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iv C o n te n ts

14 The role of drug therapy in the m anagem ent of behavioural and

psychological sym ptom s of dem entia
Roger Bullock 235

15 Treatment of delirium
E Jane Byrne 253
Concluding remarks
Stephen Curran and Roger Bullock 265
Index 267
Foreword
This book is long overdue. The increased aw areness of drugs in psychiatry in
general, and old age psychiatry in particular, m eans that a sum m ary of the key
drugs and their m ain indications w ill be w ell received by everyone involved in
the prescription and m onitoring of m edications. Psycopharm acology is a field
w h ich develops quickly, and it is hard to keep up w ith every n e w initiative or
ruling by a regulatory agency. N otw ithstanding that, this collection of contribu­
tions serves as a super addition to the literature, and provides an excellent
sum m ary of the situation at present.
The m ain areas covered include all those w hich an old age psychiatrist w ill
encoun ter in practice. After introductory chapters on basic science issues, there is
an admirable sum m ary of each of the m ain fields, both organic and functional
illness, w h ich sum m arises inform ation available to date.
As w ith m any projects, the trick is to get a niche in the market, and the editors
and their authors are to be congratulated for putting together such a fine num ber
of contributions. This book w ill serve as a baseline for everything else in this area
of work - n ot just a baseline but a gold standard. It should be w elcom ed by all
clinicians w orking in the area, and w ill serve as an excellent book for continuing
professional developm ent.
Professor Alistair Burns
Professor of Old A ge Psychiatry
University of M anchester
April 2005

v
Preface
In this book w e have brought together findings from recent research w ith a m ulti­
disciplinary perspective into the practical aspects of old age psychopharm acology.
W e strongly believe in the im portance of bringing together the best in research
and practice. W hen these are divorced, researchers m ay lose the vision of the real
purpose of their work, and practitioners m ay not have access to the m ost recent
advances in know ledge. W e hope that this book w ill help to bridge this gap.
If w e ever develop a m ental illness in later life w e w ould like people to notice it
early. W e w ou ld like them to respect our autonom y but steer us quickly in the
direction of the best help available. W e w ou ld like to be seen by appropriately
qualified people w h o could m ake a diagnosis and provide any useful m edical
treatm ent and social, psychological, nursing and therapy support and advice to
ourselves and our fam ilies. W e w ou ld like a truly personal approach to our needs.
W e believe that this applies equally to drug treatm ents, but in our experience this
is n ot alw ays the case.
Psychotropic drugs have an im portant role to play in the m anagem ent of older
people w ith m ental illness. W e hope that this book w ill help clinicians to use
psychotropic drugs m ore appropriately so as to m axim ise their undoubted clinical
benefits w h ile m inim ising som e of their u nw anted effects.
Stephen Curran
Roger Bullock
April 2005

vi
About the editors
S tep h en Curran works as a Consultant Old Age Psychiatrist in W akefield, and is a
Visiting Professor in Old Age Psychopharm acology at the University of Hudders­
field. He graduated in psychology in 1983 and com pleted his undergraduate
m edical training in 1986. He th en w orked as a Research Fellow and Lecturer in
Old Age Psychiatry at the University of Leeds before m oving to W akefield in
1998. His research interests include old age psychopharm acology, particularly the
use of qualitative m ethods to assess drug effects, and he leads the Ageing and
M ental Health Research Group at the University.

R oger B u llock com pleted his m edical and psychiatric training at Oxford and
St B artholom ew 's Hospital, London. In 1993 he was appointed Consultant in Old
Age Psychiatry in Sw indon, and tw o years later he founded the Kingshill
Research Centre. The work of the centre is to study psychopharm acology and
neuropsychology in the elderly, and to apply research from both fields to
m ainstream clinical practice. Roger is n o w Clinical Lead of the Sw indon services
and Director of the Research Centre, w h ich is n o w affiliated to the University of
Bath, w here he is a Reader in Geriatric Psychopharm acology.

vii
List of contributors
R obert C B a ld w in , Consultant in Old Age Psychiatry and Honorary Professor,
M anchester M ental Health and Social Care Trust, M anchester Royal Infirmary,
M anchester

Roger B u llock, Consultant Psychiatrist, Kingshill Research Centre, Victoria

Hospital, Sw indon, W iltshire

E Jane Byrne, Senior Lecturer/Honorary Consultant Psychiatrist, University of

M anchester, School of Psychiatry and Behavioural Sciences, Education and
Research Centre, W ythen shaw e Hospital, M anchester

Richard J C lib bens, Nurse Consultant, Older People's Services, Fieldhead

Hospital, W akefield, W est Yorkshire

M ary Crabb, Pharmacist, St Luke's Hospital, Huddersfield, W est Yorkshire

S tep h en Curran, C onsultant in Old Age Psychiatry and Visiting Professor of Old
Age Psychopharm acology, School of Hum an and Health Sciences, University of
Huddersfield, Huddersfield, W est Yorkshire

O w e n P D em p sey , General Practitioner and Lead Researcher, Lockwood

Research Practice, Huddersfield, W est Yorkshire

A liso n D iaper, Research Student, HPRU M edical Research Centre, School of

Biom edical and M olecular Sciences, University of Surrey, Guildford, Surrey

M argaret M Esiri, Professor of N europathology, The Radcliffe Infirmary, Oxford

Paul Hardy, Pharmacist, Pinderfields General Hospital, W akefield, W est

Yorkshire

D avid H ealy, Honorary C onsultant Psychiatrist/Director, North W ales Depart­

m en t of Psychological M edicine, University of W ales, College of M edicine,
Hergest Unit, Gwynedd Hospital, Bangor, G wynedd

Ian H indm arch, Professor of H um an Psychopharm acology and Head of HPRU

M edical Research Centre, School of Biom edical and M olecular Sciences, U n i­
versity of Surrey, Guildford, Surrey

C live H olm es, Senior Lecturer/Honorary Consultant in Old Age Psychiatry,

M em ory A ssessm ent and Research Centre, M oorgreen Hospital, Southam pton

N aila Jaw aid , Specialist Registrar in Old Age Psychiatry, M anchester M ental
Health and Social Care NHS Trust, M anchester Royal Infirmary, M anchester

Jam es L indesay, Professor of Psychiatry for the Elderly, University of Leicester,

Leicester General Hospital, Leicester

M ich elle C M cC ulley, Research Fellow, H um an Genetics Division, University of

Southam pton, Southam pton

viii
 List o f c o n trib u to rs ix

Sharon N ig h tin g a le, Consultant in Old Age Psychiatry, Asket Croft C om m unity
Unit for the Elderly, Leeds
A n d rew W Procter, Consultant Psychiatrist, M anchester Royal Infirmary,
M anchester
S rinivas Suribhatla, Consultant in Old Age Psychiatry, B ennion Centre, Glen-
field Hospital, Leicester

John P W attis, C onsultant and Visiting Professor of Old Age Psychiatry, School of
H um an and Health Sciences, University of Huddersfield, Huddersfield
Chapter I

Ps/chopharmacological history through

the looking-glass of advancing years
David Healy

Introduction
In 1956, Roland K uhn described the effects of im ipram ine in a 56-year-old
w om an, Paula J F, w h o had a severe delusional m elancholic disorder. Imipramine
w as subsequently dem onstrated to be effective in a patient group suffering from
vital depression w ith psychom otor retardation and often psychotic developm ents
in older individuals. At the tim e, this condition w as regarded by m any as the
distinct diagnostic entity of involutional m elancholia. The success of im ipram ine
led to an alm ost im m ediate disappearance of this syndrom e.
It m ight n ot be thought surprising that an effective psychotropic agent should
lead to the disappearance of a syndrom e, on the basis that m ost people assum e
this is w hat effective agents should do. W hat w as astonishing about this
disappearance was that, far from im ipram ine being effective in the sense that
penicillin w as for general paralysis of the insane (GPI), im ipram ine seem ed to be a
treatm ent that validated the existence of the syndrom e and the n eed for its
possible ongoing m aintenance treatm ent. Yet a few years later the diagnostic
category of involutional m elancholia had effectively disappeared.
This disappearance is at odds w ith the m ainstream of psychopharm acological
history, in w h ich classification has b een driven largely by the response (or
otherw ise) to psychotropic drugs rather than by the clinical criteria that drove
classification in the pre-psychotropic era. The disappearance of involutional
m elancholia gives a first hint that the history of psychotropic agents given to
older individuals m ight be radically different to conventional histories of the
psychotropic era. U nfortunately, there are few histories of w hat happens w h en
psychotropic drugs are given to older individuals . 1' 2 The usual assum ption appears
to have b een that w hat happens in the elderly w ill only reflect w hat is happening
in a general adult group. H ow ever, there are good grounds to think that, in
future, the books m ay reflect a quite different history, as this brief chapter seeks to
illustrate.

The conventional history of the antidepressants

The convention al origin of the antidepressant w as w h en Roland K uhn discovered
the effects of im ipram ine in 1956. U npersuaded of his reports, Geigy sought
confirm ation elsew here. At a tim e w h en com pounds could be synthesised in the

I
2 Practical old age p sy c h o p h arm ac o lo g y

laboratory and could enter m ainstream clinical use w ithin 3 m onths, im ipram ine
took 2 years to market. A major reason for Geigy's reluctance appears to have
stem m ed from the perception that depression was a relatively rare condition . 3
At alm ost the same tim e as K uhn reported on the effects of im ipram ine to
Geigy, N athan Kline m ade the discovery that one of tw o recently synthesised
anti-tubercular agents, iproniazid, had psychic energising properties. It later
becam e k n ow n as on e of the first of the m on oam in e oxidase inhibitor (MAOI)
antidepressants. Roche w ere not interested in such a com pound.
Yet ev en before Kline or Kuhn, in 1952, M ax Lurie had discovered that
isoniazid, another anti-tubercular agent, had antidepressant properties. This
discovery w as replicated in Paris in the sam e year. H owever, n on e of the
pharm aceutical com panies that Lurie approached w ere interested in the idea of
an antidepressant. The very term w as n ew , having probably b een coined by Lurie.
There had indeed b een yet another discovery of a drug w ith antidepressant
properties before K uhn and Kline. In 1955, researchers from the Institute of
Psychiatry dem onstrated in an article published in the Lancet that reserpine w as
an antidepressant. H ow ever, Ciba, the makers of reserpine, w ere not interested in
developing an antidepressant.
It w as not until the discovery of am itriptyline and its m arketing by Merck that
any pharm aceutical com pany sh ow ed an interest in developing an antidepres­
sant. Merck realised that if they w ere going to market this n ew class they w ould
also have to sell the illness, so th ey purchased 50 000 copies of Frank Ayd's
Recognising the Depressed Patient. 4 Despite this, sales of the antidepressants
rem ained flat during the 1960s and 1970s.
The antidepressant m arket on ly truly developed w h en the benzodiazepine
tranquillisers ran into difficulties in the 1980s. Concerns about dependence on
these drugs steered the m arketing developm ent of a n ew generation of drugs that
acted on the serotonin system towards an antidepressant route.
Thus the selective serotonin reuptake inhibitors (SSRIs) w ere developed in
1971 from a conjunction of clinical observations by Paul Kielholz and n eu ro­
scientific observations by Arvid Carlsson. Kielholz noted that not all of the
tricyclic and MAOI antidepressants did the sam e things to people w h o w ere
depressed, and he categorised 'antidepressants' according to w hether they w ere
energy enhancing or w h ether th ey produced 'cognitive' changes. R eview ing
K ielholz's classification in the late 1960s, Carlsson, one of the key pioneers of
neuroscience, noted that the antidepressants w hich Kielholz stated w ere more
energy enhancing acted on the catecholam ine system , w hereas those w ith
cognitive effects acted on the serotonergic system . This led Carlsson to create
the first SSRI, nam ely zim elidine, to see w hat the effects of such a drug w ou ld be.
Zim elidine was launched in 1982, but w as later w ithdraw n because of toxicolo-
gical problems. It w as succeeded by fluvoxam ine, fluoxetine, sertraline, parox­
etine and citalopram.

The unconventional history of the antidepressants

Follow ing the em ergence of the SSRIs, the antidepressant market m ushroom ed. If
antidepressants are effective, this should n ot have happened, and indeed this is
not w hat happened in the case of involutional m elancholia. The m ost parsim o­
 P sychopharm acological history 3

nious explanation of w h at happened w as that a process w as initiated w hereby

cases of V alium w ere converted into cases of Prozac. This did not happen in Japan
and m any other parts of the world w here the SSRIs did not em erge as
antidepressants so early on. In these countries the antidepressant market remains
a com paratively small one com pared w ith the market for tranquillisers.
The developm ent of the SSRIs w as predicated on the notion that agents w hich
act on catecholam ine system s w ere energy enhancing w hereas agents w hich act
on the serotonin system appeared to do som ething else that was either anxiolytic
or produced som e other cognitive effect. The SSRIs w ere therefore designed as
drugs that w ere different from the tricyclic antidepressants, rather than 'cleaned-
up' versions of the sam e (w hich is h o w th ey had originally been m arketed).
In fact the SSRIs have proved singularly ineffective for hospital depressions or
depressions of the kind that Paula J F suffered from. In contrast, selective
catecholam ine reuptake inhibitors such as reboxetine have proved very effective
in hospital depressions, but apparently m uch less effective in com m unity
depressions of the m ore anxious depressive type. This suggests that there m ay
w ell be a distinctive com ponent to the kinds of depression cases w h o end up
in hospital, particularly those w h o end up in hospital in their m iddle to later
years.
There rem ains a consensus of opinion that electroconvulsive therapy (ECT) is
an effective treatm ent for the kinds of vital depression for w hich im ipram ine was
first thou ght to be useful. ECT is n ot regarded as a treatm ent for those kinds of
anxious depressions w h ich are found in the com m unity. Broadly speaking, the
conditions thought to be responsive to ECT are the ones that in the 1980s w ere
thought to be characterised by dexam ethasone non-suppression, a set of depres­
sions in w h ich there is thought to be substantial elevation of cortisol levels,
possibly brought about by escape from circadian control. This is not found in the
depression cases in the com m unity, and SSRIs in general appear to be less
effective in dexam ethasone non-su p p ression . 5
Recently, how ever, m ifepristone, w h ich w as previously used as an abortifacient
agent, has b een dem onstrated to have an effect on severe or psychotic depres­
sions . 6 It also appears to have effects on cortisol system s that are comparable to
the effects of agents such as dexam ethasone or ECT. Should the clinical efficacy
of m ifepristone be replicated, it w ill be an interesting test of pharm aceutical
com pany perceptions of the depressive m arket to see w hether it, unlike rebox­
etine, is developed further. If this w ere to happen, there m ight be a n eed to
reinvent m elancholia (if not involutional m elancholia) and redesignate the SSRIs
as anxiolytics, a process that is arguably w ell under w ay.
There are alternative fram eworks w ithin w hich to place such a developm ent.
W hile involutional m elancholia m ay never have been the distinctive entity it was
once thou gh t to be, this clinical classification arguably em bodied som e clinical
insights of substance. The distinctive response of this syndrom e to som e agents
and not to others points to different physiological underpinnings. One possibility
is that a constitutional or tem peram ental com ponent shapes the differential
response to selective agents seen in these vital depressions. Alternatively, a
constitutional or tem peram ental com ponent m ay shape clinical presentations
so that som e affective disorders in older years have features of anxiety, w hile
others have features of a vital syndrom e. Older age m ay in fact be a key setting in
4 Practical old age p sy c h o p h arm ac o lo g y

w h ich som e of these issues that seem irresolvable in younger populations m ay be

teased out.

The conventional history of the antipsychotics

The conven tion al history of the antipsychotics has it that the discovery of
chlorprom azine w as first interpreted as the discovery of a n e w form of sleep
treatm ent. The subsequent synthesis of a num ber of non-sedative phenothiazine
agents, such as proclorperazine, led to a recognition that these n ew agents m ight
have neuroleptic rather than just sedative effects . 7
This created tw o schools of thought. One school based in Lyon argued for a
classification of neuroleptic drugs ranging from the sedative to the incisive, and
for a recognition that different agents w ould suit different clinical syndrom es and
different constitutional types. This notion underpinned the developm ent of
sedative neuroleptics such as thioridazine and levom eprom azine, in addition to
perphenazine and other m ore incisive agents. In Paris, in contrast, D eniker and
D elay argued that a neuroleptic effect w as the com m on therapeutic effect of all of
these agents, and that other properties such as sedative properties w ere simply
side-effects. The n otions of Delay and D eniker led to a research and drug
d evelopm ent agenda that focused on optim ising the core neuroleptic effect.
The battle b etw een Lyon and Paris was brief but bitter, w ith Paris trium phing.
The developm ent in 1958 of haloperidol, a non-sedative agent, appeared to
endorse the insights of the Paris school. Haloperidol becam e the ultim ate
neuroleptic, and subsequent antipsychotics w ere developed on the basis of a set
of laboratory tests aim ed at replicating its effects.
The developm ent of haloperidol alm ost led to the abortion of clozapine. On a
num ber of the em erging tests of neuroleptics the latter drug, w hich had first been
synthesised in 1958, failed. This failure led to a relatively half-hearted develop ­
m ent programme, w hich w as abandoned once the propensity of clozapine to
produce agranulocytosis w as recognised. H owever, a num ber of European
clinicians, including Jules Angst, R aym ond Battegay and Hanns Hippius, objected
and argued that clozapine w as indeed an effective antipsychotic ev en though it
appeared not to have standard neuroleptic properties. The protest kept clozapine
alive.
W ith the discovery of the effect of the neuroleptic drugs on dopam ine systems,
the develop m ent pathw ay focused on producing more selective and m ore potent
D2-receptor antagonists. This culm inated in the benzam ide group of drugs,
n am ely sulpiride, am isulpiride and rem oxipride, w hich arguably had som ew hat
few er side-effects than other agents but w ere in general no m ore potent. W ith the
re-em ergence of clozapine, argum ents w ere offered that the additional 5HT2
blockade w h ich this com pound offered m ight account for its apparently better
effects than standard neuroleptics in schizophrenia.

The unconventional history of the antipsychotics

In the m id-1960s, concerns em erged about the propensity of neuroleptics to
produce tardive dyskinesia. This syndrom e, w h ich is som etim es present in
untreated older patients w ith psychoses, appeared to occur w ith a m uch greater
 P sychopharm acological history 5

frequency and severity in patients w h o w ere taking neuroleptics. At a tim e of

rising antipsychiatric discontent w ith orthodox psychiatry, tardive dyskinesia
provided a lightning rod to focus this discontent. In 1974, Sm ithKline and
French settled their first m illion-dollar legal action w ith regard to tardive
dyskinesia, and a subsequent generation of antipsychotic drug developm ent
was abandoned.
Apart from the benzam ides, w hich w ere not developed in the USA, drug
develop m en t in this area w as only renew ed in the w ake of the re-em ergence of
clozapine. Contrary to popular m ythologies, the re-em ergence of clozapine
stem m ed n ot from any superior clinical efficacy, but rather from the fact that
this w as a com pound that did n ot cause tardive dyskinesia. The agents that came
in the w ake of clozapine, nam ely sertindole, olanzapine, quetiapine and risper­
idone, w ere also developed primarily as agents that w ou ld m inim ise the risk of
tardive dyskinesia.
Apart from a low er incidence of tardive dyskinesia, especially for quetiapine,
n o n e of these n ew er agents are m ore effective than the older agents. Risperidone
and olanzapine both produce dose-dependent extrapyramidal side-effects, and
are in fact rather typical neuroleptics. The non-extrapyram idal spectrum of side-
effects of these agents in general suggests that th ey m ay in m any w ays be less safe
than the older agents. O lanzapine and clozapine are associated w ith elevated lipid
levels, the production of diabetes and w eight gain, all of w hich can be expected to
elevate cardiovascular m ortality.
The n e w agents differ in their propensity to block D 2 receptors and also in terms
of their sedative properties. Am isulpiride and risperidone are m ost like co n v e n ­
tional neuroleptics, w h ile clozapine and quetiapine are m ore like sedative
neuroleptics such as thioridazine or levom oprom azine. Recent studies w hich
tested the ability of agents such as am isulpiride to augm ent the effects of
clozapine in clozapine-refractory patients suggest that this cycle of drug d ev el­
opm ent has returned us to the position that faced clinicians from Lyon in 1958,
nam ely that antipsychotic agents vary across a spectrum, and w hile there m ay be
som e key elem ents in com m on, such as D2-receptor blockade, the differences
b etw een agents are also significant. Classical neuroleptics m ay be effective in
particular conditions, w hile others of a m ore sedative type m ay be m ore effective
for other conditions.
W hat is clear is that this n e w generation of agents has brought an increased
interest in the use of antipsychotics in the elderly. The elderly population w ould
seem to be the best population in w h ich to test out the com peting visions of Lyon
and Paris, in that the onset of psychoses in older age throw s up a set of quite
different syndrom es to those that are found in younger populations. For exam ple,
w ill typical agents be m ore effective in system atised paranoid states, w ith atypical
or sedative agents being m ore effective in disorganised states?
There are in fact som e historical pointers that m ight guide clinical observations
in this area. In addition to being effective for psychoses, the early results obtained
w ith chlorprom azine suggested that this agent was effective in both m anic and
delirious states. A lthough the neuroleptics in general are not seen as agents that
cure psychoses, they can effectively cure delirious states.
The contributions of neuroleptic pharm acology to the m anagem ent of delirious
states w ere explored during the 1990s in an interesting set of clinical experim ents
in Japan, w hich dem onstrated that m ianserin was an effective agent in the
6 Practical old age p sy c h o p h arm ac o lo g y

treatm ent of delirium . 8 The significance of this lies in the fact that m ianserin is an
agent devoid of dopam ine receptor-blocking effects. Its efficacy in the treatm ent
of delirious states appears to stem from its 5HT2-blocking properties. This has been
confirm ed by subsequent dem onstrations of the efficacy of trazodone in delirious
states.
These findings suggest in general that agents w ith significant 5HT2-blocking
properties, such as clozapine and quetiapine, m ay be particularly effective for
disorganised or confusional psychoses in the elderly, w hereas the m ore selective
paranoid psychoses m ay respond better to agents w ith potent D2-blocking
properties, such as am isulpiride or risperidone.

The conventional history of cognitive enhancing agents

The current role of ch olinom im etic drugs in the dem entias arose som ew hat by
default. Early neuroscientific research indicated that antidepressants m ight act on
both catecholam ine and serotonergic systems, w h ile the antipsychotics acted on
dopam ine system s. This left one major brain system w ith ou t either a pathology or
a set of drugs. The cholinergic system by default becam e the system that was
linked to dem entia. This linkage w as helped by the fact that anticholinergic drugs
can produce cognitive effects.
This default option was arguably a m istake of historic proportions, in that
anticholinergic agents produce confusion or delirium in high doses, rather than
dysm nesias . 2 The am nestic effects of anticholinergic agents seem to be less clear-
cut than the am nestic effects of the benzodiazepines. For exam ple, m any older
patients w ith chronic obstructive pulm onary disease have alw ays been m ain ­
tained on anticholinergic agents w ith ou t difficulty. There w ere accordingly few
grounds for thinking that ch olinom im etic agents w ould be of significant utility in
the dem entias.
However, the cholinom im etic research paradigm led to a developm ent pro­
gram m e w hich successively w orked through a variety of cholinom im etic prin­
ciples, from replacem ent strategies w ith choline and lecithin to acetylcholine-
releasing agents, such as piracetam and acetyl cholinesterase (ACE) inhibitors, to
early ACE inhibitors such as physostigm ine and tacrine, and finally to a later
generation of cholinesterase inhibitors such as galantam ine and donepezil.
Som e recent cholinom im etic agents appear to have marginal efficacy across the
dem entia spectrum. At present, this efficacy seem s to be best interpreted in terms
of these drugs having significant effects in particular individuals or for particular
syndrom es, such as dem entia w ith Lewy bodies (DLB). This m akes sense given
that DLB appears to have a greater cholinergic deficit compared w ith other
dem enting syndrom es.
In parallel w ith these developm ents in the pharm acotherapy of the dem entias,
there has b een an increasing aw areness of the possibilities of cognitive en h a n ce­
m ent in patients w ith conditions other than dem entia. This option opened up
w ith early w ork by Krai in the late 1950s on senescent forgetfulness , 9 and has
proceeded through to concepts such as age-associated m em ory im pairm ent.
 P sychopharm acological history 7

The unconventional history of cognitive enhancing agents

Latterly, w ith the em ergence of drugs that act on cholinergic system s, a greater
appreciation of the potential role of such drugs has developed. This is perhaps best
exem plified by exam ining one of the enduring m yths of psychopharm acology.
W ith the em ergence of the m on oam ine theories of depression, antidepressants
w ere supposed to act on either catecholam ine or serotonergic system s, according
to different schools of thought. H ow ever, com m on to both schools of thought was
the n otion that other actions, such as the anticholinergic effects of the tricyclics,
could only contribute side-effects. Chief am ong these anticholinergic-induced
side-effects was urinary retention. H ow ever, it is n o w clear that the urinary
retention produced by tricyclic agents stem s from their catecholam ine reuptake-
inhibiting properties. Anticholinergics do n ot cause urinary retention.
In fact any clinical trials undertaken w ith anticholinergic agents suggest that
these drugs, w h ich clearly cause a relatively rapid onset of euphoria w h en given
in m odest doses, m ay in fact be antidepressant. M odulating the cholinergic
system has the potential to produce a range of quality-of-life-enhancing effects,
as the m arketing of ACE inhibitors as qu ality-of-life-enhancing antihypertensives
helps to dem onstrate. Restricting considerations of the role of drugs that act on
the cholinergic system to their possible effects in m em ory en h an cem en t or
m em ory com prom ise is an unduly restrictive w ay of view ing their use.
Further evidence for this thesis can be seen in the increasing use of drugs such
as donepezil in trials for childhood disorders such as attention deficit hyper­
activity disorder (ADHD). C onversely, classic rem edies for ADHD, such as m ethyl-
phenidate, have found increasing use in the behavioural m anagem ent of
d em enting conditions in the elderly in recent years.
A further recent develop m ent has b een the dem onstration that agents w hich
act on glutam ate system s, and in particular on the N-m enthyl-D -aspartate
(NMDA) receptor, m ay have effects in the dem enting disorders. Glutamate was
in fact recognised as a neurotransm itter before dopam ine, and alm ost as early on
as noradrenaline and seroton in . 10 H ow ever, despite its widespread availability in
the brain, w here it is the com m onest neurotransm itter, a range of m isconceptions
about the nature of neurotransm ission prevented an appreciation of its role, as
did subsequent difficulties in generating agents that m odulate this system
effectively. In recent years this picture has changed, and increasing num bers of
agents are being developed, w ith the potential to help both as cognitive
enhancers and as agents w h ich m ight prove useful in the m anagem ent of cerebral
insults.
The first agent of this type to com e on stream was m em antine, w hich has been
w idely available on m any European markets from the early 1990s. There is in fact
a body of evidence stem m ing back prior to the developm ent of specific NMDA-
active agents, indicating that agents such as ketam ine or phencyclidine had
prom nestic effects . 11 Future generations of such agents offer interesting prospects
because these actions on the NMDA receptor m ay also offer the possibility of
neuroprotective effects.
The issues of neuroprotection and cognitive enhan cem en t potentially frame a
n e w vision of psychopharm acotherapy. There is every chance that the answers to
the problem s posed by the affective or schizophrenic psychoses w ill em erge from
efforts to arrest neurodegeneration, rather than from the direct attack on these
8 Practical old age p sy c h o p h arm ac o lo g y

disorders that governs current drug developm ent. The issue of cognitive en h a n ce­
m ent in individuals w h o m ay not have frank disease opens up the prospects of
smart drugs. At a tim e w h e n alm ost all previous grounds for discrim ination in our
societies have been m ade illegal, w e still discriminate on the basis of intellectual
advantage. H ow ever, smart drugs are likely to erode advantages, and therefore
there m ay w ell be considerable debate surrounding the use of such com pounds
in the future. Should th ey be restricted to 'medical' conditions such as age-
associated m em ory im pairm ent, or should they be m ore freely available? Som e of
these agents m ay w ell be life prolonging , 12 - and w hat then?
The increasing usage of 'drugs for the elderly' in other areas, such as donepezil
for children, and the reciprocal use of m ethylphenidate in the elderly, suggests
that the 'permafrost' that has encased established notions of psychotropic drug
use in the elderly for so long is n o w 'm elting'. The n ew clinical realities w ill also in
due course lead to a n e w set of histories.

Conclusions
The im pact of treatm ent w ith psychotropic agents in old age psychiatry differs in
m any significant respects from that found in other areas of psychiatry. Research­
ers interested in the history of psychotropic drugs w ill in future years probably
learn m ore about the true place of these drugs in psychiatry from studying the
impact of treatm ent on the clinical syndrom es found in old age psychiatry, and
the classification of those syndrom es, than they w ill from studying the impact of
treatm ent on syndrom es m anifest in any other age group.

Key points
• The use of antidepressants, antipsychotics and cognitive enhancing
agents in old age psychiatry dem onstrates interactions b etw een sy n ­
dromes and treatm ents that are not seen as readily in other areas of
psychiatry.
• The n otion that dem entia involves a cholinergic deficit is probably a
historically grounded m istake.

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