Pediatric Psychopharmacology Evidence A Clinician's Guide

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To all children and all those supporting child mental health.
To Mom, who taught me that there is enough sun for everyone.
And to Una and Luchik, my sunshines.
Preface

The future of our society rests on how well we take care of our children’s
mental health. Unfortunately, over the last several decades, the prevalence of
pediatric mental health problems has only risen, while the number of child
psychiatrists has remained woefully inadequate. In response, our healthcare
system has increased access to pediatric mental health care by enlisting and
educating professionals allied with child psychiatry. Coming from diverse
fields of expertise, these professionals must have access to information that
optimizes their clinical decision-making and allows them to answer patient
questions in the most informed and relevant manner. This book aims to serve
as a comprehensive toolbox of such resources.
In practice, pediatric psychopharmacologists prescribe medications by
synthesizing a wide variety of variables with their clinical experience. In the
absence of a comprehensive clinical framework, prescribers may be dispro-
portionately influenced by factors such as FDA approval status, patterns
learned during their training, and media advertisement by the pharmaceutical
industry. As a result, prescribers may fall short of their goal to provide opti-
mal care.
For example, the absence of an FDA indication for a certain medication
may be assumed to signify an indication’s denial. However, in many cases,
the lack of FDA approval reflects an absence of business incentive to file such
an FDA application. For example, in the case of pediatric generalized and
social anxiety disorders, fluoxetine, sertraline, and fluvoxamine have a high
level of clinical trial evidence without a corresponding FDA indication.
Prescribers may rely on the prescribing patterns learned during their train-
ing. However, training programs may vary in their prescribing patterns. For
example, some faculty members may be more likely to recommend the use of
benzodiazepines for pediatric anxiety than may be supported by the clinical
trial evidence.
The pharmaceutical industry’s marketing efforts and the public’s percep-
tion of medications and medication classes may significantly influence pre-
scribers. For example, divalproex ER’s marketing campaign to promote its
usage, independently compounded by public apprehension toward antipsy-
chotics, may have pushed the frequency of divalproex ER’s treatment of pedi-
atric bipolar mania beyond the level supported by the clinical trial evidence.
Another factor that may influence prescribing decisions is medication
cost. For example, when lurasidone was only available as a brand medication,

vii
viii Preface

its use for pediatric bipolar depression was much lower than when it came out
as generic.
In each of these cases, disproportionate reliance on a nonclinical factor
would result in less-than-optimal treatment outcomes. The purpose of this
book is to explicitly examine the most relevant aspects of medication decision-­
making while synthesizing them with the available scientific evidence as
rated by the quality of evidence GRADE system.
Another focus of this book follows what patients and families consider
most important when choosing a medication—each medication’s pros and
cons from the patient’s perspective and the alternative treatment options. As
a result of focusing on the clinician’s and patient’s medication decision-­
making thought processes, we have developed a clinical resource that will
help clinicians achieve best practices for treating pediatric mental health
disorders.
This book’s realization is a testament to a remarkable team of child psy-
chiatry experts whose insights were invaluable.
Dr. Robert Althoff’s introduction and general principles reflect both his
knowledge of the child psychiatry research literature (as JAACAP’s Associate
Editor) and his pioneering work with the Vermont Family-Based Approach.
Dr. John Sargent, a child psychiatry expert in family therapy, led the chap-
ter on family-based psychopharmacology.
Dr. Gabrielle Carlson (AACAP’s President, 2019–2021; President of the
International Society for Research in Child and Adolescent Psychopathology)
led the chapter on the use of PRN medications.
Dr. Robert Hendren (AACAP’s President, 2007–2009) led the chapter on
over-the-counter medications and nutritional supplements.
Dr. Jean Frazier (UMass Robert M. and Shirley S. Siff Chair in Autism)
led the chapter on autism and neurodevelopmental disorders.
Dr. Lawrence Greenhill (AACAP’s President, 2009–2011) led the chapter
on ADHD medications.
Dr. Barbara Coffey (Co-Chair of the Medical Advisory Board of the
Tourette Association of America) led the chapter on tics and Tourette’s
medications.
Dr. Daniel Geller (Director of Research at the Massachusetts General
Hospital (MGH) Pediatric Psychiatry Obsessive-Compulsive and Tic
Disorder (OCD/Tic) Program) led the chapter on OCD medications.
Dr. Kevin Gray (Past Co-Chair of the AACAP Substance Use Committee)
led the chapter on substance use disorder medications.
Dr. Jeffrey Newcorn (President of the American Professional Society of
ADHD and Related Disorders, APSARD) led the chapter on medications
used for aggression.
Dr. John Walkup (AACAP’s President, 2025–2027) led the chapter on
medications for pediatric anxiety.
Dr. Jeffrey Hunt (Past Co-Chair of the AACAP Training and Education
Committee) led the chapter on medications for pediatric PTSD.
Dr. Boris Birmaher (Endowed Chair in Early Onset Bipolar Disease and
Professor of Psychiatry at the University of Pittsburgh School of Medicine)
led the chapter on medications for depressive disorders.
Preface ix

Dr. Adelaide Robb (Past Co-Chair of the AACAP Psychopharmacology

and Neurotherapeutics Committee) led the chapter on medications for bipolar
disorder.
Dr. Yael Dvir (Director of the UMass Child Psychiatry Division) and Dr.
Brian Skehan (Co-Chair of the AACAP Transitional Age Youth and College
Student Mental Health Committee) co-led the chapter on medications for
pediatric psychosis.
Dr. Anna Ivanenko (Past Chair of the Committee on Insomnia at the
Pharmacological Management of Insomnia in Children and Adolescents Task
Force of the Psychiatric Population National Sleep Foundation) led the chap-
ter on medications for pediatric sleep disorders.
We hope that you enjoy this resource. Thank you for reading and provid-
ing care for our children and their families!

Worcester, MA, USA Boris Lorberg

Acknowledgments

This book grew out of a small project clarifying the FDA indications for vari-
ous medications used in child psychiatry. Our working group was born at the
AACAP Committee for Psychopharmacology and Neurotherapeutics (then
called the Pediatric Psychopharmacology Initiative). We received invaluable
support and guidance from our committee co-chairs, Drs. Tim Wilens and
Adelaide Robb. Similarly, the unequivocal encouragement I received from
Dr. Rajesh Tampi was instrumental in my decision to embark on creating this
book.
I am grateful to all of the chapters’ authors for coming through with their
best work and for their patience with countless draft versions.
I am indebted to the University of Massachusetts’ Drs. Yael Dvir and
Kimberly Yonkers for their compassionate mentorship and support.
I credit all of the staff who ever worked at the UMass Adolescent
Continuing Care Units, with their selfless dedication and their sacrifices.
I am grateful to all of the ACCU’s adolescent patients and their families
for trusting strangers to see into their most vulnerable parts of self.
I want to acknowledge my child psychiatrist role models, Drs. Eugene
Beresin and Steven Schlozman, MGH/McLean’s child psychiatry fellowship
training program directors.
I credit Yale’s general psychiatry residency program directors, Drs.
Richard Belitsky and Robert Rohrbaugh, with encouraging me in my quest
for evidence-based psychiatry, writing in medicine, and creative
collaborations.
I am grateful to Stony Brook’s child psychiatry inpatient unit, its child
patients, its staff, and Drs. Zinoviy Gutkovich and Gabrielle Carlson for help-
ing me see that child psychiatry was my calling when I was a medical
student.
I am indebted to Drs. Joel Pardee, Ph.D. (Cornell Graduate School of
Medical Sciences), and Claude Desplan, Ph.D. (Rockefeller University), for
their generous mentorship.
I owe it to my first American mentor Dr. Joan Ingalls, EdD, who was the
first one to ask, “Boris, have you ever thought of psychiatry as a
profession?”
Lastly, this book could not have happened without the unconditional sup-
port of my family—Una, Luchik, Alla, Alex, and Svetlana.

xi
Contents

1 
Introduction to the Fundamentals of Pediatric
Psychopharmacology ����������������������������������������������������������������������   1
Maya Strange and Robert R. Althoff

Part I Transdiagnostic Topics

2 
Pediatric Psychopharmacology Integration with
Family Therapy�������������������������������������������������������������������������������� 29
Sarah Jane Frankel, Boris Lorberg, and John Sargent
3 
Rationale for Integrating Psychodynamic Theory
into Pediatric Psychopharmacology ���������������������������������������������� 49
Rangsun Sitthichai and Horacio Hojman
4 
Ensuring Appropriate Use of Psychotropic Medications
in Pediatrics: Best Practices in Medication Discontinuation
(Deprescribing)�������������������������������������������������������������������������������� 63
Wynne Morgan and Megan Baker
5 
Psychopharmacology of “As-Needed” Medications (PRNS)
for Pediatric Agitation in Inpatient and Emergency
Settings���������������������������������������������������������������������������������������������� 81
Ema Saito, Destiny Pegram, Boris Lorberg,
and Gabrielle A. Carlson
6 
Over-the-Counter Medications and Nutritional
Supplements in Child Psychiatry �������������������������������������������������� 117
Robert L. Hendren, Madeline Spiess, and Felicia Widjaja

Part II Neurodevelopmental and Impulsive-Compulsive

Spectrum Disorders

7 Psychopharmacology for Autism and

Neurodevelopmental Disorders������������������������������������������������������ 137
David M. Cochran, Isha Jalnapurkar, Alexandra Palmer,
Lauren Venuti, and Jean A. Frazier

xiii
xiv Contents

8 Psychopharmacology for Pediatric ADHD������������������������������������ 169

Lauren T. Schumacher and Laurence L. Greenhill
9 
Psychopharmacology for Pediatric Tics and
Tourette’s Disorder�������������������������������������������������������������������������� 209
Barbara Coffey
10 
Psychopharmacology for Pediatric OCD
and Related Disorders �������������������������������������������������������������������� 217
Erica Greenberg, Gabrielle Johnson, and Daniel Geller
11 
Adolescent Substance Use Disorders���������������������������������������������� 255
Matthew C. Fadus, Lindsay M. Squeglia, Lori Keough,
and Kevin M. Gray
12 
Psychopharmacology for Pediatric Eating Disorders������������������ 265
Jennifer Derenne
13 Psychopharmacology for Pediatric Aggression ���������������������������� 275
Joseph C. Blader and Jeffrey H. Newcorn

Part III Anxiety Spectrum Disorders

14 
Psychopharmacology for Pediatric Anxiety Disorders���������������� 307
Rachel Ballard, Courtney Romba, and John T. Walkup
15 
Psychopharmacology for Pediatric PTSD ������������������������������������ 347
Ingrid Lauer-Arnold, Sibel Algon, and Jeffrey Hunt

Part IV Mood and Psychosis Spectrum Disorders

16 
Psychopharmacology for Pediatric Depressive Disorders������������ 381
Manivel Rengasamy, Amit Shalev, and Boris Birmaher
17 
Psychopharmacology for Pediatric Bipolar Disorder������������������ 453
Elizabeth Hobbs, Rachel Reed, Julia Dorfman, and Adelaide
S. Robb
18 
Psychopharmacology for Pediatric Schizophrenia and
Psychotic Disorders�������������������������������������������������������������������������� 525
Brian Skehan, Yael Dvir, Joshua Feriante, and Boris Lorberg

Part V Sleep Disorders

19 
Practical Psychopharmacology of Pediatric
Sleep Disorders�������������������������������������������������������������������������������� 563
Sarah Nayeem, Ujjwal Ramtekkar, and Anna Ivanenko
Index���������������������������������������������������������������������������������������������������������� 585
Contributors

Sibel Algon Division of Child and Adolescent Psychiatry, Department of

Psychiatry and Human Behavior, Alpert Medical School of Brown University,
Bradley Hospital, Riverside, RI, USA
Robert R. Althoff Departments of Psychiatry, Pediatrics, and Psychological
Science, University of Vermont, Larner College of Medicine, Burlington, VT,
USA
Megan Baker Momentum for Health, San Jose, CA, USA
Rachel Ballard Pritzker Department of Psychiatry and Behavioral Heath,
Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA
Boris Birmaher Department of Psychiatry, University of Pittsburgh Medical
Center, Pittsburgh, PA, USA
Joseph C. Blader Department of Psychiatry and Behavioral Science,
University of Texas Health Science Center at San Antonio, San Antonio, TX,
USA
Gabrielle A. Carlson Department of Psychiatry, Stony Brook University,
Stony Brook, NY, USA
David M. Cochran EK Shriver Center, Department of Psychiatry, UMass
Chan Medical School, Worcester, MA, USA
Barbara Coffey Department of Psychiatry and Behavioral Sciences,
University of Miami Miller School of Medicine, Miami, FL, USA
Jennifer Derenne Department of Psychiatry and Behavioral Sciences,
Stanford University School of Medicine, Stanford, CA, USA
Julia Dorfman Department of Psychiatry and Behavioral Sciences,
Children’s National Hospital, Washington, DC, USA
Yael Dvir Department of Psychiatry, University of Massachusetts Chan
Medical School, Worcester, MA, USA
Matthew C. Fadus Department of Psychiatry, Massachusetts General
Hospital, Boston, MA, USA
Joshua Feriante Department of Psychiatry, University of Massachusetts
Chan Medical School, Worcester, MA, USA

xv
xvi Contributors

Sarah Jane Frankel Department of Psychiatry, University of Massachusetts

Medical School, Worcester, MA, USA
Jean A. Frazier EK Shriver Center, Department of Psychiatry, UMass Chan
Medical School, Worcester, MA, USA
Daniel Geller Massachusetts General Hospital, Boston, MA, USA
Harvard Medical School, Boston, MA, USA
Kevin M. Gray Department of Psychiatry and Behavioral Sciences, Medical
University of South Carolina, Charleston, SC, USA
Erica Greenberg Massachusetts General Hospital, Boston, MA, USA
Harvard Medical School, Boston, MA, USA
Laurence L. Greenhill Department of Psychiatry, University of California,
San Francisco, San Francisco, CA, USA
Robert L. Hendren Department of Psychiatry and Weill Institute for
Neurosciences, University of California, San Francisco, San Francisco, CA,
USA
Elizabeth Hobbs Children’s National Hospital, Washington, DC, USA
Horacio Hojman Department of Psychiatry, Faculty at the Boston
Psychoanalytic Society and Institute, Alpert Medical School at Brown
University, Providence, RI, USA
Jeffrey Hunt Division of Child and Adolescent Psychiatry, Department of
Psychiatry and Human Behavior, Alpert Medical School of Brown University,
Bradley Hospital, Riverside, RI, USA
Anna Ivanenko Division of Child and Adolescent Psychiatry, Ann and
Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA
Isha Jalnapurkar EK Shriver Center, Department of Psychiatry, UMass
Chan Medical School, Worcester, MA, USA
Gabrielle Johnson Massachusetts General Hospital, Boston, MA, USA
Lori Keough NFI Massachusetts, Adolescent Intensive Residential
Treatment Program, WRCH, Worcester, MA, USA
Ingrid Lauer-Arnold Division of Child and Adolescent Psychiatry,
Department of Psychiatry and Human Behavior, Alpert Medical School of
Brown University, Bradley Hospital, Riverside, RI, USA
Boris Lorberg Department of Psychiatry, Division of Child and Adolescent
Psychiatry, UMass Chan Medical School, Worcester, MA, USA
Wynne Morgan Department of Psychiatry, University of Massachusetts
Medical School, Worcester, MA, USA
Sarah Nayeem Department of Child and Adolescent Psychiatry, Nationwide
Children’s Hospital, Columbus, OH, USA
Contributors xvii

Jeffrey H. Newcorn Department of Psychiatry, Icahn School of Medicine at

Mount Sinai, New York, NY, USA
Alexandra Palmer EK Shriver Center, Department of Psychiatry, UMass
Chan Medical School, Worcester, MA, USA
Destiny Pegram Department of Psychiatry, University of Massachusetts
Medical School, Worcester, MA, USA
Ujjwal Ramtekkar Department of Psychiatry, University of Missouri
Columbia School of Medicine, Columbia, MO, USA
Lifestance Health, Scottsdale, USA
Rachel Reed Children’s National Hospital, Washington, DC, USA
Manivel Rengasamy Department of Psychiatry, University of Pittsburgh
Medical Center, Pittsburgh, PA, USA
Adelaide S. Robb Department of Psychiatry and Behavioral Sciences,
Children’s National Hospital, Washington, DC, USA
Courtney Romba Pritzker Department of Psychiatry and Behavioral Heath,
Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA
Ema Saito Department of Psychiatry, Zucker Hillside Hospital, Glen Oaks,
NY, USA
John Sargent, MD Tufts University School of Medicine, Boston, MA, USA
Lauren T. Schumacher Department of Psychiatry, University of California,
San Francisco, San Francisco, CA, USA
Amit Shalev Department of Child and Adolescent Psychiatry, Hadassah
Hebrew University Medical Center, Jerusalem, Israel
Rangsun Sitthichai Division of Child and Adolescent Psychiatry,
Department of Psychiatry, University of Massachusetts Medical School,
Worcester, MA, USA
Brian Skehan Department of Psychiatry, University of Massachusetts Chan
Medical School, Worcester, MA, USA
Madeline Spiess Department of Psychiatry, University of California, San
Francisco, San Francisco, CA, USA
University of California, Santa Barbara, CA, USA
Lindsay M. Squeglia Department of Psychiatry and Behavioral Sciences,
Medical University of South Carolina, Charleston, SC, USA
Maya Strange Departments of Psychiatry and Pediatrics, University of
Vermont, Larner College of Medicine, Burlington, VT, USA
Lauren Venuti EK Shriver Center, UMass Chan Medical School, Worcester,
MA, USA
xviii Contributors

John T. Walkup Pritzker Department of Psychiatry and Behavioral Heath,

Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA
Felicia Widjaja Department of Psychiatry and Weill Institute for
Neurosciences, University of California, San Francisco, San Francisco, CA,
USA
 Introduction to the Fundamentals
of Pediatric Psychopharmacology
1
Maya Strange and Robert R. Althoff

In the following text, you will find guidance on socially determined [1], for the purposes of this
the management of medication for the practicing chapter, we define adolescence as between ages
pediatric psychopharmacologist. In this introduc- 13 and 24, the time when parental involvement in
tory chapter, we provide you with the key general the adolescent’s care has, generally, decreased
information necessary for anyone prescribing and when the physiological process of pruning
psychotropic medications to children/adoles- and myelination has generally slowed [2]. We
cents. First and foremost, we stress the concept accept at the outset that there are disagreements
that youth are not “little adults.” Relative to adult on all of these age cutoff points and acknowledge
psychopharmacology, there are many differences the limitations of the choices that we have made
in the prescribing to children/adolescents, along in this chapter.
with a great deal of similarities. We will attempt What follows is a general introduction to the
to point out each. state of the art in psychiatric prescribing for
A few housekeeping items before proceeding youth:
to the details: We will use “youth” to refer to chil-
dren and adolescents as a group, unless we are • We first walk through a cursory explanation of
making a distinction between the two. We will the basic psychopharmacological principles of
generally consider children as those aged 12 and pharmacokinetics, impressing on the reader
under, and adolescents as those aged 13 and the differences between prescribing to youth
above. versus adults.
When adolescence ends is an area of ongoing • Next, we talk about the process of prescribing
study. Because adolescence itself is a construct when youth and families are involved,
that has been (and continues to be) culturally and impressing upon the reader the critical impor-
tance of a comprehensive evaluation and what
M. Strange (*) that entails.
Departments of Psychiatry and Pediatrics, University • We move then into the interdisciplinary
of Vermont, Larner College of Medicine, approach that is taken for the evaluation and
Burlington, VT, USA
e-mail: [email protected] treatment of youth, followed by a discussion
of culture and race, development,
R. R. Althoff
Departments of Psychiatry, Pediatrics, and genetics/pharmacogenetics, assessment of
Psychological Science, University of Vermont, Larner evidence quality, importance of stigma, and
College of Medicine, Burlington, VT, USA ethics of prescribing.
e-mail: [email protected]

© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature 1
Switzerland AG 2024
B. Lorberg (ed.), Pediatric Psychopharmacology Evidence,
https://doi.org/10.1007/978-3-031-57472-6_1
2 M. Strange and R. R. Althoff

Given the sheer scope of information that this • Situations where the pediatric dose may be
introduction contains, we beg apologies at the outset very close to adult dosing for effect (e.g., with
for the cursory nature with which some of this infor- lithium) despite a lower body weight.
mation is covered. In the end, however, our objective
is to cover the fundamentals that must be taken into The essential similarities and differences are
account before proceeding into the remainder of the noted below.
text where you will be met with descriptions of
many of these topics in more detail. We begin then (a) Pharmacokinetics refers to the way that a
with the most basic of principles and push forward. person’s body affects a medication. It is
described by the acronym ADME standing
for absorption, distribution, metabolism, and
1.1 General excretion (see Fig. 1.1).
Psychopharmacology • Absorption is the process of moving the
Principles medication from the exterior of the body
to the interior of the body. It involves the
Before embarking on the study of individual many possible routes of administration of
agents, it is important to understand some funda- medication and how they move the medi-
mental concepts in the ways that the makeup of a cation into the blood, plasma, or other
person affects how the body affects the medication fluid.
(pharmacokinetics) and the ways in which the • Distribution is, as the name implies, the
medication affects the body (pharmacodynamics). movement and distribution of the medica-
There are essential pharmacokinetic and pharma- tion among various body areas.
codynamic differences between youth and adults • Metabolism describes the changes that
due to the “newness” of the metabolic systems of the body makes to the medication.
the youth and because their receptor systems are Metabolism may influence the medica-
continuing to develop. This can lead to both tion’s absorption, distribution, excretion,
or action.
• Situations where relatively low doses of medi- • Excretion/elimination is the disposal of
cations can have much more profound effects the medication by the body, opposite of
on youth (e.g., with benzodiazepines). absorption.

Absorption

Rate of drug
action onset

Distribution

Duration of
drug action

Metabolism
Rate of
termination of
action
Excretion

Fig. 1.1 Pharmacokinetic principles

1 Introduction to the Fundamentals of Pediatric Psychopharmacology 3

• Next, we describe the basic metrics of ––Vd—volume of distribution is the theoreti-

pharmacokinetics and some differences cal volume that would be needed to
between youth and adults: achieve the same concentration of medi-
––Cmax—the maximum concentration that cation as in plasma. Because Vd is a
a medication reaches in the body theoretical value, it is conceivable that Vd
before the next dose of medication is could be larger than the total body vol-
administered. This can generally be ume for widely dispersed medications:
considered the “peak” concentration Medications with higher Vd are
of the medication in the body. more widely dispersed throughout
––Tmax—the time required to reach Cmax. At the body, including those that might
Tmax, the rate of absorption is equal to be stored in adipose tissue (e.g.,
the rate of elimination. Tmax may differ some of the benzodiazepines) and
depending on the route of administra- therefore would be hard to remove
tion and the rate of absorption: from the body through a process
For example, with lorazepam, the like dialysis.
peak concentration after intramus- Medications with a low Vd, by con-
cular administration is reached after trast (e.g., lithium), are more read-
1.5 h, while it is reached after ily dialyzed.
2.3–2.5 h when lorazepam is admin- ––Bioavailability—the proportion of
istered orally [3, 4]. medication that enters systemic cir-
This is an important concept to culation to exert pharmacologic
consider when choosing the route effects. Bioavailability is generally
of medication when managing, lower for medications administered
for example, the treatment of an orally due to first-pass metabolism
acute episode of dangerous (defined as the changes to the medi-
aggression. cation carried out by the gastrointes-
––t1/2—the half-life, which is the time that tinal, hepatic, and bacterial enzymes
it takes for the concentration of medi- involved with oral administration)
cation to decrease by 50%. In general, and incomplete absorption across the
it takes about five half-lives after stop- gut lumen:
ping a medication for it to be effec- For example, olanzapine adminis-
tively cleared from the body. It also tered orally has bioavailability of
takes five half-lives to reach steady approximately 60% compared to
state within the body after starting a intravenous administration.
new dose. This has important implica- (b) Pharmacodynamics refers to the ways in
tions for prescribing and discontinuing which a medication affects a person. There
medications: are several important pharmacodynamic
For example, fluoxetine has a high t1/2 concepts that could affect the way in which
of between 4 and 6 days for the parent youth will respond to medication.
medication and up to 9 days for the • Therapeutic index—the ratio of the dose
active metabolite, leading to low risk that causes therapeutic effect to the dose
of any type of discontinuation syn- that causes toxicity:
drome even when stopped abruptly. ––Some medications, even at high doses,
Contrast this with paroxetine which are unlikely to be toxic (e.g., selective
has a half-life of 21 h and has serotonin reuptake inhibitors).
increased risk of discontinuation ––Others require a specific blood level to
syndrome when stopped abruptly. be effective, while a level slightly
4 M. Strange and R. R. Althoff

above that therapeutic level can have therapeutic effect. For youth and their
toxic effects (e.g., lithium and families (see Sect. 1.4 below), this can be
carbamazepine). one of the most important concepts to
• Dose-response curve—a function of the cover when prescribing:
medication effect at various doses. ––For example, lorazepam may have an
Plotting out the dose-response can dem- effect within 30–60 min, depending on
onstrate that the effects of a medication the route of administration, whereas
could be linear or nonlinear and can give SSRIs may require weeks to achieve a
an indication of the medication’s potency, therapeutic effect.
with bearing on medication choice and • Tolerance—the gradually decreased
titration (see Fig. 1.2): effect of some medications after taking
––An example of a medication with linear them over time; therefore, higher dose
kinetics is lithium, in that changes in may be needed to achieve the same
dose lead to a proportional change in effect:
plasma concentration. ––For example, tolerance to benzodiaze-
––Nonlinear kinetics occurs when physio- pines can develop within several weeks
logic processes can affect the rate of of daily treatment.
metabolism, such as in autoinduction • Withdrawal—the adverse physiologic or
with carbamazepine or inhibition of psychological response to abrupt discon-
CYP2D6 with fluoxetine. tinuation of a substance. Withdrawal can
• Response latency—the time between the profoundly affect whether a medication is
first administration of medication and the easy or hard to discontinue:

Fig. 1.2 Dose-response curve. The EC50 is the effective drug, and the green curve on the right is the least potent.
concentration of a substance at which 50% of the biologi- For example, when considering the medications escitalo-
cal effect is observed. This can be well represented on a pram, fluoxetine, and sertraline, escitalopram would have
semilog scale. Lower EC50 indicates that the drug is more the lowest EC50 and therefore require the lowest dose,
potent as it needs a lower concentration to have a biologi- and sertraline would have the highest EC50
cal effect. Here, the red curve on the left is the most potent
1 Introduction to the Fundamentals of Pediatric Psychopharmacology 5

––For example, physiologic nicotine with- One key addition to this, however, is that one
drawal can last 2–4 weeks, while psy- should “start low, go slow, but go all the way to
chologic nicotine withdrawal can last the max optimal dose.”
for months.
(c) How these concepts are different for youth. • There is a traditional principle that all medica-
The rationale for covering some of these tions should be used at their lowest maximally
concepts up front is that these issues can effective dosage.
differ in pediatric prescribing. Starting • Understanding of pediatric pharmacodynam-
with pharmacokinetic effects, absorption ics and pharmacokinetics principles means
can be quite different for children that medications should be titrated to maxi-
specifically. mum optimal doses based on the young body’s
• In general, the GI transit time for chil- effect on the medication and the medication’s
dren is shorter until the child reaches effect on the young body.
adolescence. This means that depending • Maximum optimal dose means one that has the
on the formulation of the medication and most efficacy with the least side effects for the
where it is absorbed, some medications specific psychiatric presentation.
may be excreted before being fully • This implies a trade-off with respect to both
absorbed: efficacy and adverse effects, not simply maxi-
––This may be true for some of the long-­ mizing one or minimizing the other.
acting stimulants, for example, leading to
decreased duration of action of these Before prescribing, however, it is important to
medications and requiring more frequent carefully consider whether a specific medication
dosing than expected in older youth. is indicated.
• Distribution in the body is based on body
fat and total body water. Children (after
infancy) tend to have a higher water-to-­ 1.2 Evaluation of the Need
fat ratio (leading to a higher Vd) compared
to adolescents and adults: The initial part of a pediatric psychopharmacol-
––Therefore, high Vd hydrophilic medica- ogy visit requires a comprehensive evaluation.
tions (e.g., lithium) may need a higher There are extensive descriptions of the compre-
dose per kg in children than in adoles- hensive evaluation of youth elsewhere (e.g. [5,
cents and adults (often to the surprise of 6]) that we will not duplicate. We will instead
the adults involved in the patient’s care). highlight specific critical points.
––Medications that are low Vd lipophilic
drugs (e.g., lorazepam) may need (a) Importance of a comprehensive evaluation:
lower doses per kg in children due to The evaluation of youth prior to prescribing
decreased volume of distribution. has many similarities to the adult psycho-
• In addition, excretion in children tends to be pharmacology evaluation, but it needs to be
more rapid via both hepatic and renal even more comprehensive.
routes. While the rate of elimination tends • Too often, prescribers are asked to evalu-
to decrease into adolescence and adult- ate youth for medication treatment with
hood, some medications may require higher too little time or information. What results
relative dose per unit weight and more fre- is frustration on the part of the patient, the
quent dosing for children relative to adults. family, and the prescriber.
–– Establishing the guidelines for safety,
While there are important differences in these openness, and confidentiality—It is
concepts between youth and adults, the adage of critical to set up these guidelines
starting low and going slow is still prudent. initially: