysis, ventions increasingly address the respondent and operant com-
Journal of Behavior Therapy and Experimental Psychiatry, ponents present in dysfunctional repertoires and utilize inter-
and Behavior Therapy, have been followed by many others. vention procedures directed at changing both classes of
This group of clinical procedures emerged from, and contin- behaviors. Further, while Behavior Therapy was first (Guthrie,
ues to reflect, laboratory studies on the psychology of learning Salter, Wolpe) employed almost exclusively for office and
begun 100 years ago. Behavioral clinicians have developed outpatient clients, and behavior modification for resident or
analyses and techniques designed to clarify (1) how functional institutionalized patients (Lindsley, All yon, Azrin, Ferster,
and dysfunctional behavioral repertoires are acquired, (2) how Krasner), the full spectrum of intervention techniques are in-
these repertoires are maintained, and (3) how they can be creasingly employed across all populations and settings.
weakened or attenuated. Their laboratory legacy led behavioral
clinicians to give primacy to observable, measurable, replica-
ble, and verifiable environmental events and behaviors, and Behavioral assessment
this feature has led to the largest body of data-based, controls-
designed research published in the psychotherapeutic literature. Many common features characterize the behavioral clinician's
Much of contemporary research and applications are con- approach to identifying patient/client repertoires. The initial
cerned with demonstrations that learning plays a major role behavioral assessment interview seeks to secure certain broad
in dysfunctional, as well as functional, repertoires, and that details of the patient/client's life history: family and personal
both classes of repertoires can be modified by learning and interactions, living arrangements, education, school and work
unlearning interventions. Further, increasingly, behavio"ral in- histories, medical problems, etc. Following this, information
terventions have been found useful in the remediation and is gathered on seven additional areas:
rehabilitation of dysfunctional behavioral and emotional reper-
toires that are sequelae or by-products of a number of condi- l. The presenting problem. Specific examples from everyday
tions affecting the biological integrity of the organism (e.g., living (rather than such generalities as "I feel depressed
genetic, constitutional, nutritional, injury, disease, and various most of the time") are solicited from the patient/client.
medical disorders affecting the biochemistry and structural fea- The delineation (and treatment) of specific problem behav-
tures of the nervous system). iors, emotional reactions, and cognitive behaviors is pre-
Although today the terms Behavior Therapy, Applied Be- ferred to determining which diagnostic category the patient/
havior Analysis, and Behavior Modification are often used client fits. The use of diagnostic labels is sometimes iatro-
interchangeably, historically, they are derivations from two genic and often implies the presence of features not discerni-
major experimental areas in the psychology of learning. Behav- ble and omits other features that are discernible in the pa-
ior Therapy stemmed from the investigations of Pavlov and tient/client's repertoires.
the formulations of Hull and Guthrie, and the area is variously 2. Onset and development of problem. When in time, and
referred to as Pavlovian or classical or respondent conditioning. under what circumstances.
Behavior Modification and Applied Behavior analysis stemmed 3. Problem fluctuations. Fluctuations, since time of onset, in
from the work of Thorndike and Skinner, and concerned instru- the severity or absence of the problem(s), and identification
mental learning or operant conditioning. Respondents are of accompanying life circumstances.
largely unconditioned and conditioned reflexes, so-called in- 4. Interference by problem. How problem interferes with a
voluntary reactions, and are of special interest in the analysis range of daily required and desired activities (e.g., work,
of the components of emotional and motivational behaviors. school, relationships, sexual functioning, health). To fur-
Operants are behaviors (more often chains of behavior) that ther assist the patient/client in specifying information
have a more direct effect on the external environment, are needed in these first four areas, the behavioral clinician
the so-called voluntary behaviors seen in speech (covert and often offers the client a variety of published inventories
overt) and in the broad range of motor skills involving coordi- and checklists (not tests).
nation, locomotion, and manipulation. While in respondent 5. Functional repertoires. The delineation of the patient/
conditioning, emphasis was on the analysis of how new, neu- client's positive functional repertoires (a) to use in conjunc-
tral, antecedent stimuli came to control reflexes, in operant tion with intervention procedures and (b) to avoid or coun-
 Behavior Therapy, Applied Behavior Analysis, and Behavior Modification 23

teract the therapist and client's viewing the client as being modeling, extinction, and several other_s (us~d alone. or_ in
solely dysfunctional. combination with each other and sometimes m combmation
6. Client's goals in therapy. The delineation of the goals or with procedures described below).. .
objectives of therapy as expressed by clients (in preference Some behavioral clinicians (apphed behaviOr analysts), how-
to goals set by therapists). ever, may prefer to focus on the concurrent operants of avoid-
7. Client's definition of progress. The securing of an explicit ance and escape present with emotional respondents, and
statement of progress indicators from the client, in which employ instead, a variety of reinfo~cement p~oced?res for
clients specifically identify what observable, measurable strengthening alternative or incompatible behavi~rs (I.e., ~p­
changes in their own repertoires must take place to fulfill proach repertoires to previously feared or discomfortmg
their own criteria of progress. events). Other clinicians, cognitive-behavioral, prefer to focus
on, and alter high-frequency irrational thinking and dysfunc-
Areas (5-7) are designed to minimize the development of inap- tional self-statements (covert speech behaviors).
propriate dependency behaviors on the therapist and therapy. For individuals whose repertoires consist of one or more
The role of measurement (frequency, intensity, latency, and low strength (or absent) functional repertoires, intervention
duration) of dysfunctional behaviors is emphasized at every procedures may include one or more of the following pro~e­
stage of the assessment/intervention process. The behavioral dures (partial listing): various positive reinforcement or contm-
clinician often trains and enlists the help of the client as data- gent strengthening of functional behaviors, self-control and
gatherer. From the o~set, the p~tient/client, .s~gnific~nt oth~rs, self-management procedures, shaping through reinforcement
and affiliated care-givers are hkely to participate m keepmg of successive approximation of the functional behaviors.
a daily log of the problem behaviors. This daily lo~ is designed Since any particular dysfunctional repertoire includes a range
to identify the settings or circumstances that occasiOn pro?lem of both high-strength dysfunctional behaviors, emotional reac-
behaviors and feelings, the client's reactions to these settmgs, tions, and cognitions, and low-strength functional repertoire~,
and to record the consequences or the effects on self and others several different intervention procedures are likely to be uti-
of these behaviors. In many instances, special forms for keep- lized for the same individual. Further, depending on the partic-
ing such records have been developed to assist client/observers ular individual's history (personality), some patient/clients will
to keep track of particular problem behaviors (e.g. , J. Cautela's be more responsive to a combination of particular methods
organic dysfunction survey schedules) .. For resident popul_a- for altering their behaviors.
tions, two or more observers may be enlisted to ensure reliabil-
ity of the observations of problem behaviors.
Research
Methods of behavioral intervention Earlier, the major emphasis in behavioral clinical research
concentrated on studies of the efficacy of specific single proce-
Initial (and ongoing) assessment and evaluation procedures dures for specific dysfunctional behavior repertoires, but in-
are designed to provide a detailed analysis of the patient/ creasingly research is shifting to analysis of what combinations
client's range of behavioral, emotional, and cognitive reper- of procedures are most effective, and which components of_ a
toires. Some repertoires are appropriate and useful (functional) program are making which contribution to the total therapeut~c
and some are inappropriate and aversive (dysfunctional) for outcome. Thus, the current intensive range of research in this
relating to people (including themselves), places, situations, area seeks to determine what specific procedures, alone or in
interactions, things, tasks, knowledge, conceptions, ideas. combination, are most effective (immediate and long-term),
This discussion is primarily directed to the use of behavioral in the shortest possible time, and with the least disruption
interventions with patient/client populations seen in office set-
(side effects) of daily activities, for different kinds of problems,
tings and for whom physical and medical disorders are. not presented by individuals with their own unique predysfunc-
major factors contributing to their dysfunctional behaviOral tional histories, personalities, life-styles, and settings. Reports
repertoires. Nevertheless, the intervention procedures~ o~en of such research can be found in the Journals mentioned at
useful as adjunctive procedures to somatic and medication
the beginning of this article, as well as in three major research
interventions accompanying medical and physical rehabilita- review series: Annual Review of Behavior Therapy; Progress
tion procedures. in Behavior Modification; and Advances in Cognitive-Behav-
At least 30 different behavioral procedures for altering reper-
ioral Research and Therapy.
toires have been culled from the published literature (E. Reese)
and since often more than one procedure is employed, the
Further reading
possible combinations of distinct components yields an even
greater number of behavioral treatment programs. Hammonds B, ed. (1984): Psychology and learning. In: The Master
For individuals whose dysfunctional behavioral repertoires Lecture Series, Vol 4. Washington DC: American Psychological
consist predominantly of one or more high-frequency aversive Association
emotional respondents elicited by particular environmental Skinner BF (1953): Science and Human Behavior. New York: Mac-
events (people, situations, thoughts, performing some task, millan
Wilson G, Franks C, eds (1982): Contemporary Behavior Therapy.
medical disabilities, etc.), procedures for attenuating condi- New York: Guilford Press
tioned emotional reflexes include a variety of countercondition- Wolpe J, Salter A, Reyna L, eds (1964): The Conditioning Therapies:
ing paradigms found, for example, in systematic desensitiza- The Challenge in Psychotherapy. New York: Holt, Rhinehart and
tion, controlled relaxation, flooding, assertiveness training, Winston
Behavioral Medicine
Neal E. Miller

Behavioral medicine is an interdisciplinary field integrating programs, the incidence of smoking is approximately half that
basic research and applications from behavioral and biomedical 0f controls.
sciences that are relevant to problems of physical medicine. Alcohol abuse contributes to cirrhosis of the liver, pancreati-
The behavioral sciences involved are psychology, sociology, tis, several types of cancer, and injuries from accidents and
anthropology, and economics. In addition to the basic biomedi- violence. Studies have shown that cultural and other psychoso-
cal sciences, epidemiology and clinical observations are in- cial factors contribute to alcoholism, but we need to know
volved. far more about such causes. While a number of different social
Although the behavioral sciences have had some relationship and behavioral programs are successful in treating some peo-
to medicine for a long time, primarily in the area of mental ple, the average rate of long-term success is discouragingly
health and to some extent in the area of pediatrics, the explosive low. This suggests emphasis on prevention. The amount of
expansion of relationships with physical medicine is a phenom- research devoted to alcoholism has been extremely small com-
enon that took off in the late 1970s and is continuing to progress pared with the great social, economic, and medical importance
rapidly. One factor in the advance of behavioral medicine is of the problem.
an increased understanding of the various mechanisms by Overeating and underexercise contribute to obesity, which
which the brain, via its neural and humoral systems, controls increases the risk of hypertension, diabetes, and heart disease,
the health of the body. and complicates surgery. Reduction in obesity can be a signifi-
Behavioral medicine is concerned with psychosocial factors cant factor in treating certain cases of hypertension and diabe-
across a wide range of medical activities: etiology, prevention, tes. That some sort of influence in the social environment
compliance with medical prescriptions, improving certain diag- contributes to obesity is demonstrated by the fact that its inci-
noses and relieving the stressfulness of ominous ones, methods dence is much lower in people born into the upper social
of reducing the stressfulness of aversive medical procedures classes than those born into the lower ones. A wide variety
and their aftereffects, direct or adjunctive therapy for certain of behavioral treatments can cause some obese people to return
physical conditions, rehabilitation, and problems of old age. permanently to normal weight, but for most patients, relapse
Because of the great variety of activities in each of these rates are discouragingly high. Many advances have been made
areas, only a few illustrative examples are presented. in understanding various aspects of the complex mechanisms
Smoking is a form of voluntary behavior clearly harmful regulating food intake, but there is still no definitive way to
to health. Converging lines of biomedical evidence show that reduce obesity rates.
cigarettes are causal factors in cardiovascular disease, cancer If everyone complied with their physicians' recommenda-
of the mouth, lungs, and esophagus, emphysema, bronchitis, tions, it would be easy to get rid of the unhealthy behaviors
and chronic obstructive lung disease. Behavioral studies show that have just been described. But this does not occur with
that nicotine is a strong reinforcer for smoking. Withdrawal recommendations about life-style or other problems. In fact,
symptoms and the difficulties that many people encounter in studies have shown that approximately one-third to one-half
quitting indicate that smoking can be addictive. Some modest of patients do not take the drugs that are prescribed. Studies
success in getting smokers to stop has been achieved by pro- have shown that having the reason for the prescribed procedure
grams ranging from the use of the mass media to behavior- thoroughly understood helps but often is not enough. Other
modification techniques, and even modest successes can pro- studies have shown that compliance with recommendations
duce considerable savings in the total burden of disease to of health care therapists is increased if patients have a relation-
be expected in the long run. ship with them that is warm and affectionate and that bolsters
Since the problem of getting smokers to quit permanently the patients' self-confidence.
is extremely difficult, efforts are being concentrated on preven- Clinical experience has been confirmed by behavioral experi-
tion. After investigating the factors that cause children to start ments on animals proving that deprivation of stimulation by
smoking, programs have been developed to teach young people visual patterns during an early critical phase of development
strategies for counteracting pressures from peers, adults, and can produce a permanent deficit. Thus, the early correction
the media. Students are shown films of adolescents using vari- of conditions such as severe astigmatism that interfere with
ous techniques to resist different inducements to smoke; then clear patterned vision is important in order to avoid permanent
they participate in role-playing situations in which they resist deficits that cannot be corrected later by appropriate lenses.
such pressures. Because immediate rewards and punishments Behavioral research showing that infants have a strong ten-
are so much more effective than delayed ones, rather than dency to look at a pattern rather than an unstructured part of
emphasizing remote dangers such as lung cancer, the programs the visual field has enabled the early diagnosis of defects in
emphasize the immediate consequences of smoking, such as pattern vision and testing for the type of lenses that corrects
increased heart rate, messiness, and odors. Follow-up studies the deficit.
two years later indicate that, among students exposed to such Studies have shown that people exhibiting a combination
 Behavioral Medicine 25

of hard-driving, competitive, impatient, and hostile behavior, Yet other research shows how behavioral factors such as
which has been called type A, are approximately twice as stress can have effects on the medically highly significant im-
likely to have heart attacks as those who do not show this mune system. Finally, research using powerful new neuro-
pattern, defined as type B, even after other risk factors, such physiological, biochemical, and pharmacologic techniques is
as smoking, obesity, and hypertension, are parceled out. One providing increasing information about the brain mechanisms
such study followed 3,500 people prospectively for 8.5 years. via which psychosocial factors can exert powerful effects on
Another study, on a large sample studied as medical students the health of the body.
showed that those scoring high on a scale measuring hostility On the other side of the picture, clinical and epidemiological
and suspiciousness had substantially higher rates of mortality evidence strongly suggests that positive emotional factors, such
than those with low scores. Such studies are stimulating re- as social support, can contribute to freedom from disease and
search into the personality variables involved in adverse medi- to longevity. But the effects of positive emotional factors have
cal consequences and the psychophysiological mechanisms that not yet been investigated by rigorous studies that control for
may be involved. possibly confounding factors. For example, people with many
Clinical observations, epidemiological studies, and life- friends are probably more likely to be told that they need to
change scales strongly suggest that a variety of situations that see a doctor.
can loosely be described as stressful increase the probability Studies of the effects of stress have provided the scientific
of a variety of adverse medical consequences. Although inge- rationale and impetus for the use of behavioral techniques to
nious controls have been used, it is difficult to eliminate con- reduce stress as well as the use of other techniques such as
founding factors, such as sanitation, personal hygiene, diet, inoculation against stress and training in various coping re-
and exercise. However, a number of rigorously controlled ex- sponses such as assertiveness training.
periments, which necessarily could be conducted only on ani- The techniques of behavior modification and behavior ther-
mals, have strongly supported the foregoing suggestive results apy, originally developed primarily to deal with the behavior
by proving adverse effects of certain stressors on various as- of retarded children and neurotic patients, are increasingly
pects of the cardiovascular, gastrointestinal, and immune sys- being applied to a wide variety of problems of physical medi-
tems. cine, ranging from the prevention or retraining of unhealthy
Studies have shown the interaction between psychological habits, such as smoking, through securing better compliance
and organic factors. For example, when both groups are tested with medical prescriptions, to helping to cure conditions that
on a normal diet, the psychological stress of conflict induced have been difficult to treat by purely physical orpharmacologic
by an electrical shock on the water bottle will produce hyper- approaches. An idea central to one important area of such
tension in a population of rats selected to become hypertensive application is that when sickness behavior is reinforced more
on a high salt diet, while it will not produce hypertension in strongly than healthy behavior, it will persist after the organic
rats selected to be resistant to such a diet. With dogs, when cause has disappeared. Sympathy and attention from family
a stress of avoidance learning that would not by itself produce members and care-facility staff, release from onerous responsi-
hypertension is combined with a moderate salt load that also bilities and duties, the benefits of pain-killing or sleep-inducing
would be ineffective by itself, the combination of the two medications, and payment for disabilities are powerful rein-
produces hypertension. Similarly, when pigs or dogs are given forcers for such behaviors. Some of the sickness behaviors
experimental heart attacks by having a coronary artery tied reinforced in this way are signs of pain, such as wincing,
off, a procedure that would not by itself lead to a fatal cardiac limiting physical activity, asking for pain-killing drugs, symp-
arrhythmia, sudden death can be induced by stimulating the toms of extreme dependence, fatigue, weakness, headaches,
sympathetic nervous system or by behavioral stressors. This dizziness, and various other conditions that are either without
fits in with the observation that when a group of doctors are an organic cause or that are disproportionate so that full use
making ward rounds through an Intensive Care Unit for patients is not made of the patient's potential capabilities. In such
recovering from heart attacks, the patients are five times as cases, behavior therapy uses a variety of ingenious techniques
likely as at any other time of day to have arrhythmias producing to withhold reinforcements for sickness behavior and provide
fibrillation that would be fatal if equipment were not available them for healthy behavior. This is done first in the health
to resuscitate them. care situation and then extended to the patient's normal envi-
A specially significant analytical series of studies on rats ronment. In many cases, it may be necessary specifically to
has shown how purely psychological variables can affect the train the patient in healthy behavior as the way of achieving
pathological consequences of identical levels of a physical goals previously reached by sickness behavior. One of the
stressor. For example, when the physical strength of electrical best evaluated uses of behavior therapy has been in treating
shock was controlled by having fixed electrodes on the tails pain that has no discoverable organic basis. Phobias for proce-
of pairs of rats wired in series, a signal for one member of dures such as dental work, dialysis, injections, or having blood
each pair that enabled it to learn the discrimination of when drawn have been eliminated by training patients to relax and
it was dangerous and when it was safe caused that group to then introducing them gradually to progressively more fear-
develop one-fifth as many stomach lesions as the one without inducing steps of the procedure along with demonstrations
that signal. In another experiment, being able to control the by models who are free of fear.
shock by a simple coping response caused rats in that group The autonomic nervous system, which controls the visceral
to have fewer stomach lesions, lower levels of plasma cortico- organs and glands, had long been thought to be fundamentally
sterone, and less depletion of brain norepinephrine than the inferior to the somatic one controlling the skeletal muscles.
rats that received identical shocks but were helplessly depen- The strong traditional belief was that the autonomic nervous
dent on their partners. system could be modified only by classical conditioning, which
The foregoing rigorously controlled experimental results are was believed to be a primitive type of learning, and not by
in line with the clinical observations that an individual's per- the more flexible type of trial-and-error learning (also called
ception of a threat is more important than the objective danger operant conditioning or instrumental learning) that is influenced
and that the ability to have some form of control or to perform by rewards and punishments and believed to be primarily re-
coping responses can be more important than the overall diffi- sponsible for voluntary behavior. Effects of the higher type
culty of the situation. of learning were thought to be indirect and hence trivial, as
26 Neal E. Miller

when blood pressure is increased as a by-product of muscular intrathoracic pressure produced by a Valsalva maneuver. Al-
tension. though it is difficult to prove a negative, such tests seem to
Relatively recent experiments on both animals and people, have ruled out all types of skeletal mediation.
however, have shown that instrumental learning shaped by The apparently direct control over visceral responses medi-
rewards and punishments can significantly modify a variety ated by the autonomic nervous system opens up interesting
of visceral responses controlled by the autonomic nervous sys- new theoretical possibilities for the role of learning in normal
tem, such as salivation, heart rate and rhythm, vasoconstriction homeostasis and in the etiology and therapy of certain visceral
and vasodilation, blood pressure, and the galvanic skin re- disorders. One use of biofeedback, in combination with auto-
sponse. It is difficult to prove conclusively that the learned genic training and relaxing imagery, has been teaching ex peri-
control is direct and not mediated by some skeletal response. mental subjects to control motion sickness induced by exposure
But even in cases where the visceral response is clearly medi- to a rotating chair. Following up on the original research by
ated by a skeletal one, clinical evidence shows that the effects Dr. Cowings at the NASA Ames Research Center, a study
are not trivial. For example, some patients for whom the symp- by the U.S. Air Force showed that of 50 members of air
tom of tachycardia achieves the goal of escaping from some crew who were about to be grounded because all other methods
unwelcome type of responsibility produce their rapid heart had failed to cure their incapacitating air sickness in modem
rate by hyperventilation. Certain others, but unfortunately not high-performance planes, such training restored 40 to flying
all, who for organic reasons suffer sudden attacks or paroxys- duty. Biofeedback, in combination with other behavioral tech-
mal tachycardia can learn to abort such attacks by taking a niques, is especially useful in improving the rehabilitation of
sudden deep breath. Certain other cases with the arrhythmia patients with neuromuscular disorders and with urinary and
of bigeminy (abnormal beats alternating with normal ones) fecal incontinence. Because of the contribution of the latter
can be taught to terminate this troublesome symptom by exer- two disorders to the need for care of the elderly in nursing
cising to increase their heart rate. Persistent muscular tension homes, Faye Abdullah, the U.S. Deputy Surgeon General,
can contribute to hypertension, and physical relaxation pro- has estimated that the widespread application of behavioral
duces some relief. techniques developed for these two disorders could save more
The best evidence for direct control over an autonomically than $10 billion a year.
mediated response comes from patients paralyzed from the
neck down by high spinal lesions. Such patients, who have Further reading
suffered from orthostatic hypotension that confined them to a
horizontal posture for two or more years and who resisted Levy SM, ed (1982): Biological Mediation of Behavior and Disease:
the conventional therapy of progressive elevation to more verti- Neoplasia. New York: Elsevier Biomedical
cal postures on a tilt table, have been taught to achieve volun- Lindemann JE (1981 ): Psychological and Behavioral Aspects of Physi-
cal Disability. New York: Plenum Press
tary control over blood pressure by biofeedback training in Matarazzo JD, Miller NE, Weiss SM, Herd JA, Weiss SM, eds
which they are given moment-to-moment information about (1984): Behavioral Health: A Handbook of Health Enhancement
changes in blood pressure and rewarded for increasing it. This and Disease Prevention. New York: Wiley-Interscience
training has corrected their homeostatic defect of orthostatic Melamed BG, Siegel U (1980): Behavioral Medicine: Practical Ap-
hypotension and enabled them to achieve the much more nor- plications in Health Care. New York: Springer
mal activities that involve sitting upright. The large changes Miller NE (1983): Behavioral medicine: Symbiosis between laboratory
that such patients can learn to produce voluntarily without and clinic. Ann Rev Psychol34:1-3l
any observable changes in electromyograph recording from Miller NE, Brucker BS (1979): Learned large increases in blood pres-
their nonparalyzed muscles or in their breathing are more than sure apparently independent of skeletal responses in patients para-
lyzed by spinal lesions. In: Biofeedback and Self-Regulation, Bir-
twice as great as those they can produce by obviously great baumer N, Kimmel HD, eds. Hillsdale, NJ: Erlbaum Associates,
effort at contracting as strongly as possible all their functional pp 287-304
muscles and trying as hard as they can to contract all their Pomerleau 0, Brady JP, eds (1979): Behavioral Medicine: Theory
paralyzed ones. They are also much greater than those that and Practice. Baltimore: Williams & Wilkins
can be produced by hyper- or hypoventilation or changes in
Cocaine
Roger D. Weiss

Cocaine (benzoylmethylecgonine) is an alkaloid derived from which was pharmacologically quite similar to cocaine, much
the leaves of Erythroxylon coca, a shrub found in the eastern less expensive, and legally obtainable through prescriptions,
highlands of the Andes Mountains. Coca leaves, which contain helped lead potential stimulant abusers toward that drug rather
cocaine in concentrations ranging from 0.6% to 1.8%, have than cocaine. In the late 1960s and 1970s, greatly increased
been chewed by the inhabitants of this region for medicinal, interest in and acceptance of recreational drug use by certain
religious, and work-related purposes for at least 1,500 years. segments of the population contributed to the renaissance of
The local anesthetic properties of cocaine were initially de- interest in cocaine. Cocaine's recent surge in popularity has
scribed by Sigmund Freud and Karl Koller in 1884; the drug been abetted by its reputation as the prestigious "champagne
is still widely used for topical anesthesia of the upper respira- of drugs."
tory tract. However, the most common reason for cocaine The most common method of cocaine use consists of ' 'snort-
use today is recreational; the drug is a central nervous system ing" crystalline cocaine hydrochloride intranasally. The drug
stimulant and a powerful euphoriant. It is because of this prop- is sold illicitly as a translucent white powder, usually mixed
erty that cocaine abuse has become widespread. with adulterants such as other local anesthetics, sugars, and
amphetamine. It is arranged into thin lines 2-5 em long and
0.25 em wide, and inhaled through a straw or a rolled-up
History
dollar bill. An average line consists of 10 to 15 mg of cocaine.
Coca leaves have been used since at least A.D. 500, when Intravenous use, though unusual in occasional users, is often
several bags of the leaves were found at a Peruvian grave seen in severe cocaine abusers. In this form of drug use, heroin
site along with other items considered necessities for the is often combined with cocaine to form a ''speedball''; simulta-
afterlife. After the Spaniards conquered the Incas in the neous injection of the two drugs reduces the intensity of the
16th century, they set aside their religious objections to cocaine-induced stimulation, which some users find uncom-
the use of coca after seeing how chewing the leaves enabled fortable. "Freebasing" refers to the smoking of the alkaline
the Indians to work long hours in gold and silver mines precursor (freebase) of cocaine hydrochloride. Cocaine free-
with little need for food or sleep. Indeed, coca leaves were base is prepared by dissolving cocaine hydrochloride in water,
eventually used by the Spaniards as a form of payment to and then adding a base such as ammonia or baking soda.
the Incas. The alkaline precipitate which is thus formed can then be
Cocaine was first extracted from the coca leaf in 1855; this smoked, usually in a glass waterpipe.
discovery was followed by a flourish of experimentation with A recently developed form of freebase, known as "crack,"
the compound, peaking in the latter part of the 19th century. is cocaine freebase that has been manufactured from cocaine
Freud noted the drug's ability to relieve pain from peripheral hydrochloride by the dealer rather than the user. The resultant
lesions and thus led the way to the discovery of cocaine as a product consists of small chips that resemble white pebbles;
topical and local anesthetic. He also claimed that cocaine might these rocks of ready-to-smoke freebase may be sold for as
prove useful as a stimulant, as an aphrodisiac, and in the little as $10 each, and may contain cocaine in excess of 75%
treatment of depression, gastrointestinal disturbances, wasting purity. The low price, ease of use, high purity, and extremely
diseases, alcoholism, morphine addiction, and asthma. His addictive nature of crack have caused great concern and fear
work on cocaine was highly controversial, however, and he of an epidemic of cocaine addiction.
was accused of irresponsibility by much of the scientific com-
munity. Despite this, the general enthusiasm for cocaine led
to its incorporation into a number of tonics and patent medi- Drug effects
cines including Coca Cola. The cocaine was removed from Like other local anesthetics, cocaine is believed to inhibit nerve
Coca Cola in 1903, but even now it is flavored by decocainized impulses by altering the nerve cell membrane. It has been
coca leaves. posited that molecules of the anesthetic dissolve in the liquid
Cocaine's growing popularity was accompanied by increas- matrix of the neuronal membrane and bind to receptor sites
ing concern over the ability of the drug to cause dependence. within sodium channels. This process interferes with the open-
As more people abused the drug and deaths were reported ing of the channels and thereby inhibits the transfer of sodium
from cocaine toxicity, restrictions were placed on cocaine use. ions across the cell membrane. Depolarization of the axon
In 1914, the Federal Harrison Narcotics Act, which incorrectly cannot occur, and the nerve impulse is thus blocked. An addi-
classified cocaine as a narcotic rather than as a stimulant, tional property of cocaine which makes it particularly useful
prohibited the use of cocaine in patent medicines and effec- as a local anesthetic is its ability to cause vasoconstriction.
tively made recreational use of cocaine illegal. For years the Decreased blood flow in the anesthetized area allows for in-
drug went underground and was used by a very small segment creased visibility during surgical procedures performed with
of the population. The growing availability of amphetamine, cocaine anesthesia. Cocaine's vasoconstrictor property is par-
28 Roger D. Weiss

ticularly useful in otolaryngology, because of the high vascu- given unlimited access to intravenous cocaine will repeatedly
larity of the nose and throat. self-administer the drug to the point of severe toxicity and
Although it was once felt that the stimulant effects of cocaine even death. Repetitive use in humans may lead to sleepless-
occurred as a result of the drug's ability to increase norepineph- ness, loss of appetite, severe anxiety, paranoia, delusions of
rine turnover in the central nervous system, more recent evi- persecution, and auditory, visual, and tactile hallucinations.
dence has suggested that cocaine causes euphoria primarily Chronic cocaine abusers often spend large sums of money in
by prolonging the action of dopamine at nerve junctions where an attempt to obtain the drug and may resort to illegal activity
it serves as a neurotransmitter. This augmentation of dopa- in this pursuit. Some abusers have been known to spend up
minergic activity, which takes place most prominently in the to $2,000 a day on cocaine. Chronic intranasal use may lead
nucleus accumbens in animals, results from blockade of dopa- to inflammation or ulceration of the nasal mucosa, and chronic
mine reuptake. freebase smoking may cause pulmonary dysfunction. Intrave-
Following intranasal administration of cocaine, onset of ac- nous users are exposed to the medical hazards of unsterile
tion begins within 2 minutes. Intravenous use and freebase needles, including abscesses, hepatitis, infective endocarditis,
smoking produce almost immediate effects. Symptoms of in- and AIDS. Efforts to identify those at risk for chronic cocaine
toxication last for 20 to 40 minutes after intranasal use, and abuse have begun, though little is known at this time about
half that long after intravenous injection or freebase smoking. specific characteristics which may predispose individuals to
In general, the subjective effects of cocaine are related not develop this disorder.
only to the plasma level achieved but the rate of rise of plasma
level. The drug is metabolized in the liver and by cholinesterase Further reading
enzymes in plasma ..Cocaine is eliminated following first-order Fischman MW, et al. (1976): Cardiovascular and subjective effects
pharmacokinetics, with a half-life of approximately I hour. of intravenous cocaine administration in humans. Arch Gen Psychi-
The metabolite benzoylecgonine is excreted in the urine and atry 33:983-989
can be detected by enzyme immunoassay up to 72 hours after Siegel RK (1977): Cocaine: recreational use and intoxication. In:
the last dose. Cocaine 1977, Petersen RC, Stillman RC, eds. Washington DC:
Clinically, the most prominent effect of cocaine on mood National Institute on Drug Abuse research monograph 13
is one of euphoria. Stimulation, reduced fatigue, increased Weiss RD, Mirin SM (1984): Drug, host and environmental factors
mental clarity, diminished appetite, and garrulousness are also in the development of chronic cocaine abuse. In: Substance Abuse
and Psychopathology, Mirin SM, ed. Washington DC: American
frequently reported consequences of cocaine use. Physical ef-
Psychiatric Press
fects include tachycardia, systolic and diastolic hypertension, Weiss RD, Mirin SM (1987): Cocaine Washington DC: American
increased body temperature, and dilated pupils. The euphoriant Psychiatric Press
effects of cocaine may lead some vulnerable inwviduals to Wise R (1984): Neural Mechanisms of the reinforcing action of co-
abuse the drug chronically. Animal studies have shown that caine. In: Cocaine: Use and Abuse, Grabowsky J, ed. Rockville
cocaine is an extremely powerful reinforcer; rhesus monkeys Md: National Institute on Drug Ab·Jse
Coma
Fred Plum and Harriet 0. Kotsoris

Coma and clinical states allied to it represent severe or total circumstance that occurs following periods of prolonged cere-
global reductions of mental function due to structural or physio- bral hypoperfusion-hypoxemia, e.g., due to carbon monoxide
logical impairments of the brain. Coma is characterized by a poisoning. (4) Diffuse disorders, usually metabolic in origin
sustained loss of the capacity of arousal, preventing any expres- (metabolic encephalopathy), concurrently affect both the corti-
sion of potential mental function. The eyes are closed, sleep- cal and subcortical arousal mechanisms, although individually
wake cycles disappear, and even vigorous stimulation produces to a different degree.
no evidence of appropriate psychological response. Stupor de- As noted, coma reflects acute or subacute but always pro-
scribes a state of spontaneous unarousability in which strong found involvement of one or more of these four mechanisms.
external stimuli can transiently restore wakefulness. Stupor Acute abnormalities that are similarly distributed but less in-
implies that evidence of at least a limited degree of appropriate tense cause delirium, a condition marked by fluctuating levels
mental activity accompanies the arousal, transient though it of attention and arousal associated with impaired memory,
may be. The vegetative state is the condition wherein arousal confusion, distractibility, and, sometimes, delusions or halluci-
(i.e., sleep-wake cycles) returns or remains but appropriate nations, especially visual ones. More insidiously developing
testing measures elicit no evidence of the person's cognitive and chronically lasting disorders of cortex and subcortex us.u-
awareness of self or environment. The locked-in state describes ally spare arousal mechanisms and result in a gradual decline
a condition in which persons retain or regain arousability and in cognitive functions (dementia) without producing clouded
self-awareness but because of extensive bilateral paralysis (i.e., consciousness.
deafferentation) can no longer communicate except in severely Nearly all patients who survive coma sooner or later re-
limited ways. Brain death describes the irreversible loss of awaken, with the interval between the acute damage and the
function of all neural structures rostral to the foramen magnum. return of wake-sleep cycles being longest following extensive

Mechanisms
Eyes-closed coma always arises as a result of an acute disorder Table I. Major Causes of Stupor and Coma
that produces sudden depression or damage of specific and
Supratentorial lesions (secondarily causing deep diencephalic upper
nonspecific diencephalic and upper brainstem arousal mecha- brainstem dysfunction)
nisms. Conditions included in four major pathologic groupings Cerebral hemorrhage
can cause such severe, global acute reductions of conscious- Large cerebral infarction
ness. (I) In diffuse or extensive multi focal bilateral dysfunction Subdural hematoma
of the cerebral cortex, the cortical gray matter is diffusely Epidural hematoma
and acutely destroyed or depressed. Examples include laminar Brain tumor
cortical depression or necrosis from severe hypoxia-ischemia, Brain abscess (rare)
similar damage from sustained profound hypoglycemia, and Subtentorial lesions (compressing or destroying the reticular forma-
metabolic depression from certain stages of hepatic encepha- tion)
lopathy. As a result, cortical-subcortical physiological feedback Pontine or cerebellar hemorrhage
loops are impaired with the result that brainstem autonomic Brainstem infarction
arousal mechanisms become profoundly inhibited, producing Brainstem or cerebellar expanding tumor
the equivalent of acute reticular shock below the level of the Cerebellar abscess
lesion. (2) Direct damage to paramedian upper brainstem and Metabolic and diffuse lesions
posterior-inferior diencephalic ascending arousal systems Global cerebral anoxia or ischemia (e.g., cardiac arrest)
blocks normal cortical activation. Examples of conditions pro- Hypoglycemia
ducing such damage include midbrain infarcts or the inflamma- Severe nutritional deficiency (e.g., advanced Wernicke's disease)
tory lesions of certain selective forms of encephalitis. Anatomi- Endogenous organ failure or deficiency (e.g., lung, liver, kidney)
cally, the affected structures lie predominantly in the Exogenous poison (e.g., alcohol, sedatives, opiates)
Infections
paramedian gray matter extending roughly from the level of Meningitis
the nucleus parabrachialis of the pontine tegmentum forward Encephalitis
as far as the ventral posterior hypothalamus and adjacent pre- Ionic and electrolyte disorders (e.g., hyponatremia, water intoxica-
tecta) area. (3) Widespread disconnection between the cortex tion)
and subcortical activating mechanisms acts pathophysiologi- Status epilepticus
cally to produce effects similar to both conditions I and 2 Concussion and postictal states
above. A typical example occurs with acute, severe damage Psychogenic unresponsiveness
to the cerebral hemispheric white matter (dysmyelination), a
30 Fred Plum and Harriet 0. Kotsoris

diencephalic-midbrain damage or when repeated severe medi- affect both the supra- and subtentorial mechanisms that nor-
cal problems complicate convalescence. The degree and quality mally generate conscious behavior; accordingly, they generally
of associated cognitive recovery once the effects of acute in- produce commensurately widespread symptoms and signs of
jury-disease pass depend upon how much residual damage neurological dysfunction.
involves cerebral cortical areas and the nonspecific subcortical Except in overdose by sedative drugs, almost all examples
nuclei that interact with limbic and association cortex. Meta- of which recover with adequate treatment, brain dysfunction
bolic suppression of the brain or limited degrees of structural sufficient to produce coma implies a poor prognosis. Among
damage such as occur with concussion can be followed rela- large series of patients with nontraumatic coma lasting more
tively promptly by a complete or near complete return of brain than 12 hours or so, only about 15% completely recover their
function. More severe injury, especially to the cerebral cortical physical and intellectual functions. Likewise, among patients
mantle or its specific and nonspecific relay nuclei leaves in in sustained coma from head injury, almost half will die and
its wake increasing degrees of intellectual impairment. Com- as many as 25% of the survivors will be severely incapacitated.
plete or near complete permanent decortication such as occurs Patients with metabolic coma or young persons unconscious
with profound hypoxia, hypoglycemia, or sometimes with from head trauma generally do best, while those showing signs
closed-head injury produces the horror of the vegetative state: of severe primary or secondary brainstem damage fare worst
a body that if externally cared for will maintain its internal no matter what the cause.
homeostasis indefinitely but can no longer perceive, feel, think, Patients in coma are best treated acutely in special care
or communicate. units where they can receive close attention to their often
precarious autonomic functions and can be given specific ther-
apy directed at their underlying neurological disease. Respira-
Etiology
tory and cardiovascular support provide the mainstays with
Coma implies the imminent threat of brain failure with wide- specific measures directed at the particular disease that threat-
spread loss of cerebral function, upper brainstem function, ens to destroy the brain.
or both. Table l lists the major diseases or categories that
can produce such severe impairments. Supratentorial mass le- Further reading
sions generally cause relatively little loss of consciousness
Jennett B, Teasdale G, Braakman R, et al ( 1978): Prognosis of patients
unless they expand and distort the brain sufficiently to compress with severe head injury. Neurosurgery 4:283-288
the diencephalon caudally and produce transtentorial distortion Levy DE, Bates D, Caronna 11, et al ( 1981 ): Prognosis in non traumatic
or herniation. Upper brainstem-lower diencephalic lesions, coma. Ann lnt Med 94:293-298
by contrast, cause coma when lesions directly damage the Plum F, Posner JB (1982): The Diagnosis of Stupor and Coma. 3rd
central ascending activating systems. Metabolic disorders can rev ed. Philadelphia: FA Davis
Convulsive Therapy
Max Fink

Convulsive therapy is a psychiatric treatment for patients with Convulsive therapy is also recommended in patients with
major affective disorders. The treatments seek to change mood, depressive or manic disorders who have not responded to other
affect, and interpersonal behavior by altering brain functions treatments. It is not recommended for patients with neuroses,
by a series of grand mal seizures. A successful course requires anxiety, psychopathy, drug dependence, or character disor-
from 8 to 12 treatments, spaced 48 to 72 hours apart. Seizures ders. It remains effective in schizophrenia, but is infrequently
may be induced by chemical or electrical means with equal used, since antipsychotic drugs are believed to be easier to
efficacy. The principal benefits are the rapid relief of disordered use.
mood, improvement in the vegetative functions, and reduction
in suicidal drive. The principal risks are the development of Procedures
an organic mental syndrome, usually cognitive impairment
(memory loss), and fracture. While 8% of patients admitted Prior to ECT, the treatment procedures are explained in detail
to academic in-patient psychiatric services in the U.S. receive and consent obtained from patients and nearest kin. Special
electroconvulsive therapy (ECT), the treatments are infre- considerations for consent apply in patients who may be hospi-
quently used in municipal, state, and federal facilities. About talized involuntarily.
100,000 patients are treated annually. An intravenous line is established; methohexital and succi-
nylcholine administered; an airway established; and the patient
ventilated with 100% oxygen. Electrodes are usually applied
History over the nondominant hemisphere, and current dosages are
Convulsive therapy was developed in 1933 by the Hungarian defined as slightly above the minimum necessary to achieve
neuropsychiatrist Ladislas Meduna, following reports that epi- a seizure. Seizure ·duration is monitored by the electroencepha-
lepsy and schizophrenia were rarely found in the same patients, logram (EEG), the motor activity in a limb isolated from succi-
suggesting a biological antagonism between the two disorders. nylcholine by a blood pressure cuff inflated above the systolic
These data were supported by his studies of the concentration pressure, or by heart rate. Seizure durations less than 25 sec-
of glia in postmortem brain samples, in which he found a onds are considered inadequate and are usually repeated. Treat-
diminution of glia in the brains of patients with dementia prae- ments are given either three or two times a week, the number
cox and an overabundance in the brains of epileptics. The of treatments determined by clinical signs of relief. Treatment
first patient was treated on January 24, 1934, using intramuscu- courses range from 6 to 15 treatments, with an average of 7
lar camphor injections to induce the seizures. In 1938, the to 9.
Italian psychiatrists Cerletti and Bini demonstrated the merits Treatments are given either with ac instruments, delivering
of alternating electrical currents through bitemporal electrodes between 50 and 150 J; or brief pulse instruments, delivering
as stimulating currents. Trials of brief pulse stimuli followed, currents about one-third in intensity. Efficacy is related to
and in the past decade both current forms have been used. In current intensity and current path, so that some therapists prefer
the mid-1950s, inductions using the inhalant fturothyl (lndok- ac currents and bilateral electrode placements, especially in
lon) were found to be equally effective, but more cumbersome. the more severely ill patients. But the use of these currents
In 1961 , the safety of seizures through unilateral electrode and pathways is associated with greater degrees of cognitive
placements over the nondominant hemisphere was demon- impairment.
strated. Following a successful course, maintenance treatment is rec-
ommended, especially in patients with a history of recidivism.
Maintenance is accomplished with tricyclic antidepressants,
Indications
monoamine oxidase inhibitors, lithium, or the combination of a
ECT is recommended for patients with severe depressive disor- tricyclic antidepressant and an antipsychotic agent in patients
ders requiring hospitalization. The presence of vegetative with delusional depression. Maintenance ECT is also used.
symptoms (anorexia, weight loss, insomnia, loss of libido,
impaired concentration, amenorrhea) is a good prognostic sign.
Severe inanation, suicidal preoccupations and drive, and cata-
Consequences
tonic symptoms are indications for its use. While depressed
patients with psychotic features (delusional depression) usually Fracture, organic mental syndrome, and cardiovascular com-
fail to respond to tricyclic antidepressants alone, they respond plications leading to death are the principal risks. Fractures
rapidly to ECT. In direct comparisons in random assignment are rare under present conditions of anesthesia; as is death,
studies, convulsive therapy is more effective for major depres- which occurred in 4 of 100,000 treatments. Cognitive impair-
sive disorders than sham ECT, anesthesia alone, tricyclic anti- ment, seen as persistent complaints of memory loss, is reported
depressants, or monoamine oxidase inhibitors. in about I% of patients. The incidence is greater in patients
32 Max Fink

treated with ac instruments and bilateral electrode placements. hormone response to apomorphine, or thyrotropin-stimulating
Memory of recent events around the period of hospitalization hormone response to TRH), there is a normalization of these
and the acute illness are most disrupted. Neither remote mem- responses with treatment.
ory nor memory of events after the treatment course are af- Permeability of the blood brain barrier increases with each
fected. seizure, and this increase is usually persistent after a course
The principal behavioral changes are a heightening of mood of seizures. Neuropathologic examination of animals subjected
and affect, relief of depressive mood and suicidal ideation, to repeated seizures fail to show evidence of cellular dysfunc-
and in patients with manic states, relief of the elevated mood. tion, either acute or chronic, unless seizures have been pro-
Delusional ideation gradually disappears. Motor excitement, longed and accompanied by impairment of ventilation and
withdrawal, and apathy are relieved, and vegetative functions reduction in oxygen saturation of the blood.
improve.
Neuropsychological tests, including memory, motor func-
Mode of action
tions, reaction time, and perception, are progressively impaired
during the treatment course, but recover within four to six Present theories parallel those of the action of tricyclic sub-
weeks after the last seizure. In patients who recover from stances, emphasizing increased turnover and levels of catechol-
their depressive illness, there is an improvement in perfor- amines, and increased adrenergic or dopamine receptor sensi-
mance and cognitive tests over pretreatment values. tivity. Alternate hypotheses emphasize diencephalic effects and
During each seizure, the EEG exhibits high-voltage, high- focus on the probability that peptides with behavioral effects
frequency spike activity associated with slow wave bursts. In are released in increased amounts from hypothalamic centers
interseizure records, frequencies slow, amplitudes increase, during seizures. These hypotheses usually remark on the in-
and fast frequencies are reduced. Following treatment, slow- creased permeability of the blood brain barrier and the intracel-
wave frequencies are reduced and synchronized alpha activity lular movement of calcium ions as associated phenomena in
increases. During each seizure, there is transient hypertension, the therapeutic chain.
tachycardia, and, in many subjects, arrhythmias. Hemato-
poietic changes are minimal.
Further reading
With each seizure, there is a transient increase in cerebral
catecholamines, acetylcholine, proteins, and peptides, includ- Fink M, Kety S, McGaugh J, Williams T, eds (1974): P~ychobiology
ing prolactin, vasopressin, adrenocorticotropic hormone, and of Convulsive Therapy. Washington DC: VH Winston & Sons
thyrotropin releasing hormone (TRH) with a return to baseline Fink M ( 1979): Convulsive Therapy: Theory and Practice. New York:
levels within two hours. Increases in cholinesterase and mono- Raven Press
Lcrer B, Weiner RD. Belmaker RH, eds. (1984): ECT: Basic Mecha-
amine oxidase in the cerebrospinal fluid and a reduction of
nisms. London: John Libbey & Co
calcium in plasma, cerebrospinal fluid, and blood rriay persist. Malitz S, Sackeim HA, cds. ( 1986): Electroconvulsive Therapy: Clini-
Turnover of catecholamines and receptor sensitivity increase, cal and Basic Research Issues. New York: New York Academy
particularly dopamine synaptic activity. In patients with evi- of Sciences
dence of neuroendocrine dysregulation (as abnormal cortisol Weiner RD (1984): Does electroconvulsive therapy cause brain dam-
and failure to suppress with dexamethasone, abnormal growth age? Behav Brain Sci 7:1-53
Creutzfeldt-Jakob Disease
Clarence J. Gibbs, Jr., and David M. Asher

Creutzfeldt-Jakob disease (CJD), together with its clinical vari- for more than two years. Some cases of CJD, especially those
ants, is the more common of the two subacute human spongi- of long duration, may be difficult to distinguish from the much
form encephalopathies, the other being kuru. The spongiform more common Alzheimer's disease. Rare cases of CJD in
encephalopathies are slow infections caused by filterable self- young people may resemble subacute sclerosing panencephali-
replicating agents, the nature of which is not yet fully elu- tis, but that condition should be readily diagnosed by finding
cidated. The human diseases resemble three conditions of elevated levels of antibodies to measles virus in the cerebrospi-
animals: scrapie of sheep and goats, transmissible mink en- nal fluid .
cephalopathy, and wasting disease of mule deer and elk. The definitive diagnosis of Creutzfeldt-Jakob disease must
Creutzfeldt-Jakob disease was first described in 1921 by still be made by histological examination of brain tissue ob-
Jakob, who attributed precedence to Creutzfeldt for the earlier tained from biopsy or autopsy. The typical changes of spongi-
report of a similar encephalopathy no longer accepted as being form encephalopathy are present, most pronounced in the cere-
the same entity. The term spongiform encephalopathy was bral gray matter: they include vacuolation of neurons leading
originally proposed by Nevin to describe an encephalopathy to status spongiosus (Fig. I), severe neuronal loss, and astrog-
that he considered to be distinct from CJD, but the two terms lial proliferation and hypertrophy. Amyloid plaques similar
came to be used almost interchangeably, and, following the to those found in kuru have been reported in about 15% of
suggestion of Gibbs and Gajdusek, spongiform encephalopathy cases of CJD. No consistent histopathological changes are
became a generic term for the entire group of similar human recognized in organs outside the central nervous system (CNS),
and animal diseases. though the etiological agent has been detected in these tissues.
Between 1921 and 1968 only 150 cases of CJD had been The demonstration by negative-stain electron microscopy of
reported in the medical literature; more than 2,000 cases have unique helical fibrils (SAF, Fig. 2) in brains and spleens of
now been recorded. The disease occurs throughout the world, patients and animals with the spongiform encephalopathies,
mainly in patients of middle age, although rarely in younger and detection by gel electrophoresis and immunoblotting of
people. Males and females are represented in approximately abnormal low-molecular-weight proteins (PrP, Fig. 3) in those
equal numbers. Estimated mortality rates vary from 0.25 to tissues may eventually prove useful in confirming histopatho-
about 2 deaths per million population per year; there are several logical diagnoses of CJD. Attempts are now in progress to
geographic foci of higher frequency, especially striking in demonstrate unique proteins of diagnostic significance in cere-
Libyan Jews in Israel among whom the rate reached more than brospinal fluid (CSF) of patients with CJD. Transmission of
30 per million per year. Most cases are sporadic, but CJD spongiform encephalopathy to susceptible animals by inocula-
sometimes runs in families. In the United States about 10 tion of suspensions of tissues from patients remains the ultimate
percent of cases have a family history of presenile dementia.
The initial complaints in CJD are generally vague sensory
disturbances especially involving vision, confusion, and inap-
propriate behavior, or, less commonly, cerebellar ataxia. Dis-
ease inevitably progresses over the following weeks or months
to frank dementia and coma. Most patients have myoclonic
jerking movements at some time during illness; some have
convulsions. Spasticity or rigidity and decorticate primitive
reflexes are present late in the disease. A variety of less con-
stant findings, not necessarily symmetrical, occur, indicative
of diffuse and multifocal degeneration throughout the brain
in CJD. Clinical subtypes ofCJD are sometimes given separate
eponyms, e.g., Gerstmann-Straussler syndrome for familial
CJD with cerebellar ataxia and amyloid plaques and Heiden-
hain variant for CJD with cortical blindness . The electroen-
cephalogram in CJD often shows periodic ''suppression-burst''
complexes on a slow background. There may be moderate
elevation of protein in the cerebrospinal fluid. As disease pro-
gresses cerebral atrophy with enlargement of the ventricles may
be detected by computed tomography . Other laboratory studies
are not useful in diagnosis. The mean survival of patients Figure I. Severe status spongiosus in cerebral cortical gray matter of a
with CJD in several series is less than one year from onset, patient with familial Creutzfeldt-Jakob disease. Hematoxylin and eosin,
although about 10% of cases in our experience have lived X330.
34 Clarence J. Gibbs, Jr., and David M. Asher

test for confirming the diagnosis of CJD. A variety of labora- (SAF, Fig. 2) were first described by Merz and colleagues in
tory animals (hamsters, mice, guinea pigs) are susceptible to 1981: they appear as pairs or double pairs of helical structures
CJD, but in our experience, only chimpanzees and squirrel that resemble but are distinguishable from cerebral amyloid
monkeys have been consistently susceptible with mean incuba- fibrils of Alzheimer's disease. Prusiner and co-workers found
tion periods of less than three years. abnormal low- molecular-weight sialoglycoproteins (PrP27_ 30)
The physical structure of the etiological agent of CJD re- in extracts of tissues from animals with scrapie (Fig. 3), and
mains unknown, but its properties generally resemble those antigenically related proteins in patients with CJD. Those pro-
of the agent of scrapie. They are clearly subprotist in size teins are components of prion rods that appear to be virtually
and replicate in tissues of people and susceptible animals. indistinguishable from Merz's SAF. Both SAF and Prp27_ 30
Until recently agents of the spongiform encephalopathy group can be found in partially purified preparations of infectious
were usually called viruses, and still are by most authorities. scrapie agent. Fibrils containing antigenically related proteins
However, they display a spectrum of resistances to inactivation have recently been described in thin sections of infected brains
by a variety of organic and inorganic chemicals and physical as well. It has been proposed that SAF/PrP represents the
treatments, including both ultraviolet and ionizing irradiations, actual infectious particles of the spongiform encephalopathy
and heat, unknown among other viruses. That stimulated hy- agents or moieties or polymers of them. However, the demon-
potheses that the spongiform encephalopathy agents might not stration that at least part of the PrP27_ 30 is encoded by a normal
be viruses at all, but unique pathogens containing no nucleic host gene, and that a larger antigenically related protein, pre-
acids. Because the agents are sensitive to protein-denaturing sumably a precursor, is found in normal tissues , favors the
treatments, and are therefore believed to contain proteins, Pru- possibility that it is a pathological host protein that has not
siner proposed that they be called prions for proteinaceous been separated from the actual infectious particles by current
pathogens likely to be devoid of nucleic acids and subviral techniques.
in size. If the spongiform encephalopathy agents are small uncon-
The prion hypothesis, however, has not been well substanti- ventional viruses, it is possible that they could be the small
ated or generally accepted. The aberrant behavior of the scrapie tubulovesicular structures, approximately 23 nm across, first
agent in chemical, heat, and irradiation inactivation-kinetic observed in thin sections of scrapie-infected mouse brains by
studies has been reinterpreted as consistent with that of a small David-Ferreira, Gibbs, and co-workers in 1968, and subse-
virus, a resistant fraction of which is protected from inactiva- quently identified in a variety of experimental and natural spon-
tion by hydrophobic aggregation of its particles into masses giform encephalopathies by Narang and others. These struc-
as well as by association with host proteins. No confirmed tures have yet to be identified in negatively stained suspensions
filtration, sedimentation, or exclusion chromatographic studies of infectious material or otherwise characterized.
have unequivocally demonstrated the transmissible scrapie par- A second unresolved question concerns the natural mecha-
ticles to be subviral in size. No purified protein preparations nisms of transmission of CJD. It is important to identify these
free of nucleic acids have been found to retain scrapie infectiv- mechanisms; experience with kuru suggests that interrupting
ity. Should the transmissible agents of the spongiform encepha- the major natural mechanism of transmission of a spongiform
lopathies eventually prove to be infectious proteins, whether encephalopathy is possible by social means and served to end
encoded by derepressed host genes or by some novel mecha- the epidemic of that disease. Epidemiological surveys have
nism through which heritable information is somehow in- investigated several hypothetical mechanisms of CJD spread,
scribed in protein itself, the term prion would seem apt. If, including contamination of meat products with scrapie agent
however, the infectious particles of spongifonn encephalopa- and iatrogenic transmission of the infectious agent from pa-
thy agents do contain nucleic acid genomes, then they might tients with the disease. The hypothesis of iatrogenic spread
be better designated as unconventional viruses. has been proved, since accidental transmission of CJD by
Three structures are now under investigation as representing contaminated corneal transplants and cortical electrodes has
the particles or important parts of the particles of the spongi- been convincingly documented. The occurrence of clusters
form encephalopathy agents. The scrapie-associated fibrils of CJD in patients with a history of previous neurosurgery at

Figure 2. Scrapie-associated fibrils (SAF) in nega-

tively stained extract of scrapie-infected hamster
brain. Phosphotungstic acid, XI44,000.
 Creutzfeldt-Jakob Disease 35

to more than a million lethal doses of agent per gram when

assayed in susceptible animals. The infectious agent has been
found Jess regularly and probably in lower amounts in several
94- other tissues and in CSF; infectivity has not yet been demon-
strated in blood or other body fluids , secretions, or excretions
67- of CJD patients. However, because only a small number of
such materials have been adequately tested, because blood
from animals with experimental CJD has been found to contain
the agent, and because the minimum amount of agent needed
43- to infect human beings is not known, it is prudent to consider
all tissues and excretions of patients as potentially contami-
nated. We advise using precautions for handling CJD patients
30- and their materials similar to those for viral hepatitis.
Only three regimens are currently recommended for disin-
fecting the agent of CJD: heat, lye, and bleach. Heating, by
incineration of disposable materials or steam autoclaving for
zo- at least one hour, should be employed whenever possible.
Autoclaving at higher than usual temperatures (we recommend
132·C instead of the usual 12l ·C) is preferrable. One normal
or higher concentration of sodium hydroxide has been effective
14- in inactivating large amounts of both scrapie and CJD agents;
we recommend exposing contaminated materials to hydroxide
for at least one hour. Sodium hypochlorite (5.25%) (fresh,
Figure 3. Low-molecular-weight protein band (PrP27_30) in extract of full-strength household chlorine bleach) has considerable inac-
scrapie-infected hamster brain. Sodium dodecyl sulfate-polyacrylamide tivating potency in several experimental studies; at least one
gel electrophoresis. Silver stain. Mr, molecular-weight markers; a, hour of exposure is recommended. Sterilization with ethylene
scrapie-infected brain; b, control brain. Courtesy of Drs. M. Coker-Vann oxide gas and a variety of commercial liquid disinfectants
and P. Brown. has been found ineffective and should not be attempted. The
procedures employed for decontamination of materials poten-
tially contaminated with the CJD agent must be adapted to
a common site and in young people who received injections the particular situation in each institution. It must be stressed
of human pituitary growth hormone from a common source that empirical evidence suggests that the major risk is of acci-
also implicated iatrogenic transmission. In the great majority dental transmission of CJD to other patients and not to the
of cases, however, the hypothetical iatrogenic events remain staff, and safety precautions must not be allowed to interfere
unknown; possible mechanisms awaiting investigation include with adequate diagnosis or humane care of demented patients.
ocular tonometry, surgery of head, neck, and teeth, and trauma There is still no effective therapy for CJD or the other spongi-
surgery. form encephalopathies. Several substances apparently inter-
Familial CJD also remains incompletely understood. The fered with the appearance of scrapie when administered before
pattern of occurrence in affected families roughly resembles or shortly after animals were inoculated with low doses of
an autosomal dominant mode of inheritance. However, familial the infectious agent, possibly by blocking replication of the
CJD is otherwise clinically and histopathologically indistin- agent in the reticuloendothelial system; none reversed estab-
guishable from sporadic CJD, and the infectious agent associ- lished infection of the CNS. Occasionally remissions of CJD
ated with both forms seems to be the same. It is not known after various treatments have been claimed but never confirmed
if familiar CJD results from true genetic increased susceptibil- in subsequent attempts.
ity to infection with an ubiquitous agent that is ordinarily of
low transmissibility or from pseudogenetic person-to-person
spread; experimental studies in animals have confirmed the Further reading
existence of hereditary differences in apparent susceptibility Gajdusek DC ( 1977): Unconventional viruses and the origin and disap-
to scrapie mediated by single-genes. pearance of kuru. Science 197:943-960
Spouses and other household contacts of patients seem to Gajdusek DC (1985): Unconventional viruses causing subacute spon-
be at very low risk of acquiring CJD. Personnel caring for giform encephalopathies . pp 1519- 1557. In: " Virology" BN
patients and handling their tissues are not known to have con- Fields, ed. New York: Raven Press
tracted the disease, although it has been diagnosed in physi- Merz PA, et al (1984): Infection-specific particle from the unconven-
cians and other medical workers with possible occupational tional virus diseases. Science 225:437-440
Oesch B, et al (1985): A cellular gene encodes scrapie PrP27_ 30 protein.
exposure. It is reassuring that, in the more than 60 years since
Cell 40:735-746
CJD was first described, no pathologist has been diagnosed Prusiner SB (1982): Novel proteinaceous particles cause scrapie. Sci-
with CJD. ence 2 16:13~144
Brain tissues of patients with histologically confirmed CJD Rohwer RG (1984): Scrapie infectious agent is virus-like in size and
have been consistently infectious, containing from a thousand susceptibility to inactivatio n. Nature (London) 308:658-662
Deafness
Joseph E. Hawkins, Jr.

Deafness (anacusis) is the complete inability to hear speech the stapes footplate is sealed in the oval window by abnormal
and other sounds, however much they may be amplified . Per- deposits of bone. The operation of fenestration, producing a
sons with partial deafness (hypoacusis, dyacusis) are correctly new oval window (fenestra) in the wall of the lateral semicircu-
described as hard of hearing or as having a hearing loss. Chau- lar canal, and stapes mobilization, freeing the footplate to
cer was choosing his words carefully when he described his vibrate again, represented the first successful attempts to re-
Wyf of Bathe as only "som-del deef." store hearing to otosclerotic patients by surgical means. Unfor-
The degree of hearing impairment is usually estimated by tunately, the improvement did not always last. Stapedectomy
subjective audiometry, using pure tones or speech at precisely has now almost completely replaced older operations. The
measured intensities to compare the patient's threshold of hear- stapes is removed and a short length of wire or plastic attached
ing with that of the normal listener. The difference, in decibels to the long process of the incus is substituted, the oval window
(dB), is the patient's hearing level: the greater the hearing being covered with a bit of vein or fascia . Together with
level, the more severe the impairment. The audiogram shows tympanoplasty for the correction of other middle ear defects,
this difference plotted as a function of frequency . Deafness stapedectomy constitutes a dramatic advance in modem sur-
has been defined as a hearing level of 92 dB ISO or worse gery .
(using the audiometric calibration of the International Stan- In sensorineural hearing loss the middle ear is intact, but
dards Organization). there are generally pathological changes in both the cochlea
For some patients, objective audiometry is required. Electro- and the cochlear nerve. Most often, extensive loss of the cili-
cochleography records the electrical potentials of the cochlea ated sensory cells (hair cells) of the organ of Corti has occurred,
and cochlear nerve in response to brief sounds; evoked re- with secondary degeneration of at least some of the cochlear
sponse audiometry those of the brain stem and higher centers. nerve fibers and spiral ganglion cells. This is the type of hearing
A third objective technique measures the threshold for the loss caused by aging, ototoxic drugs (Fig. 1), and noise expo~
acoustic reflex , the brief contraction of the stapedius muscle sure. The changes tend to occur first in the basal tum of the
of the middle ear elicited by sudden, moderately intense
sounds.
If congenital, hearing impairment may be the result of one
of several types of genetic malformation of the ear, of disease
in the mother during pregnancy (e.g., rubella, syphilis), or
of perinatal disease or accident (e.g., neonatal jaundice, an-
oxia, trauma) . If acquired, the impairment may be due to
any of a variety of causes, including viral or bacterial diseases
(e.g., mumps, herpes zoster oticus, meningitis, syphilis), head
injury with temporal bone fracture, ototoxic drugs (especially
certain antibiotics and diuretics, aspirin in large doses) , expo-
sure to intense noise , blast injury, inadequate blood supply
to the ear caused by vascular insufficiency or occlusion , oto-
sclerosis, Meniere's disease, or simply the aging process itself,
the commonest cause of all. Often both ears are equally af-
fected, but in Meniere's disease and in sudden deafness only
one ear may be involved. In the latter condition , either occlu-
sion of a small artery supplying the cochlea or a viral infection
may be responsible.
The site of hearing impairment is usually peripheral , the
result of defect or pathological change in the outer, middle,
or inner ear. If the inner ear is normal and sound is prevented Figure I. Normal-appearing right cochlea from a 25-year-old woman,
from reaching the cochlea by congenital malformation or by prepared by microdissection after fixation with osmium tetroxide solution
injury to the external canal, the drum membrane, or the ossicu- approximately 23 hours postmortem. OW, oval window, stapes removed;
RW, site of round window; SL, spiral ligament; OC, organ of Corti,
lar chain of the middle ear, the resulting hearing ·loss is said
with rows of sensory and supporting cells seen as dark bands on translucent
to be conductive. Hearing for all frequencies tends to be af- basilar membrane; N, myelinated cochlear nerve fibers in osseous spiral
fected, but the loss is not complete. Amplification of speech lamina; H, helicotrema, i.e., opening at apex between scala vestibuli
sounds with a hearing aid often gives a socially adequate im- and scala tympani. Reproduced by permission from Johnsson L-G, Haw-
provement. kins JE (1972): Sensory and neural degeneration with aging, as seen in
Otosclerosis most often takes the form of a conductive im- microdissections of the human inner ear. Ann Otol Rhino[ Laryngol
pairment, in which sound does not reach the cochlea because 81 :179-193.
 Deafness 37

cochlea, which responds to the higher frequencies of sound, cells. When there is hearing Joss and tinnitus without recruit-
but they may spread to include the upper turns and thus affect ment, a so-called retrocochlear lesion, such as an acoustic
the hearing for lower frequencies as well. A slow progression neurinoma or other tumor exerting pressure on the auditory
of this type of impairment is commonly observed in presbyacu- nerve and brain system, may be present. Other types of retro-
sis, the hearing Joss that accompanies aging. During treatment cochlear lesions may be due to degenerative changes in the
with ototoxic drugs, especially with the aminoglycoside antibi- cochlear nuclei or other structures of the auditory pathways
otics and the loop diuretics in combination, a rapidly prog- in the brain stem as a result of vascular accident or disease.
ressive hearing loss can occur. Similar changes occur in several In advanced age, the central processing and perception of
inherited degenerative syndromes. Any such loss is permanent, speech may be affected by neuronal degeneration at higher
since the sensory cells are not replaced (Fig. 2) . The tissues levels of the auditory pathway.
of the cochlea may degenerate after viral diseases such as Genetic forms of deafness and their underlying pathology
mumps, after severe prolonged Meniere's disease, in cases can be studied in certain types of domestic and laboratory
of sudden deafness, and in the destructive capsular form of animals that are either born deaf or become deaf sometime
otosclerosis that is not limited to the stapes and oval window after birth. Among these are the waltzer, shaker, and certain
but violates the periosteal lining of the bony labyrinth. When other strains of mice, blue-eyed white cats, and dalmatian
the impairment is both conductive and sensorineural in charac- dogs. The changes seen in the inner ear resemble closely those
ter, it is described as mixed. occurring in some types of congenitally deaf patients. Noise-
Because sensorineural Joss tends to affect primarily hearing induced and ototoxic hearing losses have been studied ex-
for higher frequencies, presbyacusic and other patients with perimentally in guinea pigs, chinchillas, cats, and monkeys.
this form of impairment have difficulty in understanding sibi- Presbyacusic changes vary with the species examined. In
lant and fricative speech sounds and in distinguishing unvoiced the dog, they more nearly resemble those seen in aging hu-
stop consonants . They are at a particular disadvantage when man ears than do those in the largely vegetarian rhesus mon-
trying to converse in noisy surroundings (the "cocktail party key.
effect") . A hearing aid may be helpful for such a patient, In his Journey to the Western Islands of Scotland, Dr. Sam-
but the results obtained are sometimes disappointing, because uel Johnson, telling of his visit to one of the earliest schools
the patient may be unable to resolve the spectral details of for the deaf, describes deafness, with slight but pardonable
speech sounds in the presence of noise, even after amplifica- exaggeration, as "one of the most desperate of human calami-
tion. ties." The rehabilitation of the deafened patient can be diffi-
Sensorineural impairment may be accompanied by disturb- cult, time-consuming, and expensive.
ing symptoms such as tinnitus, a subjective ringing-in-the- The deaf child presents an educational challenge of enor-
ears that may also take the form of buzzing or roaring noise. mous magnitude and complexity. The deaf adolescent or adult
Tinnitus often accompanies attacks of Meniere's disease, in often suffers from an isolation that the blind do not experience,
which the acuity of hearing tends to vary from time to time so that psychiatric problems may constitute a serious additional
(fluctuant hearing Joss). There may also be an abnormally handicap. The electronic cochlear prosthesis, implanted in the
rapid increase in the perceived loudness as the intensity level inner ear to bypass the defective end organ by delivering elec-
of sound increases: a phenomenon known as recruitment of trical stimuli representing speech and other sounds directly
loudness. Furthermore, unless the impairment of hearing is to the cochlear nerve fibers, offers hope for some deaf patients.
symmetrical, sound may produce unpleasant sensations of dif- It can give them an awareness of the acoustic environment
ferent pitch in the two ears (diplacusis). as well as assistance in lip reading, even if it does not yet
The symptom of recruitment indicates a pattern of selective assure the understanding of speech. Continuing investigation
pathological change in the cochlea, with degeneration of many will show for what types of deafness the cochlear prosthesis
outer hair cells and preservation of most of the inner hair is likely to prove the greatest value.

Figure 2. Left cochlea of a 51-year-old woman

with ototoxic deafness caused by oral neomy-
cin treatment over a two-year period. The or-
gan of Corti has completely disappeared from
the basal turn, and almost all the myelinated
nerve fibers have degenerated. Supporting
cells of Corti's organ. OC. and nerve fibers,
N, are still present in the middle and apical
turns (inset). Reproduced by permission from
Johnsson L-G, Hawkins JE, Kingsley TC,
Black FO, Matz GJ (1981): Aminoglycoside-
induced inner ear pathology in man, as seen
by microdissection. In: Aminog/ycoside Oto-
toxicity, Lerner SA, Matz GJ, Hawkins JE,
eds. Boston: Little, Brown.

1 mm
38 Joseph E. Hawkins, Jr.

Further reading Jerger J, ed (1984): Hearing Disorders in Adults. San Diego: College-
Hill Press
Ballantyne J (1984): Deafness, 4th ed. New York: Churchill Living-
Schuknecht HF (1974): Pathology of the Ear. Cambridge: Harvard
stone
University Press
Davis H, Silverman SR (1978): Hearing and Deafness, 4th ed. New
York: Holt, Rinehart and Winston
Dementia
Fred Plum

Dementia is a sustained, multidimensional loss of cognitive transmitting neurons in layers 3 and 5 as well as cells in the hip-
function secondary to organic central nervous system damage, pocampus and amygdala. Silver-staining plaques and in-
unaccompanied by evidence of an acute superimposed state traneuronal fibrillary tangles, the hallmarks of the disease,
of clouded consciousness as occurs with delirium or reduced distribute themselves most prominently in the same areas in
arousal. The onset of dementia can be abrupt, maximal, and numbers that roughly correlate with the degree of dementia.
static, e.g., following cardiac arrest or severe head trauma, Immunohistochemical staining shows a prominent reduction
or progressive such as occurs in the degenerative diseases of in choline acetyltransferase (ChAT) in these regions, along
aging. Of the two forms the progressive types of dementia with a marked reduction and disruption of somatostatin-stain-
create by far the more frequent problem and, reflecting the ing neurons in layers 2, 3, and 5 as well as the hippocampus
increased longevity of the population, have become one of and amydgala. Substance P, but not other peptide transmitters
the major public health concerns of the Western world. Over examined to date, is also reduced in cortex. Cortical plaques
6% of adults aged over 65 years and 20% over the age of 80 contain an amyloid core plus assorted detritus that includes
are estimated to suffer from a medically or socially disabling material staining for ChAT and somatostatin as well as frag-
degree of dementia. ments of other nerve cells and possibly glial material. Accom-
In most dementias, the clinical history discloses the subtle panying these changes is prominent neuronal loss in the basal
onset of disinterestedness, disorientation, personality changes, forebrain nucleus of Meynert, the main source of cholinergic
and diminished attention to self-care. Relatively trivial head projections to the cortex, and, less consistently, in the mono-
trauma, intercurrent illness, or minor surgery such as cataract aminergic locus ceruleus. These neuropathological abnormali-
removal may precipitate more sudden deteriorations. Memory ties indicate a widespread degeneration of cortical-cortical con-
and nonspecific language abnormalities, particularly nominal nectivity in association and limbic areas in SDAT plus promi-
amnesia, as well as emotional lability, depressive feelings, nent loss of major nonspecific ascending cholinergic and
and sometimes, paranoid ideation are common features. A monoaminergic autonomic systems. Presently, it is not possible
few patients suffer auditory and visual hallucinations. A large to assign the primary pathologic change as arising either at
number of dementing illnesses, especially Alzheimer's disease, cortical or subcortical levels, nor can one identify any single
cause no early disturbances in motor or sensory functions. transmitter system that leads the brain into its decay. The
Others may produce extrapyramidal dysfunction, abnormalities cause of such widely diffused but, nevertheless, selective cell
of upper and lower motor neuron activities, urinary or fecal death remains unknown.
incontinence, and, rarely, seizures. Table I lists the principal In clinical studies, CT or magnetic resonance (MR) imaging
causes of progressive dementia, and Figure I gives examples of the brain usually shows moderately advanced, diffuse cere-
of some typical computerized tomography (CT) scans. bral atrophy marked by widened sulci and enlarged lateral
Most dementia reflects damage to the association cortex of ventricles. Metabolic studies of brain using positron emission
the cerebral hemispheres or the subcortical thalamic nuclei tomography (PET) disclose a generalized reduction of oxida-
that project to areas of association cortex. The neuropathology tive metabolism usually most marked in parietotemporal areas
differs from disease to disease, in some producing predominant of association cortex.
changes in neurons, in others appearing to choose both astro- SDAT ordinarily runs its course in 5 to 10 years, although
cytes and nerve cells as targets for maximal injury. a few examples develop semiacutely and families occasionally
At least half of presenile dementia (appearing before age describe patients in whom personality changes go back as far
65) and senile dementia cases are attributed to states in which as 15 to 20 years before the appearance of fully developed
the intellectual . decline is accompanied by morphological dementia. Eventually, those affected become rigid and hypoki-
changes in the brain of Alzheimer's disease (senile dementia
Alzheimer type: SDAT). SDAT is predominantly a sporadic
disorder, but appears to be linked to a genetic factor with
approximately one-third reporting similar illnesses in blood Table I. Etiology of Progressive Dementia and Approximate
relatives. An increased incidence of Down's syndrome (tri- Incidence (%)
somy 21) and lymphoma also occurs in first-degree relatives. Senile dementia of the Alzheimer type 50%
The condition affects females somewhat more frequently than Multi-infarct dementia 10-15%
males and, apart from changes in mental activity, usually Mixed SDAT and MID 10-15%
spares other neurological functions early in its course. Alcoholic-nutritional dementia 5-10%
The characteristic changes found postmortem in the brain Normal pressure hydrocephalus 5%
of SDAT include moderate gross atrophy especially involving Miscellaneous: Huntington's disease, neoplasms, chronic
the frontal and temporal lobes. Microscopically, the most subdural hematomas, Parkinson's disease, Creutzfeldt-
Jakob disease, AIDS, and unknown cause 5-20%
severe cell loss affects the large pyramidal cortical-cortical
40 Fred Plum

c
Figure I. Computerized tomographic scans showing characteristic hori- Ius due to cryptococcosis in a 68-year-old demented woman. Note the
zontal sections of brain in a normal person and in persons with dementia. considerable ventricular enlargement with relative obliteration of surface
A. Normal 53-year-old male. B. Early symptomatic Huntington's Disease subarachnoid markings. A, C, and D, courtesy of Dr. Michael Deck,
in a 50-year-old male. Note caudate atrophy (arrows), more on right Department of Radiology, New York Hospital. B, courtesy of Dr. Stanley
side of film than left. C. Primary alcoholic-nutritional atrophy in a 58- Fahn, Neurological Institute, College of Physicians and Surgeons of Co-
year-old male with Korsakoff's dementia. Note the enlargement of both lumbia University, New York, NY 10032.
the ventricular and subarachnoid spaces. D. Communicating hydrocepha-

netic and in their terminal stages approach a totally vegetative The neuropathology, as expected , consists of multiple infarcts,
state. No scientifically established treatment exists. although large and small, often accompanied by at least a moderately
experimental efforts have attempted to induce benefit from extensive amount of Alzheimer type cellular abnormalities.
the parenteral administration of cholinergic drugs. Alcoholism and, to a lesser degree, substance abuse represent
Pick's disease, a much less common presenile dementia, major causes of dementia. Exact figures of prevalence are
runs an even slower course than SDAT. Small morphological difficult to construct since the linkage to brain damage is often
differences distinguish the two conditions which may represent indirect. Alcohol ingestion, for example, precedes and may
biological variants of a similar cause. precipitate as many as 40% of serious road traffic accidents,
Intellectual Joss due to successive strokes, so-called multi- falls , and other head injuries and shows a high association
infarct dementia (MID), accounts for approximately 10-15% with nutritional insufficiency as well as suicide attempts. Swed-
of late-life mental decline. The disorder reflects the added ish investigators recently found that an estimated 40% of deaths
effects of successive, multifocal widespread damage to cerebral among men aged 46--48 years were alcohol related, and in
areas regulating specific and nonspecific psychological func- Finland, among men Jess than 40 years old with acute stroke,
tions. Mental changes commonly are accompanied by abnor- at least 20% suffered their attack shortly after an episode of
malities in cerebral, motor, and sensory functions. As a rule , heavy drinking. A Danish study has reported that 28 of 37
the vascular disorder pursues a progressive stepwise course , male heavy drinkers under the age of 35 years suffered subjec-
new episodes of minor or major deterioration reflecting addi- tive symptoms of mental impairment, and almost one-fifth
tional vascular occlusions or thromboses and producing mem- tested as being frankly demented using standard appraisals of
ory Joss, aphasia, various agnosias, or sensorimotor defects. intelligence capacity.
 Dementia 41

The mechanisms of alcoholic dementia are only partly have found a somewhat lesser reduction in cortical ChAT and
known; many undoubtedly are nutritional but some must be greater reduction in NBM neuronal loss in PD than in SDAT.
directly toxic as well. Among alcoholic men under 40 years, The finding and its possible significance awaits confirmation
about half show cerebral atrophy by CT scan, and the incidence and explanation.
rises as age advances. The structural basis of these changes HD has attracted considerable recent attention because of
is not well delineated although some evidence indicates that a substantial increase in the understanding of the disorder's
they may be partly reversible in their early form. Brain atrophy neurobiology _and genetics. HD is a progressive, eventually
and the specific abnormalities of Wernicke's disease and Kor- fatal dementia transmitted as an autosomal dominant trait with
sakoff's psychosis are almost routine among chronic, heavy complete penetrance. Clinically, the disorder appears most
alcoholics whether or not they die from the direct effects of often during the third to fifth decade of life. Mental decline,
the disease and its immediate complications. often accompanied by prominent emotional and personality
Chronic communicating hydrocephalus, a condition some- changes, usually heralds the onset, accompanied or shortly
times called low-pressure hydrocephalus because cerebrospinal followed by generalized dance-like, quick choreiform as well
fluid (CSF) pressure usually falls within or only slightly above as slower dystonic movements. Medium-sized spiny GABA-
the normal range, causes or contributes to approximately 5% ergic cells in the striatum undergo a prominent and early reduc-
of late-life dementias. The disorder is more frequent in men tion in number; several other classical neurotransmitters and
than women and most often probably results from meningeal neuropeptides show less prominent changes (Table 2). Addi-
adhesions or scarring arising long after the everyday head tional cell loss involves the ventral thalamic nucleus and sub-
trauma of younger life or an unremembered meningeal infec- thalamus, and inconsistently located neuronal dropout affects
tion. In at least half the cases no antecedent cause can be the cerebral cortex, most markedly in the frontal lobes. The
found. The mechanism of the disorder is believed to reflect brain as a whole shrinks by about 30% by the time death
impairment of CSF passage over the surface of the brain toward supervenes. Recent molecular genetic studies have identified
its absorption points in the pacchionian granulations of the a restriction fragment length polymorphism mapped to chromo-
large venous sinuses. In some instances, passage through the some 4 that is linked to the HD gene. The anomaly has been
granulations themselves may be impeded. Areas of the sub- identified in two large, geographically separated kindreds with
arachnoid spaces become plastered down, and the cerebral HD, one located on Maracaibo Bay in Venezuela, the other
ventricles enlarge with most of the brain atrophy in the early in Iowa. The finding promises to provide in the future accurate
stages of the disease involving the periventricular areas of presymptomatic and prenatal diagnosis of carriers and may
the hemispheres. Diagnosis rests largely on a characteristic pave the way to effective prevention or treatment once the
clinical history, accompanied by the appearance on CT or specific molecular nature of the genetic error is identified.
MR scans of widely dilated cerebral ventricles. Concurrently, CJD is a rare, rapidly developing and progressive dementia
the images show relatively little brain atrophy over the surface, affecting persons of either sex in their middle and late middle
especially at the cranial vertex. Affected patients develop an years. Clinically, the disease produces an afebrile, progressive
insidiously beginning and slowly progressing dull, apathetic intellectual decline of a multidimensional character combined
intellectual loss often accompanied by a broad-based, ataxic usually with the development of prominent signs of corticospi-
gait and intermittent sphincter incontinence. Neurosurgical nal and basal ganglia dysfunction. Sooner or later, focal or
shunting of the CSF from the lateral ventricle into the heart multifocal myoclonic seizures develop. Pathologically, one
or peritoneal cavity provides at least some improvement in finds in the brain a moderate neuronal loss accompanied by
about half the cases carefully chosen according to these criteria. extensive astrocyte proliferation and swelling, the latter giving
A variety of procedures have been evaluated in unsuccessful a spongiform appearance to histological sections examined
efforts to improve the prediction of who will do well following by light microscopy. CJD mainly occurs sporadically but also
surgery. emerges in small family clusters. Its cause lies in an as yet
Among less frequent structural causes of dementia, those incompletely understood or identified, nonimmunogenic infec-
associated with Parkinson's disease (PD), Huntington's dis- tious agent that can be transmitted via cerebral inoculation
ease (HD), and Creutzfeldt-Jakob disease (CJD) possess partic- into a number of animal species, including various primates
ular biological interest. and small rodents. Several months to a year or more separate
About 25% of patients with PD undergo a mental decline the time of inoculation from the development of morphological
sufficiently severe to prevent them from remaining completely or behavioral signs of infection in the recipient; this feature,
independent. Clinically, the intellectual changes usually begin plus neuropathological similarities to visna in sheep and kuru
insidiously and progress slowly with symptoms resembling in the Fore tribe of New Guinea place the disease among the
those of SDAT. Neuropathologic alterations in the brain also slow virus infections of humans. Contagiousness by the usual
resemble those of SDAT and include plaques and tangles in person-to-person contact is extremely low, indeed probably
the cortical gray matter along with reduction of ChAT in the negligible in practical terms, but human passage has occurred
cortex and basal nucleus of Meynert (NBM). Some workers from postmortem corneal transplants taken from unrecognized

Table 2. Neurotransmitter Changes in HD

Neurotransmitters decreased in HD Neurotransmitters unchanged in HD Neurotransmitters increased in HD
L GABA (and GAD I, ·Dopamine I. Dopamine•
2. Acetylcholine (and CAT) 2. Serotonin 2. Thyrotropin-releasing hormone
3. Substance P 3. Vasoactive intestinal polypeptide 3. Somatostatin
4. Enkephalins 4. Norepinephrine 4. Neurotensin
5. Cholecystokinin
From Martin (1984),
• Reported to be increased in some studies, but not in others.
42 Fred Plum

cases. Sterilization of the agent is extremely difficult, and they answer most of the standard questions correctly. By con-
person-to-person transmission has followed the reuse of intra- trast, demented patients may be slow, but they usually respond
cerebral electrodes implanted to study seizures in persons later fairly consistently, predictably getting the answers wrong. Fur-
diagnosed as having CJD. thermore, psychomotor retardation and absolute insomnia far
A small number of structural, metabolic, and infectious dis- more often mark the course of depression than dementia. De-
orders can produce a sustained decline in mental function re- mented patients often develop a disordered sleep pattern but
sembling progressive dementia in their longevity but poten- their total sleep hours decline relatively little and may even
tially reversible if detected and treated sufficiently early. In- increase. Accurate distinction between dementia and depres-
cluded in this category are selected cases of cryptic subdural sive pseudodementia is not always easy, especially when the
hematoma or brain tumor, Wilson's disease, chronic liver cir- early dement retains enough insight to become depressed over
rhosis, cyanocobalmine (B 12 ) deficiency, chronic sedative in- his failing powers. Regrettably, neither biological markers nor
gestion, thyroid, parathyroid, or adrenal endocrinopathies, and consistent clinical features will measure accurately the degree
chronic central nervous system infectious granulomatous dis- of reversible psychological dysfunction in such instances. In
eases such as syphilis, sarcoid, cryptococcus and the like. many cases, the physician can only treat the psychological
These so-called treatable dementias are relatively easy to iden- symptoms and wait, knowing that antidepressant treatment
tify by routinely employed tests, and substantial improvement often reduces suffering and that time strengthens diagnostic
often follows appropriate therapy. accuracy in the clinical management of most dementias.
Late-life nonorganic psychological depression often pro-
duces a condition called pseudodementia that sometimes can Further reading
be difficult to differentiate from organic dementia. Depressed Cummings JL, Benson DF (1983): Dementia, A Clinical Approach.
patients often become apathetic, quiet to the point of muteness, Boston: Butterworths
and demonstrate a pronounced loss of interest in their surround- Martin JB (1984 ): Huntington's disease: new approaches to an old
ings, sometimes accompanied by considerable anxiety. All problem. Neurology 34:1059-72
these symptoms can also mark the early or intermediate stages Morrison JG, Rogers J, Scherr S, Benoit R, Bloom FE (1985): So-
of dementia. Where the diseases differ lies in the often promi- matostatin immunoreactivity in neuritic plaques of Alzheimer's pa-
tients. Nature 314:90-92
nent and repeated complaints by depressed patients that they Roberts GW, Crow TJ, Polak JM ( 1985): Location of neuronal tangles
are losing their mind, unable to concentrate, unable to give in somatostatin neurons in Alzheimer's disease. Nature 314:92-
attention to things, and feel their strengths seeping away with 94
time. On examination, depressed patients may not always re- Terry RD, Katzman R (1983): Senile dementia of the Alzheimer
spond to tests of mental function. When they do, however, type. Ann Neural 14:497-506
Down Syndrome
Charles J. Epstein

Down syndrome is the set of physical, mental, and functional most appear to be nonspecific and inconsistent, and gross struc-
abnormalities that result from trisomy 21, the presence in the tural abnormalities cannot explain the neurological deficits.
genome of three rather than the normal two chromosomes However, recent studies have indicated that there may be,
21. The physical abnormalities that together give rise to the early in life, selective decreases in the density of neurons in
distinctive facial appearance associated with this condition in- particular layers of the cortex, and possibly decreased numbers
clude upslanting palpebral fissures with inner epicanthic folds, of synaptic contacts as well. It has been suggested that such
flatness of the bridge of the nose, midfacial hypoplasia, and findings may reflect maturational delay rather than frankly
a tendency to protrude the tongue, especially when very young. abnormal neuronal differentiation and migration in fetal and
Many other functionally inconsequential minor abnormalities infant trisomic brains. Neuronal deficits have also been ob-
of the ears, hands, and feet may also be present, and stature served in young adults, but it is not clear whether these repre-
is generally reduced. Approximately 40% of affected individu- sent developmental or degenerative changes.
als are born with congenital heart disease, with endocardial The possibility that metabolic and physiological, as opposed
cushion and related septal defects frequently being present. to structural, abnormalities may contribute to the neurological
Obstruction of the intestinal tract also occasionally occurs dur- dysfunction in Down syndrome has been widely considered,
ing development. Although trisomy 21 is the autosomal tri- but at present there is no convincing evidence that any specific
somy most compatible with survival through the period of metabolic aberration has a significant role in the pathogenesis
gestation, only about a third of affected embryos and fetuses of this condition. Considerable interest has focused on periph-
are actually liveborn. eral neurotransmitter function in Down syndrome, and hyper-
Individuals with Down syndrome are more than normally sensitivity to the mydriatic effect of atropine has been well
susceptible to infections, probably because of abnormalities documented. However, there are no data in support of central
of the T lymphocyte system. They also have an increased neurotransmitter abnormalities in young individuals with tri-
although still low likelihood of developing childhood leukemia. somy 21. Some data suggestive of electrophysiological aberra-
Despite these predispositions, their mean life expectancy, if tions do exist. These include abnormal patterns of visual and
they survive the first year of life, is now between 55 and 60 auditory evoked potentials and abnormal electrical properties
years. of cultured fetal trisomic dorsal root ganglion neurons.
Down syndrome is characterized by three salient clinical The third clinical abnormality of the nervous system, recog-
abnormalities of the nervous system. The first, recognizable nizable in 25 to 50% of individuals with Down syndrome
immediately after birth and prominent in the first years of living into the fifth decade, is the progressive loss of mental
life, is a significant degree of hypotonia that produces a sense function resulting from the superimposition of a dementing
of floppiness or looseness. The second is mental retardation, process on the preexisting mental retardation. Associated with
which is generally moderate but may vary from mild to severe. the development of these clinical features of dementia has
The rate of acquisition of skills and capabilities is often normal been the appearance, in virtually all Down syndrome individu-
during the first few months of life. However, there is then a als over 35-40 years of age, of the pathological and neuro-
decrease in rate so that the development of more advanced chemical changes associated with Alzheimer disease. Brains
physical and intellectual skills such as the ability to construct of adults with Down syndrome possess granulovacuolar cyto-
sentences, to walk stairs alone, and to dress may be delayed plasmic changes, senile plaques, neurofibrillary tangles, and
by a year or more. Persons with Down syndrome have learned cerebrovascular amyloid indistinguishable from those found
complex intellectual tasks such as reading, writing, and arith- in the brains of individuals with Alzheimer disease. Chemical
metic calculations, but this does not occur in all instances. similarities, including decreases of cholinergic and other neuro-
There is evidence that the intellectual achievements of affected chemical markers, have also been noted. Persons with Down
individuals reared in enriched environments, such as the home, syndrome thus constitute a unique population at very high
are greater than was previously observed in trisomies confined risk of developing Alzheimer disease, both pathologically and,
to institutions for the mentally retarded. However, although in many instances, clinically. However, the nature of the asso-
a wide variety of agents have been tried, including megavita- ciation between the two conditions is unknown. While Alz-
mins and 5-hydroxytryptophan, there is not, at present, any heimer disease may be a direct consequence of genetic im-
accepted pharmacologic treatment of Down syndrome. balance produced by trisomy 21 , it is more likely that the
The exact anatomical and physiological causes of the hypoto- trisomic condition serves to make individuals with Down syn-
nia and mental retardation in Down syndrome are unknown. drome more susceptible to those factors that lead to the devel-
Very modest decreases in head circumference and brain weight opment of Alzheimer disease in a chromosomally normal aging
appear to be present, with the cerebellum and brain stem being population.
particularly affected. Although many anatomical and histologi- The pathogenetic relationship between the presence of an
cal anomalies of the nervous system have been described, extra chromosome 21, which is presumed to result in a 50%
including heterotopias and abnormalities of dendritic spines, increase in the expression of each of the active genes on this
44 Charles J. Epstein

chromosome, and the several phenotypic features of Down proaches will reveal not only how trisomy 21 results in the
syndrome described above is unknown. Current research is abnormalities associated with Down syndrome, but also
directed toward identification of these genes and to assessing whether anything can be done therapeutically to improve the
the consequences of their overactivity. Seven chromosome mental and physical development of affected individuals.
21 genes of known function have so far been recognized,
and knowledge of these genes has in tum been used to develop Further reading
an animal model for Down syndrome. It has been shown, by
comparative gene mapping, that four of the known human Epstein CJ (1986): The Consequences of Chromosome Imbalance:
chromosome 21 genes are present on mouse chromosome 16, Principles, Mechanisms, and Models. New York: Cambridge Uni-
versity Press
and it has been inferred that many other chromosome 21 genes
Pueschel SM, Rynders JE, eds (1982): Down Syndrome: Advances
are present on mouse chromosome 16 as well. Mouse trisomy in Biomedicine and the Behavioral Sciences. Cambridge: Ware
16 thus constitutes a genetic model of human trisomy 21 that Press
is suitable for in vivo and in vitro developmental, structural, Scott BS, Becker LE, Petit TL (1983): Neurobiology of Down's syn-
and chemical studies. It is hoped that these and other ap- drome. Prog Neurobiol21:199-237
Dyslexia
Albert M. Galaburda

In the United States dyslexia refers only to developmental knowledge by James Hinshelwood. Soon thereafter additional
disorders of reading. In the United Kingdom and parts of reports came out of the European continent and the United
Europe the term dyslexia is used to refer to a variety of reading States. Hinshelwood considered the disorder to reflect prob-
difficulties, which include both developmental and acquired lems in brain development; Samuel Orton in the United States
disorders. Dyslexia is considered here as a reading disorder emphasized the relationship between dyslexia and disordered
of developmental origin. brain asymmetry, and Hallgren in Denmark underscored the
In the absence of well-characterized biological markers, familial nature of the disability. Research in recent years has
dyslexia is defined operationally as "a failure [by children] to stressed the cognitive features and classification of dyslexia
learn to read with normal proficiency despite conventional as an aid to diagnosis and as a guide to the development of
[or even specialized] instruction, a culturally adequate home, educational methods of remediation.
proper motivation, intact senses, normal intelligence and free- Dyslexics represent a heterogenous group with regards to
dom from gross neurologic deficit" (Eisenberg, 1967). The cognitive-linguistic-neurological characteristics. At least one
components of this definition, i.e., normal proficiency, ade- common subtype exhibits disordered linguistic processes.
quate instruction and proper motivation, a tolerable degree There is another group of children in whom language deficits
of visual and auditory impairment for the purpose of learning are difficult to demonstrate in the face of severe visuospatial
to read, the acceptable range of normal intelligence, etc., must and visuomotor anomalies. Despite the significant extralinguis-
be further specified, and this turns out to be a major source tic abnormalities in this latter group, it is not possible to state
of disagreement among authorities. However, it remains that that they are etiological in the reading disorder, and may simply
a small but significant proportion of school-age children fail accompany a more generalized disturbance also affecting lan-
in their attempts to learn to read despite excellent instruction guage. A third group appear to show features of the first two.
and apparent intellectual ability. Furthermore there seem to be compensatory linguistic and de-
The exact characterization of the elements making up the velopmental neural strategies available to some individuals
definition of dyslexia will determine the figures on the preva- that modify the behavioral expression in unpredictable ways
lence of the condition in the population. Thus, for example, and produce still additional smaller subgroups.
a. mere change of 5 points in the IQ range will include or A variety of neurological accompaniments are associated
exclude large numbers of children. For this reason prevalence with dyslexia. These range from so-called minor neurological
figures in the literature vary between 2% and 16% of school- signs through changes in standard patterns of brain asymmetry
age children. In studies carried out in the Isle of Wight, reading on computerized radiographic scans and changes in brain elec-
retardation defined as more than 2 standard errors below ex- trical activity to alterations in brain structure. Some of the
pected reading level in children with a mean IQ of 102.5 neurological signs relate to malfunction of cognitive processes
was present in between 3.5% and 6% of the children. The known from adult brain injury cases to be associated to specific
same studies found a male-to-female ratio of 3.3 to I; this brain regions; others may include skeletal anomalies such as
male predominance has been noted by most other studies. scoliosis, motor problems involving dexterity of one or both
Inheritance plays an important role in the transmission of hands and the extraocular muscles, and stuttering. Electroen-
dyslexia. There were early suggestions of a single autosomal cephalographic abnormalities range from focal slowing and
dominant gene, whereby male-female differences were ex- spikes to frank epileptiform activity.
plained on the basis of unequal societal interest in the search Paralleling reports of increased non-right-handedness in
for and diagnosis of dyslexia among boys and girls. More dyslexia and alterations in the standard patterns of structural
recently sex differences in dyslexia have been explained by asymmetry of the brain have also been noted. Approximately
the apparent differences between normal males and females two-thirds of unselected brains show language-related regions
in the brain organization for language. In that case genetic in the left hemisphere to be larger than comparable regions
disturbances occurring equally in boys and girls would be on the right; 10% show the reverse pattern and about 25% of
apt to produce different effects. The most recent hypothesis the brains are symmetrical in these regions. It appears that
argues for specific influences of sex hormones in utero in the dyslexics show aberrant patterns more often, and frank reversal
expression of faulty gene(s). Abnormal testosterone activity of asymmetry commonly, especially among dyslexics with
is implicated, explaining the increased prevalence in males. low verbal IQ. Five brains of dyslexic individuals, all males,
The first reference to difficulty with the written word in have been studied after death. The ages of the subjects ranged
two otherwise normal subjects appeared in Eugene Labiche's from 12 years to 30 years. In four of these brains the pattern
La Grammaire (1867). Subsequently, in the United Kingdom, of asymmetry was studied and fell into the symmetrical cate-
the first medical mention of specific reading disability (dys- gory, a finding that is statistically significant.
lexia) by W. Pringle Morgan, and the first serious attempt to All five brains of dyslexics studied for anatomical changes
discuss dyslexia in the light of contemporary neurological have shown developmental cortical anomalies. These are of
46 Albert M. Galaburda

two types: ectopias and dysplasias. Ectopias (the presence of related disorders, the latter through testosterone effects on the
structures in places from which they are normally absent) con- development of the thymus and other immune processes. Fur-
sist of collections of neurons and abnormal tufts of fibers and thermore selected strains of mice that develop similar immune-
blood vessels predominantly in the molecular layer of the cor- based disease frequently exhibit alterations in cortical develop-
tex. Often frank verrucous excrescences are seen. Dysplasias ment consisting of neuronal ectopias and dysplasias.
consist of disordered lamination of cortex and cell-free areas,
sometimes forming frank micropolygyria. The anomalies are Further reading
present predominantly in the inferior frontal gyrus and on the
superior temporal gyrus and temporoparietal junction, and in- Reviews and symposia
Eisenberg L (1979): Definitions of dyslexia: Their consequences for
volve the cortex of the left hemisphere in great excess over research policy. In: Dyslexia. An Appraisal of Current Knowledge,
that of the right. No brains free of anomaly have been reported. Benton AL, Pearl D, eds. New York: Oxford University Press
It has been suggested that pathological effects in utero preferen- Hynd G, Cohen M (1983): Dyslexia. New York: Grune & Stratton
tially affect the development of the left hemisphere and its
language areas, thus resulting in linguistic anomalies that show Anatomical findings
Galaburda AM (1983): Developmental dyslexia: Current anatomical
up most clearly in the reading process. research. Ann Dyslexia 33:41-53
The presence of brain changes in dyslexia has prompted Galaburda AM, Kemper TL (1979): Cytoarchitectonic abnormalities
the search for additional biological associations. It has been in developmental dyslexia: A case study. Ann Neural 6:94-100
found that there is an association between left-handedness, Galaburda AM, Sherman GF, Rosen GO, et al (1985): Developmental
learning disability (including dyslexia), and immune disease. dyslexia: Four consecutive patients with cortical anomalies. Ann
The immune disorders primarily involve the bowel and thyroid, Neural 18:222-233
although additional conditions are still under study. It has Biological associations
been suggested that the same hormonal influences in fetal life Geschwind N, Behan P (1982): Left handedness: Association with
responsible for altered left hemisphere development and dys- immune disease, migraine, and developmental learning disorder.
lexia account for the excess of left-handedness and immune- Proc Nat! Acad Sci USA 79:5097-5100
Eating Disorders
Domeena C. Renshaw

In the wild, land mammals are remarkably similar in their fertility, arthritis, thromboembolism, varicose veins, and her-
seasonal accumulation of body fat. They are rarely obese. nias. Sexual problems caused by low self-esteem, partner criti-
Domestic or captive animals, and active or sedentary humans, cism, and mechanical or mobility difficulties may also be
however, show much variation in fat deposits. Low activity associated with obesity. Diets and how to lose weight are
and excess food intake appear to be factors in fattening agricul- constant questions brought to physicians bv those who are
tural and domestic animals. Farming provides protection from truly obese and those fearing it.
predators and no dominance challenge, preservation (even se- A common, although arbitrary definition used for obesity
vere restriction) of territorial boundaries as in poultry and cattle is 20% above the mean ideal body weight for men and women,
coops, and controlled breeding rather than natural selection. corrected for height and age, usually taken from life insurance
Furthermore, synthetic hormones are used to enhance livestock tables. Estimates are that in the United States 20% of men
weight. These additives may have unknown health and weight- and 40% of women over 40 are obese by this measure.
gain consequences in humans. Eating disorders have received media attention in the past
The primitive task of hunting and food gathering for each 20 years. Headlines and articles about "the starving disease"
meal has evolved for humans into money gathering, then gro- or the "thin disease" (anorexia nervosa) in the 1970s were
cery shopping, and storage of the fresh or dry edibles. Scientifi- followed in the 1980s by reports of the unexpectedly high
cally enhanced food production, 24-hour diners, and fast food incidence of self-induced vomiting (bulimia) among college
outlets have made possible ingestion of the abundance available girls to keep their body weight at 15% to 25% below norm.
at any time outside or inside the home, thanks to freezers, These two sister eating disorders-anorexia nervosa and buli-
refrigerators, canning, and drying. Affluence, novelty, and mia nervosa-are inextricably bound to obesity. DSM-III diag-
aggressive advertising have greatly added to the attraction of nostic criteria for anorexia nervosa are as follows:
eating light, tasty, high-caloric snacks far beyond each person's
natural hunger-satiation rhythms. In times of plenty very few Refusal to maintain body weight over a minimal normal weight
children or adults learn to tolerate hunger feelings. Overfulness for age and height.
may be associated with a sense of emotional well-being, so Weight loss of at least 25% of original body weight.
that overeating can become customary, resulting in overweight. Disturbance of body image with inability to perceive body
It may be argued that for primitive, nomadic tribes, stored size accurately.
energy as fat had survival advantages in times of food shortage. Intense fear of becoming obese. This fear does not diminish
Were these people leaner or heavier than today? It is not as weight loss progresses.
known. Stone-age clay sculptures depict obese persons way No known medical illness to account for weight loss.
before agriculture, but these artifacts may have been of excep- Amenorrhea.
tional rather than average citizens. Modem men and women
do not claim (as in earlier centuries) that overweight is a protec- Diagnostic criteria for bulimia are as follows:
tion from future hunger, tuberculosis, or other diseases. Peri- Episodic binge eating pattern usually in less than 2 hours ac-
odic fasting (as in Lent or Yom Kippur) may be externally companied by an awareness of the disordered eating pattern
imposed by a belief system and is still widely practiced. Fasting with a fear of not voluntarily being able to stop eating;
chosen as a lifestyle leading to holiness is considered ascetic and depressive moods and self-depreciating thoughts after
in many religions and cultures. Hunger strikes evolved as a hinging.
form of temporary political protest and became well known
at the tum of this century when women in England struggled At least three of the following:
for equal rights. Rapid consumption of food during a binge;
Fasting combined with nonviolence subsequently became a Consumption of high-calorie, easily ingested food during a
powerful political means to achieve change when used by binge;
Ghandi in Africa and in India. Fasting in this sense is not Inconspicuous eating during a binge;
regarded medically as an eating disorder. Terminating binge eating by abdominal pain, sleep, social
It remains controversial whether obesity (excess adipose tis- interruption, vomiting, or self-induced vomiting;
sue) is regarded as a disease entity. It is not listed in DSM Repeated attempts to lose weight by severely restrictive diets
I, II, or III (editions 1-3 of the American Psychiatric Associa- or self-induced vomiting;
tion's Diagnostic and Statistical Manual of Mental Diseases) Eating pattern of alternate binges and fasts;
as an eating disorder with psychogenic components. Yet, un- Use of laxatives for weight control.
disputedly, it is still the most common disorder of metabolism,
and the emotional precursors and sequelae are numerous. Dis- All three groups--obese, bulimics, anorexics-have an inter-
eases closely associated with obesity include cardiovascular nally driven compulsive preoccupation with food and verbalize
diseases, hypertension, adult-onset diabetes, cholecystitis, in- dislike of being or becoming fat. Many girls may as a group
48 Domeena C. Renshaw

of plump 12-to-14-year-olds begin to diet. Most do not persist. esting to note is that although alcohol is not essential to life
but a few will keep on dieting into an anorexia or bulimia but food is, the concept of "foodaholic" has been readily
nervosa state while others will persist with overeating intP accepted due to the obese person's acceptance of job and family
lifelong obesity. In the 1980s more young women seem to consequences of the excess weight plus secret and "cheat"
choose the bulimic pathway. Obese persons will give up on eating. Overeaters Anonymous has adopted and adapted the
a diet and continue to eat despite a stated negative attitude Alcoholics Anonymous group support system. So to some
toward being overweight. Anorexics and bulimics, however, extent have bulimics in their BASH (bulimia anorexia self-
will develop such an intense morbid abhorrence of obesity help) organization. Anorexics, however, seem to me to repre-
that their paths diverge. Political fasting is done by average- sent an inverse addiction in that they may lie, cheat, and
weight persons from abhorrence of perceived social or moral pretend that they ate when they did not. Clinical management
evils. Religious fasting is done from fear of breaking taboos is difficult in all these conditions since no person can assume
or in search of higher good through self-mortification. Anorex- 24-hour guardianship for what another person eats. Psychoso-
ics abhor fat, imperfection, and indulgence. Bulimics cycle a cial management must proceed, but the search for biological
feast-vomit-fast pattern, although they also abhor fat and im- answers is also important. Theories of disturbed norepineph-
perfection in themselves. Suicide potential is of concern due rine, amines, peptides, and neuroendocrine and hypothalamic
to their mood swings, which may respond to medication. So function are being studied in obesity, bulimia, and anorexia,
saint and suffragette, actress, fashion followers, models, mys- thus far inconclusively. Could there be special limbic system-
tics, and zealots have shared fasting behaviors with very differ- hypothalamic pathways that await identification and under-
ent underlying motives, and often with much more complexity standing in all the eating disorders? And are there absent or
than any classification of eating disorders can provide. even excess connections to the sexual centers of the pituitary-
For all three groups--obese, bulimics, anorexics-the psy- hypothalamic areas?
chological level of distress may be equally high regarding
actual body weight and the affected individual's internally per-
ceived body image. Self-blame, shame, regret, remorse, and Further reading
guilt are accompanied by insecurity, anxiety, depression, and Bierman EL (1982): Obesity. In: Cecil Textbook of Medicine. Wyn-
low self-esteem. Difficulty dealing with anger and suicidal gaarden JB, Smith LH, eds. Philadelphia: WB Saunders
thoughts are constant concomitants for all three groups. Halmi KA, Falk JR, SchultzE (1981): Binge-eating and vomiting:
All appetites, whether for food, for sleep, or for sex, are, A survey of a college population. Psycho/ Med 11:707-711
in a complex way, on a somatopsychic interface where both O'Neill CB ( 1982): Starving for Attention. New York: Continuum
physiology and feelings are affected when problems occur. Palmer RL (1980): Anorexia Nervosa: A Guide for Sufferers and
Their Families. New York: Penguin Books
Appetites are all vital functions. Only the control of sexual Pope HG, Hudson JI ( 1984): New Hope for Binge Eaters. New York:
expression is not harmful to an individual (although that choice Harper & Row
may destroy a relationship). Therefore, in the treatment and Pyle RL, Mitchell JE (1983): The bulimia syndrome. Female Patient
research of eating disorders, sexuality is hardly mentioned 8:48-53
due to concern about health and survival. Exactly how the Renshaw DC (1982): Obesity and sexual problems. Female Patient
self-defeating compulsive, repetitive, often self-destructive, 7:58-60
distressing behavior of eating disorders is neurophysiologically Renshaw DC ( 1982): Sexual anorexia nervosa? Chicago Med
driven by each individual's emotions is still speculative. Inter- 85( II ):590-592
Epilepsy
Massimo A voli and Pierre Gloor

Epilepsy is a disorder of brain function characterized by the Depending on whether only a limited part of or the entire
episodic recurrence of paroxysmal neurological or behavioral brain is involved in the seizure discharge at its onset, as judged
manifestations caused by abnormal synchronous and excessive by both clinical and electroencephalographic (EEG) criteria,
discharges of large groups of neurons. The ancient Greek word epileptic seizures are subdivided into two main categories:
epilepsia literally means "seizure" and the disease itself was (l) partial (i.e., focal) and (2) generalized. Each category is
probably recognized prior to the development of the earliest further subdivided into subcategories depending on the ictal
civilizations. symptomatology of the attack. In the differential diagnosis of
epilepsy, it is necessary to consider other episodic disturbances
of CNS function (e.g., syncope, migraine, hysteria, and other
Clinical features of epilepsy psychiatric disorders) and to determine whether the attacks
are symptomatic of a structural brain lesion or a metabolic
The incidence of human epilepsy is estimated to range between
derangement or are mainly due to a genetically determined
0.5 and 2% of the general population. Epilepsy is not a unitary
brain disorder. In many cases the etiology remains unknown.
disease. It has no single cause; rather it is a multifactorial
The EEG examination, which detects signs of epileptogenic
condition reflecting acquired and genetic factors. Among the neuronal dysfunction, is the most important laboratory test
former can be listed perinatal and postnatal cerebral trauma,
used in the diagnosis of epilepsy. The practical value of the
infections of the central nervous system (CNS), brain tumors, EEG rests on its ability to detect evidence for such a dysfunc-
cerebral vascular lesions, congenital malformations, and some tion even between epileptic attacks. The EEG signs of epileptic
metabolic disorders. A period of months to years can elapse discharge can therefore be divided into (I) interictal discharges,
between the impact of the exogenous causal event and the present between seizures, and (2) ictal discharges, recorded
appearance of the clinical symptoms. Knowledge of the exoge- only during an attack. lnterictal discharges are characterized
nous factors involved in the causation of epilepsy is relevant by short-lasting EEG abnormalities, such as high-amplitude
for its prevention, since the incidence of the disorder can be spikes or sharp waves (Fig. lA), while ictal discharges are
reduced by improved perinatal care or by the prevention of more varied, but usually consist of an abnormally rhythmic
brain injuries. Genetic factors include seizures caused by a
single gene disorder (e.g., some inborn errors of metabolism),
and others that to a greater or lesser degree interact with exoge-
nous factors. In some forms of inherited seizure disorders in
animals great progress has recently been made in understanding
A~_jo1m'
their molecular biology. No similar progress has yet been made 400 ms

B-l\___~1'
for human epilepsy.
Epileptic discharge may involve any structure of the CNS
although it can originate in only some of them (most often
the cerebral cortex, including the hippocampus, or the amyg-
., _j2s mV

dala). Consequently, though its most dramatic clinical manifes- 100 ms

tation is loss of consciousness with generalized tonic-clonic
convulsions (which may be the final outcome of any epileptic
seizure), many seizures exhibit a great variety of clinical signs c
and symptoms. Their distinctive features depend upon differ-
ences in the site of origin and in the extent and pattern of j-tL~~Jsom'
spread of the seizure discharge. Thus, the salient symptomatol-
ogy of an epileptic seizure reflects the functional significance •
of the brain area involved in the seizure discharge. For exam- Figure I. A. EEG interictal spike recorded from the scalp of a patient
ple, twitching of half the face with discharge involving the suffering from partial epilepsy. B. EEG interictal epileptiform spike (upper
contralateral face area of the precentral gyrus, phosphenes in trace) and intracellular correlate (lower trace) recorded in the cat motor
half the visual field with discharge in the contralateral visual cortex after local application of the epileptogenic agent strychnine; note
cortex, evocation of past memories in temporal lobe seizure the burst of action potentials (so-called PDS), which is followed by a
discharge, etc., result from ictal activation of neuronal mecha- long-lasting hyperpolarization. Courtesy of MR Klee, from Fig. I, p
318, in Purpura DP, Yahr MD, eds (1966): The Thalamus, New York:
nisms represented in these areas, while other manifestations
Columbia University Press, reprinted with permission. C. Epileptiform
like the inability to utter or understand speech result from discharge recorded intracellularly in an in vitro slice of human temporal
disruption of the normal function of speech cortex when it neocortex removed for tumor and bathed with the epileptogenic agent
partakes in ictal discharge_ bicuculline.
50 Massimo Avoli and Pierre Gloor

pattern of EEG waves. In partial seizures the seizure discharge recordings in an epileptic focus show that at the time of the
recorded in the EEG starts in a circumscribed region of the interictal EEG spike a large amplitude membrane depolariza-
head overlying the brain area giving rise to the patient's sei- tion is associated with a high-frequency burst of action poten-
zures (the so-called epileptic focus). In generalized seizures tials and is usually terminated by a membrane hyperpolariza-
the EEG discharges appear simultaneously in all regions of tion that may be a classical inhibitory postsynaptic potential
the head. Typically, partial and the "major" form of general- (IPSP) or more likely the manifestation of a Ca ++-dependent
ized seizures (i.e., the generalized tonic-clonic convulsion) outward K + current (Fig. I B). This phenomenon is known
are followed by postictal depression of cerebral activity during as the paroxysmal depolarization shift (PDS) and is often con-
which the EEG first appears flat and then develops abnormal sidered to represent the basic underlying cellular feature of
slow waves. There is no such depression after absence atiacks, the focal interictal discharge expressed in the EEG as a spike.
the "minor" form of generalized seizures. The latter is assumed to result from the summation of many
Usually epilepsy does not significantly alter the patient's individual PDSs. A PDS-like phenomenon can also be recorded
life expectancy. However, if seizures frequently recur, the in neurons maintained in vitro when they are bathed with
condition seriously threatens the prospects for a satisfactory chemical convulsants (Fig. !C). Experimental evidence ob-
life. If a treatable etiological factor can be identified (e.g., tained in both in vivo and in vitro preparations suggests that
an intracranial tumor), causal treatment is possible and a defini- the PDS is dependent upon a network-driven synaptic input,
tive cure can be achieved. In most instances this is, however, a kind of "giant" excitatory postsynaptic potential (EPSP),
impossible and only symptomatic treatment can be offered though endogenous voltage-dependent currents may also con-
by using anticonvulsant medication, which controls seizures tribute to the depolarizing envelope of the PDS and may play
in about 60% of epileptic patients. If drug therapy fails and a role in its initiation.
if the seizures are partial, the epileptogenic focus can be surgi- An important factor in the genesis of focal interictal dis-
cally excised, provided this causes no neurological deficit. In charge might be a diminished efficiency of Cl- -currents con-
selected cases the results of this treatment are satisfactory (only trolled in forebrain neurons by the inhibitory synaptic transmit-
very rare or no seizures following surgery) in about two-thirds ter GABA. Several chemical convulsants are indeed capable
to three-quarters of patients. of decreasing the responses of neurons to the iontophoresis
of GABA and of abolishing IPSPs. Therefore the increased
effectiveness of excitatory inputs underlying the PDS might
Experimental epilepsy be caused by disinhibition. A selective loss of neurons contain-
The mechanisms underlying epileptic discharges have been ing glutamic acid decarboxylase (the enzyme required for
studied in animal models through a variety of experimental GABA synthesis) has been reported in some experimental brain
manipulations of brain structure or function. Acute or chronic lesions produced by alumina gel, cobalt, or hypoxia that are
electrical brain stimulation, topical application of chemical known to lead to the development of epileptic seizures. The
convulsants to cerebral gray matter, systemic application of specificity of these changes with regard to epileptogenesis re-
drugs, physical agents applied to the brain such as freezing- mains, however, to be demonstrated, and the underlying cellu-
all are capable of inducing electrographic EEG changes resem- lar basis of epileptic discharge in these models is less well
bling both the interictal and ictal EEG patterns seen in human understood than in epileptic discharge induced by convulsant
epilepsy, as well as behavioral seizures. drugs.
The emphasis in this review is on the electrophysiological
mechanisms of epileptic discharge. The important biochemical Experimental models of focal ictal discharge. At times focal
mechanisms related to these are not covered in detail, mainly interictal discharges induced by topical application of convul-
because the biochemical studies of epileptic discharge, in con- sants increase in occurrence and develop into an EEG pattern
trast to those of its electrophysiological manifestations, have of focal seizure activity. The cellular correlate leading to ictal
not led to a coherent view of the mechanism of epileptogenesis. activity is a progressive lessening of the post-PDS burst hyper-
Some abnormalities in amino acid metabolism, particularly polarization, suggesting that the occurrence of focal seizures
as it affects the compartmentalization of glutamic acid in intra- might be caused by further impairment of synaptic inhibition
cellular (neurons and glia) and interstitial spaces are found to or by a decrease of the post-PDS outward K +-currents. A
be associated with many forms of experimental and human role for disinhibition in the genesis of focal ictal discharges
epilepsy. It has been suggested that these changes indicate is also suggested by the findings that both IPSPs and the re-
that there is a leakage of glutamic acid from the intracellular sponses of neurons to GABA iontophoresis diminish in hippo-
to the extracellular compartment where it may exert its well- campal seizures induced by high-frequency electrical stimula-
known excitatory action and thus may be a factor in causing tion. During experimental focal seizures the membrane
seizures. It is, however, not yet clear whether these changes, potential of the ictally discharging neurons remains depolar-
rather than being causally related to epilepsy, merely represent ized. This may be a factor in permitting excessive Ca ++-influx
a consequence of epileptic neuronal hyperactivity. Other views into the discharging cells, which may cause reversible and
on biochemical mechanisms involved in epilepsy have stressed sometimes irreversible damage to neuronal function and struc-
a defect in the availability of gamma-aminobutyric acid ture.
(GABA), the main inhibitory substance in the brain. GABA Focal ictal discharges have also been studied by employing
levels are, however, often found to be normal in human epilep- chronic models of experimental epilepsy such as the alumina
tic brain tissue as well as in that of some animal models of cream focus or the kindling phenomenon. The latter is an
epilepsy. epileptogenic condition induced by repeated electrical stimula-
tion of forebrain structures, such as the amygdala, the hippo-
Experimental models offocal interictal discharge. Most experi- campus, or the neocortex. A brief and weak electrical stimula-
mental work on focal epileptic discharge has dealt with the tion that, upon its first application, is below the threshold
mechanism underlying the interictal EEG spike evoked by required for producing any detectable electrophysiological or
the acute topical application of chemical convulsants such as behavioral response will, over time and repeated once daily,
penicillin, bicuculline, or strychnine to discrete regions of the begin to elicit focal seizure discharges and ultimately general-
brain (mainly the neocortex and hippocampus). Intracellular ized seizures. Finally spontaneous seizures as well as interictal
 Epilepsy 51

A axons, transmission across electrical junctions, and ephaptic

effects probably contribute to the high degree of synchroniza-
Right Frontal
~~\Jid~NY'rr~tff\rrtf\t~~ tion that characterizes epileptiform discharges.

Experimental models of generalized spike and wave dis-

left Frontal
"~"·~WVW\~~n~~f{l.lf'tf!o/1W\~f!W'\{IJ\flf\J charges. Generalized bilaterally synchronous spike and wave
\ 1 , , I I. , (' \ \ \ ( ~ 1000 "'v (SW) discharges in the EEG can be evoked in cats by repetitive
B 1 sec low frequency (2-3/sec) stimulation of diencephalic and mes-
encephalic structures. They are more consistently evoked by
a the bilateral application of convulsants to the neocortex or
Right Parietal by their systemic parenteral administration. For instance, when
penicillin is injected intramuscularly in the cat, the resulting
generalized SW discharges and the concomitant decrease in
left Parietal behavioral responsiveness closely resemble the electrographic
and behavioral features of human absence or so-called petit
b mal attacks (Fig. 2). These represent the most common minor

Ill
1 sec
Cortical EEG clinical manifestation of primary generalized epilepsy. Penicil-
lin-induced generalized SW discharges in the cat appear to
be generated by the increased responsiveness of neocortical
neurons to thalamocortical volleys, which normally evoke spin-
(intracellular)~
Cortical Neuron
dles. The cellular substrate of the SW discharge is an alterna-
tion between periods of increased and decreased neuronal exci-
tation that is sustained within a thalamocorticothalamic loop
made more effective by the systemic penicillin (Fig. 2Bc).
c The period of increased neuronal excitation associated with
Cortical EEG bursts of action potential discharge corresponds to the spike
of the SW complex; the EEG spike may thus represent the
sum of synchronous excitatory postsynaptic potentials
(EPSPs), while the slow wave component that occurs at the
time of the longer period of decreased excitation may result
from a summation of the membrane hyperpolarizations re-
corded intracellularly during the wave of the SW complex
(Fig. 2Bb). These, at least in part, represent classical IPSPs.
Intracortical inhibitory mechanisms, presumably exerting their
action on the neuronal soma, are thus preserved in this model
of generalized epilepsy and seem to be an important component
250 ms in the cellular mechanism underlying SW discharge. The pri-
Figure 2. A. Generalized spike and wave (SW) discharge from the EEG mary feature in its genesis seems to be a state of diffuse cortical
of a patient during an absence attack. B. Generalized SW discharge in- hyperexcitability, which can be induced experimentally in cats
duced in a cat by intramuscular penicillin. a. Cortical EEG. b. Intracellular by the intramuscular injection of penicillin. The powerful acti-
correlate of the SW discharge in a neuron of the motor cortex (lower vation of intracortical inhibition that occurs under these condi-
trace); the EEG showing the rhythmic sequence of SW was recorded tions is probably a secondary effect of the increased discharge
from the nearby cortex (upper trace). c. lntracortical EEG averages and of cortical neurons that through recurrent collaterals activates
time histograms of a cortical and a thalamic cell during generalized SW intracortical inhibitory interneurons. The net result is that dur-
discharge. The EEG averages were obtained by selecting each of the ing SW discharge most of the time is taken up by inhibition.
successive peaks of spikes of SW complexes as time zero (square) for
A similar discharge pattern affects thalamic neurons during
forward and backward averaging of the EEG and for simultaneous compu-
tation of the time histograms of action potential discharge (peaks in the SW discharge. For generalized SW discharges recorded in
histograms are proportional to the number of action potentials occurring the naturally occurring photosensitive generalized epilepsy of
at that time; slow wave reversed in polarity because the EEG is recorded the baboon Papio papio, a cortical origin has been demon-
intracortically). strated.

Mechanisms of action of antiepileptic drugs

EEG spikes occur. Development of kindling is not associated Knowledge of the mechanisms of epileptic discharge is relevant
with any detectable morphological changes. There is no evi- for developing new antiepileptic drugs. Also, knowledge of
dence for a decrease in the content or in the action of GABA the mode of action of antiepileptic drugs may make it possible
in kindled brain tissue. The electrophysiological basis of kin- to test some of the current hypotheses concerning the mecha-
dling remains unclarified. Kindling displays some similarities nisms of epileptic discharge. Many of the drugs commonly
to long-term potentiation of synaptic transmission in the hippo- used to treat human epilepsy enhance GABA-mediated inhibi-
campus, but there is some evidence that the two phenomena tion (benzodiazepines, barbiturates). However, some GABA-
are not directly related. ergic agents exert a facilitatory effect on experimentally in-
Focal ictal discharges can spread to distant structures, thus duced generalized epileptiform discharges of the SW type.
becoming secondarily generalized. Although synaptic mecha- Recent experimental evidence suggests that some antiepileptic
nisms play an important role in recruiting neuronal elements drugs might increase the efficiency of repolarizing K +-currents
into participating in epileptiform activity, both at the local (benzodiazepines) and reduce inward depolarizing currents
circuit level and more distantly, other phenomena such as (valproic acid). Both actions may account, at least in part,
ectopic action potential generation with antidromic firing along for their antiepileptic effect.
52 Massimo A voli and Pierre Gloor

Further reading Magnus 0, Lorentz de Haas AM, eds (1974): The Epilepsies: Hand-
book of Clinical Neurology vol 15, Amsterdam: North Holland
Delgado-Escueta AV, Ferendelli JA, Prince DA, eds (1984): Basic Publishing
mechanisms of the epilepsies. Ann Neurol 16 (suppl) Penfield W, Jasper H (1954): Epilepsy and the Functional Anatomy
Jasper HH, Ward AA, Pope A, eds (1969): Basic Mechanisms of of the Human Brain. Boston: Little, Brown
the Epilepsies. Boston: Little, Brown Schwartzkroin PA, Wheal H, eds (1984): Electrophysiology of Epi-
Jasper HH, van Gelder N, eds (1983): Basic Mechanisms of Neuronal lepsy. New York: Academic Press
Hyperexcitability. New York: Allan R Liss
Eye Movement Dysfunctions and Mental Illness
Philip S. Holzman

Disorders of smooth pursuit eye movements have been reported tracking dysfunctions), whereas in the family members of a
in many patients with functional psychoses. Between 50% manic-depressive proband these dysfunctions occur at no
and 85% of hospitalized schizophrenic patients and between greater than normal prevalence. There is, therefore, strong
20% and 50% of manic-depressive patients show these disor- evidence that these eye movement dysfunctions are associated
ders. In contrast, the prevalence of pursuit dysfunctions in with schizophrenia and tend to occur within families in which
the normal population is about 8%. Patients with nonpsychotic there is a member with clinical schizophrenia, associations
psychiatric conditions such as personality disorders or serious that suggest a genetic transmission of smooth pursuit tracking
neurotic conditions show a prevalence of smooth pursuit eye disorders. Their presence in a proband, however, cannot be
movement dysfunctions that is no higher than that found in assumed to be pathognomonic of schizophrenia, since they
the normal population. Although such dysfunctions are typi- occur in other disorders as well.
cally associated with a variety of neurological syndromes, such A number of schizophrenic patients with unimpaired pursuit
as Parkinson's disease, multiple sclerosis, and those following movements have parents with eye tracking abnormalities. This
hemispheric and brain stem lesions, no obvious central nervous suggest~ the transmission of a latent trait with different mani-
system diseases have been reported in association with the festations in different persons and in different families. The
functionally psychotic patients who show eye tracking disor- latent trait, like that for neurofibromatosis, may express itself
ders. in the form of manifest schizophrenia, deviant eye tracking,
The eye tracking dysfunctions in schizophrenics are not pro- or in both schizophrenia and deviant eye tracking. Identifica-
duced by the neuroleptic drugs (phenothiazines, butyrophe- tion of those schizophrenic patients and family members in
nones, and thioxanthenes) usually prescribed for psychotic pa- whom the trait is present and those in whom it is absent is
tients, although there is some evidence that lithium carbonate, crucial to understanding their relationship to schizophrenia.
prescribed for many patients with major affective disorders, Smooth pursuit eye movements are measured by asking the
produces pursuit dysfunctions. A variety of central nervous subject to follow a target, which is usually a small dot of
system depressants, including alcohol, chloral hydrate, and light that moves in a sinusoidal (pendular) or triangular (con-
barbiturates, also disrupt smooth pursuit eye movements. stant velocity) wave form. Eye movements are usuallY. recorded
Inasmuch as schizophrenic patients with abnormal smooth by electrooculographic methods or by infrared reflected light
pursuit eye movements are able to execute saccades (or rapid techniques. The latter may give more precise representation
eye movements) with normal latency, accuracy, and velocity, of the movements of the eyes, although the former is quite
the smooth pursuit dysfunction in these same patients does acceptable for screening purposes.
not reflect poor motivation or inattention, variables that usually There are two types of eye movements involved in this
interfere with effective and accurate performance by such pa- phenomenon. The first is the saccadic, or rapid eye movement,
tients. Although pursuit integrity tends to degrade with increas- that occurs frequently each day. They are high velocity, high
ing age, especially after the age of 50, chronological age does acceleration eye movements, some of them reaching speeds
not account for the disorder in psychotic patients, since the of over 700 degrees per second. Normally about a quarter of
greatest majority of patients tested have been in their twenties a million such movements are made daily. These saccadic
and age-matched controls have been used. movements are active seeking and fixation movements. They
Identical pursuit dysfunctions have been reported in the first- direct the eyes to a target by high frequency bursts of nerve
degree relatives (principally parents and siblings) of schizo- impulses to activated agonist and reciprocally inhibited antago-
phrenic patients, but not of manic-depressive pntients. These nist eye muscles. The second type of eye movement is the
relatives have no history of psychosis or major mental illness. smooth pursuit or tracking movement which responds to dispar-
The prevalence of eye tracking dysfunctions within the families ities between target and eye velocities. These pursuit move-
of schizophrenic patients suggests that these dysfunctions may ments are regulated by a dual-mode control system in which
be genetically transmitted and represent a biological marker the saccadic system places the target on the fovea and the
of the vulnerability to schizophrenia. This supposition is smooth pursuit system keeps the image of the target there.
strengthened by studies of monozygotic and dizygotic twins It appears that the dysfunction in psychotic patients-princi-
who are clinically discordant for schizophrenia; in spite of pally schizophrenics--consists in the replacement of smooth
their clinical discordance, their concordance for eye tracking pursuit by saccadic movements (small saccadic jumps that
dysfunctions was over 80% in the monozygotic sets and about intermittently substitute for smooth tracking) as well as in
40% in the dizygotic sets. the intrusion of saccadic eye movements into the pursuit move-
The specificity of eye tracking dysfunctions for schizophre- ments. These latter are of various types, some of which are
nia is further bolstered by their frequent appearance in families "square wave jerks" or paired saccades that range from
with a schizophrenic proband (close to 50% of such families smaller than 0.5 degrees to 5 degrees in amplitude; these sac-
have at least one member, who is not the proband, with eye cadic intrusions are not necessarily corrective eye movements.
54 Philip S. Holzman

( SCHIZOPHRENIC ) (NORMAL CONTROL)

this stage of knowledge to decide whether the disorder is a
v failure of the smooth pursuit system or of the modulation or
E
L inhibition of the saccadic system, or both . Figure I illustrates
~
0 some of the pursuit patterns found in schizophrenic patients.
D. c LE
I Some of the neural mechanisms controlling saccadic eye
T
y movements are located principally in the brain stem. Inasmuch

}
as these patients produce saccades with normal trajectories
C. LE
and latencies, those brain stem loci appear to be normal. Since
the eye can be made to move smoothly by generating pursuit
l' movements via vestibularly driven eye movements, the extra-
p ·r·~·:,
0 ocular musculature also appears to be normal. Higher centers
s are likely implicated. Additional evidence for this hypothesis
I
B. T RE is provided by the demonstration that all psychotic patients
I who show impaired horizontal tracking when following a mov-
0
N ing pendulum show impaired vertical tracking as well; horizon-
tal and vertical tracking controls are located in different parts
A. T of the brain stem . Further, these patients show normally
smooth eye tracking movements when the eyes are moved
by the oculocephalic reflex , full-field (but not partial-field)
. 33Hr optokinetic nystagmus, as well as by vestibularly generated
smooth pursuit.
TIME----
The relationship of eye tracking dysfunctions to the symp-
Figure 1. Illustration of a schizophrenic and a normal subject tracking a toms of schizophrenia is not yet clear. Nor is there any obvious
0.33 Hz triangular wave. Saccadic intrusions are considerably more fre- relationship between these eye movement disorders in schizo-
quent in the schizophrenic patient, although they are present in the normal phrenic patients and structural brain patterns, although schizo-
subject. In addition, schizophrenic subjects show a variety of saccadic phrenic patients with enlarged ventricles on computerized to-
oscillations . mographic scans show a high prevalence of these eye
movement patterns .

The former, saccadic tracking, are generally compensatory Further reading

eye movements that correct for low gain pursuit which causes
the eye to fall behind the target; these saccadic substitutions Lennerstrand G , Zee D, Keller E, eds . (1982): Functional Basis of
Ocular Motility Disorders. Wenner-Gren Symposium Series , 37.
thus aid the eye in recapturing the target. Both types of move-
New York: Pergamon Press
ments , saccadic tracking and saccadic intrusions are found in Lipton RB, Levy DL, Holzman PS , LevinS (1983) : Eye movement
some neurological conditions and in some opthalmological dysfunctions in psychiatric patients: a review. Schizophrenia Bull
diseases, as well as in normal people. Their frequency in psy- 9:13- 32
chotic patients, however, is considerably higher than that found Stark L ( 1968): Neurological Control Systems: Studies in Bioengineer-
in the normal population. Their presence makes it difficult at ing . New York: Plenum Press
Fetal Alcohol Syndrome
William J. Shoemaker

Although suspected for centuries, the detrimental effects of use of alcohol (less than I ounce absolute alcohol per day)
ethyl alcohol on the unborn fetus were not systematically docu- has not been demonstrated and should not be overstated. FAS
mented and given the name fetal alcohol syndrome (FAS) is now the third leading cause of birth defects (after Down's
until the early 1970s. The characteristics of FAS are central syndrome and spina bifida) and is , of course, the leading pre-
nervous system (CNS) dysfunction, prenatal and postnatal ventable cause.
growth retardation, and dysmorphology of the mid-facial re- Much of the research on FAS has focused on the CNS
gion. The appearance of these children resembles those born defects. To date there are published neuropathological reports
with Down's syndrome (trisomy 21) because of the short palpe- of FAS brains from 16 children. Many of these brains contain
bral fissures and prominent epicanthic folds. This facial resem- glioneuronal submeningeal heterotopias and microscopic ab-
blance may have contributed to the Jack of recognition of normalities observed in neurons , but a distinct pattern has
FAS as a separate condition by the medical profession and not emerged. Many of the FAS children who come to autopsy
the general population; in addition, FAS children are frequently die of congestive heart failure, a common feature of FAS;
microcephalic and mildly to moderately mentally retarded . moreover, the resulting hypoxia may contribute to the neuropa-
The common practice of heavy drinkers to underestimate their thology observed.
alcohol consumption and their reluctance to recognize the con- Studies using animal models of FAS have focused on mor-
tribution of their drinking behavior to their child's condition phological, biochemical, and behavioral indices of prenatal
makes it difficult to assess the quantity of alcohol ingested alcohol exposure. Modest deficits in brain serotonin and nor-
during pregnancy by mothers of FAS children. Nevertheless, epinephrine levels have been described across a number of
it is clear that FAS children are the offspring of excessive studies; brain membrane and myelin chemistry, measured by
drinkers, many of them alcoholics. What is not clear is whether different indices, is also abnormal after prenatal ethanol expo-
there is a range of effects on the fetus caused by a correspond- sure. Many of the morphological studies have focused on the
ing range of alcohol intake. However, danger from moderate hippocampus , where aberrant connections and ectopic cells

PROTEIN
CARBOHYDRATE
FAT
VITAMINS
MINERALS
ETHANOL

~ mother's blood supply

G.I. TRACT

Figure I. Nutrient. honnonal. and circulatory ar-

rangement in pregnant women .
56 William J. Shoemaker

are described in rodents. These observations support results cerned in the myriad alterations that have been described.
observed following behavioral testing of adult rodents after Even the role of ethanol itself as the primary cause of abnormal
prenatal ethanol where memory functions that effect learning CNS development is not clear, sirice ethanol has many targets
behavior have been implicated. One of the more striking effects in the body (e.g., liver, pituitary, placenta) that contribute
described in rats exposed to ethanol prenatally is the large factors necessary for the growth and development of the fetal
increase in the opioid peptide ~-endorphin, as well as a de- nervous system. (See Fig. I)
crease in opiate receptors.
Animal studies need to be replicated in other species and Further reading
expanded in scope before a full picture of the alterations caused Ciba Foundation (1984): Mechanisms of Alcohol Damage in Utero.
by ethanol can be obtained. Nevertheless, certain features can Symposium 105. London: Pitman
be discerned. Although undernutrition is almost always present Rosett HL, Weiner L (1984): Alcohol and the Fetus: A Clinical Per-
in alcoholics, and there is experimental evidence that concomi- spective. New York: Oxford University Press
tant undernutrition interacts to make the prenatal effects of Shoemaker WJ, Baetge G, Azad R, Sapin V, Bloom FE (1983):
alcohol more severe, the biological effects of prenatal alcohol Effect of prenatal alcohol exposure on amine and peptide neuro-
transmitter systems. In: Drugs and Hormones in Brain Develop-
exposure are very different from undernutrition. The complex- ment: No. 9, Monographs in Neural Science, Schlumpf M, Lichten-
ity and rapidity of cellular events in the developing CNS are steiger W, eds. Basel: Karger
such that ethanol's direct and indirect effects would have multi- Wisniewski K. Dambska M. Sher JH, Qazi Q (1983): A clinical
ple targets and processes over the course of a 36-week preg- neuropathological study of the fetal alcohol syndrome. Neuropedi-
nancy. Thus, no single unifying event or process can be dis- atrics 14: 197-20 I
Gilles de la Tourette Syndrome
Arnold J. Friedhoff

This disorder was first definitively described in 1885 by Little is known about the etiology or pathophysiology of
Georges Gilles de Ia Tourette. Symptoms, consisting of multi- this syndrome. The disorder follows no known inheritance
ple tics, inappropriate vocalizations including grunts, coughs, pattern. It occurs more commonly in boys, and families of
and obscene words, usually begin between 2 and 15 years of patients may have a greater number of members with obsessive
age. The first symptoms are often eye blinks, progressing in compulsive disorder than control populations. Occasionally a
a fluctuating course to a more generalized disorder including so-called high-density Tourette's family has been encountered
vocalizations. Although the psychological consequences can in which the disorder appears in one or more members across
be severe, this is, at least in part, secondary to the socially several generations. This would not be expected by chance,
intrusive nature of the symptoms. The disorder itself is not because the syndrome is relatively uncommon. Estimates of
believed to produce primary mental problems except for learn- the exact number of sufferers varies depending on the diagnos-
ing disabilities, attentional disturbance, hyperactivity, obses- tic criteria used. Using criteria of early onset, tics, vocaliza-
sions, compulsions, and impulsive behavior in some patients. tions, and fluctuating course, as many as 0.05% of the popula-
About 40% of sufferers significantly improve in early adult- tion are afflicted, often being of Mediterranean origin.
hood, the remainder maintaining symptoms of fluctuating se- Because dopamine receptor blockers are beneficial, it has
verity throughout life. been proposed that the syndrome involves overactivity of the
Prior to the recognition that this was a specific disorder, dopaminergic system; however, at present, there is no direct
victims were often considered to be possessed. In more recent evidence of such a lesion. It is possible that reducing dopami-
times, because of lack of public and medical awareness of nergic activity with antagonists such as haloperidol or pimozide
the disorder, patients have often been considered to be deliber- may produce a compensatory effect rather than directly impact-
ately provocative or to be suffering from a mental illness. In ing on the pathological processes in the disorder.
either case this has often led to the use of various psychological There is some evidence that Gilles de Ia Tourette patients
therapies, which have not been effective. To counter this mis- suffer from episodic loss of inhibitory control of involuntary
conception, victims of this disorder and their families have movements. Thus motor and vocal impulses would be more
formed the Tourette Syndrome Association, which has served likely to be expressed in inappropriate circumstances than sup-
to raise the level of awareness of the disease and to stimulate pressed. Obscene words would be selectively expressed be-
research into its origins. cause they would most need to be inhibited. It can be readily
Significant control of symptoms can be obtained in about imagined that a young child finding that "bad" words, coming
75% of cases by the use of the dopamine receptor antagonist into his mind, came out of his mouth, would soon become
haloperidol. The other 25% either do not respond or are intoler- preoccupied with these words, further intensifying the prob-
ant of the side effects of this drug, frequently experiencing lem. There is, however, no direct evidence for this proposal.
sedation, loss of motivation, or extrapyramidal symptoms. Re-
cently another dopamine antagonist, pimozide, has been mar-
keted for treatment and is reported to have less debilitating Further reading
side effects. The alpha blocker clonidine has also been used Cohen OJ, Shaywitz BA, Young JG, et al (1979): Central biogenic
experimentally for treatment and is reported to have benefit. amine metabolism in children with the syndrome of chronic multiple
Another experimental approach has been through attempted tics of Gilles de Ia Tourette. JAm Acad Child Psychiatry 18:320-
compensatory down-regulation of the dopaminergic system by 341
administering L-dopa, a precursor of dopamine, the beneficial Friedhoff AJ, Chase TN, eds (1982): Gilles de Ia Tourette Syndrome.
effect occurring when the treatment is stopped. In this approach New York: Raven Press
L-dopa is given to increase the synthesis and release of dopa- Gilles de Ia Tourette G (1885): Etude sur une affection nerveuse
mine at brain synapses. This produces a temporary worsening caracterisee par I' incoordination motrice accompagnee de echolalie
et de copralalie. Arch Neurol 9:19-42, 158-200
of symptoms, but ultimately results in a compensatory decrease Shapiro AK, Shapiro ES, Bruun RD, Sweet RD (1978): Gilles de
in the number of dopamine receptors to compensate for the Ia Tourette Syndrome. New York: Raven Press
increased release of dopamine. Thus when the L-dopa treatment
is stopped net dopaminergic activity is reduced, and symptoms
have been found to remit for a time.
Hallucinogenic Drugs
John R. Smythies and C.B. Ireland

There are various types of hallucinogenic drugs that are distin- lucinogens on dopamine receptors. LSD is a mixed agonisU
guished by the psychological effects which they induce. The antagonist at central DA receptors. Many cJrugs have agonist
most familiar are the "visionary psychodysleptics" which pro- or antagonist actions at DA receptors, but it has been sug-
duce prominent visual and somatic distortions and hallucina- gested, as in the case of opiates, that it is the class of mixed
tions. Complex emotional changes ranging from ecstasy to agonisUantagonists that produce psychotic reactions. Another
terror may occur, as well as alterations in thinking. Examples hypothesis links hallucinogenic activity to the ability of the
of such drugs are LSD, mescaline, and tryptamine derivatives compound to have an effect on 5-HT and DA receptors in
such as dimethyltryptamine (DMT). The imagery-producing parallel. In binding studies, it has been shown that LSD binds
psychodysleptics such as cannabis and various coumarins (e.g., to 5-HT and DA receptors (to the former in particular in the
from Calea zacatechichi) potentiate visual imagery and pro- hippocampus, and to the latter mainly in the caudate). Other
duce characteristic distortions in time perception, body-image, evidence suggests that the more potent hallucinogens (such
and thought. Trance-producing psychodysleptics (such as ly- as LSD) decrease impulse flow in 5-HT neurons by 5-HT
sergic acid amide (obtained from Rivea corymbosa) ololiquh- agonist activity at autoreceptors at the same time as they stimu-
qui, turbicoryn, and corymbosine), as their names suggest, late DA receptors. Weaker hallucinogens such as psilocyn
produce trance-like states. Finally the deliriants (e.g., atropine) lack DA receptor agonist activity. There are also marked differ-
produce clouding of consciousness and amnesia, as well as ences among brain areas. For example, DA-sensitive adenylate
hallucinatory effects. cyclase is stimulated by LSD and by mescaline in anterior
A second method of classification of the hallucinogens is limbic cortex and the auditory cortex, but by neither in frontal
by chemical formula. There are four main groups: derivatives cortex, caudate, or retina.
of (I) phenylethylamine; (2) tryptamine; (3) lysergic acid; and LSD also binds to alpha-adrenergic and beta-adrenergic re-
(4) cannabinols. In general, hallucinogens of groups (I) and ceptors, but so does its inactive relative Brom-LSD. Hallucino-
(2) are methylated derivatives of the brain neurotransmitters, gens are also competitive antagonists at histamine receptors
dopamine and serotonin. LSD is a more complex derivative and the rank order of potency correlates with their clinical
of serotonin, and tetrahydrocannabinol has the same three- rank order. Hallucinogens also have complex interactions with
dimensional complex molecular shape as LSD (a lipophilic the opiate receptor.
triangle set at right angles on a -rr cloud). The methylation is In neurophysiological studies the seminal report was the
on the ring hydroxyls (phenethylamines, e.g., mescaline), side finding that LSD inhibits the firing of the serotonin-containing
chain nitrogen (e.g., DMT) or both (e.g., o-methylbufotenin, cells of the raphe nucleus. Cells in the visual cortex are also
OMB, or 5-methoxytryptamine-DMT). very sensitive to LSD, being either stimulated (low doses) or
The mechanism of action of the hallucinogens at the receptor inhibited (higher doses).
level has been studied intently over the last 30 years. Serotonin Hallucinogens also cause disaggregation of polysomes and
(5-HT), dopamine, (DA), histamine, and adrenergic receptors increase the acetylation of specific brain histones.
have all been implicated. Aghajanian found that LSD and At the molecular level the hallucinogenic potency of a com-
related indole hallucinogens are potent inhibitors of presynaptic pound has been shown to correlate directly with its ability to
(5-HT) receptors. However, the hallucinogen mescaline does act as a charge transfer donor (Domelsmith, 1977) (i.e., by
not produce this effect, whereas the nonhallucinogen lisuride donating electrons from the 4-position on the indole nucleus).
does, very strongly. A series of behavioral tests also implicates One surprising recent finding has been that the well-known
serotonin receptors in some aspects of hallucinogen action. hallucinogens, DMT and OMB, are normal constituents of.
Other tests involve adrenergic systems, often in complex inter- human bodily fluids such as cerebral spinal fluid (CSF) and
relationships with serotonin systems. Of particular value is rat brain. These compounds appear to be related to stress,
the stimulus control technique, in which a rat is trained to since levels are raised in rat brain by stress. CSF; blood,
react to the injection of a certain hallucinogen by emitting a and urine levels are raised in certain psychotic patients, but
particular conditioned response. The degree to which injections much larger amounts are found in some cases of liver disease
of other hallucinogens can elicit this conditioned response in- without psychosis, so the significance of this finding is debat-
forms us as to the degree of similarity or difference in their able.
mechanisms of action. Mescaline and certain indolealkylamine The hallucinogens produced by these agents also have fea-
hallucinogens (LSD, OMB, 2,5-dimethoxy-4-methylampheta- tures of psychological interest. The simplest manifestations
mine) show a good cross-reaction. These reactions are blocked are in terms of Kluver's "form constructs." These start as
by 5-HT receptor blockers. DA-related compounds (agonists certain simple geometric patterns such as checkerboards, webs,
and antagonists) have a much smaller influence on this effect. spirals, etc., that are also characteristic of the stroboscopic
However, other tests (e.g., rotational locomotion in 6-hy- patterns. These, however, rapidly become more complex and
droxydopamine-lesioned rats) indicate a further action of hal- beautiful, ending up in arabesques, patterns of jewels, etc.
 Hallucinogenic Drugs 59

Lastly, fully formed scenes emerge which many observers Further reading
state have transcendental beauty. The perception of the external
Aghajanian GK, Haigler HJ, Bloom FE (1972): Lysergic acid di-
world also changes in the direction of increased beauty and ethylamide and serotonin: direct actions on serotonin-containing
significance, as described eloquently by Aldous Huxley in neurons in rat brain. Life Sci II :615--{)22
The Doors of Perception. There is no particular connection Domelsmith LN, Munchangen LL, Houk KN (1977): Lysergic acid
between the content of the hallucinations and the previous diethylamide. Photoelectron ionization potentials as indices of be-
experience of the subject. On the other hand, there are close havioral activity. J Med Chern 20:1346-1348
similarities among the hallucinations seen by different people. Huxley Aldous (1954): The Doors of Perception. London: Chatto &
It has been suggested (Jung, 1952) that these visions originate Windus
in the collective unconscious which would explain their quite Jung CG (1952): Personal communication
impersonal nature. Osmond H, Smythies J (1952): Schizophrenia. A new approach. J
Ment Sci 98:309
It is important to stress that hallucinogens are indeed danger-
Smythies JR (1959): The stroboscopic patterns. Part I. The dark phase.
ous drugs. Psychiatrists are familiar with the acute psychoses B J Psycho/ 50:106
that such drugs can induce in many people. Furthermore, these Smythies JR, Morin RD, Brown GB (1979): Identification of di-
drugs--even in a single experience--can induce painful life- methyltryptamine and 0-methylbufotenin in human cerebrospinal
long symptoms of a psychiatric or a neurotic nature in suscepti- fluid by combined GC/MS. Bioi Psycho/ 14:549--556
ble people. In this regard marijuana can not only precipitate
such acute and chronic psychoses but in addition can often
cause a chronic organic brain syndrome with severe cognitive
and volitional impairments.
Heroin (Diacetylmorphine)
Conan Kornetsky

" 'H' is for heaven; 'H' is for hell; 'H' is for heroin." So At present heroin is not an approved drug for clinical use
begins the 1964 book, The Road to H by Chein et al. This in the United States, although it is in the United Kingdom.
book, published over 20 years ago, is still one of the most Its main use in the United States is illicit. Although a more
comprehensive social-psychological studies of street use of potent analgesic than morphine, there is no evidence that it
heroin by adolescents. Much of what was written then is still is more effective than morphine in relieving pain. Thus, except
true today. What has changed is the tremendous increase in for a possible shorter onset of action, the analgesic effects of
our knowledge concerning the action of heroin and other nar- heroin are believed to be similar to those of morphine. It
cotic analgesics in the brain. should be noted that the United States House of Representatives
Heroin (diacetylmorphine) is derived from morphine, the defeated a bill to legalize the use of heroin in cancer patients
major alkaloid of the opium poppy, Papaver somniferum. Her- in August 1984.
oin is made by exposing morphine to acetic acid, causing a Although there is illicit use of morphine, most of the non-
change in the chemical structure of morphine involving acetyla- medical use of narcotic drugs is with heroin. The advantage
tion of the phenolic and alcohol OH groups (Fig. 1). seems to accrue to the illicit manufacturer and seller, for heroin
In humans, heroin is metabolized to 6-acetylmorphine and is not only easy to manufacture but because of its greater
morphine. It is believed that heroin has no activity of its own potency it is easier to transport and smuggle into the United
but that it is a prodrug. That is, all of its pharmacologic action States. There is still belief by some that heroin has some
can be accounted for by the action of its metabolites. Binding superiority over morphine in causing euphoria. Some recent
studies have shown that the metabolites of heroin, but not studies on the relative effects of morphine and heroin on re-
heroin itself, bind to the opiate receptor. Heroin is a more warding brain stimulation also suggest that heroin may cause
potent analgesic than morphine. Its onset of action is faster, more euphoria than morphine. Although both drugs increase
but it has a shorter duration of action than morphine alone. the sensitivity of animals to this rewarding electrical stimula-
The reason for these pharmacokinetic differences are believed tion, the potency of heroin compared to morphine is signifi-
to be derived from the greater lipid solubility of heroin as cantly greater than the reported potency of heroin compared
compared to morphine and thus its greater ability to pass to morphine in relieving pain. If the threshold-lowering effect
through the blood-brain barrier. of the narcotic analgesics on intracranial rewarding brain stimu-
Heroin was first commercially produced in 1893 and mar- lation is a model for the euphoria caused by these drugs,
keted as a cough suppressant. It was clearly more potent than then it can be assumed that given equal analgesia heroin proba-
codeine, the opiate derivative usually used for cough suppres- bly causes more euphoria than does morphine, and this could
sion. Some early articles suggested that heroin was not addict- also contribute to the greater street use of heroin over mor-
ing, while others raised the possibility that it could cause de- phine.
pendence.

Further reading
Chein I, et al (1964): The Road to H: Narcotics, Delinquency and
Social Policy. New York: Basic Books
Inturrisi CE, et al (1984): The pharmacokinetics of heroin in patients
with chronic pain. New Eng/ J Med 310:1213--1217
Kaplan J (1983): The Hardest Drug: Heroin and Public Policy. Chi-
Morphine Heroin cago: University of Chicago Press
Platt JJ, Labate C (1976): Heroin Addiction: Theory, Research, and
Figure I. Structural formulas. Treatment. New York: John Wiley and Sons
Huntington's Disease (HD)
James F. Gusella

In 1872, George Huntington, a Long Island physician, drew deplete dopamine are the most effective palliative therapy for
on his own experience and that of his father and grandfather reducing the choreiform movements of HD. Somatostatin con-
to provide a graphic description of the inherited neurodegenera- centrations are increased 3- to 5-fold in the caudate, putamen,
tive disease that now bears his name. Originally known as and globus pallidus of HD brains and may well contribute to
Huntington's chorea, the disorder is characterized by pro- the symptoms of the disorder by enhancing the release and
gressive involuntary choreiform (dancelike) movements, psy- actions of dopamine.
chological change, and dementia. It is caused by a dominant Huntington's disease is an autosomal dominant disorder that
gene of as yet unknown function. The onset of symptoms displays complete penetrance since individuals bearing the de-
can occur at any time in life but most commonly begins in fective gene will invariably become affected if they do not
the fourth to fifth decade. In a small percentage of cases which die prematurely of other causes. The mean age of onset of
have been termed juvenile onset HD, the first symptoms occur symptoms is approximately 38 years, and therefore most HD
before age 10. The initial signs of motor disturbance are slight, victims have already had children before the disease appears.
involving such features as awkwardness of gait, clumsiness, On average, 50% of children who have a parent with HD
facial twitching, or subtle involuntary movement of the fingers. will inherit the disease gene with no bias toward either sex.
As the disorder progresses the involuntary movements become It has been noted, however, that symptoms tend to appear at
more frequent, pronounced, and exaggerated, impairing and an earlier age in children who inherit the HD gene from their
eventually eliminating normal day-to-day activity by interfer- father. The disorder differs from some other dominant diseases
ing with the ability to walk, stand, write, speak, and swallow. in its very low mutation rate. In fact, no unequivocal case of
In some cases, especially those with juvenile onset of symp- new mutation to HD has yet been described. The prevalence
toms, extreme rigidity is seen rather than chorea. Emotional of the disorder is approximately 1115,000 in most populations
and behavioral changes often accompany or precede the onset of Western European origin with much lower frequency in
of movement disorder and can similarly have a profound im- Oriental and pure black populations. At any given time, there
pact on ability to function and on interaction with family mem- are roughly 5 times as many individuals at 50% risk for devel-
bers. Impulsive, erratic behavior, impaired memory, poor con- oping the disease as there are affected, making this a relatively
centration, and moodiness can all be early signs of HD. In frequent genetic defect considering its severity.
particular, chronic depression occasionally precedes motor The mode of inheritance of HD, its high penetrance, and
symptoms by many years. There is currently no effective treat- the absence of sporadic cases with no family history made
ment for halting or even delaying the progression of HD. this disorder an ideal candidate for the localization of the dis-
Some 15 to 20 years after initial onset of symptoms, the HD ease gene by genetic linkage studies. Family studies of this
victim usually dies of heart disease, pneumonia secondary to type have recently received new impetus with the application
aspiration, or choking. of recombinant DNA technology to generate polymorphic
The symptoms of HD are caused by the regional loss of DNA markers that show clear-cut mendelian inheritance by
neurons by what has been termed "programmed" cell death. directly monitoring base sequence differences in the genomic
Cell loss is most notable in the striatum but is also seen in DNA. The differences are generally detected as alterations in
the globus pallidus and more diffusely in the cortex. Several the pattern of digestion of the DNA by site-specific restriction
different types of neurons have been identified in the striatum endonucleases and hence have been termed restriction fragment
based on morphology and neurotransmitters, but the relative length polymorphisms (RFLPs). In 1983, the HD locus was
rate of loss of these in HD is not known. The HD gene could mapped to the short arm of chromosome 4 by detection of
primarily affect a single cell type whose death leads to the coinheritance of the disease with such a DNA marker. This
loss of other neuronal elements, or the gene could directly represents the first successful application of this new technol-
affect several different cell types. Morphological investigations ogy to an autosomal disease. It is likely that it will act as a
have recently identified specific dendritic abnormalities in model for the localization of other human disease loci causing
spiny neurons of the caudate nucleus in HD although the bio- such disorders as familial Alzheimer's disease and Von Reck-
chemical basis for this phenomenon is not understood. linghausen neurofibromatosis.
The levels of various neurotransmitters have also been inves- The availability of a DNA linkage marker for HD will permit
tigated in the affected areas of HD brains relative to control prediction of the inheritance of the HD gene long before symp-
brains. Decreases have been recorded in striatal levels of toms have appeared, and has thereby opened new avenues of
gamma-aminobutyric acid (GABA), acetylcholine, substance research into the genetics and expression of the HD gene.
P, the enkephalins, and cholecystokinin, likely as a result For example, it may now be possible using sensitive noninva-
of, rather than a cause of neuronal loss. Dopamine concentra- sive techniques such as positron emission tomography in con-
tions have variably been reported as unchanged and increased junction with the DNA linkage marker to determine how long
in HD although dopamine receptor blockers and drugs that before the appearance of symptoms there is a detectable effect
62 James F. Gusella

of the gene on metabolism in the central nervous system. tion in genetic counseling in that genetic information with
One of the major questions concerning the HD gene is whether potentially disastrous implications for the individual and. his
it is expressed throughout life but only gradually produces progeny can be obtained many years before there is any sign
the disease phenotype, or whether it is silent for many years of the disease. It is likely, however, that the DNA marker
and only begins to be expressed later in life. The linkage linkage technique will soon provide similar capability for a
marker will also permit a better assessment in at-risk individu- number of other late-onset diseases, including some with sig-
als of changes of various biochemical parameters that have nificant psychiatric components, and the problems which must
been reported to be characteristic of HD. Investigations of be addressed in developing a structure for delivery of a pre-
peripheral tissues in this disease have uncovered a number of symptomatic test for HD will have a more general relevance.
possible effects of the HD gene including increased susceptibil- The utility of a presymptomatic test for HD would clearly
ity of HD fibroblasts to glutamate, sensitivity of HD cells to be enhanced if there were a treatment for the disorder, but
radiation, alterations in membrane fluidity, and osmotic fragil- this is unlikely to be obtained without more information con-
ity in HD erythrocytes. To date, many ofthe potential examples cerning the basis for the programmed neuronal degeneration.
of peripheral expression of the defect have been difficult to Attempts are already under way to use the knowledge of the
replicate and none has yet borne up under intense scrutiny. map position of the HD locus to develop strategies for isolating
It should now be possible to assess each of these parameters and characterizing the defective gene and its normal counter-
on a pool of at-risk individuals and only later apply the marker part. The application of recombinant DNA techniques could
to determine which of the experimental subjects actually pos- ultimately lead to an understanding of the nature of the primary
sess the HD gene. defect in this disorder, and lead the way to an effective therapy
The capacity to perform presymptomatic diagnosis in HD for halting, or at least delaying, the progression of the degener-
will also have a major impact on the potential victims of the ative process.
disease. It should allow at-risk individuals to plan their lives
with a view toward their eventual disability, should they prove Further reading
to have the HD gene. Similarly, those who have not inherited Huntington G (1872): Med Surg Reporter 26:317-321
the defective gene will be free of the constant worry and fear Hayden MR (1981): Huntington's Chorea. New York: Springer
that they might have the disease and have passed it on to Gusella JF, Tanzi RE, Anderson MA, et al (1984): Science 225:1320-
their children. Clearly the delivery of such a test presents 1326
immense problems since it currently represents a unique situa- Martin JB (1984): Neurology 34:1059-1072
Lithium in Psychiatric Therapy
James W. Jefferson and John H. Greist

While lithium was used in 19th and early 20th century medi- cium). It also has chemical similarities to Group IIA elements
cine, its ascent to current prominence began in the late 1940s such as calcium and magnesium. In the body, it is neither
when John Cade, an Australian psychiatrist, noted its antimanic metabolized nor protein bound, is rapidly and fully absorbed
effect. Subsequently, Mogens Schou and colleagues, in Den- from the gastrointestinal tract, and is excreted almost entirely
mark, established that long-term lithium therapy reduced both by the kidneys.
frequency and severity of episodes in patients with manic-
depressive disorder (bipolar affective disorder). These observa-
tions were, in part, responsible for a renewed interest in psychi- Mechanism of action
atric diagnosis since distinguishing manic-depressive disorder
from the schizophrenias now had important therapeutic impli- Despite its simple chemical structure, lithium exerts profound
cations. effects throughout the body at levels ranging from cellular to
Lithium is currently used in psychiatry to treat a number behavioral. Extensive investigations have attempted to explain
of illnesses. Its effectiveness is most firmly established in the its remarkable clinical effects, and while much is known about
treatment of acute manic episodes and in the prevention of how the drug alters hormonal, neuronal, and metabolic sys-
recurrent episodes of bipolar affective disorder. Indeed, these tems, its exact mechanism of action is unknown. It does seem
are the only indications for which labeling approval has been clear that bipolar affective disorder is not caused by lithium
received from the U.S. Food and Drug Administration (FDA). deficiency and that lithium does not exert its effect by correct-
Both clinical experience and less extensive research support ing such a deficiency. While a lithium deficiency state has
the effectiveness of lithium in some cases of acute unipolar not been experimentally produced in man, the naturally occur-
_depression, for the prevention of recurrent episodes of unipolar ring levels in blood (about 9 nglml) are about 600-800 times
depression, in schizoaffective disorder, in selected cases of lower than those required for therapeutic effectiveness, sug-
schizophrenia (usually in conjunction with an antipsychotic gesting that lithium works as a drug rather than as a mineral
drug), and as an antiaggression agent. The positive response replacement.
to lithium of some non-manic-depressive conditions suggests Given its similarities to critical body cations such as sodium,
that lithium is not specific for manic-depressive disorder and potassium, calcium, and magnesium, lithium may work
that diagnosis cannot be based solely on lithium response. through ion substitution. Studies have shown that lithium exerts
Some investigators feel lithium is useful for treating alcoholism effects on neurotransmitters such as norepinephrine, serotonin,
either indirectly by stabilizing mood or directly by reducing and acetylcholine in ways that are consistent with current theo-
alcohol consumption, but this remains controversial. While ries of affective disorders. Lithium also inhibits the activity
lithium has been investigated in a variety of other psychiatric of the enzyme adenylate cyclase, thus interfering with the
disorders, its efficacy has not been established. action of vasopressin on the kidney and leading to polyuria
The impact of lithium therapy on the course of bipolar affec- in a substantial number of patients. Inhibition of beta-adreno-
tive disorder is striking. Untreated, the illness is characterized ceptor-stimulated adenylate cyclase or prostaglandin-E 1-stimu-
by recurrent episodes of mania and depression, often lasting lated adenylate cyclase has also been postulated as a mecha-
many months and often associated with marked disability and nism of action.
sometimes death (suicide, aggravation of medical conditions, Lithium inhibits replication of DNA viruses such as types
reckless behavior). The Medical Practice Information Demon- and 2 herpes simplex, and preliminary evidence suggests a
stration Project estimated that without treatment the average use in treating herpes genitalis and labialis. Of greater and
woman with the onset of the disorder at age 25 would lose even more speculative interest is the similarity between the
9.2 years of life, 14.2 years of major life activity, and 11.9 episodic clinical course of both herpes simplex and manic-
health status years. With optimal treatment these losses would depressive disorder and the possibility that lithium works for
be r~d~ced to 2. 7, 4. 0, and 3 .4 years. The economic impact the latter through inhibiting an as yet unidentified virus.
of hthmm treatment for manic-depressive disorder in the
United States has been conservatively estimated to result in a Monitoring therapy
savings of over $400 million per year (reduced medical costs The chemical simplicity of lithium makes it easily measured
and increased productivity). in the blood, and unlike other psychiatric drugs, monitoring
of blood levels has become an integral part of lithium therapy.
Pharmacology Both flame photometry and atomic absorption spectrophotome-
try are key techniques readily available in most clinical labora-
Lithium is the simplest solid element (atomic #3, atomic tories and well suited for reliable and accurate measurement
weight 6.94) and a member of Group lA of the periodic table of serum lithium levels. Of research interest are more sensitive
(together with sodium, potassium, rubidium, cesium, and fran- methods such as flameless atomic absorption spectroscopy,
64 James W. Jefferson and John H. Greist

inductively coupled argon emission spectrometry, and mass parathyroid hormone secretion. The end result is an increase
spectrometry for measuring lithium in biological fluids. When in serum calcium and parathyroid hormone levels.
used therapeutically, lithium is present in serum in relatively While lithium has been shown to have a variety of effects
high concentrations so that the conventional techniques are on carbohydrate metabolism at both a hormonal and cellular
more than adequate. While lithium has been measured in virtu- level, its relationship to diabetes mellitus remains unclear.
ally every body fluid, there is little likelihood that blood will The weight gain which often occurs during lithium mainte-
be replaced as the standard of therapeutic monitoring. nance therapy may be, in part, due to altered carbohydrate
Several lithium preparations are available in the United metabolism.
States. These include standard and slow-release lithium carbon- Lithium stimulates granulocyte production, possibly through
ate in the form of capsules or tablets and the liquid, lithium enhanced production of colony-stimulating factor, with a resul-
citrate. A proper dosage of lithium is established by both evalu- tant increase in white blood count. This "side effect" has
ating the patient's clinical status and adjusting the serum level been utilized to treat granulocytopenic conditions such as Fel-
to a range of 0.8-1.2 mEq/L for mania and 0.6--1.0 mEq/L ty's syndrome, idiopathic neutropenia, and chemotherapy-in-
for maintenance therapy. For those values to be meaningful, duced neutropenia. An increase in circulating platelets has
lithium must be given in divided doses and blood samples also been noted.
must be drawn in the morning as close as possible to 12 hours The effects of lithium on the kidney are well established
after the last dose. Even then, these ranges are only guidelines, and clinically important. A nonspecific chronic interstitial ne-
and patients may require higher levels for benefit or tolerate phritis occurs more commonly than in control patients and a
lower levels without relapse. There is some evidence that a reversible lithium-specific lesion has been described. These
substantial number of patients can be successfully maintained structural changes are most notable in the distal convoluted
at serum levels of 0.4--0.6 mEq/L. Unfortunately, there is no tubules and collecting ducts. Changes in renal function induced
reliable way to predict in advance who these patients will by lithium include a reduction in renal concentrating ability
be. The risk of lithium toxicity increases as the serum level which appears to be a reflection of tubular interstitial nephropa-
rises, and levels above 1.5-2.0 mEq/L are likely to be danger- thy, and an increase in urine volume. The latter is due primarily
ous. to reduced renal response to ADH (vasopressin) at the level
of renal adenylate cyclase but also may involve impaired utili-
zation of cyclic AMP, impaired proximal tubular fluid reab-
Adverse reactions sorption, and a central effect on synthesis, storage, and release
Side effects of lithium range from benign and tolerable to of ADH.
life-threatening and affect every organ system. Both central Lithium also impairs renal hydrogen ion secretion, resulting
and peripheral neurological function can be altered by lithium. in a partial distal tubular renal acidosis which does not appear
The electroencephalogram (EEG) may show increased ampli- to be of clinical importance. Finally, the effect of lithium on
tude and generalized slowing with reduced alpha and increased glomerular filtration appears to be modest, and there is little
theta and delta activity, and occasionally focal changes occur. evidence to suggest that prolonged therapeutic exposure to
Somatosensory and auditory evoked potentials may also be lithium results in renal failure.
increased. In therapeutic amounts, patients may experience
tremor, fatigue, and slowed information processing. Lithium Lithium information
intoxication is predominantly a neurotoxicity which may ini- In 1975, the Lithium Information Center was established at
tially present as lethargy, dysarthria, and ataxia but which the University of Wisconsin so that medical and allied profes-
can progress to extreme neuromuscular irritability, seizures, sionals throughout the world could have convenient access to
coma, irreversible neurological damage, and death. Although a comprehensive collection of bibliographic references to the
the therapeutic index of lithium is low, proper clinical and medical and biological lithium literature. As of early 1986,
laboratory monitoring make severe intoxication uncommon. over 14,000 articles have been entered in a computer-based
The drug is most rapidly and effectively removed from the storage and retrieval system which can be rapidly searched
body by hemodialysis which is the treatment of choice for by key word, title, author, and journal in a way that is both
severe intoxication. complete and specific. The Lithium Information Center is a
Lithium has complex effects on thyroid function, the most prototype for specialized information centers that will eventu-
consistent of which is to inhibit release of T3 and T4 from ally provide a networking of computer-accessible knowledge
the gland. Other effects include inhibition of thyroglobulin systems.
biosynthesis, inhibition of thyrotropin (TSH)-sensitive ade-
nylate cyclase, and inhibition of iodine uptake and organifica- Further reading
tion. The net clinical result is the development of goiter and hypo-
thyroidism in a small percentage of patients. The periodic Jefferson JW, Greis! JH, Ackerman DL (1983): Lithium Encyclopedia
for Clinical Practice. Washington: American Psychiatric Press
assessment of thyroid function is, therefore, an integral part of Johnson FN, ed (1980): Handbook of Lithium Therapy. Lancaster,
monitoring therapy. Blood levels of T3, T4, and TSH are England: MTP Press
used routinely while the more sensitive but costly thyrotropin-re- Lazarus JH (1982): Endocrine and metabolic effects of lithium. Adv
leasing factor (TRF) infusion test remains of research interest. Drug React Ac Pois Rev 1:181-200
Calcium metabolism and parathyroid function are also af- Knapp S ( 1983): Lithium. In: Psychopharmacology I, Part I: Preclin-
fected by lithium, possibly by altering the parathyroid gland's ical Psychopharmacology. Grahme-Smith DG, Cowen PJ, eds.
''set point'' so that higher calcium levels are required to inhibit Amsterdam: Excerpta Medica
Marijuana
Robert C. Petersen

Marijuana, a mixture of the leaves, flowering tops, and other Complex performance involved in operating a car or an aircraft
parts of the plant Cannabis sativa, is a chemically complex has also been found to be significantly impaired by marijuana
substance. It contains over 400 chemical constituents including intoxication. As with alcohol, there is good reason to believe
simple acids, alcohols, more complex hydrocarbons, terpenes, that the deficiencies measured in the laboratory, on the test
and some 61 compounds unique to the cannabis plant called course, or in the driving simulator prove the hazards of use
cannabinoids. The cannabinoid .:l-9-tetrahydrocannabinol to highway safety.
(THC) is the principal psychoactive ingredient, although other
constituents may modify its action or have psychoactive effects Chronic effects
of their own. This compound is present in varying amounts.
High-grade seedless varieties of cannabis called sinsemilla may While many of marijuana's acute effects have been explored,
have percentages (by weight) of THC as high as II%. Street possible chronic effects are far more difficult to determine.
marijuana is believed to have increased in average THC con- American experience with cannabis has been brief and largely
tent-from less than I % in the 1960s and 1970s to as high as confined to the healthiest segment of the population. Research
5% in the mid-1980s. Variability in marijuana's potency and a on traditional users in countries like India or Jamaica may
failure to adequately specify the material used has often made have only marginal relevance to contemporary American pat-
the results of earlier marijuana research (before 1960) hard terns. Traditional users are usually adult males whose mode
to interpret. Cannabis cigarettes supplied by the National insti- and circumstances of use differ significantly from the newer
tute on Drug Abuse for research use typically contain 1-2%. use patterns. For example, since cannabis is often mixed with
Cannabis has been the source of fiber used in making rope tobacco when smoked by traditional users, deep inhalation
and coarse woven cloth for thousands of years. Knowledge may be less common, making the apparently large quantities
of its putative medicinal and mind-altering properties is also used deceptive. Extensive use by children and adolescents
ancient. In modem times, concern about marijuana's possible during critical stages of physical and psychological develop-
abuse and potential health hazards dates back to at least the ment may have quite different, and more serious, implications
1890s when an Indian Hemp Drugs Commission was appointed than those for adults, whether or not the drug is used tradition-
to study its effects in India where use was-and still is- ally.
traditional.
While cannabis was widely cultivated for its fiber content
in North America beginning in Colonial times, there is little Respiratory effects. Since marijuana is usually smoked and
the smoke deeply inhaled, effects on respiratory function would
evidence of its widespread use as a drug prior to the tum of
the century. Up until the 1960s use was largely restricted to not be surprising. Although not usually consumed in the same
quantities as tobacco cigarettes, marijuana "joints" are con-
a small number of adults. A marked increase in use has oc-
curred since, mostly among adolescents and young adults. By sumed almost entirely, the smoke typically unfiltered and each
the 1980s three out of five American youths between 18 and puff retained in the lungs for several seconds. Research on
25 had tried the drug with a third continuing to use it with healthy young adult male volunteers in a chronic marijuana
smoking study has found mild, but measurable evidence of
some regularity.
airway obstruction after one and a half to two months of smok-
ing five cannabis cigarettes daily. Studies exposing animals
Acute effects to marijuana smoke which produced similar blood cannabinoid
Acute effects of marijuana intoxication (or "high") range from levels to those in human daily users have found degenerative
subjectively experienced increase of esthetic sensitivity and lung changes following periods of use corresponding to an
heightened sexual sensation to mild tachycardia and other mea- eighth to a half the animal's life span. Clinicians who have
surable changes in performance. A sense of relaxation and studied heavy American users of hashish overseas have found
tranquillity is commonly reported, but heightened levels of cellular changes in bronchial tissue similar to those in heavy
anxiety and paranoid feelings are also common. There is little cigarette smokers, but at younger ages. Studies of isolated
question that marijuana at common dosage levels interferes human lung tissue cultures have found precancerous changes
with many aspects of psychomotor and cognitive function in in lung tissue exposed to marijuana smoke. When marijuana
ways that adversely affect learning and skilled performance smoke residuals have been skin tested in animals, tumors simi-
while high. Dozens of experimental studies confirm that such lar to those produced by tobacco tar have resulted. The brevity
cognitive processes as arithmetical reasoning, verbal and non- and generally low level of American exposure to marijuana
verbal problem solving, and short-term memory are adversely make it unlikely that marijuana-related cancer, emphysema,
affected. Marijuana's effects on immediate memory and an or other serious pulmonary consequences would be detectible
increased distractability while high may be common elements. by large-scale epidemiological studies at this time.
66 Robert C. Petersen

Cardiovascular effects. Although temporary increases in heart A variety of other problems have been linked with marijuana
rate and increased blood concentrations of carboxyhemoglobin use, including possible chromosome abnormalities, alterations
following marijuana use have been viewed as generally benign in cell metabolism, and impairment of the immune response.
in young users, these effects may be more serious in those In these areas research to date has resulted in conflicting find-
with already impaired cardiovascular function. The effects of ings and must be regarded as inconclusive.
smoking a marijuana cigarette are greater than those of a to- Extensive research on possible adverse consequences of mar-
bacco cigarette in producing exercise-induced angina in pa- ijuana has also led to renewed interest in its possible therapeutic
tients with impaired cardiovascular circulation. applications. Thus far the most promising of these has been
as an antiemetic in controlling the nausea and vomiting that
Reproductive effects. Reductions in testosterone levels and re- accompany cancer chemotherapy. Marijuana or its principal
duced sperm counts in human males have been reported by psychoactive ingredient have also shown some usefulness in
some investigators. Although the values were still within nor- glaucoma treatment. While the drug reduces intraocular pres-
mal limits, the reductions may have significance for the mar- sure by a different physiological mechanism from that of other
ginally functioning. Effects on human females are still less drugs used in glaucoma treatment, its side effects on memory
certain. A possible reduction in fertility has been reported in and other psychological functioning are more often disturbing
one study. A higher incidence of the fetal alcohol syndrome to elderly patients. Other uses that have been suggested or
in infants born of mothers who used marijuana during preg- considered have either not been adequately assessed or have
nancy has also been reported, but the difficulties of separating not lived up to preliminary expectations.
the effects of marijuana from those of concurrent alcohol and Despite the marked increase in research on marijuana, many
tobacco use make the role of cannabis uncertain. important questions regarding its effects remain unanswered.
Most crucial of these are the implications of frequent use for
Brain damage and persistent personality alteration. The ques- the developing child or adolescent and the chronic effects of
tion whether chronic heavy marijuana use causes brain damage long-term heavy use. While there is little hard experimental
is not easily answered. Although one poorly controlled human data in these areas, clinical observations suggest that there is
study and a preliminary animal study have suggested the possi- a serious basis for concern.
bility, two more carefully controlled human studies using com-
puterized tomographic techniques have found no evidence of
this in chronic users. However, long-term daily administration Further reading
to laboratory animals has been reported to cause possibly per-
Hollister LE (1984): Health aspects of cannabis use. In: The Cannabi-
manent effects on learning of various types. A loss of conven- noids: Chemical, Pharmacologic and Therapeutic Aspects, Agurell
tional motivation, the "amotivational syndrome" has been S, Dewey W, Willette R, eds. New York: Academic Press
clinically described in some heavy users. It is, however, often Institute of Medicine (1982): Marijuana and Health. Report of a
difficult to distinguish the role of marijuana from that of other Study by a Committee of the Institute of Medicine, Division of
drug use and preexisting motivational or psychological prob- Health Sciences Policy. Washington DC: National Academy Press
lems. A third of a national sample of high school seniors Petersen RC, ed (1980): Marijuana Research Findings: 1980. Na-
using marijuana daily reported loss of interest in non-drug- tional Institute on Drug Abuse Monograph Series. Washington DC:
related activities and impaired school or job performance that US Government Printing Office
they attributed to marijuana use.
Mental Illness, Genetics of
Steven Matthysse

Only adoption studies can provide solid evidence for the exis- even though the illness is milder. Indeed, an increased proba-
tence of heritable factors. Twin studies, showing that the con- bility of any trait in relatives of probands adopted at birth
cordance rate in monozygotic twins exceeds that in dizygotic (relative to matched controls) is evidence for the operation
twins, are weakened because monozygotic twins are likely to of transmissible factors in the probands' illness. The investiga-
be treated more similarly by significant persons in their envi- tors maintain that the exclusion of inadequate and schizoid
ronment, and may also tend to identify psychologically with personalities from the "latent schizophrenia" category was
each other. Studies of family process, showing that families part of the original design. Counting families may be a safer
with disturbed communication patterns are more likely to have way to estimate significance levels than counting individuals,
a schizophrenic child, are not compelling evidence for nonge- but the investigators analyzed their data both ways, and the
netic factors, because the disturbed behavior ofthe parents could results remained significant. The remaining objection, that the
be a consequence of the behavior of the child, or a parallel five chronic schizophrenics were found in only two families,
effect of the same genes that caused schizophrenia in the off- is a valid observation, but the investigators did not claim that
spring. There are, however, adoption studies in both schizo- all forms of schizophrenia are equally heritable; they view
phrenia and affective disorder that point toward the existence the illness as probably heterogeneous. (Kety, 1983, cited be-
of heritable factors. low, summarizes the Danish adoption study data with response
The most comprehensive adoption study of schizophrenia to critics.)
is that of Kety, Wender, Rosenthal, Schulsinger, and associ- There also are adoption studies in affective disorder. Al-
ates, beginning in 1963 in Denmark. Out of a total national though on a smaller scale than the Danish schizophrenia study,
sample of adoptees, 17 chronic schizophrenics were selected, the results support the existence of heritable factors, especially
and normal controls were matched for age, sex, socio-eco- in severe depression and manic-depressive illness. There is
nomic status of the adopting family, and time spent with the evidence also that suicide has a strong genetic component.
biological parent (which in all cases was brief). The biological Out of the 57 biological families of adoptee probands who
relatives of the index cases included 5 chronic schizophrenics had committed suicide, suicide occurred in 11 families (12
(7.1%), compared to none in the controls; and 12 "latent relatives), whereas in the control group there were only two
schizophrenics" (17. I%), compared to 6 in the controls suicides among the relatives, both in the same family.
(6.1%). There was also an increased prevalence in the half- The most rapidly growing aspect of human genetics is gene
siblings where the shared parent was the father, so that the mapping through linkage to restriction fragment length poly-
proband and the affected relative had no common maternal morphisms (RFLP). The discovery of genetic linkage-co-
influence, even during gestation. segregation with a Mendelian marker trait within families-
Various objections have been raised to these studies: (1) provides unequivocal evidence for genetic transmission. It also
There was no estimate of inteijudge reliability in diagnosis. demonstrates that a major locus is involved; it potentially offers
(2) The rate was higher in second-degree than in first-degree the opportunity for prenatal detection; and it can ultimately
relatives, whereas first-degree relatives ought to be at greater lead to identification of the gene, by mapping to a well-under-
risk, in a genetic theory. (3) The "latent schizophrenics" were stood region of a chromosome.
not really schizophrenic at all. (4) Certain diagnoses (inade- The technique rests upon the existence of certain enzymes
quate and schizoid personality) were excluded from the "latent that cut DNA at points where they encounter precisely specified
schizophrenia" category after the data were collected, inflating sequences. Variations in the DNA sequence from individual
the significance levels. (5) The five chronic schizophrenics to individual will cause the cuts to occur at different places,
were in just two families. (6) For statistical purposes, families resulting in fragments of different length. These variations
should be counted, not individuals, since, except for the index can be used for linkage analysis in just the same way that
case, family members were not separated from each other. traditional blood group markers of HLA-polymorphisms are
None of these objections is compelling. Poor inteijudge reli- used. They have the advantage that sequence variation in the
ability would militate against finding significance, not create regions of DNA that are not expressed in the final protein
it if the null hypothesis were true. The higher rate of illness (" introns") can also provide linkage markers. The noncoding
in second- than in first-degree relatives can be accounted for regions may be more variable than the coding regions, because
by the nature of the sample. Since the cause of the adoption, of diminished pressure from natural selection.
in most cases, was illegitimacy, there were almost no full The recent success of RFLP methods in mapping the gene
siblings, and nearly all the first-degree relatives were parents. for Huntington's disease to the short arm of chromosome 4
Parents would be expected to have a lowered rate of schizo- by J. Gusella and co-workers has drawn the attention of investi-
phrenia, because schizophrenic patients are less likely to have gators in psychiatric research. To detect polymorphisms, this
children. group used a recombinant phage probe, 08, derived from a
An increased risk for ·'latent schizophrenia" in families of human gene library and mapped to chromosome 4. The restric-
schizophrenic probands is evidence for genetic transmission, tion fragment data suggested the existence of two "sites"-
68 Steven Matthysse

small regions of DNA whose exact sequences determine sus- the approximate lower limit of resolution that can be achieved
ceptibility to cutting by the restricting enzyme-which are by linkage techniques in human pedigrees. This level of resolu-
polymorphic (variable) in the population. In an American and tion remains coarse from a genetic point of view. One centi-
in a very large Venezuelan pedigree, Huntington's disease morgan corresponds to approximately I million base pairs,
cosegregated with the G8-detectable restriction sites. or I ,000 genes. If there is some knowledge of the anatomical
The major difficulty in applying this powerful technique to pathways and physiological mechanisms underlying the trait
psychiatric disorders is that they are certainly not inherited for which a genetic locus is sought, functional considerations
as classical Mendelian traits, which is the context in which can be used to narrow the search for the gene. Either eDNA
linkage analysis developed. The incidence of schizophrenia or peptides coded by each gene can be used to construct histo-
in the first-degree relatives of schizophrenics-3.2%, accord- chemical stains, and if these stains show that the gene product
ing to Tsuang-is far too low for classical Mendelian inheri- is localized to brain regions known to be relevant to the trait
tance. being mapped, the likelihood that the right gene has been
Whenever a disease has non-Mendelian transmission charac- found will be enhanced.
teristics, the possibility has to be considered that the disease Hybridization and peptide immunohistochemistry are both
itself is not the most appropriate trait for genetic investigation. powerful techniques. In a hybridization study by Hudson and
Partial penetrance is not an explanation, but a sign that the co-workers, an 800-base pair DNA fragment corresponding
list of causal factors is incomplete. To speak of vulnerability to the structural gene for rat growth hormone was cloned and
as inherited only obscures the task of elucidating the actual used as a template for synthesis of Ia~led eDNA. Hybridiza-
traits that are inherited and of finding out how they create a tion to the eDNA revealed specific labeling in the anterior
predisposition to disease. pituitary. Sutcliffe and co-workers selected eDNA clones hy-
Two recent studies of schizophrenia have adopted this point bridizing only to brain mRNA. After sequencing them, they
of view. L.A. De Amicis and R.L. Cromwell measured reac- translated the open reading frames into amino acid sequences
tion time crossover in schizophrenic patients (a paradoxical (according to the genetic code), and chemically synthesized
lengthening of reaction time when warning cues are given at short peptides within those sequences. Antibodies were raised
a constant interval before the test stimulus, frequently found against the synthetic peptides, and these were made into histo-
in schizophrenics, but rarely in normals). Their first-degree chemical stains by the indirect immunoperoxidase method.
relatives had a tendency to show crossover, even though they One such stain, derived from a eDNA clone whose function
had no psychotic symptoms. P.S. Holzman examined smooth- was originally unknown, reacted with a new fiber system,
pursuit visual tracking, which is disturbed in about 50% of widely distributed in the brain. Viral and plasmid vectors can
schizophrenic patients, but only infrequently in normals. Schiz- also be used to synthesize peptides (or antigenic sub-sequences
ophrenic patients who had no disturbance in visual tracking of peptides) from DNA clones.
were also included in the sample, and their relatives tended The success of these molecular techniques depends, in an
to have bad tracking even if they were nonpsychotic. essential way, on the progress of neuroscience in localizing
It may tum out that no single trait, detectable at the present the pathways, cell types, organelles, and macromolecules in-
state of technology, is the sought-for Mendelian risk factor, volved in human traits. An increasing partnership between
but that an unobservable or latent trait with Mendelian charac- genetics and neurobiology is to be expected, as scientific con-
teristics underlies both the disease in question and the other cerns focus more and more on molecular mechanisms in mental
traits that seem related to it. A neurological disease process disease.
might produce unpredictable combinations of symptoms, de-
pending on where it happened to strike in the nervous system. Further reading
The vulnerability of different target areas might be influenced
by multigenic factors distinct from the disease process itself. Botstein D, White RL, Skolnick M, Davis RW (1980): Construction
For example, smooth-pursuit visual tracking disturbance and of a genetic linkage map in man using restriction fragment length
schizophrenia might both be manifestations of a yet unknown polymorphisms. Am J Hum Genet 32:314-331
Gottesman II, Shields J ( 1982): Schizophrenia: The Epigenetic Puzzle.
latent trait, and this trait might be determined by a major New York: Cambridge University Press
gene with higher penetrance than either smooth pursuit or· Kety SS (1983): Mental illness in the biological and adoptive relatives
schizophrenia. There are methods for using latent traits in of schizophrenic adoptees: Findings relevant to genetic and environ-
genetic analysis, even if their concrete biological interpretation mental factors in etiology. Am J Psychiatry 140:720-727 (Contains
is still unknown. a summary of the Danish adoption study data, with responses to
The obstacles to discovering linkage for non-Mendelian traits critics.)
are much greater than for traits that obey the classical laws Kidd KK, Matthysse S ( 1978): Research designs for the study of
of genetic segregation. Reduced penetrance (or multigenic ef- gene-environment interactions in psychiatric disorders: Report of
fects, which have the same consequences for linkage analysis) a Foundations' Fund for Research in Psychiatry panel. Arch Gen
Psychiatry 35:925-932
decreases the probability of success.
Mendelwicz J (1981): Adoption study in affective illness. In: Biologi-
Heterogeneity is also an obstacle to linkage analysis. If very
cal Psychiatry, Perris C, Struwe G, Jansson B, eds. New York:
large families are studied, each one is a universe unto itself, Elsevier
and heterogeneity among families does not prevent the discov- Schulsinger F, Kety SS, Rosenthal D, Wender PH (1979): A family
ery of linkage in a subset. If only small families are available, study of suicide. In: Origin, Prevention, and Treatment of Affective
however, there is a high risk that the sum of the lod scores Disorders, Schou M, Stromgren, E, eds. New York: Academic
(logarithm to the base 10 of the odds in favor of linkage) Press
across families will not reach significance, even if linkage is Sutcliffe JG, Milner RJ, Shinnick TM, Bloom, FE (1983): Identifying
present in some of them. The more that can be done to sub- the protein products of brain: Specific genes with antibodies to
divide the trait or illness into etiologically homogeneous chemically synthesized peptides. Cell 33:671-682
subtypes, the greater the likelihood linkage analysis will suc- Tsuang MT, Winokur G, Crowe RR ( 1980): Morbidity risks of schizo-
phrenia and affective disorders among first degree relatives of pa-
ceed. tients with schizophrenia, mania, depression and surgical condi-
One centimorgan (eM, the chromosomal map distance corre- tions. Br J Psychiat 137:497-504
sponding to I% probability of recombination at meiosis) is
Mental Illness, Nutrition and
John W. Crayton

Long-standing public interest in diet and nutrition as a means Vitamins

to better mental health has been matched in the last 10 years
While there is considerable controversy over whether subtle
by a rapidly expanding scientific interest in the relationship
or subclinical vitamin deficiencies can affect mental or be-
between food and behavior. There are, however, fundamental
haviorial functioning and even contribute to the development
research problems in this area: (I) accurately assessing an
of mental illnesses, there is little question that marked vitamin
individual's nutritional status is difficult; (2) nutritional require-
deficiency can have a major impact on mental functioning.
ments and response to nutrients vary widely from person to
Cases of vitamin B 12 deficiency without the usual hematologi-
person; (3) the frequently subtle effects of nutrients, or lack
cal abnormalities but with a frank psychosis are not uncom-
thereof, on behavior defy reliable and reproducible measure-
mon. Less common are cases of pyridoxine deficiency con-
ment with currently available behavioral assessment instru-
ments; (4) brain mechanisms underlying food-behavior phe- tributing to the development of mental illness. Increased
nomena are largely unknown. requirements for vitamins may contribute to the commonly
observed depression associated with contraceptive hormone
preparations. The elderly seem particularly susceptible to the
Developmental aspects development of vitamin deficiency disorders, including mental
Generalized maternal malnutrition results in a decrease in both dysfunction. Their nutritional deficiencies may be due to a
the number imd size of individual nerve cells in experimental lack of access to adequate nutrition, a habitually deficient diet,
animals. The behavioral effects of this nerve loss may be broad altered requirements in old age, or added requirements due
and difficult to measure, but there is evidence from human to illness.
studies that maternal malnutrition may have significant effects Korsakov's psychosis is a particularly interesting model of
a vitamin deficiency related condition. Studies suggest that
on offspring behavior. The developing fetus is vulnerable to
several specific maternal nutritional deficiencies suffered dur- alcoholics who develop Korsakov's have an abnormal sensitiv-
ing the peri conceptual phase (preconception to implantation). ity to thiamine deficiency; certain thiamine-dependent enzymes
Iodine-deficient mothers may produce offspring with cretinism. in these individuals have markedly abnormal saturation curves.
Insulin-dependent diabetic mothers whose diabetes is not well One implication of these studies is that Korsakov's psychosis
controlled may produce offspring with a variety of congenital might be preventable if adequate thiamine intake were main-
malformations or mental retardation. Mothers with untreated tained in alcoholics.
phenylketonuria may produce mentally retarded offspring. Pre-
liminary evidence suggests that mothers who have previously
given birth to children with neural tube defects have a reduced Minerals
incidence of this defect in subsequent offspring if they take
vitamin B 12 supplements prior to conception. The minerals zinc, copper manganese, cobalt, iron, and cad-
The period of fetal development from implantation to the mium are important cofactors in brain functioning. Hurley's
12th week postconception is a vulnerable period in particular studies in 1981 of zinc deficiency relate directly to central
for the offspring of protein-calorie malnourished mothers. nervous system development. Experimental animals made zinc
Studies of victims of the World War II Dutch famine suggest or manganese deficient during pregnancy produce a high pro-
that children born of mothers suffering protein-calorie malnu- portion of offspring with structural abnormalities of the nervous
trition during this phase had a high incidence of prematurity, system. The relevance of these studies to human mental illness
stillbirths, and neonatal deaths. Long-term follow-up of surviv- is unclear, since these levels of deficiency have not been stud-
ing children revealed a high incidence of neural tube defects, ied in humans.
cerebral palsy, and obesity. Copper is a cofactor in the rate-limiting step in the synthesis
Malnourishment after the first trimester is less critical for of catecholamine neurotransmitter substances. Alterations in
the development of optimal brain development, and the effects copper levels thus might be expected to have some effect on
are more subtle and more subject to reversal by subsequent behavior, and one form of schizophrenia has been attributed
nutritional supplementation. Studies of Korean orphans mal- to elevated levels of copper. It is unlikely, however, that altera-
nourished for various periods of time postnatally indicate that tions in diet significantly affect brain copper levels.
those children renourished before the age of 3 fared better The most common dietary mineral deficiency is of iron.
than children renourished later. These studies also suggest Children with relatively minimal iron deficiency-levels which
that the psychosocial richness of the environment also contrib- do not produce anemia-perform less well on standardized
utes to the subsequent behavioral and learning outcome of neuropsychological tasks compared with non-iron-deficient
these children. children.
70 John W. Crayton

Dietary neurotransmitter precursors A variant ofthis food sensitivity and behavioral dysfunction
Observations that dietary precursors of brain neurotransmitter hypothesis is the notion that wheat gluten proteins can contrib-
substances can influence the levels of those substances and ute to the expression of schizophrenic symptomatology. Some
the brain functions mediated by them have led to strategies schizophrenic subjects placed on a gluten-free diet appear to
for the treatment of mental disorders via dietary manipulation. show more rapid improvement than those receiving a regular
Addition of precursors to the diet can affect the levels of in- diet. P.ttempts to replicate this finding with other schizophrenic
doleamines, catecholamines, acetylcholine, glycine, and hista- patients have not, however, indicated a major role for a wheat
mine. gluten/schizophrenia relationship, although some individuals
with schizophrenic symptoms may be gluten sensitive.

Adverse reactions to foods and psychopathology

It has been proposed that some susceptible individuals with Further reading
sensitivities to particular foods may develop a wide variety
of mental dysfunctions as a result of ingestion of that food. Growdon JH (1979): Neurotransmitter precursors in the diet: Their
use in the treatment of brain diseases. In: Nutrition and the Brain
Depression, anxiety, tension, irritability, hyperkinesis, learn- Wurtman R, Wurtman J, ed. 3:117-181
ing disabilities, schizophrenia, and difficulty controlling ag- Pollitt E, Leibel R (1976): Iron deficiency and behavior. Pediatrics
gressive impulses have been attributed to these adverse food 88:372-381
reactions. While there is an extensive anecdotal literature ad- Stein Z, Susser M., (1976): Maternal starvation and birth defects.
dressing this issue, the nature of the relationship between food In Birth Defects: Risks and Consequences. Hook, Ernest B., (ed)
ingestion and behavioral dysfunction is unclear. No adequate Academic Press, New York pp 205-220
mechanisms have emerged to explain these observations. Simi- Weiss B (1982): Food additives and environmental chemicals as
larly, the widely held notion that food additives and sugar sources of childhood behavior disorders. JAm Acad Child Psychiat
can produce abnormal behavior in children lacks a strong scien- 21:144--152
Winick M, Meyer KK, Harris RC (1975): Malnutrition and environ-
tific underpinning. It is, however, noteworthy that in rigorous
mental enrichment by early adoption. Science 190: 1173-1175
studies of additives and sugar, some individuals appear to
show behavioral reactions to these substances.
Mental Retardation
Hugo W. Moser

The American Association on Mental Deficiency recommends of mental retardation may have serious consequences. Simon
that mental retardation be defined as ''significantly subaverage Olshansky has written: ''To schools the category of mental
general intellectual functioning resulting in or associated with retardation is a way of classifying some students with learning
concurrent impairments in adaptive behavior and manifested problems; to the person so labeled the categorization is an
during the developmental period." While at first glance this attack from which recovery is rarely complete."
definition may appear to be self-evident and innocuous, it
was arrived at only after a great deal of discussion and takes The two-group approach
into account biological, psychological, social and even eco- Under this current definition between 2% and 3% of the general
nomic factors. Particularly important points are the insistence population would be classified as mentally retarded. It has
that general intellectual function must be significantly subaver- been found useful to subdivide the mentally retarded population
age. Intellectual function here is operationally defined as the into two groups, the characteristics of which are outlined in
results obtained by assessment with one or more individually Table 1.
administered standardized general intelligence tests. With these Group 1 includes 75-85% of the total. Here the intellectual
tests the average IQ is set at 100, and the standard deviation impairment tends to be relatively mild, and sociocultural depri-
has been found to be 15. Significantly subaverage intellectual vation and economic status are significant factors. The causes
function is defined as that which is more than 2 standard devia- responsible for the suboptimal function in this first group are
tions below the mean IQ, that is, 70 or below. This upper a matter of controversy. What is the relative importance of
limit of 70 is meant to be a guideline, and depending upon genetic and environmental factors? This question is difficult
circumstances it can be extended to 75. Another significant to answer. First the group is almost certainly heterogenous.
aspect of the definition is that for a person to be classified as Second, while there is no demonstrable abnormality of brain
mentally retarded, the significantly subaverage intellectual structure or function, techniques used to demonstrate such
function must be accompanied by impairment in adaptive be- abnormalities are still primitive and could fail to detect them.
havior. This requirement is added in order to avoid inappropri- Third, twin studies and other epidemiological studies have
ate reliance on, or tyranny of, an IQ number. It is well known shown, not surprisingly, that intelligence is influenced strongly
that IQ tests may underrepresent a person's potential, such by genetic factors. In spite of these considerations, recent
as when a North American IQ test is administered to a person intervention studies have shown that early educational and
who has been educated in another language or culture. Impair- social intervention techniques can do much to prevent the
ment in adaptive behavior is defined by Grossman as "signifi- suboptimal cognitive development of children at risk of group
cant limitations in an individual's effectiveness in meeting 1 sociocultural mental retardation. This finding is highly en-
the standards of maturation, learning, personal independence couraging and has practical and theoretical significance. It
and/or social. responsibility that are expected for his or her suggests that it is possible to interrupt the vicious cycle in
age level and cultural group, as determined by clinical assess- which the disadvantaged parents who function at a suboptimal
ment and, usually standardized scales." The developmental cognitive level have children who again function suboptimally.
period is defined as the period of time between conception The mechanism by which these techniques of early intervention
and the 18th birthday. The definition of mental retardation is provide favorable effects is not clear. The implications in terms
restrictive because we have learned that the inappropriate label of human values and national policy are significant.

Table 1. Two Groups of Mentally Retarded

Characteristic Group 1 Group 2
Names physiological organic
subcultural pathological
culturofamilial
familial
Estimated incidence 20-30 per 1,000 3 per 1,000
Most frequent IQ score 50-70 less than 50
Most common age of ascertainment during school years preschool
Apparent change of prevalence with apparently diminishes after school years no change
age
Demonstrable brain abnormality no yes
Relationship to socioeconomic status more common among socioeconomically none or slight
deprived or disrupted families
72 Hugo W. Moser

Group 2, or pathological mental retardation, is somewhat Table 2. Causes of Severe Mental Retardation
more readily approachable by techniques familiar to neuro-
%of Total
scientists. It is convenient to set an IQ of 50 as the dividing
line between the two groups. It has been found that the preva- Prenatal
lence of this form of mental retardation (group 2) is relatively Genetic chromosomal (Down's, fragile X, sex chro-
constant throughout the world: It varies between 3 and 4 per mosome disorders) 29
1000. Over 90% of persons with an IQ of less than 50 have Single mutant genes (phenylketonuria, hypothyroid-
ism, and many others) 5
demonstrable abnormalities of brain structure or function. The
Multiple congenital anomaly and mental retardation
IQ 50 dividing line is not absolute: There are mentally retarded syndromes 12
persons with demonstrable brain pathology whose IQ is higher Acquired; fetal alcohol syndrome, intrauterine infec-
than 50, and extreme cultural deprivation alone can lead to tions (rubella, cytomegalus virus, etc.) 15
apparent IQ levels of less than 50. Perinatal
Fetal anoxia, asphyxia, 12
Causes of severe mental retardation infections, etc. 3
Postnatal 11
The causes of severe mental retardation have been the subject Psychosis 1
of intensive studies (Table 2). They have been shown to be Unable to determine cause 18
prenatal in 55% of cases and chromosomal in 29%. The term
chromosomal disorder refers to a group of disorders in which
there is an abnormality of the number or appearance of chromo-
somes which can be detected with the light microscope. It is encouraging to note that several forms of severe mental
Down's syndrome is the most common chromosomal disorder retardation can now be prevented or treated. Greatest success
associated with mental retardation, followed by the fragile has been achieved with the immunization programs against
X-syndrome. In this X-linked disorder, there is a fragile site rubella and measles-the mass screening of newborns for phe-
on the distal portion of the X chromosome, an abnormality nylketonuria and hypothyroidism and the prompt and success-
which is brought about when cells are grown in a medium ful institution of dietary therapy for the former and thyroid
which contains low levels of folic acid or chemicals such as replacement for the latter. Other notable successes are immuni-
5-ftuorodeoxyuridine. The single mutant genes include inborn zation programs for Rh-negative mothers, which prevent the
errors of metabolism and in the aggregate account for 5% of previously dreaded disorder erythroblastosis fetalis. Study of
severe mental retardation. Included here are several hundred fetal cells or amniotic fluid obtained by aminocentesis can
separate entities. The most common are phenylketonuria, con- prenatally diagnose Down's syndrome, malformations such
genital hypothyroidism, and the urea cycle disorders. Intra- as anencephaly or spina bifida, and more than 100 inborn
uterine infections, such as rubella, cytomegalovirus, and errors of metabolism. These and other approaches have the
herpes simplex account for 7%; perinatal events for 12%; and potential of bringing about a significant reduction in the inci-
postnatal for 11%. Truly remarkable advances in neonatal care dence and extent of disability of severe mental retardation.
have reduced greatly the percentage of surviving low birth- Some of these treatable causes are highlighted in Table 3. In
weight infants who suffer brain damage. By the same token addition, recent and future advances in molecular biology and
the total number of low birthweight infants has increased, so developmental neurobiology make it likely that additional
that the number of low birthweight infants who survive with causes of severe mental retardation can be understood and
brain damage has remained relatively constant. prevented or treated.

Table 3. Causes of Severe Mental Retardation

Potential for Approximate Estimated
Prevention Condition Incidence or Treatment
Down's syndrome 1:1000 Partial reduction (about 15-30%) through awareness of
greater risk for mothers age 35 or above and prenatal
studies for those at risk.
Fragile X ?approx. 1: 1000 in males Potential for prenatal diagnosis in pregnancies known to
be at risk.
Neural tube defects 1 : 750 mental retardation in about Alpha-fetoprotein screening in pregnancies at risk can
two-thirds bring about 15% reduction. Potential for screening ma-
ternal plasma alpha fetoprotein to permit better identifi-
cation of those pregnancies that are at risk.
Fetal alcohol syndrome I :700 Potential for prevention through public education.
Congenital hypothyroidism I :4500 Mental retardation can be prevented completely by mass
screening of newborns and thyroid hormone administra-
tion to affected infants.
Phenylketonuria 1:14,000 Mental retardation can be prevented completely by mass
screening of newborns and administration of special
diet.
Intrauterine viral infections 1:5000 Ruoella preventable nearly 100% through mass immuniza-
tion programs.
Mental retardation due to perinatal 1:2500 Two preventive approaches: reduce inCidence of premature
anoxia or asphyxia particularly in births, particularly in adolescent mothers; further im-
low birthweight infants provements in neonatal care-regional centers and neo-
natal intensive care units.
 Mental Retardation 73

Further reading Olshansky S (1970): Work and the retarded. In: Diminished People,
Bernstein NR, ed. Boston: Little, Brown, pp 29-46
Crome L, Stem J (1972): Pathology of Mental Retardation, 2nd ed. Moser HW (1977): Mental retardation. In: Horizons of Health, Wech-
Edinburgh: Churchill Livingstone sler H, Gurin J, Cahill GF Jr, eds. Cambridge: Harvard University
Grossman HJ (1983): Classification in Mental Retardation. Washing- Press
ton DC: American Association on Mental Deficiency Moser HW, Ramey CT, Leonard CO (1983): Mental retardation.
Hagberg B, Kyllerman M (1983): Epidemiology of mental retardation: In: Principles and Practice ofMedical Genetics, Emery AL, Rimoin
A Swedish survey. Brain Dev 5:441--449 DL, eds. Edinburgh: Churchill Livingstone, pp 352-366
Monoamine Oxidase (MAO) Inhibitors in Psychiatric Therapy
Dennis L. Murphy

Iproniazid and several other hydrazine inhibitors of the oxida- to be a more effective antidepressant in severely depressed
tive deamination of brain catecholamines and indoleamines patients than deprenyl or the partially selective MAO-B inhib-
were the first drugs shown to be effective in the treatment of itor pargyline, suggesting that the major antidepressant effects
major depressive disorders. Although iproniazid itself proved of the MAO inhibitors are more likely to be mediated via
to be hepatotoxic and is no longer used clinically, and the central noradrenergic or serotonergic neurotransmitter systems
tricyclic antidepressants came to be regarded as safer and more than by changes in phenylethylamine or dopamine metabolism.
broadly effective drugs, other monoamine oxidase (MAO) in- A cascade of cellular events appears to be involved in the
hibitors continue to be widely used, especiaily in tricyclic- mechanism of action of these drugs. Acutely, especially with
resistant depressed patients. high MAO inhibitor doses, an increase in the intracellular
To meet Food and Drug Administration requirements, the concentrations of brain monoamines occurs. Not only are neu-
therapeutic efficacy of several of the standardly used MAO ron-specific amines increased (e.g., norepinephrine levels in
inhibitors (tranylcypromine, isocarboxazid, and phenelzine) noradrenergic cell bodies and presynaptic processes) but other
was reevaluated in the early 1980s, and antidepressant effects amines, whose concentrations are normally very low in brain
comparable to those of the tricyclics were demonstrated. In (e.g., tryptamine, phenylethylamine, and epinephrine) are
addition, several newer types of MAO inhibitors have been even more markedly elevated. Vesicular concentrations of
developed, some with definite therapeutic potential which are amines are increased, as are cytoplasmic concentrations, which
also of interest as tools to explore the importance of different normally are very low. A slowing of neuronal firing rates
monoamine systems in brain function and in the mechanism has been demonstrated in both serotonin-containing neurons
of action of antidepressants. in the median raphe and in norepinephrine-containing neurons
Most of these drugs are phenylethylamine derivatives, pro- in the locus ceruleus. Further adaptive consequences of MAO
ducing irreversible inhibition by covalently binding to the inhibitors include a reduction in amine synthesis, which has
FAD-containing active site of MAO via such substituent groups been most clearly demonstrated within the noradrenergic sys-
as a hydrazine (-N-N-, e.g., phenelzinP-, isocarboxazid), cyclo- tem. After more chronic treatment, reductions develop in
propylamine (-C--c-, e.g., tranylcypramine), or acetylenic beta-adrenoreceptor numbers and in beta-receptor functional
\I activity-as measured by norepinephrine stimulated cyclic
c adenosine monophosphate formation-as well as in alpha2 -
group (---c==c-, e.g., pargyline, clorgyline, deprenyl). Be- adrenergic binding sites and serotonin binding sites. These
cause brain MAO has a half-life of 12 days, these drugs have receptor changes are generally similar to those found after
a very long biological duration of action, with consequences tricyclic antidepressant treatment in animals, and have been
for clinical use that include some difficulties in titration of hypothesized to be involved in the therapeutic actions of antide-
dosage, lack of drug plasma level monitoring utility, and pro- pressant drugs.
longed toxicity, when it occurs. A series of new, reversible Some physiological consequences of these cellular events
MAO inhibitors, including moclobemide, CGP-ll305A, ci- that are found in humans include an essentially complete sup-
moxatone, and amiftamine, are under intensive early clinical pression of rapid eye movement sleep, a change produced
study to determine if equal efficacy, improved dosage control, by clorgyline but not deprenyl, and hence attributable to
and fewer side effects might be found. MAO-A inhibition. Decreased blood pressure, associated with
The acetylenic inhibitors, clorgyline and deprenyl, are of decreased plasma concentrations of norepinephrine and its me-
special interest because they act selectively to inhibit the two tabolite, 3-methoxy, 4-hydroxyphenylglycol, suggests a sup-
major subforms of the enzyme, MAO type A and MAO type pression of central sympathetic outflow. Not unexpectedly,
B, respectively. In rodent and human brain, clorgyline inhibits orthostatic hypotension is a side effect encountered with these
the deamination of serotonin, a substrate for MAO-A, at tissue drugs. At the same time, however, increased cellular concen-
concentrations over l ,000-fold lower than those needed to trations of norepinephrine may be released in the periphery
inhibit the deamination of phenylethylamine, an MAO-B sub- upon the ingestion of foodstuffs containing tyramine or similar
strate. Conversely, deprenyl selectively inhibits the deamina- indirectly acting sympathomimetic drugs, producing the most
tion of phenylethylamine and other subtrates of MAO-B, a dangerous side effect and liability of MAO inhibitor treatment,
difference that has been put to clinical use in the treatment a hypertensive crisis. Dangerous interactions also occur cen-
of Parkinson's disease. Dopamine is predominately an trally if, during chronic MAO inhibitor treatment, tricyclic
MAO-B substrate in humans, and deprenyl appears to potenti- antidepressants or some synthetic narcotics like meperidine
ate the actions of L-dopa in alleviating some symptoms of are administered.
this disease without potentiating noradrenergically mediated Nonetheless, large-scale studies involving several thousand
cardiovascular effects, a complication found when nonselective patients have shown a very low incidence of major complica-
MAO inhibitors are combined with L-dopa. Clorgyline appears tions when dietary and drug interaction precautions are pro-
 Monoamine Oxidase (MAO) Inhibitors in Psychiatric Therapy 75

vided to patients prior to MAO inhibitor treatment. In fact, may differ in their spectrum of efficacy, a point for further
with the current increased interest in depressed patient sub- study.
groups and the improved diagnostic delineation of psychiatric
syndromes, clinical trials of MAO inhibitors have been on Further reading
the increase in the 1980s. The older literature suggested that Beckmann H, Riederer P, eds (1983): Monoamine Oxidase and Its
a heterogeneous, ill-defined subgroup of atypical depressives Selective Inhibitors: New Concepts in Therapy and Research. Basel:
might respond preferentially to MAO inhibitors. More re- Karger
cently, patients meeting diagnostic criteria for panic disorder, Murphy DL, Garrick NA, Cohen RM ( 1983): Monoamine oxidase
agoraphobia, bulimia--disorders frequently associated with inhibitors and monoamine oxidase: Biochemical and physiological
depression-as well as some more clearly identified subgroups aspects relevant to human psychopharmacology. In: Drugs in Psy-
chiatry, Vol I. Antidepressants, Burrows JD, Norman TR, Davies
of major depressive disorder patients have been found to re-
E, eds. Amsterdam: Elsevier/North Holland Biomedical Press
spond to one or another MAO inhibitor in randomized, double- Squires RF ( 1978): Monoamine oxidase inhibitors: Animal pharmacol-
blind trials. Some evidence suggests not only that the substrate- ogy. In: Handbook of Psychopharmacology, Vol 14, Iverson LL,
selective inhibitors like clorgyline and deprenyl may have Iversen SO, Snyder SH, eds. New York: Plenum Press
different clinical effects, but also that other MAO inhibitors Tipton KF, Dostert P, Strolin Benedetti M, eds (1984): Monoamine
among both the irreversible and the newer reversible drugs Oxidase and Disease. London: Academic Press
Mood Disorders
Alan J. Gelenberg

Emotional reactions are part of our biological heritage as social Pathology of mood
mammals. For us, as for our prehuman and preprimate for- Since Biblical times, and doubtless before, some troubled souls
bears, emotions appear to have survival value-for species, have been tortured by bouts of depressed mood. For weeks,
as well as for individuals. Particularly in the vulnerable years
for months, even for years they might lie in apathy, or languish
of infancy (an especially long period in Homo sapiens), the in states of hellish agitation and torment. The depressed indi-
behavioral expression of emotions, with their frequent accom-
vidual could be plagued with self-doubt, guilt, and recrimina-
paniment of interpersonal responses, enhances the likelihood tions. Probably he would lose interest in formerly pleasurable
of biological survival. For example, a newborn experiences
activities, often including eating and sex. Sleep, weight, and
the Joss of physical support: his eyes open wide, his heart other bodily functions would typically be altered. Such a pa-
races, he cries; the observer interprets the child's experience
tient might lose touch with reality, experiencing un~alidated
as anxiety, feels his own discomfort, moves to readjust the sensations (hallucinations) or adopting false, fixed beliefs (de-
infant to provide support. Or, a baby's mother goes away. lusions). Not infrequently, the sufferer would attempt or actu-
After an initial bout of protest, the child lapses into a period ally succeed in committing suicide. Sometimes the depre~sion
of apathy and despair ("anaclitic depression"). This will en- would be preceded by an unidentifiable loss or emottonal
gender in most adults a desire to provide emotional s~pport trauma, but at other times it might occur spontaneously, or
for the child, such as physical support was rendered m the possibly as part of some rhythmic cycle (perhaps associated
earlier instance. And similarly, even in adulthood we commu- with a change of seasons).
nicate both physiological and psychological needs through our Less common, but perhaps more impressive to observers,
emotional expressions, needs usually meetable and met by are episodes of pathological elation that occur in some individ-
kith and kin. uals afflicted alternately with bouts of depression. A patient
Our feelings run the gamut from anger, sadness, and guilt in the throes of mania typically manifests a euphoric mood,
to joy. In a normal individual these reactions, or affects. as with unreasonable confidence in his own abilities and unbridled
psychiatrists call them, will be appropriate in degree and kmd optimism about the future. (At times the eu~horia s~i~ches
to the circumstances that evoke them. For example, we expect gears into irritability and possibly a pathological susptctous-
profound sadness in reaction to the death of a loved one; ness-paranoia). A manic patient is likely to monopolize con-
elation or indifference would be cause for surprise. On the versations, tie up the telephone, run up outrageous bills, and
other hand, prolonged dejection in reaction to a relatively triv- expend almost limitless energy with little apparent need to
ial loss would be equally perplexing. sleep.
In what has become a well-worn psychiatric simile, what Perhaps between 5% and 15% of the population can expect
weather is to climate, affect is to mood. One may observe a at least one episode in their lives of what is currently termed
relatively full range of an individual's affective responses dur- major depression. Diagnosed on the basis of observations and
ing a serious and involved interview. But to discern his mood- historical information, a major depressive episode consists of
the undertone of his state of mind over many days, weeks, a moderate to severe lowering of mood for at least a period
or longer--one must combine direct observations, ~istorical of weeks accompanied by a requisite number of associated
questions, and interviews with people who ~~ow htm .. The symptoms, including disturbances of sleep, appetite, and en-
normal individual, absent extraordinary conditions, cames a ergy, and mental changes such as a preoccupat~on with de~th
fairly neutral mood, from which he reacts to pleasant or un- or suicide. For at least half those who expenence a maJOr
pleasant events with the appropriate emotion. . depressive episode, similar episodes will recur in the_ future,
Our understanding of the biology of normal emotwns and at times frequently and to a debilitating degree, and m some
mood remains primitive. Probably the hypothalamus, the lim- taking on a chronic course without periods of remission.
bic system, and portions of the cortex ~re in~olved i~ the When episodes of depression alternate with periods of ma-
subjective experience and behavioral mamfestatwns of differ- nia, psychiatrists diagnose the bipolar form of mood disorder.
ent emotions. Limited experimental evidence suggests a pos- The lifetime prevalence of this illness is probably between
sible role for the neurotransmitters norepinephrine and seroto- 0.5% and I%, although its social impact in the marketplace
nin and for the endogenous opioid systems in the mediation and on families probably is greater on a case-by-case basis
of affective states. But it remains for future investigations to than that of recurrent depressions alone.
map out the definitive neuroanatomy, neurophysiology, and In some individuals, episodes of depression appear clearly
neurochemistry of mood to bring modern scientific understand- related to life events, such as the loss of a job or the breakup
ing to profound and ancient experiences. of a relationship. At times, the link between events and emo-
 Mood Disorders 77

tiona! reaction appears "neurotic," as when a man reacts to Treating depression and mania
success by becoming depressed. At other times, episodes of In the early part of this century, biological therapies of mood
depression or elation appear entrained to natural rhythms such disturbances were very limited. For the agitation, anxiety, or
as daily, monthly, or annual cycles. In still other patients, insomnia of depression, as for the elation of mania, a doctor
mood swings come and go with little predictability and few could offer only sedatives-such as bromides, barbiturates,
apparent correlates. or chloral hydrate. But in addition to their limited effectiveness,
For some, depression becomes almost a way of life. But these agents have a fairly narrow range of safety, with a rapid
where "character" or "personality" begins and illness leaves passage from sedation to cessation of breathing and other vital
off is scientifically undefined. Perhaps some individuals adopt functions. When amphetamines and other stimulants became
depressive behaviors to satisfy ill-defined intrapsychic needs available, they were widely tried in depression, but their effi-
or to evoke desired behaviors in those around them. Alterna- cacy likewise is limited, and problems of tolerance and abuse
tively, chronic depression could reflect a lifestyle adapted to further limit their clinical utility. (Stimulants have been enjoy-
an illness of biological dysregulation. ing a limited renaissance of late in some medical circles, but
Disturbances of mood tend to run in families, yet in epide- definitions of their role, if any, in the treatment of mood disor-
miological surveys it is hard to disentangle the contributions ders must await more investigation.)
of nature from those of nurture. However, studies of biological Although the role of psychotherapeutic interventions was
markers, of dizygotic versus monozygotic twins, and of adop- never formally studied, most clinicians found them more useful
tees and their families suggest that at least some components in milder forms of depression, where patients were more amen-
of some forms of mood disorder are genetically transmissible. able to talking and self-reflection. Although some practitioners
The best evidence exists for bipol~r illness, although many believed (and continue to believe) in a role for insight-oriented
relatives of bipolar patients have a unipolar (recurrent) depres- verbal psychotherapy in the treatment of profound and psy-
sive disorder. It is interesting to speculate on what actually chotic depression and in mania, there is no rigorous evidence
might be inherited: an illness, some form of regulatory distur- in support of this practice.
bance, a deficiency in some "pleasure center," or a handi- In the 1930s, investigators discovered the healing power
capped ability in an indeterminate interpersonal function or of induced seizures, and electrically provoked convulsions be-
ability to calm, soothe, or derive pleasure in oneself. came an accepted form of treating severe depression. (To this
Much interest in the biology of mood disorders has followed day, the mechanism by which electroconvulsive therapy (ECT)
in the wake of discovery of antidepressant drugs. Yet despite performs this function remains unknown, although few psy-
a plethora of hypotheses, our understanding of the pathology chiatrists question its efficacy.) In the 1950s, two serendipitous
of emotion, much as that of its normal physiology, remains discoveries gave rise to two chemically and pharmacologically
rudimentary. Early theories postulated deficits in cerebral lev- distinct groups of antidepressant drugs: the tricyclics (named
els of norepinephrine and serotonin, and while these two neuro- for their chemical structure) and the monoamine oxidase
transmitters still enjoy the lion's share of biological attention, (MAO) inhibitors (named for their inhibition of the enzyme
more recent theories have been focused on altered sensitivity that catabolizes several important neurotransmitters). And only
of their receptors, both pre and postsynaptic. However, the a few years earlier, Cade reported on the antimanic properties
direction of this putative altered sensitivity-whether ,in- of the cation lithium. These discoveries gave rise to a renais-
creased, decreased, or unstable-remains undetermined. Other sance in biological psychiatry, which continues today. The
neurotransmitter systems, such as that involving acetylcholine, advent of drugs to treat mania and depression has spawned
also might be involved, and it would not be surprising to vigorous research into the pathophysiology of the disorders
find the ultimate answer involving interrelationships among a and the biological mechanism of the treatment; the use of
number of systems. Moreover, different patients may suffer drugs has also afforded relief to millions of sufferers from
from different biochemical lesions. these painful and sometimes fatal conditions.
Psychiatrists have long envied specialists in infectious dis- Antidepressant drugs bring significant relief to 7~0% of
ease, who practice in the ideal "medical model." These fortu- patients suffering from major depression. Most likely to. re-
nate physicians can treat readily defined illnesses caused by spond are patients suffering from the melancholic or "endoge-
identified pathogens. The ability to isolate bacteriological and nous'' form of this disorder, in which mood is relatively auton-
viral causes has freed them from a need to focus on the patterns omous (i.e., displaying little tendency to vary with the
of fever and other clinical signs. But although psychiatrists immediate environment); accompanying symptoms include
have many notions about biological subtypes of major depres- early morning awakening, feeling worse earlier in the day,
sion and their differing likelihood of response to pharmacologic and loss of appetite and weight. Research continues into the
treatments, we still lack definitive biological tests that are possibility that some types of antidepressants, specifically the
essential for defining and scientifically treating disease states. MAO inhibitors, may be particularly effective for yet other
In recent years much effort has gone into the development of kinds of depression. Some individuals with recurrent episodes
such tests, such as those based on probing neuroendocrine of severe depression benefit from long-term maintenance ther-
responses and on the excretion of endogenous amine metab- apy with antidepressant drugs, which suppress or prevent the
olites. Despite great expenditure of time and funds, however, recurrence of future episodes.
rigorous biological diagnosis of major mood disorders remains Since the introduction of the original tricyclic and MAO
elusive. inhibitor antidepressants in the 1950s, a number of similar
The personal, social, and financial costs of mood disord- agents have been introduced in the U.S. and other markets.
ers are tremendous: suicides, "accidents," hospitalizations, These related drugs have extended physicians' options some-
wrecked or compromised careers, impaired parenting, broken what, as some patients are more likely to respond to one drug
marriages, squandered capital. Thus society has a moral as than another. Similarly, since the drugs have different side
well as a pragmatic stake in identifying cases, facilitating treat- effects, the clinician is better able to tailor drug to patient.
ment, and promoting research toward prevention and cure. In recent years a number of new drugs have been introduced,
78 Alan J. Gelenberg

which are relatively distinct chemically (and sometimes phar- complications. Newer forms of drug therapy are currently be-
macologically) from the original agents. However, many are ing investigated for the treatment of both depression and mania.
associated with new forms of toxicity, which encumber their In addition to the biological treatments of mood disorders,
clinical utility. Furthermore, while it is generally acknowl- modern investigations also have focused on interpersonal inter-
edged that none of the newly introduced drugs is superior to ventions. In particular, cognitive and behavioral treatments
the old standbys, there is increasing concern among clinicians have been defined and are currently being studied as possible
that some are not equal in efficacy to the older agents. The approaches to specific types of depression and as adjuncts to
search continues for antidepressant drugs that are more effec- biological treatments.
tive and have fewer adverse effects and less toxicity. As is typical in medical science, interest in understanding
Lithium has become a mainstay in the treatment of bipolar of disorders follow improved treatments. The last 30 years
illness. It is effective in the treatment of acute mania, although have brought major advances in the treatment of more severe
in its more severe forms mania may require the use of an forms of mood disturbance, and physicians and scientists may
antipsychotic drug. Probably lithium's greatest utility comes be hopeful that the coming decade will bring still further ad-
in the long-term management of bipolar illness, where most vances in therapies and accompanying improvement in our
patients enjoy a marked diminution in the number of episodes understanding of these life-threatening, disruptive, and ex-
of mania and usually of depression as well. Lithium may also tremely painful illnesses.
play a role in the long-term maintenance therapy of patients
with only recurrent depression and no episodes of mania.
Both lithium and antidepressant drugs affect uptake of neuro- Further reading
transmitters in presynaptic nerve terminals and also alter sensi-
Baldessarini R (1983): Biomedical Aspects of Depression and Its
tivity of pre and postsynaptic neuronal receptors. Despite our
Treatment. Washington: American Psychiatric Press
emerging knowledge about these effects, the actual mecha- Bassuk E, Schoonover S, Gelenberg A (1983): The Practitioner's
nisms of action of these agents are still unclear. Guide to Psychoactive Drugs. New York: Plenum Publishing Cor-
ECT remains a backup therapy in patients with severe de- poration
pression (or even mania) when drugs are ineffective or medi- Consensus Statement on Long Term Prevention of Recurrent Mood
cally contraindicated. Much of the mythology about ECT is Disorders. Am J Psychiatry 1985. 142(4):469-476
based on the earlier techniques employed, while the modern Gelenberg A, ed. Biological Therapies in Psychiatry (monthly). Little-
form is particularly safe and associated with relatively few ton, Mass: PSG
Morphine
Terrance M. Egan

Morphine is the chief active ingredient of crude opium, the on the nitrogen of the semisynthetic morphine derivative, oxy-
dried sap of the poppy Papaver somniferum. The drug has morphone, produces naloxone (Fig. 18), a pure narcotic antag-
pronounced actions on both the central nervous system (CNS) onist.
and peripheral nervous system, and is clinically useful as an The earliest record of the medicinal use of morphine (as
analgesic and antitussant, and in the control of diarrhea. It is opium) is Sumerian (300-400 sc), probably in the treatment
also a powerful narcotic which is widely abused for its euphoric of diarrhea. Morphine inhibits peristalsis, and causes spasm
qualities, often resulting in drug addiction. of the smooth muscle of the intestine, especially at the sphinc-
Laboratory synthesis of morphine is possible but difficult, ters. These actions result from a direct action of the drug on
so the drug is usually obtained from crude opium. The method the nerves of the gastrointestinal tract and probably do not
of collecting opium is described in Assyrian tablets dating to require the involvement of the CNS. However, most of the
the 7th century sc. The unripe seed capsule of the poppy other desirable and undesirable actions of morphine do involve
plant is incised, causing a milky exudate to seep from the the CNS. The most popular medicinal use of the drug is as
wound. This exudate, when dried and powdered, is opium. an analgesic in the control of dull intermittent pain. Its principal
Opium contains phenanthrene and benzylisoquinoline alka- action is to dissociate pain from its implication, that is, to
loids. The chief phenanthrene, making up about 10% of the separate the perception of pain from the emotional reaction
crude opium, is (-)-morphine. Morphine was isolated from to it. The analgesia is selective; the drug is not effective against
opium by Serturner, a German pharmacist's apprentice, in acute, intermittent pain, and other sensory modalities are
the early 1800s. Serturner extracted an alkaloid, which he spared. Morphine is thought to act at several different levels
called morphine after Morpheus, the Greek god of sleep and of the CNS to produce this effect. Morphine is also effective
dreams, that retained many of the familiar pharmacologic prop- in suppressing cough; however, the related opiate alkaloid,
erties of opium. The importance of Serturner's discovery was codeine (another natural substituent of opium), is usually used
not immediately appreciated. Morphine is a base of pKa 8.5, for this purpose.
and is therefore poorly absorbed from the gastrointestinal tract, Expression of the actions of morphine results when the drug
making it ineffective when given orally. However, the isolation combines with specific proteins contained within cell mem-
of morphine was followed shortly by an increase in the popular- branes of target tissues. These proteins constitute several
ity of the use of the hypodermic needle in medicine. Parenteral classes of ligand-specific opioid receptors. The existence of
administration of morphine was widely used for the control these receptors was first predicted from the early work of
of pain during the American Civil War, leaving a large number Martin (1967), and was subsequently verified by several labo-
of soldiers addicted to the drug. ratories. At present, there are at least three separate subclasses
The structure of morphine was determined by Gulland and of opioid receptors, denoted by the Greek letters f.L, 8, and
Robinson (1926) (Fig. lA). (-)-Morphine is a phenanthrene K. Of these three, morphine has the highest affinity for the
alkaloid; however, the drug is probably best classified as an j.L-receptor, and, in functional studies, appears to be a good
N-methylpiperidine compound with bulky ring substituents. f.L-selective agonist. The presence of opioid receptors suggests
This distinction is born out of the study of the relationship that endogenous ligands for these receptors exists. A number
of the structure of the molecule and its ability to produce of peptide hormones have been isolated. These peptides bind
analgesia. Modification of the phenanthrene nucleus produces opioid receptors with high affinity, and in so doing, produce
only quantitative changes in analgesic activity. For example, many of the actions of morphine.
meperidine lacks most of the phenanthrene ring structure yet
retains analgesic action. In contrast, modification of the piperi-
dine ring results in both quantitative and qualitative changes,
and is generally thought to be essential for activity (however,
close examination of the structure of methadone, which lacks
an intact piperidine ring, shows that there are exceptions to
this rule). In simplified form, there are three parts of the mor-
phine molecule required for activity: (1) a phenolic ring, (2)
a quaternary carbon (Cl3) to which the phenolic ring is at-
tached, and (3) a nitrogen atom separated from the quaternary
carbon by a two-carbon chain (CIS, Cl6) (once again, there
are exceptions). In morphine, a methyl group is attached to
the nitrogen. When an allyl group is substituted for this methyl, (B)
(A)
the resulting compound, nalorphine, shows both agonist and
antagonist activities. Likewise, substitution of allyl for methyl Figure 1. A. Morphine. B. Naloxone.
80 Terrance M. Egan

The relative importance of the events that follow the combi- Further reading
nation of morphine and receptor are still disputed. At least
Akil H, Watson SJ, YoungE, Lewis ME, Khachaturian H, Walker
three such events are well documented. First, several lines JM (1984): Endogenous opioids: Biology and function. Annu Rev
of evidence suggest that morphine causes an inhibition of Neurosci 7:223-255
adenylate cyclase. Second, in both brain and gut neurons, Johnson MR, Milne GM (1981 ): Analgetics. In: Burger's Medicinal
morphine causes naloxone-reversible hyperpolarizations by in- Chemistry, 4th ed, Wolf ME, ed. New York: John Wiley
creasing the membrane conductance to potassium ion. Third, Musto, OF (1973) The American Disease: Origins of Narcotic Con-
morphine causes a decreased transmitter release. That there trol. New Haven: Yale University Press
is a causal relationship between combinations of these effects
seems likely, but is unproved.
Neuroleptic Drugs
Solomon H. Snyder

Neuroleptic drugs are agents of diverse chemical structure but tablished that patients in remission will experience a relapse
have a single major clinical action, the relief of psychotic of symptomatology if neuroleptic treatment is stopped. This
symptoms, especially schizophrenic ones. These drugs are also raises the issue of the duration of maintenance neuroleptic
referred to as major tranquilizers and antipsychotics. The term therapy for schizophrenics in remission. It is not clear whether
neuroleptic is most commonly used, since it is more specific. lifelong therapy is required or whether drug administration
By contrast, the terms antipsychotic and tranquilizer are em- call be gradually reduced without the risk of serious relapse.
ployed in different contexts with diverse clinical conditions Neuroleptics reduce the global severity of the schizophrenic
and can apply in principle to many classes of drugs. illness. However, detailed studies of specific psychological
The first neuroleptic drug was chlorpromazine. Since chlor- symptoms suggest that neuroleptics act upon certain symptoms
promazine comes from the phenothiazine chemical class and more than others. Schizophrenic symptoms have been subdi-
since many other phenothiazine drugs have been employed vided by some psychiatrists into positive and negative symp-
as neuroleptics, the term phenothiazine has often been used toms. The positive symptoms primarily reflect the florid, acute
interchangeably with neuroleptic. However, other chemical psychotic symptoms such as hallucinations and delusions. Neu-
classes, especially the butyrophenones and the thioxanthenes, roleptics are particularly effective in relieving these symptoms,
have the same pharmacologic and therapeutic properties as including the typical schizophrenic disorder in thinking. Nega-
the phenothiazines. tive symptoms refer to the affective withdrawal and autistic
Understanding the pharmacologic actions of neuroleptics in behavior manifested by many schizophrenics and are most
animals and humans requires an appreciation of the history marked in chronic schizophrenic patients. Even in the absence
of these drugs in clinical medicine. Chlorpromazine was syn- of overt psychotic symptomatology such patients appear to
thesized by the Rhone-Poulenc Drug Company in France as be emotionally withdrawn from their environment. Most neuro-
an antihistamine related to the antihistamine promethazine, leptics are less effective in relieving negative than positive
which also was of the phenothiazine chemical class. The neuro- symptoms, but one chemical class of neuroleptics, the diphe-
surgeon Henri Laborit evaluated promethazine as a possible nylbutylpiperidines, appears to be substantially more effective
adjunct to preoperative anesthesia and was impressed with than other neuroleptics in relieving negative symptoms of
its ability to quiet patients without putting them to sleep. He schizophrenia. The diphenylbutylpiperidines are comparable
examined chlorpromazine as an alternative which was even to other neuroleptics in reversing positive symptoms.
more sedating but still did not render patients unconscious. Neuroleptics are also effective in relieving acute manic
These properties suggested to Laborit that chlorpromazine symptoms. However, it is not clear to what extent they act
might be useful in psychiatric patients to relieve their agitation selectively upon the psychotic symptomotology rather than
without interfering with consciousness. The psychiatrists Jean merely calming the patient. Often, manic patients treated with
Delay and Pierre Deniker examined chlorpromazine for these neuroleptics appear to continue the manic pressure of ideas
indications and were quite impressed with its ability to quiet and of speech but are slowed by the chemical straitjacket of
hyperactive patients. They found beneficial effects especially the drug.
in manics and schizophrenics. Though chlorpromazine was Neuroleptic drugs have been employed in neurotic patients
sedating, Delay and Deniker felt that they could detect definite for their sedating and calming actions. However, neuroleptics
alleviation of psychotic thinking. Over the next several years do not relieve anxiety in a selective fashion as do benzodiaz-
numerous psychiatrists confirmed the drug's ability to diminish epine drugs such as diazepam (Valium). Moreover, neuroleptics
psychotic behavior and especially to influence in a favorable can produce serious side effects, some of which are irreversi-
fashion schizophrenic thinking disorders. ble. Accordingly, proper clinical practice restricts the use of
neuroleptics to psychotic patients.
A substantial number of different neuroleptic drugs are mar-
Clinical actions
keted in the United States and an even greater number are
It is now generally accepted that the major utility of the neuro- marketed in Europe and other countries of the world. All the
leptics lies in the treatment of schizophrenia. Neuroleptics major commercially marketed neuroleptics have similar anti-
are the only drugs which reduce psychotic symptoms of large psychotic effects. They differ principally in their absolute po-
numbers of schizophrenics to a level where hospitalization is tency and in their spectrum of side effects. Some of the more
no longer required. In most patients neuroleptics do not '·cure'' commonly employed agents of the phenothiazine class include
schizophrenic symptoms. However, in a substantial number chlorpromazine (Thorazine), thioridazine (Mellaril), perphen-
long-lasting and extensive remissions are possible. The inabil- azine (Trilafon), prochlorperazine (Compazine), trifluoperazine
ity of neuroleptics or any other drugs to abolish the schizo- (Stelazine), and fluphenazine (Prolixin). The thioxanthene
phrenic disease process is apparent from the requirement for chemical class of drugs chemically resembles the phenothi-
maintenance neuroleptic therapy. Numerous studies have es- azines. Extensively used thioxanthenes include thiothixene
82 Solomon H. Snyder

(Navane) and flupentixol. The butyrophenones differ markedly ment with the drugs provokes a neuronal attempt to compensate
in their chemical structures from the phenothiazines or the for the acute effects of the drugs.
thioxanthenes. However, they exert essentially the same spec- Sedation and orthostatic hypotension occur frequently with
trum of pharmacologic actions. Haloperidol (Haldol) is the some neuroleptics. Orthostatic hypotension refers to a fall in
most widely used butyrophenone neuroleptic and the only one blood pressure when a patient stands up and is often associated
commercially marketed in 1984 in the United States. Diphenyl- with fainting spells. Sedation and hypotension occur more
butylpiperidines are chemically derived from the butyrophe- with phenothiazine neuroleptics, especially those which are
nones and include agents such as pimozide, fluspirilene, and least potent on a milligram basis, such as chlorpromazine and
penfluridol. thioridazine. Among various neuroleptic drugs sedation and
hypotension tend to go hand in hand so that most researchers
feel that these two symptoms are mediated by the same or
Side effects ~imila_r mechanisms. Since sedation-hypotension and neurolog-
For many drugs side effects are regarded as unimportant but ICal s1de effects are the two major classes of side eff~cts,
troublesome actions of drugs. For the neuroleptics side effects psychiatrists select neuroleptics for their patients based on sen-
are an essential part of the action of all the currently employed sitivity to these particular actions. The neuroleptics most prone
neuroleptics and provide insight into the mechanism of their to produce sedation and hypotension are least likely to produce
therapeutic effectiveness. Moreover, the side effects elicited e~trapyramidal side effects and those with the greatest propen-
by neuroleptics are often severe and limit the clinical use of Sity for extrapyramidal side effects elicit the lowest incidence
the drugs. Since the efficacies of the numerous commercially o_f sedation and hypotension. For young students and profes-
marketed neuroleptics are similar, a physician typically selects siOnal people who must be alert in their work, drugs such as
a particular neuroleptic for a given patient based on the sensitiv- the butyrophenones are first prescribed because they are least
ity of the patient to side effects. likely to impair alert behavior. If a patient is overly sensitive
The neurological side effects provoked by neuroleptic drugs to such side effects, then the physician may switch to other
account for the designation "neuroleptic." These side effects drugs that are less likely to cause extrapyramidal effects.
involve the extrapyramidal motor system and often resemble
the symptoms of Parkinson's disease. In their first studies of Mechanism of action
chlorpromazine Delay and Deniker observed that, as they in-
creased d~ses to levels which produced therapeutic effects, In efforts to identify the mechanism whereby drugs exert their
they almost invariably observed Parkinson-like side effects. therapeutic action, pharmacologists frequently administer the
Accordingly, they concluded that the neurological actions of drugs to animals and measure various physiological and bio-
the drugs were related in some way to their therapeutic actions. chemical parameters. In early studies with phenothiazines
The designation neuroleptic derives from Greek words meaning many different effects were observed. Phenothiazines are
"to clasp the neuron" and implies a relationship of neurologi- highly reactive chemical substances and influence all sorts of
cal to therapeutic effects. Neuroleptic drugs often elicit typical biochemical processes including protein synthesis, mitochon-
Parkinsonian symptoms essentially indistinguishable from the drial respiration, carbohydrate disposition, and the metabolism
symptoms of patients with idiopathic Parkinson's disease. Such of all known neurotransmitters. The major task of researchers
manifestations include rigidity, difficulty in moving, and has been to distinguish which of these effects are responsible
tremor. Other neurological effects also occur with neuroleptic for the therapeutic actions of the drug and which are secondary
drugs and appear to reflect influences upon the same extrapy- or unrelated. The availability of an extensive number of clini-
ramidal motor areas of the brain. Acute dyskinesias may be cally employed neuroleptics has facilitated such an evaluation.
manifest with abrupt distortions of the neck, designated "torti- Scientists have compared the relative potencies of neuroleptics
collis," or with abnormal movements of the eyes, referred in producing various biochemical actions with their relative
to as "oculogyric crises." A more frequent but subtler, extra- clinical potencies. Examined in this way, most of the reported
pyramidal motor abnormality produced by neuroleptics is des- effects of neuroleptics fail to correlate with clinical activity.
ignated "akithisia." Patients with akithisia have difficulty sit- Research on neurotransmitter receptors has provided direct
ting still. They subjectively report a muscular itchiness and evidence for what is generally regarded as the therapeutic ac-
constantly pace up and down the room in efforts to relieve tion of neuroleptics. In 1963 Arvid Carlsson observed changes
the peculiar feelings in their muscles. A physician should be in the metabolism of the neurotransmitter dopamine elicited
alert to akithisia, since it is frequently mistaken for agitation with greatest potency by haloperidol, with lesser potency by
with medical personnel prescribing increasing doses of the chlorpromazine, and with no effect by the phenothiazine anti-
drug, which only makes the akithisia worse. The neurological histamine promethazine, which lacks antipsychotic effects.
side effects of neuroleptics occur most frequently with the Thus these initial observations reflected a correlation between
butyrophenones and with the phenothiazines which are most therapeutic potency and biochemical effect. The pattern of
potent on a milligram basis, such as fluphenazine. change in dopamine metabolism suggested that neuroleptics
Tardive dyskinesia is one of the most serious neurological accelerate the turnover of dopamine. Carlsson speculated that
side effects of neuroleptics. Symptomatically it looks like the this augmented turnover reflected more rapid firing of dopa-
opposite of the acute parkinsonian side effects. While parkinso- mine neurons. He suggested that neuroleptics block postsynap-
nian symptoms include rigidity and a paucity of movement, tic dopamine receptors and that, by some feedback mechanism,
patients with tardive dyskinesia manifest excess motor activity, the dopamine neurons fire more rapidly in an effort to overcome
especially in the muscles of the tongue and face. The fact the receptor blockade.
that the symptoms of tardive dyskinesia are the opposite of When it became possible to measure dopamine receptors
the acute parkinsonian effects of neuroleptics suggests that by monitoring the binding of radioactive neuroleptics to brain
tardive dyskinesia involves a compensation to the acute actions membranes, it was possible in our own laboratory as well as
of neuroleptics. Tardive dyskinesia occurs predominantly in that of Philip Seeman in Toronto to show directly that neurolep-
patients treated for long periods of time with large doses of tics block dopamine receptors and that the relative potencies
neuroleptics. It has been suggested that such long-term treat- of an extensive series of neuroleptics in blocking receptors
 Neuroleptic Drugs 83

correlates closely with their clinical potencies. This correlation hypotension produced by neuroleptics is closely correlated with
holds for the 0 2 subtype of dopamine receptors but not for the extent of blockade of alpha-adrenergic receptors at thera-
0 1 receptors. 0 1 dopamine receptors are linked to a stimulation peutic doses. Blockade of muscarinic acetylcholine receptors
of adenylate cyclase and were shown by Paul Greengard at diminishes the propensity of neuroleptics to elicit acute pyrami-
Yale University to be blocked by phenothiazines potently but dal side effects. Thus, neuroleptics which are most potent in
not by butyrophenone neuroleptics. Many neuroleptic drugs blocking muscarinic cholinergic receptors, such as thiorid-
are potent blockers of other neurotransmitter receptors such azine, produce the lowest incidence of acute extrapyramidal
as histamine H 1 , alpha 1 adrenergic, muscarinic cholinergic, side effects. This mechanism fits with the well-established
and serotonin S 2 receptors. However, effects on the other re- clinical evidence that anticholinergic drugs relieve extrapyra-
ceptors do not correlate with therapeutic potency. Accordingly, midal side effects of neuroleptic drugs. Moreover, anticho-
it is generally accepted that 0 2 dopamine receptor blockade linergic drugs have been used with considerable success in the
accounts for the therapeutic actions of neuroleptic drugs. treatment of idiopathic Parkinson's disease.
Dopamine receptor blockade can also explain side effects
of neuroleptics. Idiopathic Parkinson's disease is caused by a
degeneration of dopamine neurons with cell bodies in the sub- Further reading
stantia nigra and terminals in the corpus striatum. By blocking Creese I, Hamblin MW, Leff SE, Sibley DR (1983): CNS dopamine
dopamine receptors in the corpus striatum, neuroleptic drugs receptors. In: Handbook of Psychopharmacology, vol 17, Iversen,
produce a functional dopamine deficiency, accounting for their LL, Iversen SD, Snyder SH, eds. New York: Plenum Press, pp.
parkinsonian side effects. Chronic blockade of dopamine re- 81-138
ceptors provokes a synthesis of new dopamine receptors by Lee T, Seeman P, Tourtelotte WW, Farley IJ, Homykeiwicz 0 ( 1978):
neurons receiving dopamine neuronal input. These new recep- Binding of 3H-neuroleptics and 3H-apomorphine in schizophrenic
brains. Nature 274:897-900
tors cause a supersensitivity to dopamine. It is thought that Moore RY, Bloom FE ( 1978): Central catecholamine neuron systems:
this increase in dopamine receptor number can explain the Anatomy and physiology of the dopamine systems. Ann Rev Neu-
symptoms of tardive dyskinesia. rosci I: 129-169
Actions of neuroleptics at other neurotransmitter receptors Snyder SH (1984): Drug and neurotransmitter receptors in the brain.
are relevant to side effects of the drugs. The sedation and Science 224:22-31
Neuropharmacology
Jack R. Cooper

Neuropharmacology is the study of drugs that affect the ner- receptors, it is now possible to rapidly screen new compounds
vous system where drugs are defined not only as agents that by determining their ability to displace the radioactive ligand
are foreign to the organism but include endogenous substances from its binding site to a brain homogenate or synaptosomal
such as L-dopa. In the central nervous system (CNS), neuro- membrane preparation. Further, with the identification of re-
pharmacology encompasses the psychotropic drugs which alter ceptor subtypes (e.g., there are now four adrenergic receptors
mood and behavior, general anesthetics, analgetics, anticon- classified as o: 1, o: 2 , ~ 1 , and ~ 2 ), it is now possible to synthesize
vulsants, hypnotics, analeptics, and narcotics. In the peripheral agents that are relatively specific in their affinity for these
nervous system, neuropharmacology includes drugs that block subtypes and therefore relatively specific in their therapeutic
axonal conduction, neuromuscular blocking agents, and an activity. In addition, the identification of a receptor for mor-
extraordinary range of drugs that affect the autonomic and phine led to the search for a naturally occurring opioid and
enteric nervous systems. Since neuropharmacology is not a to the discovery of a whole class of opioid peptides with a
specific discipline with its own technology such as neuro- widespread distribution in nervous tissue. The isolation of en-
physiology or neurochemistry, neuropharmacologists, depend- dorphins and enkephalins is now encouraging pharmaceutical
ing on their training, represent virtually every field of biomedi- houses to develop stable analogs of these endogenous antinoci-
cal science. As long as their primary concern is with neuro- ceptive peptides. Another major advance in drug synthesis
active drugs, investigators can choose to be classified as that is attributable to the receptor concept is just emerging.
neuropharmacologists regardless of whether they are endocri- That is, with the isolation and purification of receptors and a
nologists, immunologists, physiologists, or chemists. knowledge of their three-dimensional structure, at least at the
Because of our neuroscientific naivete at the molecular, cel- active site, it should be possible with current computer technol-
lular, and especially behavioral levels, most of the currently ogy to design conformationally specific agonists or antagonists.
used neuropharmacologic agents have been discovered seren- This not only would prevent the side effects of current drugs,
dipitously: it is rare to encounter a therapeutic agent that has but also would obviate the kind of molecular roulette that
been the result of a rational drug search based on a fundamental medicinal chemists now employ in rearranging structures of
discovery. An example of this rarity is the neuromuscular prototypical drugs. Finally, in the design of new drugs, one
blocking drug, d-tubocurarine, discovered by Claude Bernard cannot fail to note the future impact on neuropharmacology
in his investigation of the mechanism of action of the poison of molecular neurobiology. It may be possible to combine
used by Amazonians to coat their arrows. However, the in- monoclonal antibodies that recognize specific neural elements
creasing sophistication of neurophysiological, neurochemical, with drugs to produce a drug delivery system that will ensure
and neuroanatomical techniques has produced a quantum leap a precise distribution of the drug to its appropriate site. In
in our understanding of the nervous system that may make addition, recombinant DNA technology, with its ability to
rational programs for drug development commonplace. To ex- isolate, identify, and modify genetic material, may be the
plain this statement, a little background information may be neuropharmacology of the 21st century. For example, Parkin-
helpful. With the notable exception of local anesthetics which son's disease is apparently caused by the destruction of nigro-
block axonal conduction, virtually all neuropharmacologic striatal dopaminergic neurons, and is currently treated with
agents act on synapses to affect transmission. Historically, L-dopa, the precursor of dopamine. Conceivably, gene replace-
based on the discovery that eserine produced its acetylcholine- ment therapy may in the future substitute for L-dopa by produc-
like effects because it inhibited acetylcholinesterase, which ing a whole new set of neurons.
hydrolyzes acetylcholine, it was assumed that most drugs act In general, drugs that affect the nervous system have tradi-
by inhibiting an enzyme. It is now known, however, that tionally been assumed to exert their activity by interacting
this is a fairly uncommon event and that almost all drugs with one of the neurotransmitters, i.e., acetylcholine, noradren-
that affect the nervous system owe their activity to their interac- aline, dopamine, serotonin, gamma-aminobutyric acid, gly-
tion with a receptor. These receptors are found both presynapti- cine, glutamate, or aspartate. It was thought that if we knew
cally, where they alter the amount of neurotransmitter or neuro- the circuitry involving these transmitters, we would understand
modulator released, and postsynaptically, where they alter the brain function and, consequently, drug action. However, with
ensuing signal. Postsynaptic receptors can be affected by drug the recent recognition of pre- and postsynaptic modulation of
treatment so that the affinity of their endogenous ligand can synaptic transmission, coupled with the discovery of close to
be either reduced or increased and their density at the neuronal three dozen neuroactive peptides in the brain, not to mention
surface can be either decreased (down-regulated) or increased a number of small molecules such as adenosine, all of which
(up-regulated). primarily appear to modulate activity, our ignorance of brain
This receptor concept of drug action has revolutionized the circuitry has deepened. Since modulation confers a fine tuning
production of new neuroactive drugs. With the availability of the nervous system, a requisite for elaborating behavioral
of ligands of high specific radioactivity and specificity for changes, it is conceivable that the mechanism of action of
 Neuropharmacology 85

the psychotropic drugs is referable to an effect on these modula- macologists will continue to use drugs as probes in an attempt
tors, or their receptors, particularly the peptides, and not di- to unravel the extraordinarily complex wiring of the brain.
rectly on the neurotransmitters and their receptors. In one
sense, this bewildering array of new endogenous neuroactive
agents is depressing to brain theorists. To neuropharrnacolo- Further reading
gists, however, it indicates the ability of the brain to regulate
Cooper JR, Bloom FE, Roth RH (1986): The Biochemical Basis of
its activity using seemingly innumerable pathways and opens Neuropharmacology. New York: Oxford University Press
up many potential sites of drug intervention. Regardless of Iversen S, Iversen LL (1981): Behavioral Pharmacology. New York:
the difficulty in devising new agents for memory or aging, Oxford University Press
or control of neurological and mental dysfunction, neurophar-
Phencyclidine
Robert C. Petersen

Phencyclidine, or PCP, chemically one of the arylcyclohexyla- episodes without additional drug use as much as a year later
mines, was originally developed as a dissociative anesthetic have been reported. Serious depression subsequent to use is
in the late 1950s. It was abandoned (for humans, but not also common.
other primates) in the mid 1960s because patients so often Since two of the effects of PCP are markedly distorted-
showed marked confusion and irrational behavior mimicking paranoid thinking and reduced pain perception-violent behav-
schizophrenia during postoperative recovery. Although PCP ior that is not easily controlled sometimes results. Death from
is the best known of about 30 psychoactive analogs, others, accidental injury is a frequent concomitant of use. Swimming
including PCE, TCP, PHP, PCC, and the shorter acting anes- is reported by users to be especially pleasurable while PCP
thetic, ketamine, are chemically related and have similar psy- intoxicated, but the sensory distortions that the drug induces
chophysiological effects. make such activity extremely hazardous, and drowning acci-
Unfortunately, the ease with which PCP could be synthe- dents are common.
sized coupled with the emergence of a psychedelic drug fad Since there is still no specific antagonist for PCP, treatment
resulted in its widespread abuse beginning in the 1960s. Ini- varies, depending on the dose, from simple reassurance in a
tially PCP developed a poor street reputation because overdoses calming environment to intensive life support measures to com-
were common when it was taken orally. However, illicit users bat the respiratory depression, convulsions, and coma that
soon discovered that by smoking PCP they could reduce the can lead to death from larger doses. Although detailed treat-
likelihood of many serious side effects while preserving the ment recommendations are beyond the scope of this review,
sought-after mind alteration. caution must be exercised. Depression and possible suicide
attempts after the acute crisis is passed are a continuing hazard.
Whether difficulties with memory and thinking following
Biological and behavioral effects
chronic use persist and for how long remains unclear. Since
Effects on the central nervous system are as follows: ( l) Low PCP users frequently use alcohol and other illicit drugs as
doses lead to "drunkenness" with numbness of the extremities. well, separating the chronic effects of PCP from those of other
(2) Moderate doses produce analgesia; still higher doses an- drugs is difficult. The possibility that PCP abuse may also
esthesia. (3) Psychic states resembling sensory isolation are affect the body's immune response has recently been raised
produced, although markedly distorted sensory impulses do by laboratory studies of cell cultures. Since PCP readily crosses
reach the neocortex. (4) Cataleptiform motor responses occur. the placental barrier, it is a potential hazard to the fetus. Infants
(5) Large doses can produce convulsions and, as a result of exposed to the drug in utero have been characterized by sudden
respiratory depression, death. (6) Marked interspecies differ- outbursts of agitation, increased lability, and poor consolabil-
ences occur: In primates, including humans, depressant effects ity, although they did not differ from a control sample in
predominate, whereas in other species stimulant effects are scores at three months on the Bayley Scales of Infant Develop-
common. Sympathomimetic effects in humans include in- ment.
creases in heart rate and blood pressure. Catecholamines are Improved PCP detection techniques using homogenous
potentiated through a cocaine-like action. enzyme immunoassay procedures make emergency determina-
tions of serum levels more rapid and convenient. Since phency-
clidine is a principal cause of emergency psychiatric hospital-
Phencyclidine abuse ization, routine testing for its presence in recent admission
The exact extent of PCP abuse is not known. Since the drug cases is indicated. Studies of PCP's pharmacokinetics pro-
so frequently masquerades as other drugs and goes by such a vide a convincing rationale for vigorous acidification of urine
bewildering array of street names ("angel dust" is only one and diuresis in treating phencyclidine intoxication.
of many), even users are sometimes unaware they have taken Despite two decades of abuse, important questions about
it. National drug abuse survey data suggests use peaked in this drug remain unanswered. Although the more dramatic
the 1970s and is now declining. The frequency with which adverse consequences of use have received publicity, little is
serious side effects accompany recreational use is also uncer- known about their frequency of occurrence. While we know
tain. There is, however, good reason to believe that in some primates will self-administer PCP and there is evidence of
areas PCP has been a leading cause of inpatient psychiatric specific opiate/phencyclidine binding sites in the human brain,
admissions. Since the drug's effects so frequently mimic those the neurophysiological basis for PCP abuse is still not well
of an acute schizophrenic episode, their true source often goes understood. Phencyclidine was initially viewed as prototypical
undetected. Whether the drug directly induces the psychotic of a potentially wider range of easily synthesized mind-altering
episode or whether it precipitates a psychosis in those who drugs with marked potential for abuse, but this feared conse-
are already vulnerable is uncertain. Recurrent schizophrenic quence has not as yet occurred.
 Phencyclidine 87

Further reading Khansari N, Whitten HD, Fudenberg HH (1984): Phencylidine-

induced immunodepression. Science 225(4657):76--78
ChasnofflJ, Burns WJ, HatcherRP, Burns KA (1983): Phencyclidine: Petersen RC, Stillman RC, eds (1978): Phencyclidine (PCP) Abuse;
Effects on the fetus and neonate. Dev Pharmacal Ther 6(6):404- An Appraisal, NIDA Research Monograph, DHEW Publ No
408 (ADM) 78-728. Washington DC: US Government Printing Office
Clouet DH (1986): Phencyclidine: An Update, NIDA Reasearch Mon- Walberg CB, McCarron MM, Schulze BN (1983): Quantitation of
ograph, DHHS Publ No (ADM) 86--1443, Washington, D.C.: US phencyclidine in serum by enzyme immunoassay: Results in 405
Government Printing Office patients. J Anal Tox 7(2):106--110
Phenylalanine and Mental Retardation (PKU)
William L. Nyhan

Phenylketonuria (PKU) is the most important and most fre- Biochemical features
quent disorder of aromatic amino acid metabolism. It results
Phenylalanine hydroxylase is an enzyme whose activity is ex-
from a defect in phenylalanine hydroxylase, the enzyme that
pressed only in liver. In classic PKU the activity of this enzyme
normally converts phenylalanine to tyrosine. The disorder was
is virtually undetectable. Furthermore, no cross-reacting mate-
discovered some 50 years ago by Foiling who observed a
rial is observed when reacted with antibody that detects the
deep green color on the addition of ferric chloride to the urine
normal human enzyme. In the presence of a block at this
of two mentally retarded siblings and characterized the com-
level phenylalanine accumulates in body fluids. Concentrations
pound responsible as phenylpyruvic acid, the phenylketone
in plasma virtually always exceed 20 mg/dl.
for which the disorder has been named.
When phenylalanine accumulates it is converted to phenyl-
PKU is the model disorder among genetically determined
pyruvic acid, phenyllactic acid, and phenylacetic acid. This
diseases. Early treatment to prevent the accumulation of phe-
compound is conjugated to form phenylacetylglutamine. Phe-
nylalanine and its metabolic products effectively prevents the
nylalanine is also converted to o-hydroxyphenylacetic acid.
clinical manifestations of the disease. Screening programs in The diagnosis of PKU is made by routine screening of all
which the phenylalanine concentration of the blood of the
infants in the first weeks of life. In the United States this is
infant is assessed permit early diagnosis and treatment of the
generally carried out on discharge of the newborn from hospi-
entire population of most developed countries and a public
tal. It is desirable that testing be done after at least 24 hours
health approach to the control of genetic disease. More recently
of feedings containing protein. As many as 8% of patients
the gene for phenylalanine hydroxylase has been cloned and
may be missed because the screen is done before levels of
restriction fragment length polymorphisms have been demon- phenylalanine have risen. A physician can be surer that his
strated that permit heterozygote detection and prenatal diagno- patient is not one of the 8% by retesting at 2-4 weeks.
SIS.
The test is done on spots of dried blood on filter paper. A
positive ·test maybe repeated or followed up directly with a
quantitative determination of the concentrations of phenylala-
Clinical manifestations nine and tyrosine in plasma. Patients with PKU have markedly
elevated concentrations of phenylalanine and usually reduced
Classic PKU is characterized by severe mental retardation. levels of tyrosine. In transient tyrosinemia of the newborn,
The IQ is usually below 50. The earliest symptom n:ta~ be especially common in premature infants, phenylalanine levels
vomiting. It may be of sufficient severity to lead to a misdiag- are high enough to trigger the screen but concentrations of
nosis of pyloric stenosis. Infants may also manifest i?"itability tyrosine are always higher.
and a mild eczematoid rash. In an older untreated patient there In order to distinguish the patient with classic PKU from
may be severe itching. An unusual odor, caused by the accumu- some of the milder hyperphenylalaninemias that may not need
lation of phenylacetic acid, has been described as mousy, treatment, it is useful to hospitalize the patient so that the
barny, musty, or wolflike. Patients are blond~, blue-_eyed, a~d intake of phenylalanine can be closely monitored and fresh
fair in over 90% of cases. However, the disease IS seen m urine specimens obtained. A standard challenge employed is
dark-skinned people, including blacks, where the untreated 3 days of a I : 2 dilution of evaporated milk formula. In classic
patient is usually less deeply pigmented than other members PKU the concentration of phenylalanine is over 20 mg/dl and
of the family. usually over 30 mg/dl, and that of tyrosine is under 5 mg/dl.
Neurological manifestations may be seen in a third of un- Patients with classic PKU will excrete phenylpyruvic acid and
treated patients who are spastic, hypertonic, and have increased o-hydroxyphenylacetic acid. Therefore, the urine should be
deep tendon reflexes, but in only about 5% are these manifes~a­ tested with FeCI 3 or chromatographed for phenolic acids.
tions severe; some are athetoid. Another third have very mild Rarely an immature infant may fail to excrete these metabo-
neurological signs, such as a unilateral Babinski response. A lites. Thus any infant with a plasma concentration of phenylala-
third are without neurological manifestations. Seizures occur nine over 20 mg/dl should be treated with a diet restricted in
in about a fourth of patients and about 80% have electroen- phenylalanine.
cephalograph (EEG) abnormalities. Hyperactivity and problem In the U.S. collaborative study, challenge with phenylala-
behavior are common, as are purposeless movements and ste- nine was carried out at 90-120 days and again after l year
reotypes. . of age. The standard 3-day challenge of 24 ounces daily of
Somatic development is usually normal, but the patient may I : I mixture of evaporated milk provides 180 mg/kg/day of
be short. Minor malformations have been reported in some phenylalanine for a 3-6-month-old infant. The dose is adjusted
patients. to 180 mg/kg/day for the l year old. In classic PKU the re-
 Phenylalanine and Mental Retardation (PKU) 89

sponse to the challenge is a sharper rise in the serum concentra- act1v1ty, levels of phenylalanine are substantially lower than
tion of phenylalanine to 30--40 mg/dl in 48 hours, at which in classic PKU. In general these patients have serum concentra-
level the challenge is terminated. This type of dosage should tions of phenylalanine less than 20 mg/dl when the infant is
not be used for a diagnostic challenge in an older child where receiving 180 mg/kg of phenylalanine. In contrast, the infant
requirements are much lower than that of the infant. Sympto- with classic PKU is unable to tolerate more than 75 mg/kg
matic hypoglycemia has been reported with the use of this of phenylalanine. It is generally agreed that if patients with
much phenylalanine in a 15-year-old patient. hyperphenylalaninemia have levels above 20 mg/dl they should
be treated with phenylalanine restriction and if they do not it
should be unnecessary to treat them.
Genetics
PKU is an autosomal recessive disease. Its frequency has be-
come clear through genetic screening programs. In the United Abnormalities in pteridine cofactor metabolism
States, it approximates I: 15,000. Phenylalanine hydroxylase requires a tetrahydrobiopterin co-
Heterozygote testing has been addressed by phenylalanine factor for the hydroxylation of the amino acid. In the course
loading tests, but while accurate when positive, this approach of the reaction, an oxidized quinonoid dihydrobiopterin is
is not reliable in excluding heterozygosity. In fact, assay of formed. This must be reduced to the tetrahydro form before
the activity of phenylalanine hydroxylase in biopsied liver may it can be active again as a cofactor. The reduction is catalyzed
be confusing, in this case because of the inability to distinguish by dihydropteridine reductase. The biopterin cofactor is syn-
the heterozygote from the homozygote. The cloning of the thesized from guanosine triphosphate through a series of steps
gene and the assessment of restriction fragment length poly- in which neopterin and sepiapterin are intermediates.
morphism has permitted the first reliable approach to the deter- Thus it is not surprising that genetically determined defects
mination of the heterozygosity. It is not available in every have turned up in the processes of cofactor metabolism that
family, but a majority of those tested are sufficiently poly- lead to hyperphenylalaninemia. Two general types of disorder
morphic to be informative. In these families the method is have been described. In one there is defective activity of dihy-
also useful for prenatal diagnosis, and the prenatal diagnosis dropteridine reductase, and in the other the defect is in biopterin
of an affected fetus has been carried out by Woo. Furthermore, cofactor synthesis.
this method should permit analysis of the samples obtained The clinical manifestations appear to be the same. Most
by chronic villus biopsy at 8-10 weeks of gestation, consider- patients have been recognized because of the presence of pro-
ably earlier than is possible with aminocentesis where at least gressive cerebral disease despite excellent control of the plasma
2 weeks would be required to grow the cells following the levels of phenylalanine. Tetrahydrobiopterin is also the cofac-
procedure at 15 weeks. tor for the hydroxylation of the tryptophan and tyrosine. There-
fore, in these patients there should also be abnormal synthesis
of serotonin, dihydroxyphenylalanine (DOPA), and norepi-
Treatment nephrine, all neurotransmitters, and this could have relevance
to the cerebral abnormalities. Involved patients are markedly
PKU is treated by providing a diet sufficiently low in phenylala-
hypotonic and spastic. They display distonic posturing. Mental
nine that the concentrations of phenylalanine in the blood are
retardation is profound, and drooling is a prominent feature.
maintained between 3 and 15 mg/dl. Infants detected in the
Seizures, including myoclonic seizures, are seen, and the EEG
neonatal screening programs and treated in this manner should
may be abnormal.
develop normally and their IQs should be in the normal range.
The diagnosis of these disorders can be made in a number
Preparations are available, such as Lofenolac (Mead-Johnson),
of ways. The simplest is the administration of tetrahydrobiopte-
which make infant feeding relatively simple, and lists of the
phenylalanine contents of foods and of low protein foods are rin. A dose of 2 mg/kg leads to a prompt decrease to normal
helpful in management. Treatment must be monitored by the in the concentration of phenylalanine in both patients with
reduct~e defects and with synthesis defects. This is so simple
regular determination of the blood concentration of phenylala-
nine. In this way one can avoid problems of poor compliance, that where the compound is available it should be given to
on the one hand, and overtreatment with signs of phenylalanine every infant with a tentative diagnosis of PKU. The patient
deficiency, on the other. with PKU will have no change in the level of phenylalanine
The time at which dietary therapy may be discontinued is following administration of the cofactor. It is important that
unclear. It appears that its stringency can be relaxed sometime the patient be on a diet containing normal amounts of phenyla-
between 6 and 15 years, but recent information indicates that lanine, not the therapeutic diet employed for patients with
some control should be continued through these years. Preg- PKU. A few patients with reductase defects have been missed
nancy in a female with PKU conveys a great risk of severe using the BH4 loading test, but Danks has pointed out that
mental retardation in the offspring. Treatment of the mother his recommendation was for parenteral administration of BH 4
and the failures have been with the oral use of the compound.
during pregnancy is of only limited effectiveness. Treatment
In those that respond, further workup consists in the assay of
begun prior to conception may be more promising, but infor-
mation is so far limited. dihydropteridine reductase in cultured fibroblasts, lympho-
blasts, or freshly isolated lymphocytes. Those who do not have
reductase defects can be studied for biologically active pteri-
dines using a bioassay with Crithidiafasciculata, high-voltage
Other disorders of phenylalanine metabolism electrophoresis, or chromatography for the pteridines of the
The advent of the screening programs has brought to light urine. Others have approached the detection of these defects
some additional disorders that were previously not recognized. in hyperphenylalaninemic patients by routinely examining the
Among these are the so-called phenylalaninemias that appear blood for BH 4 and studying the urine for pteridines using high-
to be defects in phenylalanine hydroxylase less severe than performance liquid chromatography (HPLC). This can be done
that of classic PKU. Because the enzyme is capable of partial with direct electrochemical detection in which each of the
90 William L. Nyhan

compounds is detected. More often the analysis is carried out 5-hydroxytryptophan and DOPA. Some success has been re-
of the oxidized pterins and various ratios of biopterin and ported with treatment, before the availability of the cofactor,
neopterin expressed. Patients with synthesis defects fall into with phenylalanine restriction and the administration of these
two classes. In those with a defect in the initial guanosine biogenic amine precursors.
triphosphate (GTP) cyclohydrolase step all pterins are low in
blood and urine. In patients with the more common defect in
the area of dihydrobiopterin synthetase, the concentrations of Further reading
BH4 are very low and those of the neopterin high. The ratio
Foiling, A (1934): Uber ausscheidung von Phenylbrenztraubensaure
of neopterin to biopterin is very high. In patients with reductase in den Ham als Stoffwechselanomalie in Verbindung mit Imbezilli-
defects there appears to be a lack of feedback inhibition and tat. Hoppe-Seyler's Z Physiol Chern 7.27:169
so there is massive overproduction of urinary pterins. The Kaufman S, Berlow S, Sumer GK, et al (1978): Hyperphenylalanine-
level of BH 4 is always low, but high or normal levels of the mia due to a deficiency of biopterin. New Eng/ 1 Med 299:673
other pterins have been observed. It may be that assay of the Kaufman S, Holtzman NA, Milstien, S, Butler, IJ, Krumholz, A
reductase enzyme is the only reliable way of detecting all (1975): Phenylketonuria due to a deficiency of dihydropteridine
patients with this defect. This can now be done on dried spots reductase. New Eng/ 1 Med 293:785
of blood on filter paper. Another possibility for the detection Nyhan WL ( 1984): Phenylketonuria. In: Abnormalities in Amino Acid
Metabolism in Clinical Medicine. Norwalk, Conn: Appleton-
of synthesis defects is the measurement of tetrahydrobiopterin
Century-Crofts, pp 129-148
in plasma. It is high in PKU and increases in response to a Nyhan WL, Sakati NO (1976): Phenylketonuria (PKU). In: Genetic
phenylalanine load in normal individuals or those with PKU and Malformation Syndromes in Clinical Medicine. Chicago: Year-
or with reductase defects but does not change in those with book Medical Publishers, pp 6-9
synthesis defects. Woo SLC, Lidsky A, Chandra T, et al (1983): Prenatal diagnosis
The treatment of these patients should be with tetrahydro- and carrier detection of classical phenylketonuria by cloning and
biopterin. In addition it has been recommended that these pa- characterization of the human phenylalanine hydroxylase gene. Clin
tients be treated with the serotonin and dopamine precursors, Res 31:479A
Premenstrual Syndrome
Stephanie J. Bird

Premenstrual syndrome (PMS) has become a widely recog- Premenstrual changes in physiological and psychological
nized phenomenon by the medical, psychological, and scien- states are noted by the majority of women, although they are
tific communities. Though more than 150 symptoms have been not always recognized as correlating with the luteal or premen-
associated with it, those most often described are mood swings, strual phase of the cycle. There is considerable variation in
breast tenderness, bloating, migraine headaches, irritability, the severity of these changes and in the extent to which they
and fatigue. Other symptoms commonly identified are tension, are disabling. Some women experience severe, incapacitating,
depression, anxiety, food cravings, abdominal discomfort, recurring symptoms. Many women notice detectable somatic
acne, edema, swelling of the extremities, and dizziness. De- and psychological changes which are not so severe that they
pending upon the symptoms and their severity, premenstrual are subjectively (or objectively) considered incapacitating or
changes may be simply an annoyance, or, if sufficiently severe even sufficiently troubling to be thought of as a syndrome
or prolonged, they can be incapacitating. (i.e., indicative of an underlying disease process). Some
PMS is not easily defined. It is clear that it is distinct from women detect changes, such as increased energy, creativity,
dysmenorrhea, the painful cramping associated with menstrua- and sex drive, which they consider positive. A relatively small
tion, and the result of elevated levels of prostaglandins. There number of women note no changes at all. Thus, there is a
is controversy regarding the number and combinations of continuum of symptomatology, and only those premenstrual
symptoms, their time course, and their severity, as well as changes sufficiently severe to be troubling or incapacitating
their etiology. Some researchers believe that there may be as can justifiably be identified as PMS.
many as four or five different types of PMS. Abraham has Because of its link with the menstrual cycle, the majority
identified a major depressive syndrome including depression of current hypotheses regarding the pathogenesis of PMS pos-
and insomnia, a water retention syndrome marked by edema tulate some type of sex hormone-associated disorder. This
and bloating, an anxiety syndrome, and an increased appetite seems feasible since steroid receptors have been localized to
syndrome. Endicott, Halbreich, and colleagues have also ob- neurons in various brain regions and the influence of steroid
served the major depressive and water retention syndromes, hormones on the sensitivity of those neurons to other endoge-
but describe a general discomfort syndrome, an impulsive syn- nous neuroactive substances has been demonstrated, i.e., part
drome, and an impaired social functioning syndrome rather of the effect of these hormones is to modulate the effect, and
than the anxiety and increased appetite syndromes. General thus action, of other neuroactive substances. In addition to
discomfort syndrome includes headaches, back, joint, or mus- the direct action of steroid hormones on neuronal function,
cle pain, and abdominal discomfort. Impulsive syndrome in- however, there is increasing recognition of the role of other
cludes any two of the following characteristics: violent con- compounds associated with the hypothalamic-pituitary-repro-
duct, lack of self-control, impulsive behavior, and outbursts ductive organ axis, such as the gonadotrophins and releasing
of irritability. Impaired social functioning syndrome is a com- hormones, in central nervous system function. Thus, it is likely
plex of any three of eight symptoms including an increased that sex hormones and other endogenous compounds associated
tendency to "nag," mood changes, social withdrawal, and with the reproductive cycle are involved in aspects of brain
decreased activity. It should be noted that not all clinicians function not considered components of reproductive function.
specializing in PMS find the symptom clusters described, but Until recently a widely held view had been that menstrual
instead find that their patients report symptoms which cut disorders are psychological in origin, arising from personality
across the groups, most frequently mood swings, migraines, maladjustment or neuroticism and lack of acceptance of the
breast tenderness, and bloating. feminine role. In a critical review, Gannon has found that
In theory, PMS is by definition premenstrual, i.e., symptoms studies which putatively support that theory lack appropriate
recur cyclically prior to the onset of menses and cease with data upon which to base such conclusions. The precise nature
the beginning of menses. However, several variations in the and etiology of PMS are unclear. However a number of find-
pattern of symptom occurrence have been observed. First, ings indicate it has physiological rather than psychological
symptoms may continue into the menses rather than ceasing roots. There is common experience of premenstrual changes
with the onset of menstrual flow, and thus are more accurately among women of widely divergent educational and cultural
para- or perimenstrual. Second, although symptoms may occur backgrounds, a continuum of symptom severity across individ-
only pre- or paramenstrually, for some women symptoms occur uals, and the observation of premenstrual changes in behavior
at ovulation and either (1) disappear and recur premenstrually, in primates. Furthermore, the premenstrual, rather than men-
(2) continue, gradually increasing in severity, until menstrua- strual, occurrence of PMS coupled with the fact that few
tion, or (3) continue at maximum severity throughout the luteal women actually have 28-day cycles or even cycles of regular
(postovulatory) phase. For a diagnosis of PMS, clinical consen- duration, and therefore rarely know precisely in which phase
sus requires that prospective monitoring demonstrate the of their cycle they are (other than the menstrual phase )-make
marked diminution, if not disappearance, of symptoms during a purely psychological aetiology difficult to explain. However,
the postmenstruum and until ovulation. discussion of somatogenic as opposed to psychogenic origins
92 Stephanie J. Bird

draws a somewhat artificial dichotomy: while hormones influ- Further reading

ence higher brain function including behavior, behavior affects Abplanalp JM, Haskett RF, Rose RM (1980): The premenstrual syn-
hormone levels and activity. In addition, societal pressures drome. Adv Psychoneuroendocrinol 3:327-347
have a direct influence on brain function through their effect Abraham GE (1980): Premenstrual tension. Curr Prob Obstet Gyn
on how the individual perceives her environment, the presence 3(12): 1-39
of threats and danger, her own ability to affect the world, Endicott J, Halbreich U, Schacht S, Nee 1 (1981 ): Premenstrual
and so on. Additional research is under way to clarify the changes and affective disorders. Psychosom Med 43:519-529
effect of stress on PMS, the possible relationship of PMS to Gannon L ( 1981 ): Evidence for a psychological etiology of menstrual
psychiatric disorders, and the influence of sociocultural factors. disorders: a critical review. Psycho/ Rep 48:287-294
PMS, like other complex behaviors, is the result of dynamic Reid RL (1985): Premenstrual syndrome. Curr Prob Obstet Gyn and
lnfertil. 8(2): 1-57
interactions of various social and psychological, as well as Reid RL, Yen SSC (1981): Premenstrual syndrome. Am J Obstet
neurobiological factors. Gyn 139:85-104
Psychiatry, Biological
Herbert Pardes

Biological psychiatry covers an extensive and rapidly changing tions and delusions), but for interpersonal difficulties, psycho-
area. Limited in the 1950s and early 1960s largely to psycho- social approaches focusing on the family appear necessary
pharmacology, some attempts at diagnosis, and early broad- along with attention to the patient's psychosocial needs (work,
brush attempts at explicating etiology (most notably through income, housing friends, etc.). This use of multiple interven-
genetics), the advance of biological psychiatry grew steadily tions has its parallel in the use of combined pharmacotherapeu-
in the succeeding fifteen years, and today it is flush with excite- tic and psychotherapeutic intervention in anxiety and depres-
ment. What follows are some major trends and investigative sive disorders.
lines. Tardive dyskinesia is an omnipresent liability in the use of
phenothiazines. A syndrome characterized by involuntary
movement of face and extremities, it is estimated to affect
Psychopharmacology 14% of patients who have four years of cumulative neuroleptic
Prior to the use of drugs, psychiatric treatment was limited exposure. Theories that it is caused by dopamine hypersensitiv-
to convulsive therapies, some psychotherapies, removal of the ity remain to be proved, and various treatment strategies (inter-
patient from the ostensibly traumatizing environment, and vari- mittent treatment, low doses) are being explored.
ous rest and rehabilitation strategies. The introduction of phe- Electroconvulsive therapy is used for some patients with
nothiazines for psychotic symptoms allowed the return of state affective disorders and for some catatonic patients. Carbamaze-
hospital patients to the community. Subsequent development pine, a drug previously used as an anticonvulsant, has been
of monoamine oxidase (MAO) inhibitors, benzodiazepines, effective in some manic-depressive patients who are unrespon-
tricyclics, and lithium enlarged the therapeutic armamentarium sive to lithium.
while bringing many side effects. Psychopharmacology may benefit from such new technology
Benzodiazepines have proved useful for relief of anxiety as positron emission tomography (PET) which may determine
and also as a substitute for sedative and hypnotic drugs. Addic- in advance the relative action of new drugs on major target
tion and withdrawal syndromes complicate their use. Current receptors versus their unintended influence on other receptors.
approaches (Shader and Greenblatt) stress nonpharmacological The explanation, mitigation, and prevention of tardive dyskine-
methods as treatment of choice in situational and nonincapaci- sia and the sorting out of differential values of various drugs
tating anxiety. When anxiety is severe and prolonged, adjunc- for specific conditions (even antidepressants now have been
tive treatment is appropriate with antidepressants for phobic found to have substantial antianxiety effects) are major themes
and panic states, and anxiolytics (e.g., benzodiazepines) for in psychopharmacology research.
generalized anxiety disorder and mixed anxiety and depression.
While benzodiazepines are currently the drug of choice among
anxiolytics, newer nonbenzodiazepine compounds may pro- Diagnosis and epidemiology
vide increased safety. The third edition of the Diagnostic and Statistical Manual
The tricyclics enjoy preeminence for the treatment of depres- on Mental Disorders (DSM-111) of the American Psychiatric
sion, though lithium (which is effective in 70% of cases of Association, the recently introduced system for psychiatric
manic-depressive illness) is available along with various diagnosis, reduced the stress on clinical inference in favor of
proven psychotherapies. While lithium is especially helpful observable phenomena as a basis for diagnosis. While chal-
in preventing recurrences of mania, tricyclics have recently lenged as discarding the value of inference and implying clo-
been shown far more effective in preventing recurrences of sure on diagnosis prematurely, DSM-III has increased the reli-
depression in unipolar depressives and in treating the acute ability of psychiatric diagnosis. It exemplifies a move in
unipolar depression itself. Adding lithium to a tricyclic (e.g., psychiatry to greater refinement and differentiation generally.
imipramine) does not increase effectiveness. Lithium is as ef- Using refined interview techniques and scales based on symp-
fective as imipramine in preventing recurrent depressions in toms and disease syndromes rather than on general psychologi-
a bipolar illness, but adding imipramine to lithium does not cal function and well-being, psychiatric epidemiology has been
increase effectiveness. developing more solidly based data on the incidence and preva-
Choice of treatment for depression is especially important lence of the mental disorders estimated to plague 33 to 38
in the elderly for whom depression is the most common emo- million Americans.
tional disorder. The many second-generation drugs now avail- Subtyping of affective disorders has been followed by sub-
able makes picking correct treatment more complicated. typing of anxiety disorders. Some evidence suggests that panic
MAO inhibitors have enjoyed a revived use after earlier anxiety is qualitatively separable from other anxiety disorders.
disfavor due to side effects. They are now being invoked in- Vulnerable subjects may have attacks precipitated with labora-
creasingly for affective disorders, anxiety states, and phobias. tory infusion of lactic acid. Furthermore, antidepressants may
For schizophrenics pharmacologic agents (e.g., phenothi- selectively suppress panic attacks.
azines) can alleviate the most disruptive symptoms (hallucina- Subtyping schizophrenia has been generally acknowledged
94 Herbert Pardes

as a commendable research strategy. Still, no biological marker ports the idea of transmission from affected to nonaffected
has been fully accepted in psychopathology. Perhaps shifting individuals. A viral transmission has been postulated in indi-
the biological marker from the dependent variable to an inde- viduals who may otherwise be genetically predisposed. Other
pendent criterion would allow new diagnostic entities created suggestions include that of an underlying autoimmune mecha-
around a marker rather than around symptoms. nism.
Laboratory tests, hitherto unused in psychiatric diagnosis, As mentioned earlier, subtyping of schizophrenia with an
appear increasingly likely to prove of value. The dexametha- attempt to delineate smaller and more homogenous categories
sone suppression test (DST), a test based on the existence in of disease that might be more readily susceptible of solution
many depressed patients of an abnormal cortisol response to is an important current research perspective. Also treatment
the synthetic steroid hormone dexamethasone, while of little has assumed a multimodality character, given the failure of
value in general medical settings, may have some value as a drugs alone to control symptomatology and restore function.
confirmatory test in endogenous or major depressive disorders. Alzheimer's disease, a neuropsychiatric disorder affecting
Sensitivity and specificity vary greatly, however, in different some 6% of people over 65 and increasing to as high as 20%
clinical settings. Though currently limited in value DST, thyro- in the mid-80s is also the most common cause of mental deteri-
tropin-releasing factor (TRF), and possible urinary tests for oration. With a projected increase in the over-65 population
selecting appropriate treatment in depression all point to in- to some 18% of the U.S. population from the current figure
creasing laboratory participation in clinical psychiatry. of 11%, the projection is for larger numbers of patients with
Alzheimer's. This disease attacks many cognitive functions
and perniciously nullifies the personality. As many as 15%
Psychiatric disorders
of the cases represent a misdiagnosis of depression; this is
Nearly one in four women and one in ten men will suffer important because depression is treatable.
depression some time in their lives. This is a treatable disorder Some patients with Alzheimer's disease may have a genetic
with estimates of 80-90% of depressions responding to inter- basis. Other research has shown that acetylcholine-releasing
vention. The most tragic complication is suicide, which befalls neurons with cell bodies in the basal forebrain selectively de-
some 15% of people suffering from depression. Suicide has generate in Alzheimer's disease. These cholinergic neurons
risen dramatically in adolescents between 15 and 24, young innervate widely the cerebral cortex and related structures and
urban blacks, and the elderly. The course of depression has apparently play a major role in cognitive functions, especially
been found to be more pernicious than earlier thought with memory.
about 20% of people with depression continuing to be ill 2 Attempted treatments to this point have been only effective
years later and another 30-40% having a recurrent episodic in modifying some of the secondary symptoms such as the
course. behavioral disturbances which are part of the. disorder. For
Attempts to understand the etiology of depressions have the basic cognitive deterioration, attempts to capitalize on the
evoked a continuing debate as to the importance of endogenous cholinergic theory with treatments that restore acetylcholine
versus environmental factors. It is suggested that some individ- activity have to this point proved ineffective. An interesting
uals have a genetic predisposition to develop affective disor- similarity in the pathology found in older patients with Dpwn's
ders. Attempts to tie psychiatric disorders to neurotransmitter syndrome and those with Alzheimer's disease has been noted,
correlates is so far seen as generally simplistic. but· its significance is not understood.
The tie between the brain pathways that use norepinephrine These are a sampling of the many clinical psychiatric disor-
as a transmitter and depression has been bolstered by experi- ders. The principles of subtyping and increasing refinement
mental evidence. However, the evidence has suggested various and differentiation characterize the current evolution of clinical
mechanisms to account for the relationship. These range from psychiatry. This refinement should be fostered further by the
decreased function to overactivity for norepinephrine-using many dramatic developments in neuroscience such as imaging
neural pathways. The continuing accretion of findings substan- techniques, molecular genetics in its application to neurobiol-
tiating such a relationship, yet appearing at times to be directly ogy and behavior, the enhanced capacity for detecting neuro-
contradictory as to the mechanism, account for some of the transmitters, mapping and quantifying receptors, and the
pessimism and catalyze the examination of still other ways emerging research on the biology of higher functions. This
by which the norepinephrine system and perhaps other neuro- latter focus on the interface of biology and behavior is of
transmitter systems may be linked with depression. There is particular consequence for psychiatry since the disorders with
hope newer mechanisms for determining genetic markers may which it deals are largely abnormalities of behavior. The vigor
catalyze the investigation of the etiology of affective disorders. of the neuroscience developments with their implications for
There is considerable evidence that children of parents with understanding behavior and fostering its favorable modification
affective disorders are at significant risk for a variety of behav- suggests that the next 10-20 years will show substantial ad-
ioral abnormalities out of proportion to other children in the vance in the differentiation of psychiatric concepts and clinical
population. application.
Schizophrenia, which affects some 1% of the population,
is the core psychiatric disorder that probably attracts the most
Further reading
public attention. Deinstitutionalization policies, which offered
some benefit in getting long-standing inhabitants of state hospi- Buschsbaum MS, Haier RJ (1983): Psychopathology: Biological ap-
tals back into the community, have also had the effect of proaches. Annu Rev Psycho[ 34:410-430
pouring into the streets a large number of homeless people. Coyle JT, Price DL, Delong MR (1983): Alzheimer's disease: A
Furthermore, the disease, which affects young adolescents and disorder of critical cholinergic innervation. Science 219:1184-1190
Goldin ER, Gershon EJ (1983): Association and lineage studies of
young adults particularly at the onset, is crippling in function genetic marker loci in major psychiatric disorders. Psychiatr Dev
and evokes public attention by virtue of its florid symptomatol- 1:387-418
ogy. Kandel ER (1979): Psychotherapy and the single synapse: The impact
Genetic predisposition to some schizophrenias seems sure. on psychiatric thought on neurobiological research. N Eng[ J Med
However, some familial and epidemiological evidence sup- 301:1028-1037
Psychoanalysis
Charles Brenner

Psychoanalysis denotes a form of therapy that is, at the same unimportant, but, in fact, it is crucial. An independent ob-
time, a source of psychological data. The word also denotes server, provided he is experienced and unprejudiced, can learn
the theories or generalizations derived from those data. As far more about the aspects of mental functioning that are sub-
an investigative technique, the psychoanalytic method seems jectively important than anyone can learn by introspection.
the best method currently available for the study of a certain During the century since Freud devised the psychoanalytic
aspect of the functioning of the human cerebral cortex, namely, method and began to apply it, more has been learned about
the aspect which includes ideas, thoughts, plans, fantasies, the mind than during all the centuries that preceded Freud's
emotions-in brief, whatever persons feel to be of prime im- work. At present the psychoanalytic method is the best means
portance to them in their mental lives. we have for studying this aspect of the functioning of the
Before the development of the psychoanalytic method, these human cerebral cortex.
data, usually called subjective data, were observable in a sys- Psychoanalysts assume that the mind is like every other
tematic way only by introspection. The findings of introspec- aspect of mass/energy in space/time in that it is accessible to
tion were obviously unreliable, but the reason for their unreli- scientific study in the usual way. Although psychoanalytic
ability was not apparent until the psychoanalytic method was data are subjective, psychoanalysts deal with them in ways
introduced. Data made available by the psychoanalytic method which are no different in principle from the ways in which
show that all persons are at pains to conceal or disguise from any scientific investigator deals with data. Psychoanalytic gen-
themselves many important motives for thought and behavior. eralizations or theories are like any other scientific theories
Thus the data of introspection have been systematically falsi- with respect to their relationship to data of observation.
fied by the observer, whatever effort the observer may have Among the findings of psychoanalysis, the ones of most
made to report them honestly. general importance have to do with psychic determinism and
The psychoanalytic method is superficially simple. Two peo- with unconscious mentation. Other important generalizations
ple meet daily for a convenient period of time, usually 50 have to do with childhood sexuality, with the importance of
minutes, in a setting designed to minimize extraneous stimuli: pleasure seeking (libidinal) and aggressive motives in mental
a quiet room with a couch on which the subject (analysand) life, and with the importance of psychic conflict related to
can lie comfortably and a chair on which the observer (analyst) libidinal and aggressive wishes originating in childhood. Be-
can sit out of range of the analysand's vision. The analysand cause it began as psychotherapy, psychoanalysis was, at the
speaks, the analyst listens. In addition, there is an agreement start, primarily concerned with the nature and origin of psycho-
between the two that is of fundamental importance to the genic symptoms. Thus its theories about sexuality and psychic
method itself. The analysand undertakes to tell without reserve conflict were, at first, discoveries about psychopathology.
whatever he is aware of, whatever is passing through his mind, Their significance was soon extended, however, and by now
whether it be thoughts, emotions, or physical sensations. The the psychoanalytic theory of conflict relates to normal psychic
analyst agrees to restrict himself to listening, to trying to make phenomena as well as to pathological ones. The study of the
sense of what he hears and otherwise observes (bodily move- psychic significance of dreams, of everyday slips and errors,
ments, tears, laughter, tone of voice, etc.) and to communicate and of jokes were of particular importance for this develop-
his conclusions to the analysand from time to time. It is essen- ment.
tial to add that the analysand is a patient and the analyst a The psychoanalytic method continues to be a specialized
therapist. The one comes to the other for help with whatever form of psychotherapy which requires a course of specialized
psychogenic distress (symptoms) he is suffering from. The training to master. The findings (psychological theories) of
analyst offers the prospect of cure or improvement. The appli- psychoanalysis, however, are of very general significance. A
cation of the psychoanalytic method is of necessity limited knowledge of them is indispensible to all who are seriously
to a therapeutic situation for an obvious reason. It is only in concerned with humankind and its works, i.e., to students of
a therapeutic situation that one person will speak to another behavior, of the social sciences, of art, of literature, and of
without reserve for 50 minutes a day for an extended period general psychology no less than to psychotherapists.
of time.
It is apparent that the data made accessible by the application
of the psychoanalytic method are the same in kind as the Further reading
data of introspection. They are subjective, psychical data. The Brenner C (1973): An Elementary Textbook of Psychoanalysis. 2nd
difference between the two methods is that in the one case ed. New York: International Universities Press
the data are observed by the subject, in the other, by an inde- Brenner C (1982): The Mind in Conflict. New York: International
pendent observer (analyst). The difference seems, a priori, Universities Press
Psychopharmacology
Susan D. Iversen

Psychopharmacology is concerned with the effects of drugs punishing stimuli, like electric shock. The benzodiazepine mi-
on animal and human behavior. It encompasses any chemical nor tranquilizers have the opposite profile. Accordingly, pun-
that influences behavior by a direct or indirect effect on the ishment procedures are essential for screening new anxiolytic
central nervous system. Drugs can be self-administered to alter drugs.
normal behavior or clinically administered to control abnormal To cite another striking example, electric shock presented
behavior; they can be administered acutely or chronically; and on schedules of punishment suppresses behavior, but in differ-
they can prove toxic in the long term. Psychopharmacology ent circumstances animals learn a new response to terminate
is a relatively new but rapidly developing branch of natural or avoid the same shock (negative reinforcement). Chlordiaze-
science that evolved from the discovery that organisms do poxide (CDP) abolishes the suppression of response to a pun-
not behave randomly but lawfully as defined by the structure ishing stimulus but the antischizophrenic drug chlorpromazine
of the environment. In much the same way that antihyperten- does not. In contrast, the antipsychotic drug impairs escape
sive drugs modify the relationships of the cardiovascular sys- and avoidance behavior, but CDP does not.
tem and control harmful high blood pressure, so psychoactive However, some drug effects are not readily reflected in
compounds result in orderly modifications of behavior. There changes in the response rate or pattern. Within this category
are a number of outcomes to this discovery: the classification are drugs which cause changes in sensory thresholds, discrimi-
of drugs by their effects on normal animal or human behavior, nation, and memory processes. Here it is sufficient to present
rather than by physiological, biochemical, or pharmacologic a stimulus and to determine the probability and accuracy of
criteria; the use of drugs as tools for probing the normal organi- the response to that stimulus. Failure to detect the stimulus,
zation of psychological processes underlying behavior in ani- discriminate it from others, or to retain the information results
mals and humans; and a rational use of drugs to control and in loss of performance. The physical characteristics of the
restructure abnormal behavior. stimulus or the period of time for which it has to be retained
Learning theorists have been defining the parameters of be- can be varied to assess the limits of threshold, discriminability,
havioral control throughout the 20th century, but B.F. Skinner and memory. Discrete trial procedures serve these purposes.
introduced the technology for precisely establishing and mea- In these procedures, the animals are not free to respond at
suring learned responses. The free operant method, derived all times, but instead, the exposure to the situation in which
directly from Skinner's work, depends on quantifying rates the animal can respond is divided into discrete periods, called
of performing a particular act, like lever pressing or key peck- trials. Typically, one or more stimuli are presented in conjunc-
ing. Rates of responding can be sensitive indices of motivation, tion with each trial, and performance is measured in terms
emotion, arousal, and motor performance and of the effects of the probability of emitting the correct response in relation
of drugs on such mechanisms. Reinforcement and punishment to those stimuli. Such methods are widely used in human
or, in everyday terms, pleasant and unpleasant events deter- experimental psychology, and sophisticated methods of analyz-
mine the rate and pattern of conditioned responding. The prob- ing response probabilities are available.
ability of occurrence of a response increases if followed by a Many psychoactive drugs influence the visceral nervous sys-
reinforcement, but if followed by punishment its occurrence tem. It is known that this sensory information reaches the
decreases. Though an animal in a free operant situation is brain and no doubt contributes to the accuracy with which
free to respond at any time, the schedule on which the reinforc- animals and humans are able to distinguish different drug
ing or punishing event is presented determines the subsequent states. Unconditioned visceral stimuli come to modify subse-
rate and pattern of response. A fixed-interval schedule of rein- quent behavior by the process of classical conditioning; after
forcement (reward at regular intervals of time) results in pauses pairing of a neutral signal with an unconditioned stimulus
followed by bursts of responding before the next reward. Ratio which elicits a specific unconditioned response, the neutral
schedules (reward after a set number of responses), however, stimulus comes to elicit that response. Attention is now being
generate sustained high rates of response with very brief post- given to drugs as unconditioned stimuli, but equally important
reinforcement pauses. Multiple schedules can be programmed is the effect of drugs on established classically conditioned
to generate varying rates and patterns of response over time. responses of the autonomic nervous system.
Psychoactive drugs from different classes modify schedule Finally, the study of such instinctive unlearned behaviors
controlled behavior in characteristic ways, and if a battery of as feeding, drinking, mating, rearing young, arousal, aggres-
schedules involving rewarding and aversive stimuli is used a sion, and exploration, all implicated in fundamental homeosta-
profile for a particular drug class can be defined. For example, sis, provides a new impetus for psychopharmacology. Direct
stimulant drugs like amphetamine and minor tranquilizers, like observation is the most appropriate for studying the effects
chlordiazepoxide (CDP) or diazepam, change behavior main- of drugs on such mechanisms. In many neuropsychiatric condi-
tained by reinforcement schedules in opposite ways; ampheta- tions disturbances of motivation and emotion are more dramatic
mine enhances low response rates on interval schedules but than those of cognition.
does not release responses suppressed by the presentation of Twenty years ago very little was known about the effect
 Psychopharmacology 97

of psychoactive drugs on the biochemistry and the electro- same behavioral response. But equally important, the environ-
physiology of the brain. The revolution that has taken place ment in which the drug is experienced becomes part of the
in neuropharmacology has shown how many psychoactive tolerance syndrome. Physiological tolerance to the analgesic
drugs modify the chemical and electrical properties of brain. effect of morphine is readily demonstrated, but if morphine
In the early days of behavioral pharmacology it was neither is administered repeatedly in a highly discriminable environ-
necessary nor possible to implicate real brain mechanisms in ment and analgesia testing is performed in an equally dis-
the account of how drugs lawfully modified behavior. The criminable but different environment, the degree of tolerance
challenge now is to complete the equation and understand seen on the pain threshold response is significantly reduced.
how drugs influence the brain mechanisms underlying behav- It is believed that the change in the drug response becomes
ioral organization. A number of animal models have developed classically conditioned to the stimuli of the environment. These
to predict psychoactive drug actions in humans. For example, findings have important implications for the control of human
models in which basal ganglia dopamine function is depressed, drug addiction since it is claimed that withdrawal from the
enhanced, or unbalanced by dopamine receptor antagonists, drug is unlikely to succeed if the stimuli conditioned to the
used to treat schizophrenia, provide a sensitive behavioral in- drug state (e.g., syringe and needle paraphernalia, street corner
dex for comparing the potency of novel dopaminergic drugs. drug scene) continue to influence the drug-seeking behavior
The revolution in neuropharmacology has also encouraged of the addict.
the view that since therapeutically useful drugs interact with Many other variables influence the response to a psychoac-
neurotransmitters in brain, it is possible that neurochemical tive drug; tolerance to the physiological effects of the drug,
imbalance underlies the neuropsychiatric conditions in which genetic makeup, psychological set at the time the drug is taken,
they are beneficial. It seems worthwhile therefore to use such behavioral history, and experience with other drugs. Although
knowledge to develop animal models of the abnormal behav- it is difficult to predict drug response, the technology of behav-
iors seen in illness. Psychoactive drugs may then be evaluated ioral pharmacology provides the means to do so.
for their ability to restructure abnormal behavior patterns. Phar-
macologic, neurological, or environmental variables may be
manipulated to modify and disrupt behavioral baselines. For Further reading
example, chronic amphetamine administration in a range of Cooper JR, Bloom FE, Roth RH ( 1982): The Biochemical Basis of
species, but especially in monkeys, induces a form of psychotic Neuropharmacology, 4th ed. Oxford: Oxford University Press
behavior likened to schizophrenia; electrical stimulation of the Heise GA, Milar KS (1984): Drugs and stimulus control. In: Hand-
noradrenaline neurons of locus coeruleus in monkeys induces book of Psychopharmacology, vol 18, Iversen LL, Iversen SD,
a behavioral profile including intense fear reactions and anxi- Snyder SH, eds. New York: Plenum Press, pp 129-190
ety; and chronic unavoidable shock induces a form of behav- Iversen SD, Iversen LL (1981): Behavioural Pharmacology. New
ioral despair, characterized by immobility and withdrawal York: Oxford Press
Morse WH, McKearney JW, Kelleher RT (1977): Control of behavior
which has been likened to human reactive depression.
by noxious stimuli. In: Handbook of Psychopharmacology, vol 7,
Whether psychoactive drugs are used to enhance perfor- Iversen LL, Iversen SD, Snyder SH, eds. New York: Plenum Press,
mance or control abnormal behavior, the response to the drug pp 151-180
does not remain constant over time. Psychological tolerance Wikler A (1965): Conditioning factors in opiate addiction and relapse.
is the most striking example of this, which results in larger In: Narcotics. Wilmer DM, Kassenbaum GG, eds. New York:
and larger doses of the drug being required to achieve the McGraw-Hill, pp 85-100
Psychosis
Gardner C. Quartan

A psychosis is a human behavioral state characterized by delu- began to be studied. These included pathology of sexual behav-
sions, hallucinations, incoherent communication, loosening of ior such as the perversions, episodes of severe obsessive com-
association between ideas, markedpoverty of content of pulsive thinking and behavior, phobic behavior, episodes of
thought, markedly illogical thinking, or behavior that is grossly anxiety and panic, and some disorders of memory, sensation,
disorganized or catatonic. The term is unsatisfactory for scien- and motor function, strongly influenced by suggestion and
tific purposes. hypnosis. This group came to be called the psychoneuroses
A brief review of the history of the use of the term will in contrast to the other disorders of behavior known as psy-
demonstrate shifts in meaning that are still confusing today. choses. By the mid-20th century psychoneurosis was shortened
In late Greek psychosis was used to connote animation or to neurosis, and the neat nomenclature of the 19th century
the principle of life. Greek and Roman physicians used terms was destroyed, leaving in its place confusion over mind-body
based on other roots, e.g. , insania and furia, to refer to mental issues, the intent of the user with respect to the importance
illnesses we would label as psychotic. During the middle ages of nervous system changes etiologically, and with many of
and even up to the beginning of the 19th century, individuals, the connotations of the older usage pattern arising intermit-
today regarded as ill, were believed by Europeans to be pos- tently and irregularly.
sessed by the devil. With the increasing impact of rationalism This shift in usage required a set of criteria for distinguishing
and the scientific method, on the one hand, and humane con- a psychotic state from a neurotic one. Three different types
cern for the unfortunate, on the other, the recognition devel- of criteria were used between 1950 and 1980, sometimes sepa-
oped gradually that the condition of these individuals need rately, sometimes combined, but rarely with clarity. Each of
not be explained by supernatural phenomena. This induced these can be found in medical dictionaries.
the doctors of the time to look for causes of mental illness in The first criterion is based on the assumption that a given
correlations between the clinical manifestations of illness and episode of illness can be ranked on a single scale of serious-
pathology recognized in the tissues of the body at autopsy. ness. The psychotic states are serious; the neurotic, less so.
However, the effort to identify tissue pathology correlated This usage is unsatisfactory because it is difficult to identify
with the behavioral disorders created a special problem not a single dimension of seriousness along which all mental illness
present for other illness. The abnormal thinking of the individ- can be ranked, because it does not provide an easy and opera-
ual, who 100 years later would be called psychotic, seemed tional way of establishing the cutting line that divides the
to involve another ontological category, the realm of the mind neuroses from the psychoses, and because some neurotic states
or spirit. In other words, the same factors in Western cultural seem at times to be more serious than some of the milder
and intellectual history that Jed to the distinction between mind conditions still identified as psychoses.
and body, and to the distinction between materialism and ideal- The second criterion is based on the concept of the presence
ism, created a need to distinguish a substrate that was patholog- or absence of insight. The psychotic individual is said either
ical in ordinary bodily disease from that substrate that was not to know that he is sick, or if he understands that others
pathological in mental disease. In the first half of the 19th believe him to be sick, he does not share this belief. The
century, the term neurosis referred to an abnormal state of neurotic individual, in this usage of these terms, has some
the nervous system, i.e., of the body, and a correlative term, understanding that his condition is pathological; however, he
psychosis, referred to an abnormal state of the mind. still cannot control it, and his suffering and inconvenience
Four features of the use of the terms neurosis and psychosis are real. This criterion is also unsatisfactory for scientific pur-
in much of the 19th century must be kept in mind. First, the poses because the presence or absence of insight is both infer-
user needed to believe that the mind was, in some metaphysical ential and not easy to justify on the basis of evidence. It is
sense, a different realm of being from the body. Second, the difficult to establish any set of operations that provides an
one who employed the word psychosis did so with the under- unambiguous cutting line that says how little insight you have
standing that the psychoses exhausted the domain of psycho- to have to be called psychotic.
logical pathology. Third, this definition of psychosis is conno- The third criterion is based on the presl!nce or absence of
tative rather than denotative, and it does not help in defining specific signs or symptoms of the abnormal condition. The
the lower threshold of unusual behavior that establishes abnor- third edition of the Diagnostic and Statistical Manual of Mental
mality. In other words, the normative problem is ignored and Disorders of the American Psychiatric Association ( 1980)
the need to create a clear criterion for the threshold is evaded. (DSM III), for instance, identifies as psychotic symptoms,
Last, the psychiatrist of the 19th century was quite comfortable the following: delusions, hallucinations, incoherence, loosen-
inferring pathology in either the mind or nervous system when ing of associations, markedly illogical thinking, and behavior
the evidence for that pathology was not particularly good. that is grossly disorganized or catatonic. This criterion has
Unfortunately this uniform pattern of usage was not to last. the advantage that it represents an effort to establish specific
Late in the 19th century a new group of mental disorders conditions that have to be met if an illness is to be called a
 Psychosis 99

psychosis. It has the disadvantage that it is a disjunctive defini- genes at conception, (2) factors in the fetal environment influ-
tion. One individual may be declared psychotic because he encing brain development, (3) factors in the postfetal brain
has delusions but is otherwise apparently normal; another, environment that alter brain structure or function, e.g., drugs,
because he shows disorganized behavior. This can lead to infection, nutrition, tumors, trauma to brain, etc., and (4)
subsets of patients that may have quite different clinical pic- factors in the postfetal environment that act through sensing
tures and prognoses, and where the etiological patterns may and coding systems of brain, e.g., sensory deprivation, mean-
tum out to be based on different classes of determinants. Fur- ing deprivation, deficient or atypical learning, or stress-all
thermore, each of these criteria is based on inference, and conditions that can alter brain programming.
there is a normative element that may depend on the culture In manic-depressive and schizophrenic psychoses there is
and educational level of the user. Furthermore, failure to detect evidence for a role of genetic factors. The presence of a specific
the presence of one of these features does not always mean genotype, however, is insufficient to completely determine
it is not present. the psychotic behavior because individuals who have inherited
Behaviorism (particularly radical behaviorism), positivism, the required genotype do not always manifest psychosis. It is
and analytic philosophy, in the first half of the 20th century, not known whether all schizophrenic-like individuals have an
were strongly antimetaphysical, and therefore, those influenced abnormal gene product playing an etiological role. The genes
by them attempted to solve the mind-body problem in a non- play a predisposing or determining role in some but not all
metaphysical fashion. The separation of mind and body was the other psychoses.
treated as a category mistake. (It would be a category mistake Factors in the fetal environment that influence brain develop-
to believe that a university and the buildings of that university ment, if they affect behavior, are most likely to produce mental
were two separate entities rather than two linguistic ways of retardation syndromes. Sometimes this retardation is accompa-
describing the same entity.) Under this interpretation, the cre- nied by episodes of psychosis. In the absence of retardation,
ation of an entity called mind is a category mistake. Delusions, disorders of development probably contribute to psychosis later
and the other defining features of psychosis, are considered in life, but clear-cut evidence for this is not yet well estab-
patterns of function of the brain. lished.
Sociologists have pointed out that whether a person in a Environmental influences after birth, affecting brain directly,
given society is called psychotic or not is a function of the are well known to produce psychosis, even if there is no evi-
characteristics of the response to that person by the other people dence for a psychotic genotype. Brain tumors in the frontal
in the society. Erving Goffman has argued that a psychotic and temporal lobes are sometimes associated with psychotic
person fails to follow the complex rules that govern verbal behavior. Other forms of gross brain pathology, particularly
and nonverbal interpersonal interactions, particularly between in the temporal lobe and when accompanied by seizures, can
strangers. This may be because the individual does not know produce abnormal behavior often misdiagnosed as schizophre-
the rules, knows them but is, for some reason, incapable of nia. Neurosyphilis was a common cause of psychotic behavior
following them, or simply does not follow them because he characterized by grandiose delusions until about 1940 when
is engaged with an agenda of his own that is incompatible treatment produced a dramatic reduction in prevalence of neu-
with his paying attention to these rules. The observer may rosyphilis. Meningitis and encephalitis due to a variety of
not be able to discriminate among these, and that is why for- organisms occasionally produce psychotic behavior. Nutri-
eigners and handicapped persons are often thought, errone- tional, metabolic, and endocrine disorders sometimes become
ously, to be suffering from a mental disease. A small group important determinants of odd behavior. A large number of
of sociologists and psychiatrists have taken the position that drugs, acting on the brain in different ways, can contribute
there is no such thing as mental illness; there is only the to the development of psychosis. One of the most interesting
labeling of patterns of behavioral deviance. This extreme posi- of these is amphetamine, which can produce psychotic signs
tion ignores the brain events that many scientists believe are in some rare individuals with doses as low as 20 mg but
necessary to abnormal behavior. This argument is challenging, which will do so in almost any individual if the dose is suffi-
however, because it calls attention to the limits of behaviorism ciently high. Some drugs that produce psychosis act on the
by making it clear that the patterns of behavior of the psychotic catecholamine transmitter systems, others are anticholinergic,
individual that seem odd may be based on the discrimination still others are sedative. Many drugs that can produce a psycho-
by the observer of very subtle peculiarities in interpersonal sis are not yet well understood.
interaction rather than on the detection of well established Factors in the environment that act through sensory and
signs of illness, and that this discrimination will depend on coding systems of the brain are more difficult to evaluate. A
the cultural pattern of both the psychotic and the observer, significant number of individuals who appear to have no evi-
on the context in which the odd behavior is emitted, and on dence of preexisting brain pathology sometimes become psy-
the sensitivity of the observer to possible determinants of the chotic in situations in which there is extreme sensory depriva-
deviations from the expected. This subtlety of discrimination tion. At our present state of knowledge we cannot rule out
may be incompatible with the reliability and operational explic- undetected predisposing factors. In the first half of the 20th
itness of sorting behavior expected in modem science. century the psychoses were often divided into organic and
functional subtypes. It was assumed that the organic psychoses
were caused by genetic factors or clear-cut brain pathology.
Explanation of psychosis
The functional disorders were considered to be of unknown
No general explanation of psychosis exists at the present time etiology, to be due to a pathology of brain function that was
that identifies the conditions that are necessary or sufficient not associated with tissue damage, or to be primarily a response
for the manifestation of all patterns of behavior we usually to pathological learning of coping skills or a response to certain
call psychotic. types of stress. Because the term functional had all these conno-
It is convenient to divide hypothetical determining events tations, the organic-functional distinction has become useless.
into those which are, in some sense, input into the organism, Acute schizophrenia-like illness often appears in groups of
and those which are the intervening patterns of brain activity individuals under extremely stressful conditions, such as mili-
that are the basis for the normal or psychotic behavior. Among tary indoctrination training, religious seminary training, and
the important input events, we may consider: (I) selection of wartime activities, but proving the etiological role of these
100 Gardener C. Quarton

experiences is very difficult. The chronic schizophrenia-like specific mechanisms of the nervous system. Unfortunately it
disorders are somewhat more common in the lower socioeco- is usually the case that nervous system tissue damage is so
nomic classes. This may suggest that the stress associated widespread that, although it helps identify regions of brain
with poverty or lack of training in coping skills play a role, that are relevant, it does not pick out the precise system that
but it could just as well be that behavior among the lower is involved. By combining clues from pharmacology that give
classes is more likely to be identified as psychosis than it is us some transmitter specificity and clues from neuropathology
among those with better social support systems. During the that identify key regions of brain that are involved, we may
period from 1950 to 1975 it was common to talk of the role gain insight into the pathology of psychosis.
of family communication patterns in producing a predisposition The second major approach is to begin with the categories
to psychosis in children. Research has shown that the families of behavior that become abnormal in psychosis, then look
of schizophrenics show patterns of within-family communica- for the brain mechanisms that are required for those normal
tion that differ from controls. In particular there is some evi- functions, and finally to search for patterns of abnormal func-
dence that schizophrenic families are less explicit or less open tion in those systems that are associated with psychosis. Re-
in communicating about intense emotions. It is difficult to search on the brain mechanisms involved in attention, initiation
come to a final conclusion at this time about the importance of behavior, coordination of affective behavior with decision
of stress and abnormal learning and psychological development and optimization, concept formation, inferential reasoning,
as predisposing factors in specific types of psychosis. It is learning, memory, language, and many other functions may
possible to conclude, however, that there is no single class provide us with crucial clues.
of input factors playing a crucial etiological role for all episodes A third approach to the explanation of psychosis is to follow
of behavior that can be called psychotic. up on the correlates of psychosis that we come upon acciden-
It may be more important to look at the systems of the tally. This correlational approach is very popular today, and
brain that are involved in producing the normal behavior that it is probably due to the difficulty of following the first two
becomes abnormal in psychosis. It is possible that a number approaches in any systematic fashion. Almost every possible
of input factors of different categories all act in different ways way of measuring body processes and psychological function
on the same final common path somewhere in the complex has been tried with psychotics, comparing the same individual
systems of the brain that are the substrate for the higher cogni- in and out of the psychotic state, and comparing groups of
tive functions. psychotics with controls. The results of this research strategy
Investigators have identified four ways of studying the brain have not been encouraging.
mechanisms that are required for complex cognitive and emo- The last strategy used to develop an explanation of psychosis
tional behavior and also for pathological behavior. In the first is to attempt a more systematic categorization of the heteroge-
place, it is possible to infer plausible relevant brain mecha- neous class of psychotic episodes. We already know that it
nisms from the way in which input factors that are known to is possible to become psychotic under the influence of many
produce psychosis act on brain. For instance, because amphet- different classes of determinants. If we subdivide the whole
amine and similar drugs can play a role in producing psychotic group into smaller subgroups, each of which is reasonably
behavior, it is reasonable to explore the role of catecholamine homogeneous, we may have a better chance to develop satis-
transmitter systems in more detail. This has led to the so- factory explanations.
called dopamine theory of schizophrenia pathogenesis. There
is evidence supporting this theory that cannot be reviewed
here, but our understanding of these systems is as yet very
incomplete. Drug research may suggest specific biochemical, Further reading
physiological, and anatomical investigations. Tumors and in- American Psychiatric Association ( 1980): Diagnostic and Statistical
fections that are known to produce psychosis also can be shown Man/UJl of Mental Disorders, 3rd ed.
through detailed neuropathological investigation to involve
Psychosurgery
Lyle W. Bivens

Psychosurgery is the surgical removal or destruction of brain The controversy over psychosurgery involves scientific,
tissue or the cutting of brain tissue to disconnect one part of philosophical, political, and moral issues. In order to under-
the brain from another with the intent of altering behavior. stand the nature and source of the psychosurgery controversy,
Usually it is performed in the absence of direct evidence of it is necessary to make explicit some of the different viewpoints
existing structural disease or damage in the brain. that are often unstated when the psychosurgery issue is dis-
The surgical treatment of epilepsy, while in one sense a cussed.
form of psychosurgery since behavioral symptoms are altered, A fundamental concern about psychosurgery derives from
should be excluded from this discussion when the disease can different philosophical views of the relationship between mind
be clearly diagnosed and there is convincing evidence that (self) and brain. Much opposition to psychosurgery, and often
epilepsy is caused by organic pathology in the brain. Of course the most vociferous opposition, is based on the conviction
any other neurosurgical treatment to repair or remove damaged that any physical damage to the brain is tantamount to destruc-
brain tissue, or to remove tumors, is not psychosurgery. tion of the "self." This viewpoint is most strongly illustrated
In neuroanatomical terminology, the suffix -tomy refers to by some of the rhetoric used by opponents of psychosurgery
the destruction of brain tissue or the cutting of fibers in the who equate it with "murder of the mind." Proponents of
brain. Lobotomy therefore is the destruction of tissue in the psychosurgery, while usually not articulating an alternative
frontal lobes of the brain, or the cutting of fibers connecting philosophy, do not equate the brain with the self and take a
the frontal lobes with the rest of the brain. Thalamotomy refers pragmatic approach to mental or behavioral disorders in which
to the destruction of portions of the thalamus. The suffix the primary criterion for selection of a treatment is whether
-ectomy refers to the actual removal of tissue. Thus, a frontal it works.
lobectomy is the removal of the frontal lobes of the brain. A closely related issue is reflected in the different viewpoints
Topectomy refers to selective removal of portions ofthe cortex, about the causal factors in mental illness. Some psychosur-
usually from the frontal region of the brain. geons rationalize surgical treatment on the hypothesis that men-
Ever since the first radical lobotomies were performed in tal or behavioral disorders arise from biological dysfunction
which virtually all subcortical connections of the frontal lobe in the brain and that appropriate treatment must be based on
were severed, surgeons have attempted to refine the technique manipulating or changing the biological substrate of behavior.
to limit the brain destruction in hope of reducing adverse side Others, however, hold the view that disturbed behavior is a
effects. Topectomy, which damaged less brain tissue than the result of adverse environmental influences and that the solution
early lobotomies, was tried. The development of undercutting to mental illness or behavioral disorders is to manipulate or
techniques, whereby the subcortical connections of a selective change environmental variables. While both these views are
part of the cortex are severed but the cortex itself is left intact, extreme positions held only by a few, and are untenable in
further refined the technique of topectomy. view of our current knowledge about the complex interrelations
The search for limitation of destruction of brain tissue (and between environmental and biological causative factors, they
presumably of adverse side effects) culminated in stereotaxic illustrate another philosophical argument that, in frequently
techniques, or the positioning of a small electrode in the brain. more subtle form than illustrated here, is one of the roots of
Geometric coordinates and x-ray inspection are used to place the psychosurgery controversy.
the electrode in a precise location, and then the tissue at the Although virtually all psychosurgical procedures and techni-
electrode tip is destroyed by passing a current through the cal innovations, including the first lobotomies, were suggested
electrode. With the development of stereotaxic techniques, by experimental brain research with animals, the scientific
structures deep within the brain become accessible for destruc- rationale for any psychosurgical procedure is still quite tenu-
tion, and amygdalotomy, thalamotomy, and hypothalamotomy ous. Generalizations from animal research have often been
began to replace lobotomy as psychosurgical procedures. based on incomplete understanding of the complexity of behav-
Psychosurgery was recommended for curing or ameliorating ior, logical deductions of dubious validity, and an uncritical
schizophrenia, depression, homosexuality, childhood behavior acceptance of similarities of brain-behavior relationships in
disorders, criminal behavior, and other psychiatric problems. animals and humans. Although we know a great deal about
For a period from about 1936 to 1955 lobotomy was enthusias- how the brain influences a variety of specific and limited animal
tically embraced by a large number of medical and psychiatric behaviors, our understanding of complex human emotional
practitioners in the United States and in England. The greatest and cognitive behaviors is extremely limited. On the other
proportion of psychosurgical treatments was upon schizo- hand, proponents of psychosurgery argue quite rightly that
phrenic patients, who were often difficult to manage and totally many medical therapies are based on a pragmatic criterion of
unable to function in society. Perhaps as many as 50,000 effectiveness rather than an understanding of the physiological
psychosurgical procedures were performed in the United States mechanisms underlying the disease or its treatment.
between 1936 and the mid-1950s. In contrast to most physical illnesses, many functional men-
102 Lyle W. Bivens

tal and behavioral disorders are poorly defined and difficult The data presented did not indicate that the procedure had
to diagnose, making the decision to treat with surgical means been used for social control or that the procedure had been
sometimes uncertain. Such problems also occur when judging applied disproportionately to minority or disadvantaged popu-
the outcome of psychosurgical treatment, since the criteria lations. Specifically, it was reported from correspondence with
for cure or ameliorization are not clear or universally agreed the most active psychosurgeons in the United States that out
upon. of a combined total of 600 patients, 1 was black, 2 were
A key issue in the psychosurgery controversy is whether Oriental Americans, and 6 were Hispanic Americans. Seven
psychosurgery is an experimental procedure. Most psychosur- operations were reported to have been performed on children
geons regard it as an accepted practice of proven efficacy, since 1970, and three prisoners underwent psychosurgery in
while critics see it as an experimental therapy based on alleged Vacaville, California, in 1972. Most psychosurgery patients
unpredictability of outcome, lack of evidence about efficacy, were middle class, had been referred to neurosurgeons by
and lack of scientific rationale. psychiatrists, and were about equally divided between male
Alternative therapies to psychosurgery are another divisive and female. More recent estimates of the frequency of psycho-
issue. Although a great deal of research is being done on surgical procedures are that the annual rate is considerably
drug therapies and various forms of psychotherapy or behavior lower now than in the period studied by the commission, due
therapy, there are numerous instances in which none of these at least in part to the widespread publicity accorded the com-
alternatives seems to offer any relief, and the patient is faced mission and its studies of the topic.
with a dehumanizing fate in an institution, often with pharma- Probably the best-controlled study of psychosurgery is a
cologic restraints that equal or exceed any personality destruc- continuation of a study begun by the national commission
tion that is claimed to be ·caused by psychosurgery. In these and currently supported by the National Institute of Mental
instances, psychosurgery might be seen as a reasonable last- Health. Suzanne Corkin and her colleagues at the Massachu-
resort therapy. On the other hand, there is no agreement or setts Institute of Technology have been studying the long-term
guidelines among practitioners about the duration, intensity, safety and efficacy of bilateral cingulotomy performed to treat
or degree to which other therapies should be tried before resort- severe pain or certain psychiatric disorders that have not re-
ing to psychosurgery. Critics of psychosurgery claim, often sponded to other treatments. A series of 179 patients were
correctly, that confinement in an institution is no guarantee studied before and after surgery with a broad range of cogni-
of adequate attempts at therapeutic measures short of psycho- tive, personality, neurological, and psychiatric measures. Early
surgery and that psychosurgery is frequently performed before results of this study have shown that this operation, which
other alternatives are sufficiently tried. removes or destroys tissue by radiofrequency lesions in the
Closely related to the problem of psychiatric diagnosis is cingulate gyrus (area 24 of Brodmann) and interrupts the cingu-
the extent to which mental or behavioral disorders are socially lum bundle, has few if any undesirable side effects. The short-
defined. This issue most often surfaces in the context of the term results also indicate that patients treated for severe chronic
psychosurgical treatment of aggressive or violent behavior in pain were significantly improved on measures of psychiatric
which critics of psychosurgery express the fear that it will be status and pain perception. Patients suffering from severe de-
used for nefarious purposes as a means of controlling political pression were also significantly improved, but obsessive-com-
or social dissidents. Stated in more general terms, critics charge pulsive or schizophrenic patients did not improve on a six-
that psychosurgery has been or can be used to change behavior month postoperative measure of global mental health.
for the convenience or comfort of persons other than the pa-
tient. Thus, there is claimed to be a bias toward the use of
psychosurgery in blacks, women, and other minority or disad- Further reading
vantaged population groups. Corkin S, Twitchell TE, Sullivan EV (1979): Safety and efficacy of
Because of widespread public and congressional concern cingulotomy for pain and psychiatric disorder. In: Modern Concepts
about psychosurgery in the mid-1970s, the U.S. Congress in- of Psychosurgery, Hitchcock et al, eds. Amsterdam: Elsevier
corporated a mandate to study psychosurgery into the legisla- National Commission for the Protection of Human Subjects of
tion establishing the National Commission for the Protection Biomedical and Behavioral Research ( 1979): Report and Recom-
of Human Subjects of Biomedical and Behavioral Research. mendations: Psychosurgery. Department of Health and Human Ser-
Research supported by the commission revealed that about vices, Pub No (OS) 77-002. Washington DC: US Government
Printing Office
400 operations were being performed annually (for the period
Valenstein ES (1973): Brain Control: A Critical Examination of Brain
1971-1973) by approximately 60 surgeons. The findings indi- Stimulation and Psychosurgery. New York: Wiley
cated that no significant psychological deficits are attributable Valenstein ES, ed. (1980): The Psychosurgery Debate: Scientific,
to the psychosurgery in the patients evaluated and that psycho- Legal, and Ethical Perspectives. San Francisco: WF Freeman
surgery was efficacious in more than half the cases studied.
Schizophrenia
Erik Stromgren

When in 1908 Eugen Bleuler introduced the term schizophre- founded on the ideas of Kraepelin, he added many important
nia, he did not intend to create a new concept. He just wanted observations and ideas to the understanding of schizophrenics.
to suggest a new term for the concept of dementia praecox, First of all, he distinguished between "basic" symptoms and
which had been developed by Emil Kraepelin during the pre- "accessory" symptoms, respectively (the terms "primary"
ceding 15 years and had received widespread acceptance. and "secondary" symptoms have also been used). Bleuler,
Kraepelin' s demonstration that dementia praecox and manic- like Kraepelin, regarded the etiology of schizophrenia as or-
depressive illness constituted two groups of disorders that were ganic, the basic symptoms being caused directly by the organic
basically different from all other psychoses and from each brain process, namely, disturbances of the association pro-
other helped to clarify a clinical field that until then had been cesses and emotional reactions and "autistic" disturbances
more or less chaotic. As late as the middle of the 19th century of contact with other human beings. All other symptoms--
many psychiatrists believed that there was only one mental delusions, hallucinations, catatonic symptoms, etc.--he re-
disorder, and that the different clinical forms merely repre- garded as psychologically understandable reactions to the pres-
sented different stages of the same disease. Gradually, how- ence of the basic symptoms. The distinction between basic
ever, it became clear that those psychoses that could be demon- and accessory symptoms was strengthened by the observation
strated to be caused by a physical morbid process had that the basic symptoms never disappeared, but accessory
characteristic psychiatric syndromes the presence of which symptoms were often subject to change and might disappear
would always indicate that the disorder was somatically deter- intermittently or permanently.
mined: in acute stages, disorders of consciousness and delir- Although Bleuler's delimitation of schizophrenia was very
ium; in chronic stages, dementia, deterioration of memory similar to Kraepelin's delimitation of dementia praecox, he
and other intellectual functions. In the majority of psychoses, did add descriptions of some mild cases of schizophrenia that
however, no such "organic" symptoms were present, and Kraepelin would probably not have included in his concept.
there were no signs of physical effects on the brain. These Both investigators stressed the bad prognosis of the disorder,
psychoses were called, in distinction to the "organic" group, although in a small percentage recovery seemed to occur.
"functional" or "endogenous." Kraepelin's longitudinal stud- Since the days of Kraepelin and Bleuler the question of
ies on functional psychoses showed a tight correlation between the delimitation of schizophrenia has been the subject of end-
symptomatology and course: when the symptoms were mainly less discussions, some psychiatrists advocating a very narrow
affective, in the form of mania or depression, the prognosis delimitation, others being inclined to include the great majority
was in principle good. On the other hand, if the symptomatol- of nonorganic psychoses within the concept. A number of
ogy was dominated by delusions, hallucinations, withdrawal, symptoms are, however, by all psychiatrists regarded as highly
emotional blunting, odd and incomprehensible behavior and indicative of a schizophrenic process: delusions, mainly of
speech, the prognosis in most cases was bad. These observa- persecution, hallucinations, mainly acoustic, disorders of
tions led to the distinction between manic-depressive disorder thought, unusual and incomprehensible associations, inade-
and dementia praecox. In the latter disorder the symptomatol- quacy of emotional reactions, odd and inadequate behavior,
ogy varied from case to case, and in the same patient over emotional. and behavioral withdrawal, loss of sense of reality.
time. Kraepelin distinguished four clinical types: hebephrenia, Most of these symptoms may occur also in other disorders
characterized mainly by withdrawal and emotional blunting; and can therefore not be regarded as pathognomonic. Certain
paranoid form, dominated by delusions; catatonia, character- combinati~s of such symptoms are, however, seriously in-
ized by disturbances in attitudes and movements; and dementia dicative of schizophrenia. Much attention has been paid to some
simplex, characterized by arrest of most mental functions. of the symptomatological criteria described by Kurt Schneider
The distinction between hebephrenia and dementia simplex as essential for the diagnosis of schizophrenia. Among symp-
was, however, not very clear. toms that appear in schizophrenia he suggests that some are
In 1911 Eugen Bleuler published his classic monograph on of the "first rank." These symptoms have empirically turned
dementia praecox or the group of schizophrenias. The reason out to be of special importance when psychiatrists make a
why Bleuler found the term dementia praecox inadequate was diagnosis of schizophrenia. They are the following: patient
that these patients were not ''demented''; their· intellectual hearing his own thoughts spoken aloud; hearing voices talking
faculties seemed unchanged; further, the disease did not always to each other about the patient; hearing voices which comment
start "praecociter," i.e., in youth. The term "schizophrenia" on the patient's behavior; feelings of patient's body being
(splitting of mind), on the other hand, pointed to fundamental influenced by outside forces; feelings of thoughts being re-
features of the symptomatology. The title of the book stressed moved or foreign thoughts being inserted into the mind; feeling
that Bleuler did not regard schizophrenia as a nosological en- that thoughts are broadcast to other people; feeling that emo-
tity; several pathogenic agents might lead to the same clinical tions, drives, and intentions are dictated by external forces.
picture. Although Bleuler mentioned that his contribution was Schneider concludes: ·'When it is stated that a patient has
104 Erik Stromgren

such experiences, and there is no evidence of a physical disor- When the psychopharmacological era started, and spectacu-
der, we in all modesty are talking about schizophrenia.'' lar therapeutic results were obtained, it was natural to assume
What is essential is, in any case, that these symptoms are that the biochemical changes occurring during such treatment
present in spite of clear consciousness. If the "schizophrenic" (with regard to biogenic amines, transmitters, etc.) could lead
symptoms occur in patients with delirium or other disturbances to the detection of biochemical processes that might be of
of consciousness, they are in no way indicative of schizophre- etiological importance for schizophrenia. Little insight has
nia. been gained in this way, however, one reason being that drugs
that can help schizophrenics have therapeutic impact on other
disorders, so the biochemical findings made cannot possibly
Etiology be specific for schizophrenia. The situation is much more com-
plicated than in manic-depressive disorder, where at least one
We have no reason to believe that schizophrenia is a nosologi- drug (lithium) has a specific therapeutic relationship to the
cal entity, and there is no basis for singling out special sub- disorder, and where studies on the effect of that drug are
groups of schizophrenia as belonging to specific etiological therefore much more promising.
entities. Most explorations into etiology have therefore been Although no physical factors have been demonstrated that
based on heterogeneous patient groups. This explains the diver- are essential to the etiology of schizophrenia, it would be
sity of results. naive to assume that such factors do not exist. It is, on the
In the beginning of the 20th century it was generally accepted other hand, natural that the inconclusive results of the search
that the etiology of schizophrenia was mainly hereditary. The for physical etiological factors could stimulate the interest in
first systematic studies of twins supported this viewpoint, con- the search for psychosocial causes. Here again the results are,
cordance among monozygotic twins being about 75%. The unfortunately, meager. It has not been possible to demonstrate
results of a number of later studies, however, indicate that factors that are of convincing importance for the onset of
the concordance is about 40%, regardless of whether the twins schizophrenia. In most cases it seems impossible to understand
have been living together or have been separated at early age. why the schizophrenia started at all, and why it started at a
Although heredity thus plays an important role in the origin particular moment. The premorbid situations of schizophrenics
of schizophrenia (which has also been demonstrated by family are so different that no generalizations are possible. It is amaz-
and adoption studies), it is clear that the greater part of the ing that schizophrenia seems to have practically the same inci-
etiology must be exogenous. Whether these exogenous factors dence in all populations studied. Such studies have been per-
are mainly physical or psychosocial has yet to be determined. formed in populations with different cultures, political
Some physical agents can give rise to psychoses that are clini- structures, and socioeconomic levels. Differences in preva-
cally indistinguishable from schizophrenia. A number of drugs lence of schizophrenia among different parts of the populations
(amphetamine, other stimulants, marijuana, etc.) can give rise seem primarily to have been caused by a drift of the schizo-
to such schizophrenia-like psychoses, which in most cases phrenics to special sections of the populations. The socioeco-
disappear when the drug is no longer available. A number of nomic level of parents of schizophrenics is average.
brain disorders (Huntington's chorea and encephalitis) may The ubiquity of schizophrenia in all human populations,
have a similar action that is of special interest since the anatom- regardless of the immense diversity of environmental condi-
ical site of the underlying processes is well known. Specula- tions, would seem to indicate that noxious factors relevant to
tions concerning the possible site of a supposed schizophrenic the development of schizophrenia must be active in situations
process are therefore not unrealistic. Although a number of common to all human beings. Focus has been on the emotional
organic etiologies to schizophrenia-like psychoses are thus well relationship between children and parents (or other emotional
known, it should be remembered that only in a small percentage key persons). In many cases of schizophrenia, infancy and
of all schizophrenias can such physical factors be ascertained. early childhood relationships have been shown to be of a most
Anatomical, biochemical, and pharmacologic studies of the noxious nature. In the majority of cases, however, such situa-
brains of schizophrenics have given controversial results. Some tions have not been ascertained. Manfred Bleuler, who has
investigators have claimed to have disclosed biochemical ab- performed the most intensive personal studies of schizophren-
normalities in the brains of schizophrenics; other researchers ics, found that many of his patients had been subject to severe
have been unable to reproduce the results. It is obvious that stress in childhood; the nature of the stress was, however,
it is difficult to carry out such studies and to collect data, very different, and generalizations with regard to pointing out
mainly because untreated schizophrenics are very rare. certain conflicts as essential could not be made.
Changes in the brains of schizophrenics who have received The basis for formulating a theory concerning the etiology
different treatments known to cause changes in the biochemis- of schizophrenia is very weak. However, based on what is
try of the brain give inconclusive results. A further problem known with reasonable certainty today, the following summary
is the possibility that a schizophrenic process might be intermit- statement may be permissible:
tent; the biochemical findings would then be different in active A genetically determined vulnerability seems to play a role
and inactive phases of the process. At present no biochemical in the origin of schizophrenia. This genetic basis differs from
process has been demonstrated in the brains of schizophrenics case to case, certainly quantitatively and possibly qualitatively.
that could distinguish them from normal persons or from other Early acquisition of minimal brain damage may enhance the
psychotics. vulnerability. During early childhood these vulnerable individ-
Anatomical findings are no more conclusive than the bio- uals may, in reaction to frustrations in the emotional relation-
chemical findings. Claims have repeatedly been made that ship to their peers, develop an ambivalent fear of establishing
aerograms and computerized tomography (CT) scanning have emotional contact, which enhances their vulnerability to frus-
disclosed areas of atrophy in the brains of schizophrenics. trations and their tendency to react with withdrawal from emo-
The importance of such findings is, however, dubious since tional attachment, and from reality as well, thus developing
it has become clear that reductions in brain mass can be re- autism that seems to be the central, maybe pathognomonic
versed and that they may be caused by drug treatment. Further feature of schizophrenia. From case to case there are probably
research that takes into account the different sources of error great differences with regard to the relative impact of genetic,
is urgently needed. somatic, and psychological factors.
 Schizophrenia 105

Therapy disorders not elsewhere classified,'' the latter group comprising

the subgroups "schizophreniform disorder," "brie~ reacti~e
The possibilities for therapy of schizophrenia have improved psychosis," and "atypical psychosis." Sch.izop~remfo.rm dis-
radically during recent decades. Before the potent phys1cal orders are said to have symptomatology 1dent1cal w1th that
therapies were introduced, it was known that the course of of schizophrenia, with the qualification that the duratio? must
schizophrenia in most cases depended on environmental factors be Jess than 6 months but more than 2 weeks. If the d1sorder
such as mental stimulation and occupational therapy. Such lasts for less than 2 weeks, it is called a ''brief reactive psycho-
factors are essential even in the era of somatic therapies. The sis"· in addition, the psychosis must follow a psychosocial
trend is to begin treatment with psychotropic drugs and suppor- stres,sor· if such stressor is not present, the case is called "atypi-
tive psychotherapy, usually starting during short hospitali~a­ cal psy~hosis." If a schizophrenia-like psych?sis a~ises ~fter
tion and continuing within the framework of a commumty middle age, it is also labeled atypical psychosiS. It 1s obvwus
mental health setup. In most cases improvements can be ob- that there is a radical and disturbing discrepancy between DSM
served, including social and familial adaptation. In very few III and lCD 9 in these respects. DSM III contains a further
cases, however, do schizophrenics become symptom-free; at innovation, the schizotypal personality disorder, which is not
least some degree of autism is left. regarded as a form of schizophrenia; many psychiatrists feel
that these cases should be classified as schizophrenia, pseudo-
Relationship to other groups of disorders neurotic or pseudopsychopathic. Such cases seem to have a
genetic relationship to schizophrenic psychoses and may be
Although there is a core group that would be diagnosed as included in the so-called "schizophrenic spectrum."
schizophrenics by the majority of psychiatrists, there are other
more peripheral groups included in schizophrenia by so~e
psychiatrists and regarded as separate groups .by others. Th.ls Diagnostic criteria
is especially true for patients who are predommantly paranmd Since the delimitation of the concept of schizophrenia has
and show little or no other schizophrenic symptomatology. varied between different psychiatric schools, statistics on the
Paranoid psychoses arising in elderly persons and associated incidence of schizophrenia have been difficult to compare.
with hallucinations, but with well-preserved personality and The differences have also hampered research and comparisons
little autism, are sometimes singled out as ''paraphrenia.'' of therapeutic results. It is therefore natural that there has
Some "borderline states" of pseudoneurotic or psychopathic been interest in establishing recognized diagnostic criteria that
schizophrenia have been shown to have close genetic relation- could secure that groups of schizophrenics that are compared
ships to schizophrenia. Schizophrenia-like psychoses in epilep- really are comparable. In recent years a number of syste~s
tics have, on the other hand, been demonstrated not to have of "research diagnostic criteria" (ROC) have appeared. It IS
any 'genetic relationship to schizophrenia. Schizophrenia-like obvious that groups delimited by means of the same ROC
psychoses arising in connection with severe, acute mental are more comparable than groups described by means of sub-
stress are likewise without genetic relationships to schizophre- jective clinical criteria that have never been standardized. On
nia. Many schools of psychiatry label these as "reactive" or the other hand, there is no basis for the contention that by
"psychogenic" psychoses. means of such RDCs, which contain relatively few items,
any homogeneous groups or nosological entities can be delim-
International nomenclatures and classifications ited. Diagnostic criteria are adequate for differentiation of two
different groups; they are less useful in delimiting one homoge-
The International Classification of Diseases of the World neous group. For this purpose much more differentiated and
Health Organization (lCD, 9th edition) introduces section 295 validated interview schedules are necessary, for instance in
"schizophrenic psychoses," with a detailed description of the the form of the Present State Examination (PSE) devised by
type of psychoses included under this heading, a descripti?n J.K. Wing. The PSE has been widely accepted as a useful
that can no doubt be regarded as applicable to the great maJonty
tool, not least within the cross-national investigations orga-
of schizophrenic cases. Section 295 comprises a number of
nized by the World Health Organization, for instance, in the
subgroups that should naturally be included under schizo-
International Pilot Study of Schizophrenia (lPSS).
phrenic psychoses: simple type, hebephrenic type, catatonic
type, paranoid type, latent schizophrenia, and residual schizo-
phrenia. There are two more controversial subgroups. In Further reading
"acute schizophrenic episode" there is a dreamlike state with Bleuler E (1911): Dementia praecox oder Gruppe der Schizophrenien.
slight clouding of consciousness. Such cases would not be In: Handbuch der Psychiatrie. Spezieller Teil, 4. Abteilung, 1.
included in schizophrenia by most psychiatrists, clear con- Hiilfte, Aschaffenburg G, ed. Leipzig and Wien: Franz Deuticke.
sciousness being regarded as one of the features essential for English ed. ( 1950): Dementia Praecox or the Group of Schizophre-
the diagnosis of schizophrenia. In "schizoaffective type," nias. New York: International Universities Press
there is a mixture of schizophrenia-like features, and many Bleuler M ( 1972): Die schizophrenen Geistesstorungen. Stuttgart:
psychiatrists regard these cases either as a separate group or Georg Thieme Verlag. English ed. (1978): The Schizophrenic Dis-
orders. New Haven and London: Yale University Press
as a subgroup of affective psychoses.
Neale JM, Oltmanns TF (1980): Schizophrenia. New York, Chiches-
The Diagnostic and Statistical Manual of Mental Disorders ter, Brisbane and Toronto: John Wiley & Sons
(DSM III), which appeared in 1980, introduced a radical re- Wing JK, Wing L, eds. (1982): Handbook of Psychiatry. Vol 3:
classification of schizophrenia, distinguishing between '' schiz- Psychoses of Uncertain Aetiology. Cambridge, London, New York,
ophrenic disorders," "paranoid disorders," and "psychotic New Rochelle, Melbourne and Sydney: Cambridge University Press
Sleep Disorders
Thomas Roth, Timothy Roehrs, and Frank Zorick

Sleep disorders medicine has become an important clinical show signs of a sleep disturbance and patients complaining
and research discipline for two reasons. The first is the docu- of daytime somnolence show evidence of increased daytime
mentation of sleep-wake complaints. A recent national survey sleep tendency before treatment is instituted.
found that one-third of the American population reported some The development of all-night sleep recording (clinical poly-
degree of insomnia, with 17% of the population considering somnography) and repeated test of daytime sleep tendency
their insomnia serious. In addition, up to 6% of the population (multiple sleep latency test) enables clinicians and researchers
complain of excessive sleepiness during the day. The second to validate and measure the presence and severity of sleep
and more immediate impetus to sleep disorders medicine was complaints. In the absence of positive findings on these tests,
the discovery of sleep-specific pathologies. That is, individuals it is inappropriate to treat a patient for a sleep disorder. This
who show normal physiological functioning during the neural is not to say that patients with sleep complaints but no objective
state of wake can show significant pathology when in one of evidence of a sleep disorder should be considered as malinger-
the two neural states of sleep (REM, or rapid eye movement, ers or simply dismissed. Rather these patients' symptoms,
and NREM, or non-REM). In addition, in perfectly healthy and hence their treatments, are not related to abnormalities
individuals, control of basic physiological functions such as of sleep-wake mechanisms.
respiratory drive, cardiac rhythm, and thermoregulation have The duration of the symptom is equally important. Generally
different laws during wake and sleep. In fact, control of these in medicine, symptomatic treatment is reserved for transitory
functions varies within the two neural states that constitute problems. A recent National Consensus Conference on Drugs
sleep. and Insomnia concluded that the same is true for the symptom
Historically, sleep-wake complaints in the population were of insomnia. While hypnotics are consistently effective and,
dealt with at a superficial level. Insomnia typically was viewed thus, indicated in transient and short-term insomnia, they are
as a single entity primarily caused by psychological-psychiatric not recommended as the standard primary treatment in patients
conditions. On the other hand, daytime sleepiness was synony- with chronic insomnia. In evaluating daytime sleepiness, dura-
mous with narcolepsy. That is, patients who complained of tion of the problem is similarly important. When extreme day-
excessive daytime sleepiness regardless of their signs and time sleepiness is present for short periods of time, acute sleep
symptoms were invariably diagnosed as narcoleptic. In fact, deprivation is typically the cause. However, when the sleepi-
it is interesting to note that since patients with daytime somno- ness is chronic, sleep loss per se accounts for only a small
lence often exhibit different signs and symptoms, different proportion of patients who suffer from daytime sleepiness.
types of narcolepsy were postulated (e.g., REM narcolepsy The second major concept to be derived from the diagnostic
and NREM narcolepsy). With increased research interest in classification system is that sleep disturbances vary in type
sleep disorders and the development of standardized methods and etiology. Some patients exhibit sleep disturbances charac-
for the all-night evaluation of physiological functioning of terized by prolonged periods of wakefulness. This type of
these patients, it soon became evident that a host of different disturbance is most pronounced in patients with insomnia asso-
abnormal physiological events (e.g., periodic leg movements, ciated with depression or restless legs. These two categories
apneas, alpha intrusions) occur in these patients' sleep, and of patients show a most pronounced sleep disturbance in terms
these events can lead to sleep disturbance and, hence, sleep- of increased wakefulness during the night. Another type of
wake complaints. sleep disturbance is characterized by multiple brief arousals
The diagnostic classification system of sleep-wake disorders during the night. This disturbance typically is seen in patients
developed in 1978 advanced our understanding of sleep disor- with nocturnal myoclonus or apneas during sleep. A third
ders. The intent of this system was to provide clinicians with type of sleep disturbance is characterized not by a change in
a listing of the signs and symptoms of the various sleep disor- the continuity of sleep, but by the superimposition of wake
ders, as well as their differential diagnoses. The systematic electroencephalographic activity (EEG) on the sleep EEG. This
use by sleep clinicians of this diagnostic system over the past finding, alpha-delta sleep, is seen in patients with fibromyositis
six years has led to three major conceptualizations about the syndrome or some depressions. It is interesting that such pa-
nature of sleep disorders. tients do not have typical insomnia complaints (i.e., difficulty
First, it emphasized that insomnia and daytime sleepiness falling asleep or frequent nocturnal awakenings), but rather
are symptoms, not specific diseases entities. As with any other they complain about the quality of their sleep. They report
symptom in medicine, the severity and duration of the symp- no sleep, light sleep, or unrefreshing sleep. Finally, some
tom is important in assessing its significance, diagnosis, and patients show a sleep disturbance characterized by normal
treatment. In assessing severity, it must be recognized that sleep, which because it is out of phase with a person's bed-
although a patient may complain severely, the complaints may times, results in a prolonged period of wakefulness following
be associated with no objective evidence of any sleep distur- or preceding the normal sleep. These are circadian rhythm
bance. It is essential that patients who complain of insomnia disorders where there is a mismatch between the person's
 Sleep Disorders 107

sleep-wake rhythm and his bedtimes. Acutely, this can be the night lead to long periods of wakefulness and subjective
seen in people experiencing jet lag or shift work, and chroni- complaints of insomnia. Frequent arousals lead to an accumula-
cally in people with phase delay or phase advance syndromes. tion of a sleep debt, which in turn leads to brief arousals and
These disturbances of sleep can be caused by primary sleep a complaint of daytime somnolence. This explanation seems
pathologies, by waking medical or psychiatric disorders, by more plausible as studies in several diagnostic groups including
external agents such as drugs, or by environmental factors. nocturnal myoclonus and apnea show that patients complaining
All waking medical diseases continue to affect the patient when of daytime sleepiness show more frequent and briefer arousals
he falls asleep and, thus, have the potential to cause sleep than patients complaining of insomnia. Regardless of the expla-
disturbances. For example, any disorder associated with pain nation, the point is that a single sleep disorder may result in
or discomfort (e.g., reflux) during wakefulness has the poten- a variety of sleep-wake complaints or even no complaints.
tial to cause repeated arousals and awakenings during sleep. Thus, unless one wants to treat patients purely on a sympto-
In addition, since the control of physiological functions differs matic level (hypnotics for insomnia and stimulants for daytime
in sleep and wakefulness, some disorders become exacerbated sleepiness), the focus should not be solely on the symptom.
as the patient goes from waking to sleeping. Many patients More appropriately, the specific sleep disturbance must be
with waking lung disease experience exacerbation of their con- recognized, understood, and treated.
dition while asleep. In some this is more pronounced in REM This brief review of the nature of sleep disorders emphasizes
sleep than in NREM sleep owing to the differential control the increased understanding of sleep disorders at a clinical
of respiration in these two sleep states. Waking psychiatric level. However, the understanding of the pathophysiology of
diseases, as noted earlier, are often associated with disturbed these disorders has not kept pace with the ability to identify
sleep. One of the hallmark symptoms of endogenous depres- them clinically. A survey of current treatments for the various
sion is disturbed nocturnal sleep, especially early morning sleep disorders makes it clear that more research into the patho-
awakenings. Drugs can also lead to sleep disturbances. It is physiology underlying these disorders is needed if the patho-
obvious to most individuals that stimulants such as ampheta- physiology is to be reversed. All primary sleep disorders are,
mines, methylphenidate, and caffeine can cause disturbance by definition, central nervous disorders. That is, there is a
of sleep. However, other drugs such as hormones (e.g., corti- certain level of functioning in wake, and with a change in
sone, progesterone), respiratory stimulants (e.g., theophyl- neural state (sleep) there is a change in physiological function-
line), and autonomic agents cause sleep disturbance as well. ing. For example, the vast majority of patients with sleep
Finally, drugs used to promote sleep are typically general cen- apnea syndrome show normal respiratory function while
tral nervous system (CNS) depressants. Yet, it is critical to awake, but frequent airway obstructions while asleep. In fact,
recognize that these drugs have the potential to disturb sleep. during REM sleep, the hemodynamic consequences of these
Alcohol is the best example of this. Despite the fact that alcohol obstructions are. more pronounced than during NREM sleep.
hastens sleep onset, it has been shown, in both human and Of the currently available treatments for apnea, tracheostomy
animal studies, to lead to severe sleep disturbance. In fact, a provides an artificial airway below the site of obstruction,
review of the sleep-pharmacology literature indicates that virtu- continuous positive airway pressure attempts to reverse the
ally all classes of drugs that promote sleep can in certain negative pressure caused by inspiratory effort, and other surgi-
situations lead to sleep disturbances. Finally, sleep distur- cal treatments (uvulopalatopharyngoplasty and mandibular ad-
bances can be found in drug-free individuals who are perfectly vancement) attempt to increase airway size. None of these
healthy when awake, but suffer from primary sleep disorders. are intended to reverse the CNS defect in apnea syndrome.
Apneas during sleep and nocturnal myoclonus are the clearest Similarly in nocturnal myoclonus, no medications have been
examples of primary sleep disorders. These physiological ab- shown to inhibit these muscle bursts, and all currently effective
normalities may be totally occult while the person is awake treatments blunt nonspecifically the CNS arousal associated
(except for a sleep-wake symptom) and can only be detected with these bursts. Narcolepsy, which has been recognized as
by evaluating physiological functioning during sleep. a CNS pathology for over one hundred years, can still only
The third major concept to be derived from the diagnostic be managed symptomatically by the use of stimulants. In sum-
classification system and its use deals with the relation of mary, sleep disorders medicine has made major strides in terms
sleep-wake complaints to sleep disturbance. The diagnostic of the identification and clinical management of these disor-
classification system is a symptom-oriented system. Its two ders. The future goal for this field lies in the identification
major divisions list the disorders associated with the symptoms and reversal of the underlying pathophysiology of these disor-
of insomnia and the disorders that lead to symptoms of daytime ders. The realization of this goal is dependent on future re-
sleepiness. With the exception of narcolepsy, every major dis- search on the neurophysiology and neuropathology of sleep.
order appears on both listings. What this means is that there
are multiple etiologies that can cause sleep disturbances, and Further reading
each of these can in turn lead to a complaint of insomnia or
a complaint of daytime sleepiness. There are two possible Association of Sleep Disorders Centers ( 1979): Diagnostic Classifica-
explanations for this. First, all patients have comparable sleep tion of Sleep and Arousal Disorders, prepared by the Sleep Disor-
disturbances, but some patients focus their attention on their ders Classification Committee, Roffwarg HP, chairman. Sleep
2:1-37
sleep, and hence complain of insomnia, while other patients
Orem J, Barnes C (1980): Physiology in Sleep. New York: Academic
focus their attention on their waking function, and hence com- Press
plain of daytime sleepiness. An alternative explanation is that Guilleminault C (1982): Sleeping and Waking Disorders: Indications
the subjective experience of impaired sleep and the subjective and Techniques. Menlo Park, Calif: Addison-Wesley
experience of impaired alertness are two points on a continuum Hauri P (1982): The Sleep Disorders. Current Concepts. Kalamazoo,
of sleep fragmentation. That is, infrequent arousals during Mich: Upjohn Company
Stress, Neurochemistry of
Adrian J. Dunn

Most neurochemical parameters are altered during or following and the periphery. Most notably, corticosterone increases the
some form of experimental stress. But, because all stressful activity of adrenal medullary phenylethanolamine-N-methyl-
treatments (stressors) are complex, involving a variety of stim- transferase (PNMT), the enzyme that converts NE to epineph-
uli, it is difficult to be certain that the responses are associated rine, hence increasing the ratio of epinephrine to NE secretion
unequivocally with stress per se. While the concept of stress from that gland. But glucocorticoids also play a permissive
is generally understood, there is no generally accepted defini- role in the adaptation of adrenergic receptors, both in the brain
tion. Stress is subjective; what is stressful for one person may and in the periphery. Other neurochemical responses to stress
not be so for another, and even what is stressful for one person may be secondary to any of these .
on one occasion may not be so on another. Thus, most defini-
tions of stress cite the person's response, the most widely
accepted being the activation of the pituitary-adrenal axis. This
definition derives from the work of Selye, who discovered CIRCADIAN
the adrenocortical activation in stress and promulgated the RHYTHMS
theory that stress is a nonspecific (adrenocortical) response.
Surprisingly, his theory and the definition that arises from it
ignore the stress-related activation of the adrenal medulla and
the sympathetic nervous system, established by the pioneering
work of Cannon. Most modem researchers accept the ubiquity
of the adrenocortical response in stress, but would not agree
that the stress response is physiologically nonspecific (for ex-
ample, the physiological response to cold exposure is not the
same as that to heat).
Activation of the adrenal medulla results in secretion of
epinephrine and, in most species, norepinephrine (NE) into
the general circulation. The sympathetic nervous system con-
tributes NE both locally and into the general Circulation. Acti-
vation of the hypothalamic-pituitary-adrenal (HPA) axis results
in the secretion of corticotropin-releasing factor (CRF) from
the hypothalamus, adrenocorticotropin (ACTH) from the pitui-
tary, and glucocorticosteroids (cortisol and/or corticosterone,
depending on species) from the adrenal cortex (see Fig. l).
13-Lipotropin 13-LPH) and small amounts of 13-endorphin
are also released concomitantly from the anterior pituitary.
Physiologically, the common responses to all stressors appear
to be the activation of the sympathetic nervous system (consid-
ered to include the adrenal medulla as argued by Cannon),
and the activation of the HPA axis. This results in elevation
of the plasma, epinephrine, and NE, as well as ACTH and
glucocorticoids. Stressors also activate cerebral noradrenergic
neurons, which can perhaps be regarded as the counterpart
in the central nervous system (CNS) of the peripheral sympa-
thetic nervous system.
Activation of these two systems (the entire sympathetic and
the HPA) comprises the core of the stress response; however,
the systems are not independent (Fig. 2).
There is extensive evidence that catecholamines are involved Figure I. The hypothalamic-pituitary-adrenocortical (HPA) system. Nor-
in the regulation of HPA activity; noradrenergic neurons are adrenergi.c (NE), cholinergic (AC h) , and serotonergic inputs to the hypo-
thought to inhibit CRF release via a hypothalamic a -receptor, thalamus alter the release of corticotropin-releasing factor (CRF), which
while in rodent pituitary a 13-receptor activates the release of stimulates release of ACTH from the anterior pituitary (PIT). which in
ACTH. CRF and ACTH affect CNS catecholaminergic systems tum stimulates release of glucocorticoids from the adrenal cortex. Gluco-
(generally an activation). Also, glucocorticoids exert consider- corticoid feedback occurs at all levels, whereas ACTH feedback may
able control over catecholaminergic systems in both the CNS occur on the brain. From Dunn and Kramarcy (1984) .
 Stress, Neurochemistry of 109

to prefrontal and cingulate cortices, but some data implicate

other regions, e.g., the nucleus accumbens, and the response
may be more general. This DA response is readily detected
in frontal cortex by assay of turnover, e.g., the production
of the catabolite, 3,4-dihydroxyphenylacetic acid (DOPAC).
HPA SA It occurs following a variety of stressors, including psychologi-
SYSTEM cal (conditioned) stress. Other data suggest that cerebral epi-
SYSTEM nephrine-containing neurons are also activated during stress,
although the generality of this response remains to be deter-
CRF
mined. Thus it may be that neurons containing all three cate-
cholamines in the brain contribute to the stress response.
The data for an involvement of cerebral serotonin (5-HT)
CENTRAL
PITUITARY SYMPATHETIC CATECHOLAMINERGIC in stress are less clear. While numerous articles indicate altera-
SYSTEM SYSTEMS tions of 5-HT content or metabolism in stress (especially in-
creases in the production of serotonin's major catabolite, 5-
hydroxyindolacetic acid, 5-HIAA), in most cases very severe
ACTH
treatments have been used. Some evidence is consistent with
the possibility that the changes in cerebral 5-HT are secondary
NOREPINEPHRINE
DOPAMINE
to increases of circulating corticosterone.
EPINEPHRINE A few data exist to suggest effects of stress on other neuro-
transmitters. These especially include acetylcholine and
gamma-aminobutyric acid (GABA), but changes in the metab-
NOREPINEPHRINE olism of these seem to be less sensitive measures of stress.
GLUCOCORTICOIDS EPINEPHRINE The changes in GABA are particularly interesting because of
NOREPINEPHRINE the intimate relationship between this neurotransmitter and the
benzodiazepines (the so-called minor tranquilizers), which find
HORMONAL RESPONSE NEURONAL RESPONSE extensive clinical use for their antianxiety (i.e., anxiolytic)
effects.
Neurochemical effects secondary to the activations of cate-
THE STRESS RESPONSE cholaminergic systems include an activation of adenylate cy-
clase and consequent increases in cyclic AMP. Chronic stress
Figure 2. A schematic indicating the overall arrangement of the hypo-
increases the activity of the biosynthetic enzymes for catechola-
thalamic-pituitary-adrenocortical (HPA) and sympathoadrenomedullary
(SA) systems. The central noradrenergic system appears to be activated mines, especially in the sympathetic nervous system, but also
in parallel with the peripheral sympathetic nervous system and can be in the brain. These occur largely as a result of increased neu-
considered the counterpart in the central nervous system of that system. ronal activity, but glucocorticoids appear to be important regu-
The other cerebral catecholaminergic systems (i.e., dopamine and epineph- lators and, in some cases, mediators. There also appear to
rine) may also be activated in stress. The diagram illustrates the parallel be a desensitization of adrenergic receptors, indicated both
activation of both the HPA and SA systems and their interaction in the by a decreased number of binding sites for ~-adrenergic ligands
adrenal gland. From Dunn and Kramarcy (1984). and a decreased responsivity of adenylate cyclase to NE. These
changes resemble those that occur following chronic treatment
with agonist drugs, in particular the tricyclic antidepressants.
The catecholamine responses
Activation of the HP A axis
Numerous studies have shown that stressful treatments .can
decrease cerebral NE content. This effect presumably reflects Activation of the HP A axis results in the secretion of CRF,
increased release of NE coupled with the inability of synthetic ACTH, and glucocorticoids into the circulation. Thus, second-
mechanisms to keep pace, because it occurs only after more ary effects may occur from any of these hormones, or even
intense or prolonged stress. Electrophysiological recording and from ~-endorphin, which may be released concomitantly with
studies of biochemical turnover provide more sensitive mea- ACTH from the pituitary during stress. Some of these effects
sures of noradrenergic activity and can detect activation of may reflect feedback mechanisms involved in the regulation
cerebral nonidrenergic neurons following briefer and milder of the HPA axis, but others are clearly independent. Glucocor-
stressful treatments. Changes of NE turnover can be estimated ticoid administration to rats early in life can cause long-lasting
by following its disappearance after blockade of synthesis with impairments of brain weight, cell proliferation, dendritic
drugs such as a-methyl-p-tyrosine. But, because such drugs branching, and myelination. There is good evidence that gluco-
themselves activate the HPA axis, measurement of the produc- corticoids may play a role in the normal regulation of myelina-
tion of catabolites, such as 3-methoxy ,4-hydroxyphenyl- tion. Thus glucocorticoids may mediate the adverse effects
ethyleneglycol (MHPG) or its sulfate derivative is preferred. of stress in immature or even fetal animals. Glucocorticoids
This activation of cerebral NE neurons seems to be general have also been implicated in age-related changes in the brain.
in stress, and occurs under the same conditions as activation Clinically, glucocorticoids are used extensively to reduce vaso-
of the sympathetic nervous system. The noradrenergic response genic brain edema, reflecting a role in ion and water transport.
seems to be regionally nonspecific, in keeping with the anatom- Well-documented effects of glucocorticoids on the brain in-
ical and biochemical data indicating that NE cell bodies in clude induction of glycerol phosphate dehydrogenase, an en-
the locus coeruleus send collaterals to widespread areas of zyme intimately involved in lipid metabolism, and alterations
the brain. in the metabolism of several neurotransmitters, especially the
Extensive data now indicate that certain of the cerebral dopa- catecholamines and 5-HT, but also acetylcholine and GABA.
mine (DA) systems are also activated during stress. This ap- Effects secondary to ACTH release may include a small
plies particularly to the mesocortical DA system which projects general increase of protein and perhaps RNA synthesis, in-
110 Adrian J. Dunn

creases in cyclic AMP and specific phosphoproteins, increases mals (so-called "learned helplessness") are associated with
in putrescine, and a stimulation of several neurotransmitter deficits in noradrenergic function (correlated with depletions
systems, including the catecholamines, DA and NE. The last of cerebral NE, especially in locus coeruleus).
indicates an interaction between the two branches of the stress A full understanding of the stress response awaits knowledge
response. of the true biological role of catecholaminergic systems. Al-
Few data exist as yet on the effects of CRF, but it is already though NE has been postulated to play a role in neuroplasticity
clear that this peptide is capable of eliciting a powerful sympa- and has long been implicated in higher nervous functions such
thetic activation, in addition to triggering an HPA response. as learning and memory, it also appears to play relatively
mundane roles in limiting blood How and regulating the blood-
brain barrier.
Function of the neurochemical stress responses
An important question is the extent to which the neurochemical
changes that have been observed during stress may underlie Further reading
the adaptation of the organism to stress. The increases in bio- Axelrod J, Reisine TD (1984): Stress hormones: Their interaction
synthetic enzymes for the catecholamines permit coping with and regulation. Science 224:452-459
increased demands on the noradrenergic neurons, but do not Dunn AJ (1984): Effects of ACTH, [3-lipotropin, and related peptides
in themselves permit adaptation. The down-regulation of adre- on the central nervous system. In: Peptides, Hormones and Behav-
nergic receptors that occurs in chronic stress presumably repre- ior, Nemeroff CB, Dunn AJ, eds. New York: Spectrum Publica-
sents an adaptation of the brain to deal with excess NE release, tions, pp 273-348
and this could explain the behavioral adaptation. On the basis Dunn AJ, Kramarcy NR (1984): Neurochemical responses in stress:
of similarities in the effects of chronic stress and tricyclic Relationships between the hypothalamic-pituitary-adrenal and cate-
cholamine systems. In: Handbook of Psychopharmacology, Vol
antidepressant therapy on adrenergic receptors, Stone has pos- 18, Iversen LL, Iversen SD, Snyder SH, eds. New York: Plenum
tulated that similar mechanisms may be involved. A simple- Press, pp 455-515
minded view would suggest that prophylactic antidepressant Mason JW ( 1971 ): A re-evaluation of the concept of' 'non-specificity''
therapy could protect against the effects of stress, and indeed in stress theory. J Psychiat Res 8:323-333
there is some evidence to support this idea. However, another Stone EA (1975): Stress and catecholamines. In: Catecholamines and
view suggests that the situation is far more complex. Weiss Behavior, Vol 2. Friedhoff AJ, ed. New York: Plenum Press, pp
has postulated that behavioral (motor) deficits in stressed ani- 31-72
Substance Abuse
Steven M. Mirin

For centuries individuals have ingested, smoked, inhaled, or depressants such as the benzodiazepines and hypnotic-seda-
injected chemical substances that alter thinking and mood. tives. In general, the rate of tolerance development is a function
For the vast majority of these individuals experimental or recre- of the drug consumed, the doses used, the frequency of admin-
ational drug use is a transient phenomenon. For a small minor- istration, and the response the drug elicits in those cells respon-
ity, however, use becomes, over time, abuse, with harmful sible for its metabolism and those cells through which its phar-
effects on physical, emotional, social, and occupational func- macologic effects are mediated.
tioning. Drug tolerance is frequently, but not invariably, accompa-
In general, drugs subject to abuse exert direct pharmacologic nied by physical dependence. This implies a state of altered
effects on the brain that result in the alteration of mood. More- cellular physiology developed in response to repetitive drug
over, there is substantial evidence that the reinforcing proper- use. Consequently abrupt, or even gradual, withdrawal of a
ties of these drugs can also be demonstrated in animals. For dependence-producing drug may result in the development of
example, acute administration of drugs like heroin or cocaine a characteristic abstinence syndrome. Dramatic abstinence syn-
will produce a brief, but memorable, euphoria which motivates dromes may be seen following abrupt withdrawal of opiates
the user to repeat the experience. Monkeys exposed to injec- and CNS depressants and, to a lesser extent, CNS stimulants
tions of these drugs will perform operant work such as bar and marijuana. The signs and symptoms of drug withdrawal
pressing in order to obtain more injections, even in the absence are usually the antithesis of those pharmacologic effects origi-
of physical dependence or drug withdrawal symptoms. nally produced by the drug. For example, heroin addicts who
In addition to the recreational use of drugs for their primary experience tension relief and euphoria and who manifest pin-
reinforcing effects, psychoactive drugs are also used by some point pupils and decreased gastrointestinal motility during epi-
individuals to self-medicate feelings of anxiety or depression. sodes of drug administration respond to heroin withdrawal
Thus, a chronically anxious individual may find that the anti- with anxiety, depression, dilated pupils, and diarrhea.
anxiety effects of a benzodiazepine or the sedative effects of With this as an introduction, the following sections will
alcohol may provide effective, but temporary, relief. Similarly briefly review each of the major classes of commonly abused
a depressed individual who is experiencing feelings of helpless- drugs with emphasis on the relationship between their effects
ness and hopelessness may find that the self-administration on the brain and their abuse potential.
of a central nervous system (CNS) stimulant like cocaine will
temporarily reverse this negative feeling state.
The opiates
Regardless of the initial motivation for use, repetitive self-
administration of psychoactive drugs can have serious adverse Pharmacology. The opiates include the natural alkaloids of
consequences. Among these are the development of psycholog- opium such as morphine and codeine, the semisynthetic deriva-
ical dependence, drug tolerance, and physical dependence. tives such as heroin and hydromorphine, and purely synthetic
Psychological dependence refers to a felt need to use a particu- agents such as meperidine and methadone. Opiate drugs may
lar drug (or class of drugs) because its pharmacologic effects be ingested or administered intravenously or intramuscularly.
are deemed essential for normal psychological functioning. Intravenous administration produces a rapid elevation in the
If denied access to their drug of choice, psychologically depen- blood levels of these drugs, and the blood level achieved ap-
dent individuals experience considerable anxiety, fearing the pears to be correlated with the degree of intoxication produced.
loss of what they consider to be an important tool for coping As with most psychoactive drugs the opiates appear to exert
with internal or external stress. As a result, they will take their effects on the brain and other organ systems by binding
steps to assure access to their drug even if it means forgoing to receptor sites on cell membranes. These so-called opiate
their usual social or work obligations. receptors, which have been identified in various areas of the
With some drugs of abuse such as opiates and CNS depres- brain as well as in the gastrointestinal tract, may also be the
sants and stimulants repetitive use is accompanied by the devel- binding sites for naturally occurring opioid peptides called
opment of tolerance, a condition in which increasingly larger enkephalins and endorphins.
doses of a particular drug must be taken in order to reproduce Acute opiate intoxication is characterized by a brief but
the drug's original pharmacologic effects. Drug tolerance may intense euphoria, followed by relaxation, drowsiness, mental
result from an increased rate of drug metabolism, or a change clouding, apathy, and motor retardation. Somatic effects in-
in the sensitivity of certain target cells to the drug's pharmaco- clude slowing of the gastrointestinal tract, respiratory depres-
logic effects. In addition, individuals who develop tolerance sion, and a drop in pulse and blood pressure. In cases of
to one drug often manifest tolerance to other drugs in the intentional or unintentional overdose, death may occur as a
same pharmacologic class. For example, chronic users of CNS result of respiratory depression or cardiovascular collapse.
depressants like alcohol may manifest tolerance to other CNS Repetitive use of opioid drugs leads to the development of
112 Steven M. Mirin

tolerance to their euphorigenic, analgesic, sedative, and respi- The CNS depressants
ratory depressant effects and, in some cases, profound physical
dependence. Conversely, abrupt withdrawal of these drugs in Pharmacology. The CNS depressants include the barbiturates
physically dependent individuals leads to the development of sedative-hypnotics, and benzodiazepines. These drugs shar~
a characteristic abstinence syndrome whose symptoms essen- the com~~n ability t.o. induce sedation or sleep by depressing
tially reflect increased CNS and autonomic nervous system CNS activity. In addltlon, the benzodiazepines appear to have
arousal. The onset, duration, and severity of this abstinence specific antianxiety effects. Though the precise mechanism
syndrome depends on the particular opiate used, the degree of action of the CNS depressants is not well worked out
of tolerance and physical dependence developed, the time some drugs in this group, particularly the benzodiazepines:
elapsed since the last dose, and the psychological response probably alter the activity of those CNS neurons which use
of the patient to the physical discomfort of drug withdrawal. gamma-aminobutyric acid (GABA) as a neurotransmitter.
Thus, for a relatively short-acting drug like heroin, withdrawal CNS depressants may be administered orally or parenterally
symptoms may begin as soon as 6 hours after the last dose and are well absorbed from the gastrointestinal tract. Their
on~et of action i~ de~.ndent, in part, on their lipid solubility,
and peak 48 to 72 hours later. In contrast, withdrawal from
methadone, a longer acting agent, usually begins 24 to 48 which affects their ability to cross cell membranes. Their dura-
hours after the last dose and may persist over a 3- to 5-week ti?n .of action is. determined by the rate at which they are
d1stnbuted to vanous body tissues as well as the rate of meta-
peri~d: Wi~hdrawal symptoms can be alleviated by renewed
admmistratJon of any opiate, taking advantage of the cross bolic degradation and renal excretion.
tolerance that exists between these drugs. In treatment settings, Intoxication with CNS depressants is a direct result of the
methadone, a synthetic opioid with a relatively long duration effects of these agents on the cerebral cortex and brain stem.
Sever~ intoxic.ation is usually the result of purposeful overdose,
of action (i.e., 24 to 36 hours) is helpful in this regard. Indeed,
often m a smcide attempt. Overdose cases are complicated
the. bindin.g of methadone to opiate receptor sites not only
relieves withdrawal symptoms but will also block the euphoria by the fact that simultaneous administration of more than one
CNS depressant may overwhelm available liver enzymes, re-
which accompanies acute administration of drugs like heroin.
sulting in a clinical effect which is greater than the sum of
Chronic use of methadone in this fashion is accompanied by
the effect of either agent administered alone. The self-adminis-
the development of tolerance to the sedative, analgesic, and
tration of such drug combinations (e.g., alcohol with a benzo-
depressant effects seen during the acute phase of treatment.
diazepine) is an important cause of overdose deaths.
Consequently, chronic maintenance on high doses of metha-
With repetitive use of CNS depressants, both tolerance and
done is an effective and popular treatment for recidivist opiate
physical dependence develops. Tolerance appears to be of two
addicts who would otherwise relapse to the use of illicit heroin
types, metabolic tolerance, in which liver enzymes are elabo-
or other shorter acting opioids.
rated, allowing for more rapid metabolism of these drugs,
Another drug used to ameliorate the symptoms of opiate
and pharmacodynamic tolerance in which the body tissues
withdrawal is clonidine, a nonopiate antihypertensive agent
appear to develop a subsensitivity to their effects. Finally,
which acts by stimulating alpha-2 receptors located in the neu-
tolerance development to a particular CNS depressant (includ-
rons of the locus ceruleus (LC) region of the midbrain. This
ing alcohol) confers some degree of cross tolerance to other
region gives rise to long neuronal processes that form the
drugs in this general class.
noradrenergic pathways of the CNS. Clonidine-induced stimu-
lation of alpha-2 noradrenergic receptors reduces the firing
Use and abuse of CNS depressants. Federal statistics indicate
rate of LC neurons through a type of feedback inhibition,
that more than I 00 million prescriptions are written each year
thus decreasing noradrenergic activity in both the CNS and
for CNS depressant drugs. Of these, the vast majority are
the periphery. Since many of the symptoms of opiate with-
for the benzodiazepines like diazepam, chlordiazepoxide, and
drawal are due to noradrenergic hyperactivity, clonidine is
flurazepam, but there are a host of other drugs with sedative
an effective treatment for opiate withdrawal symptoms.
and antianxiety effects that are in wide use. In general, these
drugs are initially prescribed for the symptomatic treatment
Use and abuse of opiate drugs. In addition to the development
~f insomnia and anxiety. Unfortunately, prolonged administra-
of tolerance and physical dependence, the chronic user of opi-
tion of these agents leads to the rapid development of tolerance
ate drugs often experiences the psychosocial sequelae of drug
to bot.h their hypnotic and anxiolytic effects. Cons"quently,
dependence. The latter may include disruption of interpersonal
there IS often a tendency to gradually increase the dose over
ties, occupational failure, and the development of a deviant
time with the subsequent development of even greater tolerance
lifestyle necessary to support the illicit use of these drugs.
and physical dependence.
Treatment approaches are customarily aimed at controlling
Some individuals abuse depressant drugs such as barbiturates
drug use and helping individuals to develop an alternative
or sedative-hypnotics intermittently during sprees of intoxica-
lifestyle. Pharmacologic approaches to limiting illicit drug use
tion. Others abuse depressants in an attempt to alleviate the
include the use of methadone and narcotic antagonist drugs,
symptoms of withdrawal from other drugs such as opiates or
which are structurally similar to the opiates and bind tightly
alcohol. Abusers of such CNS stimulants as amphetamine and
to opiate receptor sites, blocking the pharmacologic effects
cocaine may also use alcohol, sedative-hypnotics, or benzo-
of subsequently administered opiate drugs. In individuals who
diazepines in an attempt to modify stimulant-induced jittery-
are physically dependent, administration of narcotic antago-
ness, hyperactivity, and insomnia.
nists such as naltrexone or naloxone will precipitate a severe
Most patients who have been taking CNS depressants in
withdrawal syndrome.
moderate to high doses over more than several weeks will
Among the nonpharmacologic approaches to the treatment
experience at least mild abstinence symptoms if the drugs
of chronic opiate users are individual, group, and family ther-
are withdrawn abruptly. Abstinence symptoms may include a
apy. In patients with a history of frequent relapse, prolonged
~ebound increase in rapid eye movement (REM) sleep with
residence in a drug-free therapeutic community may help the
~ncreased dreaming, middle-of-the-night awakening, irritabil-
individual focus on learning to cope with life's travails without
Ity, and anxiety. In more severe cases, hypotension, hyperther-
the use of mind-altering chemicals.
 Substance Abuse 113

mia, delirium, seizures, and death, due to cardiovascular col- been replaced in popularity by cocaine, the abuse of which
lapse, may occur. The onset of withdrawal symptoms is, in is becoming a major public health problem. Cocaine is most
part, dependent on the duration of action of the drug used. commonly self-administered intranasally (snorted) although in-
Thus abrupt withdrawal of a short-acting agent like pentobarbi- travenous use and "freebasing" (i.e., smoking of the basified
tal may be followed by abstinence symptoms within 12 to 16 extract) are increasingly common as well. The vast majority
hours. In contrast, withdrawal of a longer acting drug, like of cocaine users do so for social or recreational purposes.
diazepam, may not produce withdrawal symptoms until 7 to Among chronic high-dose users, however, recent studies have
10 days have elapsed. Severe depressant withdrawal syndrome demonstrated that there is a substantial minority who are at-
should be treated in a hospital setting. The primary goal of tempting to self-treat an underlying psychiatric disorder; most
treatment is to reduce CNS irritability. This is usually done commonly depression or manic depressive illness.
by reinstituting treatment with a CNS depressant and gradually Finally, chronic high-dose use of amphetamine, metham-
withdrawing the agent under medical supervision. phetamine, or cocaine may be accompanied by the development
Treatment of depressant abuse should attempt to address of a toxic psychosis characterized by suspiciousness, fear,
root causes. In this regard, some depressant abusers suffer increased aggression, delusions of persecution, ideas of refer-
from underlying psychiatric disorders including depression, ence, and visual and auditory hallucinations. Superficially this
panic and anxiety states, and a host of characterologic prob- state resembles paranoid schizophrenia. Withdrawal of the drug
lems. Thus, treatment should be directed at the alleviation of of abuse is usually followed by recovery, though some patients
these problems through the use of individual, group, and family continue to manifest psychotic symptoms for months after-
therapy and, where necessary, psychotropic medication. ward. Chronic stimulant abuse usually requires treatment in
an inpatient setting. Rebound depression may be treated with
psychotherapeutic support and in some cases with antidepres-
The CNS stimulants sant drugs. Avoidance of relapse requires that the underlying
Pharmacology. CNS stimulants like amphetamine, meth- psychiatric and characterologic disorders found in these pa-
amphetamine, and cocaine exert their stimulatory effects on tients be addressed as well.
the brain by facilitating the release of the neurotransmitter,
norepinephrine (NE) from CNS neurons. They also increase
The hallucinogens
the availability of this neurotransmitter at functionally impor-
tant receptor sites in the CNS by interfering with the reuptak!(, Pharmacology. A wide variety of agents derived from either
and subsequent metabolic breakdown, of NE by CNS neurons. natural sources (primarily plants) or synthesized in the labora-
The stimulant drugs also inhibit monoamine oxidase, an en- tory have the ability to induce perceptual distortions and hallu-
zyme important in the degradation of NE. In high doses, these cinations in those who either ingest them or administer them
drugs also appear to exert similar effects on dopamine-contain- intravenously. These drugs have been variously labeled psy-
ing neurons. This may contribute to their tendency to produce chedelic (i.e., mind expanding) or psychotomimetic (i.e.,
psychosis in chronic, high-dose users. mimicking psychosis); however, neither term precisely de-
In general, administration of CNS stimulants produces in- scribes their effects.
creased mental alertness, wakefulness, a sense of initiative The commonly abused hallucinogens fall into two chemical
and confidence, and elevated mood. The drugs also suppress classes: The indolealkylamines include LSD, psilocybin, and
both appetite and REM sleep. Acute stimulant intoxication is dimethyltryptamine (DMT) and are structurally similar to the
characterized by restlessness, hyperactivity, irritability, talka- neurotransmitter 5-hydroxytryptamine (serotonin). The phe-
tiveness, anxiety, and labile mood. At higher doses, these nylethylamines include mescaline and dimethoxy methylam-
drugs induce agitation, tremor, confusion, and dysphoria. In phetamine (DOM) and are structurally related to the neuro-
addition, some individuals become suspicious and even para- transmitters norepinephrine and dopamine.
noid. In general, the intoxication syndrome is self-limited and
wanes as the drugs are metabolized. With its extremely short Use and abuse of hallucinogens. Since the hallucinogens have
duration of action (20 minutes or less), cocaine inspires a no well-defined therapeutic use, all use may be defined as
tendency toward repeated use in order to maintain the drug- abuse. In humans the hallucinogens induce a toxic psychosis
induced euphoria. characterized by perceptual changes (e.g., illusions and hallu-
With repetitive use, tolerance and mild physical dependence cinations), confusion between sensory modalities (synesthe-
develop to most of the effects of CNS stimulants. Under these sias), a subjective sense that time is slowed, Joss of body
conditions abrupt discontinuation of drug use may be followed and ego boundaries, and emotional lability. The duration of
by a characteristic withdrawal syndrome marked by lethargy, hallucinogen intoxication varies from I to 24 hours depending
fatigue, and depression. These withdrawal effects, in tum, on the agent used. Aftereffects, like psychic numbness, may
may precipitate further drug use. last for days, however.
For some hallucinogen users drug-induced perceptual
Use and abuse of CNS stimulants. Though stimulants like changes, coupled with a generalized loss of body and ego
amphetamine and methylphenidate have some role in the short- boundaries, is extremely anxiety provoking. Consequently, the
term treatment of obesity and the longer term treatment of most common adverse reaction following the use of LSD or
narcolepsy and attention deficit disorder, they also have signifi- other hallucinogens is acute panic, during which the user fears
cant potential for abuse. Thus, some individuals take these that he is "losing his mind." Panic symptoms may be allevi-
drugs chronically for their mood-elevating effects while others ated by the presence of supportive friends and a decrease in
engage in sporadic, high-dose use in search of intoxication the amount of sensory stimulation. Another adverse reaction
and euphoria. This last motivation is particularly common to hallucinogen use is the development of a toxic delirium
among those who self-administer methamphetamine and co- characterized by hallucinations, delusions, agitation, disorien-
caine. tation, and paranoia. In individuals with underlying mood dis-
In the 1960s, amphetamine and methamphetamine were pop- orders or schizophrenia, hallucinogen use may exacerbate the
ular drugs of abuse. More recently, however, these drugs have illness. Finally, some users have recurrent drug-like experi-
114 Steven M. Mirin

ences (i.e., flashbacks) that may occur for weeks to months dose consumed, its route of administration, and other physio-
following even the one-time use of a hallucinogenic substance. logical and interpersonal variables. The expectations of the
Though not much is known about the psychological sequelae user and the setting in which the drug is consumed are ex-
of chronic hallucinogen use, it is the general clinical impression tremely important in this regard. The most common effects
that such individuals are unusually passive and suffer from a are feelings of well-being, euphoria, and relaxation, along with
variety of personality disorders. altered time sense and a heightened awareness of one's envi-
ronment. Thought processes are slowed and short-term mem-
ory is impaired. Some users feel that they derive special in-
Phencyclidine (PCP) sights while intoxicated and even trivial events may have pro-
Pharmacology . Phencyclidine, also known as PCP or "angel
found meaning in the intoxicated state. Daily use of marijuana
dust,'' is an animal tranquilizer which has achieved a fair results in the development of mild tolerance and physical
degree of popularity as a drug of abuse. The drug has stimulant, dependence. In chronic, heavy users, abrupt withdrawal pro-
depressant, hallucinogenic and analgesic effects. It can be duces restlessness, irritability, disturbed sleep, anorexia,
taken orally, intranasally, and intravenously, and it can be sweating, tremor, and gastrointestinal upset.
inhaled through the lungs when smoked. It is metabolized by
the liver and stored in fatty tissues. At low doses, the serum Use and abuse of marijuana. Though the vast maJOrity of
half-life of PCP is approximately 45 minutes. However, fol- individuals who try marijuana may be classified as experi-
lowing administration of large doses, the half-life may be as menters, approximately 35% become regular users and about 5%
long as 3 days due to sequestration in fatty tissue. become daily users of the drug. Among the latter group, one
In low doses, PCP is a CNS depressant. It produces impaired finds an increase in the prevalence of both drug-induced and
perception, incoordination, generalized numbness, and a nondrug psychopathology when compared to experimenters
blank-stare appearance. At higher doses, there is more disrup- and casual users. Moreover, chronic heavy users also tend to
tion of CNS functioning, with slurred speech, ataxia, increased abuse other psychoactive drugs, including alcohol.
deep tendon reflexes, and catalepsy. Large doses may also In inexperienced users, acute intoxication may precipitate
produce hypertension, seizures, respiratory depression, coma, a panic state which may simulate acute psychosis, though
and death. reality testing remains intact. As in the case of the hallucino-
gens, large doses may also produce toxic delirium marked
Use and abuse of PCP. The abuse of PCP apparently stems by confusion, feelings of derealization, paranoia, visual and
from the drug's ability to induce feelings of disassociation auditory hallucinations, and dysphoric mood. In general, both
and perceptual distortions. Acute intoxication, which may last panic and toxic delirium are time-related, lasting for a few
4 to 6 hours after a single dose, is often accompanied by hours to a few days, and waning as the drug is gradually
increased sensitivity to external stimuli and elevated mood. metabolized.
Some patients exhibit bizarre posturing or catatonia as well. Chronic heavy marijuana use may be accompanied by what
PCP use may also produce a psychotic state that can persist some authors have described as an "amotivationa l syndrome"
for days or weeks. Patients with a prior history of psychosis characterized by decreased drive, diminished attention span,
appear to be particularly vulnerable to this complication. The poor judgment, apathy, and impaired communication skills.
psychosis itself is characterized by increased motor activity, Though they may continue to perform tasks that do not require
insomnia, agitation, paranoid delusions, and increased sensi- the ability to concentrate, social, occupational, and interper-
tivity to external stimuli. Assaultive behavior is not uncom- sonal functioning are impaired. Chronic high dose marijuana
mon. In the absence of specialized medical treatment, the use may also lead to the development of a psychotic state
psychotic episode may resolve over a period of 5 to 15 days. which clinically looks very much like PCP psychosis. This
Finally, there is some evidence that chronic PCP use can condition has been described primarily in heavy users residing
induce profound anxiety, impairment of cognitive functioning, in countries where hashish, a more potent, concentrated form
social isolation and withdrawal, and unpredictable violence. of marijuana, is used.

Marijuana Summary
Pharmacology . Of all the drugs mentioned here, with the ex- The propensity for any individual to abuse psychoactive drugs
ception of alcohol, marijuana is probably the most widely is the result of developmental, social, cultural, and interper-
used. Surveys suggest that upward of 60 million people over sonal factors. Personal attitudes toward drug taking and drug
age 13 have tried the drug at least once. The major active intoxication, the attitudes of one's peer group toward such
ingredient in marijuana is delta-9-tetrahydrocannabinol (THC). behavior, and the availability of the drug itself are also impor-
There is approximately 5-20 mg of THC in an average mari- tant. Moreover, in some instances genetic and biological vul-
juana cigarette, about half of which is absorbed into the blood- nerability also plays a role. The ability of these drugs to induce
stream during the smoking process. Oral administration of euphoria and relieve tension is extremely reinforcing in both
marijuana results in somewhat lower absorption of THC, as animals and humans and sometimes leads to repetitive use with
well as slower onset of action. the concurrent development of tolerance and physical depen-
Once absorbed, THC is stored in fatty tissues and some is dence. Moreover, once individuals become physically depen-
bound to plasma protein. Metabolism is via liver enzymes, dent, continued drug taking becomes necessary in order to
followed by excretion through the gastrointestinal tract and avoid the development of abstinence symptoms. Finally, there
kidneys. As a result of sequestration in fatty tissue, some is also evidence that abstinence symptoms may be experienced
THC can be found in plasma for as long as 6 days after the by previously dependent individuals as the result of behavioral
administration of a single dose. conditioning. All these factors make substance abuse an ex-
The effects of marijuana intoxication are colored by the tremely complicated behavior to change. Consequently, sue-
 Substance Abuse 115

cessful treatment of such individuals requires the development Grinspoon L, Bakalar JB (1976): Cocaine. A Drug and Its Social
of a multimodal, eclectic approach which takes this complexity Evolution. New York: Basic Books
into account. Meyer RE, Mirin SM (1979): The Heroin Stimulus. New York:
Plenum Press
Mirin SM, Meyer RE (1978): The Treatment of Substance Abusers.
Further reading In: Principles of Psychopharmacology, Clark WG, del Guidice J,
Bourne PG (1976): Acute Drug Abuse Emergencies. New York: Aca- eds. New York: Academic Press
demic Press
Tolerance and Physical Dependence
William R. Martin

Tolerance and physical dependence are complex biological is called dispositional or metabolic tolerance and probably
responses to the chronic administration of drugs and are proba- accounts for about half the tolerance induced by chronic admin-
bly intimately related to basic neurophysiological processes istration of pentobarbital. Tolerance that cannot be accounted
such as habituation and accomodation. Chemical stimuli and for by increased metabolism of drugs is called functional toler-
receptive mechanisms were probably among the first sensory ance, and for most drugs that alter central nervous system
mechanisms to evolve to assist in satisfying food needs and function, this is thought to be mediated by changes in brain
in avoiding toxic chemicals. To facilitate acquisitive and avoid- function.
ance movements, negative feedback mechanisms probably de- The degree of tolerance to some effects of central nervous
veloped at a very early stage of evolution. Further, a large system drugs is ambiguous since the effects of drugs in tolerant
portion, perhaps all, of the communication between neurons animals is different than in naive animals. For those effects
in the central nervous system is conducted using chemical where tolerance can be measured unambiguously the degree
(neurotransmitters, modulators, and hormones) stimuli andre- of tolerance induced varies greatly among drugs. The degree
ceptors. Finally, virtually all drugs that induce tolerance and of tolerance can be estimated by calculating a tolerance index-
dependence exert their actions, either directly or indirectly, the ratio of the amount of drug necessary to produce an effect
by altering neurotransmitter-receptor interactions (Table 1). of a certain magnitude in tolerant and nontolerant animals or
Chronic administration of drugs diminishes some of their tissue. Tolerance indices of between 10 and 100 and even
major effects. For example, 30 mg morphine may produce higher have been observed for some LSD-like hallucinogens
severe respiratory depression in some subjects; however, in and for some opioids, and the tolerance index for pentobarbital
individuals who have become tolerant to morphine, a dose is between 2 and 3. These observations also suggest that the
of 60 mg will not overtly or markedly alter respiration. How- brain has several mechanisms for developing tolerance. These
ever, tlte respiratory function of morphine-tolerant subjects is mechanisms have provided a tool for classifying drugs with
not normal; their rate is somewhat slowed and the ability of similar mechanisms of action using the phenomena of cross
C02 to stimulate respiration is diminished. Similarly the ability tolerance. Cross tolerance is said to exist when the induction
of morphine to produce feelings of well-being are diminished of tolerance to one drug confers tolerance to another drug.
by repeated administration, and subjects who receive large This technique has been used extensively to show that several
doses of morphine chronically become hypophoric. Animal chemicals of diverse structure share a common mode of action
studies have explored the effects of chronic administration of with LSD. Similar studies have been conducted using subtypes
morphine on its ability to diminish responses to painful stimuli of opioids.
and have shown that the dose-response curves in naive and Physical dependence is a group of phenomena characterized
tolerant animals are parallel but the curve of the tolerant animal by the emergence of a unique pattern or syndrome of signs
is shifted to the right. Evidence from both humans and animals and symptoms when the drug is withdrawn from subjects who
indicates that both cognitive processes and learning are in- have ingested several or many doses or is displaced from its
volved in the development of drug tolerance. Thus many indi- receptors by a competitive antagonist. When the drug is with-
viduals who are particularly susceptible to the depressant ef-
fects of alcohol may avoid complex motor function and hence
Table 1. Types of Drugs of Abuse, the Neurotransmitters that they
partially conceal their inebriation. Mimic or Modulate, and the Receptors with Which they Interact
Tolerance to some actions of drugs may develop rapidly
and can be demonstrated after a single dose. Because of the Receptor and
rapidity with which it develops it is called acute tolerance. Drug Type Neurotransmitter Receptor Subtypes
Tolerance to other actions of drugs may require many large Opioid analgesics endorphins, enke- J.L, K, 8, E, a
doses administered for several days. Because of these charac- phalins, and dy-
teristics it is called chronic tolerance. norphins
Because of these diverse characteristics of tolerance to the Alcohol GABA
actions of drugs, it would seem probable that tolerance is Tobacco acetylcholine nicotinic cholinergic
not one phenomenon but several and that there are probably and other nicotinic
several mechanisms involved in its development. Many species receptors
decrease the effect of drugs by metabolizing them more rapidly Amphetamines dopaminergic and
with a liver microsomal enzyme system comprised of many noradrenergic
Benzodiazepines GABA
closely related enzymes with different specificities. Some drugs GABA
Sedative-hypnotics
metabolized by these enzyme systems also induce or increase LSD-like hallucino- serotonin and trypta- serotonin and trypta-
the amount of the enzyme, thus enhancing the inactivation gens mine mine
of the drug and related drugs and reducing their effects. This
 Tolerance and Physical Dependence 117

drawn the resulting abstinence syndrome is called withdrawal When patients are chronically administered depressant drugs
abstinence; when an antagonist is used to precipitate abstinence such as alcohol, barbiturates, and antianxiety drugs, some de-
the resulting syndrome is called precipitated abstinence. The gree of tolerance develops to their effects; however, as with
withdrawal and precipitated abstinence syndrome usually are dependence on opioids, the patient ingesting depressants is
similar but may differ in certain respects. far from normal. They may show signs of drunkenness and
Tolerance and physical dependence are thought to be particu- incoordination, thinking may be slowed, and mood may be
larly pernicious aspects of certain drug actions for three rea- labile, ranging from feelings of well-being to hostility, aggres-
sons. (I) The degree of tolerance and the level of dependence siveness, irritability, and depression. Chronic use of depres-
are thought to be related to the amount of drug administered sants may markedly inhibit rapid eye movement sleep. Less
and the frequency and duration of administration. Thus when is known about signs and symptoms of abstinence in patients
tolerance begins to develop, the amount of drug required to who are dependent on alcohol, barbiturates, and other sedative-
produce the same therapeutic effect is larger, which in tum hypnotics and antianxiety drugs. Among well-identified signs
increases both tolerance and physical dependence. (2) Symp- and symptoms are tremor, weakness, involuntary twitching,
toms of abstinence are uncomfortable to the patient. When nausea, vomiting, loss of appetite, grand mal seizures, ortho-
the patient learns that the symptoms of abstinence can be re- static hypotension, dizziness, insomnia, anxiety, and delirium
lieved by the dependence-producing drug, the drug-procuring that may or may not be associated with fever. Rapid eye move-
activity "hustling" is established, which may lead to antisocial ment sleep may be markedly increased. The abstinence syn-
behavior. (3) The continuing use of drugs of abuse may pro- drome associated with dependence on depressants is much
duce long-lasting changes in brain function called protracted more life-threatening than the abstinence syndrome associated
abstinence, which may also contribute to relapse of detoxified with opioid dependence. The ability of various depressants
addicts. Protracted abstinence impacts negatively with person- to substitute for each other in dependent patients has not been
ality diatheses that predispose individuals to use drugs that well investigated. Drugs such as pentobarbital and paraldehyde
produce feelings of well-being. will clearly suppress the abstinence syndrome in alcohol and
Various types of drugs produce different types of physical barbiturate dependence; however, in some patients very large
dependence. Tolerance and physical dependence produced by doses may be required to suppress seizures and delirium. Not
opioids have been most carefully studied. It is known that a all signs and symptoms emerge at the same time. Tremors
clinically significant degree of physical dependence in humans almost invariably appear during the first 24 hours of abstinence.
can be produced by small doses of morphine (30 mg/day) Epileptic phenomena usually do not appear until the second
administered for about a month. Further, an abstinence syn- day, and delirium usually does not occur until the fourth to
drome can be precipitated after only a single large dose or seventh day of abstinence. It is not known why different signs
several smaller doses of methadone. Thus physical dependence and symptoms of abstinence from depressants such as alcohol
can be induced rapidly and with only small doses of morphine- and barbiturates appear at different times. Although the rate
like drugs. Opioid receptors are distributed throughout the of elimination of the drug may play a role, other processes
brain. and opiate drugs alter the function of most regions of may be important. The discovery of competitive antagonists
the brain. Thus it is not surprising that signs of abstinence of the benzodiazepine depressant has shed some light on this
involve many physiological systems. Further signs of opioid issue. When antagonists are administered to benzodiazepine-
abstinence are opposite to those of opioid primary effects: dependent animals to precipitate abstinence, tremor appears
(1) Thus morphine depresses spinal cord reflexes evoked by within 10 to 15 minutes; however, several hours may elapse
painful stimuli and pain perception; these reflexes are overly before seizure activity becomes manifest. This time course
responsive to painful stimuli in abstinence, and patients com- of benzodiazepine abstinence is quite distinct from abstinence
plain of joint and muscle pain. (2) Morphine depresses the precipitated by opioid antagonists in opioid-dependent sub-
medullary respiratory center's responsivity and sensitivity to jects. The opioid abstinence syndrome appears in its complete
carbon dioxide; its responsivity and sensitivity is enhanced and maximally intense form within a few minutes after the
during abstinence. (3) Morphine constricts pupils by stimulat- administration of the antagonists and starts declining in inten-
ing the mesencephalic Edinger-Westfal nucleus; pupils are di- sity shortly thereafter. These observations suggest that opioid
lated during abstinence. (4) Morphine depresses the release and depressant dependence differ in their basic mechanisms.
of luteinizing hormone by acting on the hypothalamus and Not all drugs that induce central nervous system functional
this is associated with a decrease in libido; abstinence is associ- tolerance produce the same degree of physical dependence.
ated with high levels of plasma luteinizing hormone and testos- Thus the chronic ingestion of large doses of marihuana or
terone and spontaneous ejaculations occur. The morphine absti- hashish induces tolerance but only a mild degree of physical
nence syndrome involves enhancement of spinal cord dependence characterized by nausea, vomiting, diarrhea, loss
nociceptive reflexes; medullary hyperexcitability is indicated of appetite, tremor, sweating, irritability, restlessness, and
by tachycardia, tachypnea, increased blood pressure, and in sleep disturbances. On the other hand, LSD-like hallucinogens
part by increased arousal and nausea and vomiting; at a mesen- that produce profound changes in perceptions and moods as
cephalic level by mydriasis; and at a hypothalamic level by well as marked changes in autonomic and motor reflex function
altered hormonal function and hyperthermia. There are many do not induce physical dependence.
changes in affect produced by opiates. In nondependent opiate Tolerance and physical dependence have captured the imagi-
abusers affect is characterized by feelings of well-being, en- nation of many investigators who have attempted to understand
hanced self-image, and feelings of effectiveness in interper- these two phenomena. Insofar as is known, opioid drugs such
sonal interactions. When patients are abstinent from opiates as morphine depress nerve function by acting as agonists which
they feel weak, tired, apathetic, withdrawn, unpopular, and decrease neuronal function and excitability by increasing K+
ineffective. They overreact to the discomfort associated with and/or decreasing calcium flux across certain nerve mem-
painful sensations, nausea, vomiting, and intestinal cramps. branes. Depressants such as barbiturates and benzodiazepines
Many of these feelings are probably mediated through higher are thought also to decrease neuronal excitability by increasing
centers. Thus a schizophrenic patient who was withdrawn from the effects of the inhibitory nerve transmitter gamma-aminobu-
morphine following a prefrontal lobotomy did not complain tyric acid (GABA) which increases Cl- flux across nerve cell
even though he exhibited typical signs of opiate withdrawal. membranes. It is important to recognize that the two groups
 118 William R. Martin

of drugs that induce tolerance and the most overt types of

physical dependence enhance endogenous inhibitory transmit-
ter activity. Further, the two types of inhibitory processes
that are mimicked or enhanced--opioidergic and GABA-
ergic-are different in several ways in that they involve differ-
ent processes, are involved in different neuronal circuits, and
hence produce different physiological changes. Further, both
types of inhibitory processes are ubiquitous in the nervous
system.
--+
INHIBITORY
--{
EXCITATORY
It is therefore not surprising that dependence on these two PROCESSES PROCESSES
types of drugs creates abstinence syndromes with many signs
and symptoms. Drugs that produce excitatory effects such as Figure 1. Schematic diagram of a neuronal net illustrating the effect of
the LSD-like hallucinogens and amphetamines, although capa- an inhibitory or a depressant drug in up-regulating receptors and neuro-
ble of inducing tolerance, do not produce physical dependence transmitters, resulting in the production of tolerance and dependence.
characterized by a severe abstinence syndrome. This suggests
that the clinically significant types of physical dependence
are a consequence of the brain's effort to adapt to central
inhibitory processes. The nature of these adaptive processes of the decreased excitation of B. This results in a relative
is still uncertain; however, all theories of physical dependence increase in activity of neuron A and an increase in transmitter
postulate negative feedback mechanisms of one sort or another synthesis by neuron A. Both effects would result in tolerance;
that operate on receptors, neurotransmitters, other pathways, the increased neurotransmitter synthesis, in physical depen-
or homeostats. To state this general hypothesis in specific dence. Redundant pathways (C-D) may also mediate the same
terms for different levels of organization the following formula- function and be under negative feedback control from neuron
tions have been proposed. If nerve cell receptors are not stimu- B. Drug d would then increase the activity of neuron C, result-
lated by endogenous or exogenous agonists resulting in a de- ing in increased synthesis of the neurotransmitters by neuron
crease in the formation of active drug-receptor complexes, C and give rise to both tolerance and physical dependence.
several up-regulatory processes may be recruited. The resulting When drug dis not present or withdrawn, the activity of neuron
decrease in active drug receptor complexes may be a conse- D would be markedly above its activity prior to the administra-
quence of the destruction of presynaptic elements either by tion of drug d (abstinence with physical dependence) because
lesions or chemicals, drug or neurotransmitter-induced depres- of receptor up-regulation and neurons B and D and transmitter
sion of presynaptic element function, or the occupation of up-regulation at neurons A and C.
postsynaptic receptors by antagonist. Thus the adaptive mecha-
nisms recruited to counteract the depression induced by in-
creased activity of inhibitory processes must occur at the inhib- Further reading
ited neuron or secondary neurons whose activity is decreased. Jaffe JH (1980): Drug addiction and drug abuse. In: The Pharmacolog-
It is important to recognize that inhibitory agonists such as ical Basis of Therapeutics, 6th ed, Gilman AG, Goodman LS,
opioids and depressants that act directly on receptors or modu- Gilman A, eds. New York: Macmillan
late receptors must continue to exert their inhibitory activity Jones RT (1980): Human effects: An overview. NIDA Research
in the tolerant and dependent animal since their chronic admin- Monograph 31 , 54-80
istration continues to suppress the abstinence syndrome. Kalant H, LeBlanc AE, Gibbins RJ (1971): Tolerance to, and depen-
Figure 1 illustrates some of the postulated mechanisms dence on, some non-opiate psychotropic drugs. Pharmacal Rev
23(3): 135-191
whereby inhibitory drugs can evoke tolerance and dependence. Martin WR (1982): Hyp.tOtics. In: Psychotropic Agents Part Ill, Hoff-
Assume that drug d inhibits neuron A which would result in meister F. Stille G, eds. Berlin: Springer-Verlag
decreased transmitter release at synapse A-B. This effect would Martin WR, Sloan JW ( 1977): Neuropharmacology and neurochemis-
have the following actions: (1) There is up-regulation of the try of subjective effects, analgesia, tolerance, and dependence pro-
receptors responsive to the neurotransmitter whose release has duced by narcotic analgesics. In: Drug Addiction I, Martin WR,
been depressed (neurons Band D). (2) The amount of negative ed. Berlin: Springer-Verlag
feedback from neuron B to A is decreased as a consequence Wikler A ( 1968): The Addictive States. Baltimore: Williams & Wilkins
Contributors

David M. Asher Laboratory of Central Nervous System Studies, Albert M. Galaburda Neurological Unit, K-4, Beth Israel Hospital,
National Institute of Neurological and Communicative Disorders and Boston, Massachusetts 02215, U.S.A.
Stroke, National Institutes of Health, Bethesda, Maryland 20205, Dyslexia
U.S.A.
Creutzfeldt-Jakob Disease Alan J, Gelenberg Psychiatrist-in-Chief, The Arbour, Jamaica Plain,
Massachusetts 02130, U.S.A. and Chief, Special Studies Clinic, Massa-
M. Avoli Department of Neurology and Neurosurgery, McGill Univer- chusetts General Hospital, Boston, Massachusetts 02115, U.S.A., and
sity, Montreal Neurological Institute, Montreal, Quebec, H3A 2B4, Associate Professor of Psychiatry, Harvard Medical School, Boston,
Canada Massachusetts 02115, U.S.A.
Epilepsy Mood Disorders
Stephanie J, Bird Science, Technology, and Society Program and The
Clarence J, Gibbs, Jr. Laboratory of Central Nervous System Studies,
Center for Technology, Policy and Industrial Development, Mas-
National Institute of Neurological and Communicative Disorders and
sachusetts Institute of Technology, Cambridge, Massachusetts 02139,
Stroke, National Institutes of Health, Bethesda, Maryland 20205,
U.S.A.
U.S.A.
Premenstrual Syndrome
Creutzfeldt-Jakob Disease
Lyle W. Bivens Director, Division of Basic Sciences, National Institute
of Mental Health, Rockville, Maryland 20857, U.S.A. P. Gloor Professor, Department of Neurology and Neurosurgery,
Psychosurgery McGill University, Montreal-Neurological Institute, Montreal, Quebec,
H2A 2B4, Canada
Charles Brenner 1040 Park Avenue, New York, New York 10028, Epilepsy
U.S.A.
Psychoanalysis Donald W. Goodwin Department of Psychiatry, University of Kansas
Medical Center, Kansas City, Kansas 66103, U.S.A.
Jack R. Cooper Department of Pharmacology, Yale University School of
Alcoholism
Medicine, New Haven, Connecticut 06510, U.S.A.
Neuropharmacology John H. Greist Department of Psychiatry, University of Wisconsin,
Joseph T. Coyle Division of Child Psychiatry, The Johns Hopkins Medi- Center for Health Sciences, Madison, Wisconsin 53792, U.S.A.
cal Institutions, Baltimore, Maryland 21205, U.S.A. lithium in Psychiatric Therapy
Alzheimer's Disease
James F. Gusella Director, Neurogenetics Laboratory, Massachusetts
John W. Crayton Department of Psychiatry, The University of Chicago, General Hospital, Boston, Massachusetts 02114, U.S.A.
Chicago, Illinois 60637, U.S.A. Huntington's Disease (HD)
Menta/Illness, Nutrition and
Joseph E. Hawkins, Jr. Professor Emeritus, Otorhinolaryngology;
Adrian J, Dunn Department of Neuroscience, JHM Health Center, Kresge Hearing Research Institute, University of Michigan Medical
University of Florida College of Medicine, Gainesville, Florida 32610, School, Ann Arbor, Michigan 48109, U.S.A.
U.S.A. Deafness
Stress, Neurochemistry of
PhilipS. Holzman Department of Psychology, Harvard University, Cam-
Terrance M. Egan University Laboratory of Physiology, Parks Road,
bridge, Massachusetts 02138, U.S.A.
Oxford, England
Eye Movement Dys.fimctions and Menta/Illness
Morphine
Charles J. Epstein Departments of Pediatrics and of Biochemistry C.B. Ireland Professor of Psychiatry, Department of Psychiatry, and
and Biophysics, University of California, San Francisco, California Neurosciences Program, University of Alabama at Birmingham, Birmin~
94143-0106, U.S.A. gham, Alabama 35294, U.S.A.
Down Syndrome Hallucinogenic Drugs

Max Fink Department of Psychiatry, School of Medicine, SUNY at Susan D. Iversen Neuroscience Research Centre, Merck Sharp &
Stony Brook, Long Island, New York 11794, U.S.A. Dohme Research Laboratories, Terlings Park, Harlow, Essex CM20
Convulsive Therapy 2QR, England
Psychopharmacology
Arnold J, Friedhoff Department of Psychiatry, New York University
School of Medicine, Millhauser Laboratories, 550 First Avenue, New James W. Jefferson Department of Psychiatry, University of Wisconsin,
York, New York 10026, U.S.A. Center for Health Sciences, Madison, Wisconsin 53792, U.S.A.
Gilles de Ia Tourette Syndrome Lithium in Psychiatric Therapy
120 Contributors

Harold Kalant Professor, Department of Pharmacology, University of Leo J. Reyna Behavioral Sciences Center, Nova University, Fort Lauder-
Toronto, Toronto, M5S lAS, Canada and Director, Biobehavioral dale, Florida 33314, U.S.A.
Research Department, Addiction Research Foundation, Toronto, M5S Behavior Therapy, Applied Behavior Analysis, and
2Sl, Canada Behavior Modification
Addiction Elliott Richelson Professor and Consultant, Departments of Psychiatry
Conan Kornetsky Boston University School of Medicine, Boston, Mas- and Psychology and of Pharmacology, Mayo Clinic and Foundation,
sachusetts 02118, U.S.A. Rochester, Minnesota 55905, U.S.A
Heroin (Diacetylmorphine) Antidepressants
Harriet 0. Kotsoris Department of Neurology, The New York Hospi- Timothy Roehrs Sleep Disorders and Research Center, Henry Ford
tal-Cornell Medical Center, New York, New York 10021, U.S.A. Hospital, Detroit, Michigan 48202, U.S.A.
Coma Sleep Disorders
William R. Martin Professor and Chairman, Department of Pharmacol- Thomas Roth Sleep Disorders and Research Center, Henry Ford Hospi-
ogy, University of Kentucky College of Medicine, Lexington, Kentucky tal, Detroit, Michigan 48202, U.S.A.
40536, U.S.A. Sleep Disorders
Tolerance and Physical Dependence Arnold B. Scheibel Departments of Anatomy and Psychiatry and Brain
Steven Matthysse The Mailman Research Center, McLean Hospital, Research Institute, UCLA Medical Center, Los Angeles, California
Belmont, Massachusetts 02178, U.S.A. 90024, U.S.A.
Menta/Illness, Genetics of Aging of the Brain
Neal E. Miller Professor Emeritus, Rockefeller University, 1230 York David V. Sheehan Professor of Psychiatry and Director of Clinical
Avenue, New York, New York 10021, and Research Affiliate, Yale Research, University of South Florida College of Medicine, Tampa,
University, New Haven, Connecticut 06520, U.S.A. Florida 33612, U.S.A.
Behavioral Medicine Anxiety and Anxiety Disorders
Steven M. Mirin Associate Clinical Professor of Psychiatry, Harvard Kathy H. Sheehan Department of Psychiatry, University of South
Medical School, Medical Director, Westwood Lodge Hospital, West- Florida College of Medicine, Tampa, Florida 33612, U.S.A.
wood, Massachusetts 02090, U.S.A. Anxiety and Anxiety Disorders
Substance Abuse William J. Shoemaker Director, Neurobiology Laboratory, Department
Hugo W. Moser Director, John F. Kennedy Institute for Handicapped of Psychiatry, University of Connecticut Health Center, Farmington,
Children and Professor of Neurology and Pediatrics, The Johns Hopkins Connecticut 06032, U.S.A.
University, Baltimore, Maryland 21205, U.S.A. Fetal Alcohol Syndrome
Mental Retardation John R. Smythies Department of Psychiatry, and Neurosciences Pro-
Dennis L. Murphy Chief, Laboratory of Clinical Science, NIMH, gram, University of Alabama at Birmingham, Birmingham, Alabama
Bethesda, Maryland 20895, U.S.A. 35294, U.S.A.
Monoamine Oxidase (MAO) Inhibitors in Psychiatric Therapy Hallucinogenic Drugs
William L. Nyhan Department of Pediatrics, School of Medicine, Solomon H. Snyder Departments of Neuroscience, Pharmacology and
University of California, San Diego, La Jolla, California 92093, U.S.A. Experimental Therapeutics, Psychiatry and Behavioral Sciences, The
Phenylalanine and Mental Retardation (PKU) Johns Hopkins University School of Medicine, Baltimore, Maryland
Edward M. Ornitz Department of Psychiatry, Division of Mental 21205, U.S.A.
Retardation and Child Psychiatry, and Brain Research Institute, Univer- Neuroleptic Drugs
sity of California, Los Angeles, California 90024, U.S.A. Larry R. Squire Veterans Administration Medical Center, San Diego,
Autism California 92161, U.S.A., and Department of Psychiatry, University of
Herbert Pardes Professor and Chairman, Department of Psychiatry, California School of Medicine, La Jolla, California 92093, U.S.A.
Columbia University, College of Physicians and Surgeons, New York, Amnesia
New York 10032, U.S.A. Erik Stromgren Professor of Psychiatry, Institute of Psychiatric Demog-
Psychiatry, Biological raphy, Psychiatric Hospital, DK-8240 Risskov, Denmark
Robert C. Petersen Formerly Assistant Director of Research, National Schizophrenia
Institute on Drug Abuse, Rockville, Maryland 20957, U.S.A. Norman J. Uretsky Division of Pharmacology, College of Pharmacy,
Marijuana Ohio State University, Columbus, Ohio 43210, U.S.A.
Phencyclidine Amphetamines
Fred Plum Chairman, Department of Neurology, Cornell University Roger D. Weiss Assistant Professor of Psychiatry, Harvard Medical
Medical College, New York, New York 10021, U.S.A. School, Boston, Massachusetts 02115, U.S.A. and Director, Alcohol and
Coma Drug Abuse Treatment Center, McLean Hospital, Belmont, Mas-
Dementia sachusetts 02178, U.S.A.
Gardner C. Quarton University of Michigan, Ann Arbor, Michigan Cocaine
48107, U.S.A. Frank Zorick Sleep Disorders and Research Center, Henry Ford Hospi-
Psychosis tal, Detroit, Michigan 48202, U.S.A.
Domeena C. Renshaw Professor, Department of Psychiatry, Director, Sleep Disorders
Sexual Dysfunction Clinic, Loyola University of Chicago, Maywood,
Illinois 60153, U.S.A.
Eating Disorders