IACAPAP Textbook of Child and Adolescent Mental Health

Chapter

A.7

INTRODUCTION

PRINCIPLES IN USINGPSYCHOTROPIC MEDICATION
IN CHILDREN AND
ADOLESCENTS
2019 edition
Boris Lorberg, Chiara Davico, Dmytro Martsenkovskyi &Benedetto VitielloBoris Lorberg MD, MBA
Assistant Professor of
Psychiatry and Pediatrics,
University of Massachusetts
Medical School, Worcester,MA, USA
Conflict of interest: nonereported.

Chiara Davico MD
Child and Adolescent
Neuropsychiatry, Universityof Turin, Regina Margherita
Children’s Hospital, Italy
Conflict of interest: nonereported.

This publication is intended for professionals training or practicing in mental health and not for the general public. The opinions
expressed are those of the authors and do not necessarily represent the views of the Editor or IACAPAP. This publication seeks todescribe the best treatments and practices based on the scientific evidence available at the time of writing as evaluated by the authorsand may change as a result of new research. Readers need to apply this knowledge to patients in accordance with the guidelines andlaws of their country of practice. Some medications may not be available in some countries and readers should consult the specific drug
information since not all dosages and unwanted effects are mentioned. Organizations, publications and websites are cited or linked toillustrate issues or as a source of further information. This does not mean that authors, the Editor or IACAPAP endorse their content or
recommendations, which should be critically assessed by the reader. Websites may also change or cease to exist.
©IACAPAP 2019. This is an open-access publication under the Creative Commons Attribution Non-commercial License. Use,
distribution and reproduction in any medium are allowed without prior permission provided the original work is properly cited andthe use is non-commercial.
Suggested citation: Lorberg B, Davico C, Martsenkovskyi D, Vitiello B. Principles in using psychotropic medication in children
and adolescents. In Rey JM, Martin A (eds), IACAPAP e-Textbook of Child and Adolescent Mental Health. Geneva: International
Association for Child and Adolescent Psychiatry and Allied Professions 2019.

Principles of pharmacotherapy A.7

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IACAPAP Textbook of Child and Adolescent Mental HealthL

ack of adequate and fair access to pediatric mental health care has long beena sad and universal phenomenon. According to a 2003 WHO report, 44%70% of youth with mental illness in high income countries did not receive
mental health treatment in any given year. In low- and middle-income countries(LAMICs), this gap was closer to 90%. Over 90% of LAMICs had no mental
health policies that included children and adolescents (WHO, 2003).

Dmytro Martsenkovskyi MD

Notwithstanding the above generalizations, psychopharmacotherapy ispracticed within the context of regional mental health care systems. Prescribing
varies widely, both across and within countries. This variability cannot be fully
explained by differences in nosology or illness prevalence, thus suggesting that
cultural, geographic, economic, regulatory, and other factors play a major role inprescribing practices (Vitiello, 2008) (see Table A.7.1).

Benedetto Vitiello MD

Relative to other areas of medicine, perception of psychiatric disorders
appears to be more influenced by cultural values. For example, use of stimulantsfor ADHD in the US is greater among the white population than among childrenof African American or Hispanic background (Cohen et al, 2013). Stimulant
medication use is lower in the US West Coast than in the rest of the country(Zuvekas & Vitiello, 2012) These ethnic differences appear to be independent of
economic factors. Levels of parental concern about risks of adolescent addiction are

Department of Psychiatry
and Narcology, Bogomolets
National Medical University,
Kyiv, Ukraine
Conflict of interest: nonereported.

Professor of Child andAdolescent Neuropsychiatry,
University of Turin, Italy,& Professor (adjunct) of
Psychiatry, Johns Hopkins
University, Baltimore, Maryland,
USA
Conflict of interest: consultant
to Shire and Medice 2018 and2019.

Table A.7.1 Factors that may contribute to the variability of psychotropic
prescribing
FactorExamplesGeographic differences innosology

Some EU countries rely on the ICD classification system
while DSM is preferred in the US

Geographic variations indiagnosis

ADHD may be under-diagnosed in some areas and overdiagnosed in others

Prevalence of psychopathology

Completed suicides vary according to country

CulturalPsychosocial interventions preferred over medication
treatment in some cultures but not in others

Economic

Insufficient manufacturing capacity; limited personal
finances

Differences in healthcare
systems

Countries with a universal health care system havegreater consistency of pharmacotherapy

Regulatory

Prohibition of some medications in some countries (e.g.,
stimulants, buprenorphine)

Racial disparity

Stimulant prescription for ADHD is greater for white
relative to non-white youth in US

Marketing

Branded medications are marketed (especially in highincome countries), while generics are notPrinciples of pharmacotherapy A.7

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IACAPAP Textbook of Child and Adolescent Mental Healthdifferent across cultures with parents of African and Hispanic children expressing
more concerns than parents of white children (Zhu at al, 2009).
Relative to other high-income countries, use of psychotropic medications
is substantially higher in the US; for example, it has more than 80% of the world
usage of psychostimulants. It is estimated that about 3.5% of US children aretreated with stimulant medication for ADHD, and use has been consistently
increasing over the years (Zuvekas & Vitiello, 2012). Likewise, antidepressant andantipsychotic use is many times greater in the US than in other countries (Fegert
et al, 2006).

Use of psychotropic
medications is substantiallyhigher in the US than inother developed countries.

Differences in prescription rates appear to be influenced by economic factors
also. For example, there is a significant variation among countries in prescriptions
for the treatment of comorbidities associated with autism spectrum disorder, witha correlation between per capita gross domestic product and prescription rates(Hsia et al, 2014). It is likely that pharmaceutical industry’s marketing efforts playa significant role in prescribing practices.
Overall, approaches to mental health care vary considerably based on
cultural factors. The implications of this variability for disease outcome and patient
prognosis are serious and yet to be understood.

HISTORICAL CONTEXT AND SOME CORE
QUESTIONS
Medications to treat mental conditions (psychotropics) have become
increasingly used in child and adolescent psychiatry around the world. Fromthe serendipitous discovery by Bradley of the effects of amphetamines on childhyperactivity in 1937 to the multisite clinical trials of the 21st century, pediatric
psychopharmacology has evolved from an area of research to a standard of clinicalcare (Vitiello & Davico, 2018). Nevertheless, the role of pharmacotherapy in
pediatric mental health remains the object of debate and controversy. With thenotable exception of medications for ADHD—which were first introduced inpediatric population and subsequently extended to adults—most psychotropic
medications were first developed to treat psychiatric conditions in adults, andonly later extended to children. Appropriate concerns have been raised about boththe validity of applying adult diagnostic categories to children and the validity of
extrapolating safety and efficacy information collected in adults to children.
Growing research has provided a better understanding of the benefits andrisks of the pediatric use of some psychotropics. For many others, however, thecurrent knowledge base is incomplete. This inadequacy is especially evident withrespect to their long-term use. In psychiatry, medications are seldom curativeand long-term treatment is often required, thus raising concerns about boththe persistence of the therapeutic effect and the safety of prolonged exposure to
psychotropic agents at a time of rapid development. A related question is whether
treatment in childhood will lead to better functional outcomes later in life.
Unfortunately, controlled clinical trials are usually brief, and studying long-term
treatment effects is methodologically difficult.
In this chapter, we hope to provide clinicians with key elements and a generalframework for the pharmacotherapy of psychiatric disorders during development.

Principles of pharmacotherapy A.7

In 1937, Charles
Bradley, a psychiatrist,
administered dlamphetamine to “problem”
children at the BradleyHome in Providence,
Rhode Island (US), in
an attempt to alleviateheadaches. Bradley
noticed an unexpected
effect: improved school
performance, social
interactions, and emotional
responses. Bradley’s
studies went largely
ignored for nearly 25 years.
However, they proved to
be an important precursor
to studies on the use ofamphetamines in ADHD
(Strohl, 2011).

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IACAPAP Textbook of Child and Adolescent Mental Health

Figure A.7.2 General approach to pharmacotherapy inchild psychiatry
Conduct a comprehensive
diagnostic evaluation

Does the child have a condition, such as a
psychotic disorder or mania, for which medication isnecessary?

YES
NO
Start medication
Is there any psychosocial intervention that has beenshown to be effective in this condition?

YES

NO

Consider using
psychosocial
intervention first:
effective?

NO

YES

No need for
medication

Has medication
been shown to beeffective for thiscondition?

YES

Consider using
medication alone orwith psychotherapy as
appropriate

NO

Explore otheroptions“But family and manyfriends were judgmental:
How could we start a fiveyear-old on medication,
especially one as smart as
our son, who had taught
himself to read before
age four? They seemedto assume that he wasdifferent because he wasso smart. Anyway, the logic
went, a lot of boys are ahandful at that age, andthat's not a reason to put afive-year-old on medication.
They concluded that the
problem was that I was a
psychiatrist. Clearly, I was
pathologizing a boy who
was just being a boy. How
else would you expect a
mom who is a psychiatrist
to handle a rambunctious,
precocious five-year-old
besides putting him on
medication?” (Gold, 2010).

For detailed information on specific medications the reader is referred to thechapters covering the relevant disorders.

WHEN TO USE PSYCHOTROPIC MEDICATION IN
YOUTH?
A comprehensive diagnostic evaluation and psychosocial formulation is
the necessary first step (Figure A.7.2). Patients with psychotic disorders often

Principles of pharmacotherapy A.7

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IACAPAP Textbook of Child and Adolescent Mental Healthrequire pharmacological treatment as a first step to control symptoms and restore
functioning. For more details on pharmacological treatment of psychosis, see
Chapter H.5.1.
Patients with non-psychotic disorders may often be successfully treated with
non-pharmacological interventions first. For example, behavioral therapy can be
an effective first step in the management of patients with mild major depression,
OCD, and anxiety disorders. Not all children, however, improve with purely
psychosocial interventions and, for them, medication may be necessary to improvetheir functioning. Of note, psychotherapy and medication are not mutually
exclusive: in many conditions, such as depression and anxiety, combined use as
been found to be more beneficial than monotherapy (Vitiello, 2009a).

Evidence of the long-term
effectiveness and safety ofpharmacological treatmentsin children and adolescentsis largely lacking.

A key consideration in choosing among therapeutic options is the strengthof the evidence supporting the efficacy and safety of the treatment for the specificcondition and the age of the child (Gray, 1997). Thus, the strongest level ofevidence comes from at least one systematic review of multiple, well-designed,
randomized controlled trials (Type I). A lower level of evidence comes from at least
one randomized controlled trial (Type II).
Thanks to clinical research conducted since the 1990’s, there is a growing
body of evidence for the short-term efficacy of many medications (summarized inTable A.7.3). Much less strong is the evidence of their long-term effectiveness andsafety. For more details on assessment of treatment evidence see Chapter A.6 andFigure A.6.8.
Several placebo-controlled discontinuation studies have shown that longterm treatment can be effective in maintaining improvement and preventing
symptom recurrence. For example, in youth suffering from depression, continuing
antidepressant treatment significantly reduces the risk of relapse (Emslie et al,2008). Likewise, discontinuing risperidone in children with autism and severe
behavioral disturbances increases the risk of recurrence of aggression, selfinjury, and tantrums compared with continuing treatment (Research Units on
Pediatric Psychopharmacology Autism Network, 2005a). In addition, a numberof naturalistic follow-up studies provide useful information on the long-term
outcome of youths treated for several years, even though treatment effects are
difficult to determine due to the lack of a control condition.
Beyond the level of evidence for each medication, prescribers also needto understand their regulatory environment. Some psychotropics have received
approval for pediatric indications by drug regulatory agencies (i.e., the FDA in the
US or the EMA in the European Union), while others are used off-label.
In the US, many medications that have a high level of evidence also carryan FDA approval—for example, methylphenidate is FDA approved for ADHD inchildren aged 6 and older (see Table A.7.3). On the one hand there are medications
that have a high level of evidence but do not have FDA approval—for example,
sertraline has Type I level of evidence for efficacy in anxiety disorders in childhood,but no FDA indication. On the other hand, there are medications that have a
low level of evidence, yet have FDA approval—for example, haloperidol has little
evidence of efficacy among preschoolers, but it has an FDA indication for pediatricuse starting at age 3.

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IACAPAP Textbook of Child and Adolescent Mental Health

Table A.7.3 Selected psychotropic medications and level of evidence for
efficacy in children (<18 years)
Evidenceforefficacy1

US FDA-approved indication
and age, in years, for which itis approved

ADHD

Type I

6 and older

Amphetamines

ADHD

Type I

3 and older

Atomoxetine

ADHD

Type I

6 and older

ADHD

Type I

6 and older

Tourette’s disorderType I

ADHD

Type I

6 and older

Major depression

Type I

8 and older

OCD

Type II

7 and older

GAD/SP

Type II

OCD

Type I

Major depression

Type IIGAD/SP		

Type I

Citalopram

Major depression

Type II

Escitalopram

Major depression

Type I

12 and older

OCD

Type II

7 and older

GAD/SP

Type I

Major depression

Type V

ADHD

Type II

Major depression

Type V

OCD

Type II

10 and older

Tourette’s disorderType I

3 and older

Psychosis

Type II

3 and older

Hyperactivity, severe
behavioral problems, explosive
hyperexcitability

Type II

3 and older

Tourette’s disorderType I

12 and older

Schizophrenia

Type II

13 and older

Bipolar disorderType I

10 and older

Aggression 		Type I“Irritability” in autism:
5-16 years of age

Tourette’s disorderType I

Medication

Condition

Methylphenidate anddexmethylphenidate

Clonidine
Guanfacine
Fluoxetine

Sertraline

Fluvoxamine
Venlafaxine
Bupropion
Clomipramine

Haloperidol

Pimozide

Risperidone

Principles of pharmacotherapy A.7

6 and older

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IACAPAP Textbook of Child and Adolescent Mental Health

Table A.7.3 (Continuation). Selected psychotropic medications and level ofevidence for efficacy in children (<18 years)
Condition

Evidenceforefficacy1

US FDA-approved indication
and age, in years, for which itis approved

Schizophrenia

Type II

13 and older

Bipolar disorderType II

10 and older

Schizophrenia

Type II

13 and older

Bipolar disorderType II

10 and older

Aggression

Type I“Irritability” in autism:
6 and older

Schizophrenia

Type II

13 and older

Bipolar disorderType II

10 and older

Bipolar disorderType III

7 and older

Aggression		

Type II

Bipolar disorderType II

Aggression 		Type II

Carbamazepine2

Bipolar disorderType V

Oxcarbazepine

Bipolar disorderType V

Bipolar depression

Type V

Medication

Quetiapine

Aripiprazole

Olanzapine
Lithium
Valproate2

Lamotrigine

2

2

ADHD: attention deficit hyperactivity disorder; OCD: obsessive compulsive disorder; GAD: generalized anxiety
disorder; SP: social phobia.
1
Strength of the evidence: Type I: strong evidence from at least one systematic review of multiple well-designed
randomized controlled trials. Type II: strong evidence from at least one properly designed randomized controlled
trial. Type III: evidence from well-designed trials without randomization, single group, pre-post, cohort, time series
or matched case-control studies. Type IV: evidence from well-designed non-experimental studies from more than
one center or research group. Type V: opinions of respected authorities, based on clinical evidence, descriptive
studies or reports of expert committees (Gray, 1997).
2
Approved for the treatment of epilepsy from infancy.

Likewise, controlled clinical trials support the efficacy of methylphenidate
in preschoolers (age 3-6 years) with ADHD but it does not have an FDA indication
for use before the age of 6 years, while amphetamines, which have not beenadequately evaluated in controlled studies under age 6, have FDA approval startingat age 3. Thus, the on-label vs. off-label status of medications results from evidenceof effectiveness as well as other factors, including the historical and regulatory
context of their introduction.
These inconsistencies are largely due to the fact that the FDA approval
process was not designed to regulate clinical practice. Instead, it reflected the US
legislative efforts to regulate the marketing and sale by pharmaceutical companiesof new patented medications.
FDA approval processes underwent many changes since its inception in the
1940s. Older medications, such as haloperidol, had a much less transparent andPrinciples of pharmacotherapy A.7

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IACAPAP Textbook of Child and Adolescent Mental Healthmore expert-driven approval process with unclear impact of evidence. With respect
to sertraline, it became “generic” (its patent duration expired) before the evidence
for pediatric generalized anxiety disorder was shown. Once a medication becomesgeneric, applying for FDA approval (or “label”) no longer makes financial sense
for the manufacturers since it carries great administrative costs with no returns forthe pharmaceutical companies. As a result, the vast majority of medications used inclinical practice in both medicine and psychiatry, for both adults and children, areused “off-label.” Use of a medicine off-label is not in itself an inappropriate practiceas it is often supported by considerable empirical evidence and may be consistent
with treatment guidelines.
These concepts are important to understand and explain not only to parents,
but also to policy-makers. For example, officials in many countries make decisions
to purchase medications based on FDA approval status—or of its counterpart,the European Medicines Agency—and not on the overall evidence of efficacy andsafety.
Availability (status of manufacturing, trade, etc) also impacts prescribing
practice. Examples range from the transient intramuscular lorazepam shortages
in the US due to supply chain problems to the virtual lack of psychostimulants
in Ukraine due to the complexities of introducing a controlled substance intoa developing democracy. Lack of effective medications can encourage growth ofalternative treatments that either have no evidence of efficacy or have evidence of
causing harm.
In another example, the WHO list of essential medicines for mental andbehavioral disorders includes both medications that have a high degree of efficacy
and safety (for example, fluoxetine for depression, anxiety, and OCD) as well asothers that lack evidence for efficacy, safety, or both. For example, diazepam is noteffective for the long-term treatment of pediatric anxiety and amitriptyline is not

Table A.7. 4 WHO essential medicines for mental andbehavioral disorders (2017)•

Chlorpromazine•

Fluphenazine•

Haloperidol•

Risperidone•

Clozapine•

Amitriptyline•

Fluoxetine•

Carbamazepine•

Lithium•

Valproic acid (sodium valproate)

Medicines for anxiety disorders•

Diazepam

Medicines used for obsessive
compulsive disorders•

Clomipramine

Medicines for disorders due topsychoactive substance use•

Nicotine replacement therapy•

Methadone

Medicines used in psychotic
disorders

Medicines used in depressive
disorders
Medicines used in bipolar disorders

Principles of pharmacotherapy A.7

If you want to learn more
about the issues aroundoff-label prescribing of
psychotropic medication tochildren with an European
focus click on the figure toaccess a position statementby the British Association for
Psychopharmacology.

8IACAPAP Textbook of Child and Adolescent Mental Healtheffective for pediatric depression (see Table A.7.4).

PHARMACOKINETICS
Drug absorption, distribution, metabolism, and excretion all change
during child development. As a result, extrapolation of doses and frequencyof administration for children based on data obtained from adults can lead toinappropriate treatment. Although children have smaller absolute body size,
the relative mass of their liver and kidney tissue is greater than in adults when
adjusted for body weight. Children also have relatively more body water, less fat,and less plasma albumin to which drugs can bind. Consequently, the volume of
distribution of a medication tends to be greater in children than in adults. As
a result of the above differences, children have greater drug extraction during
the first pass through the liver, lower bioavailability, and faster metabolism andelimination. This means that simply decreasing adult doses based on child weight
may result in under-treatment.
In adolescence, together with a marked growth in body size, there is a
redistribution of the body compartments. In males, the percentage of total body
water increases and that of body fat decreases, while the opposite occurs in females.
For a summary of pharmacokinetic differences between children and adults (seeTable A.7.5)

Pharmacokinetics
What the body does tothe drug: absorption,
distribution, metabolism,and excretion.
Pharmacodynamics
What the drug does to the
body: the biochemical andphysiological effects ofdrugs on the body.
Half life
The time required to reduce
the plasma concentration to
one half of its initial value
Plasma steady state
Steady state occurs when
the rate of drug absorption
into the blood equals therate of elimination from it.
The time to reach steadystate concentrations isdependent on the half-lifeof the drug.

Once absorbed, most drugs undergo biotransformation (metabolism) thatturn the parent compound into more polar, and therefore easier to eliminate,byproducts (metabolites). Typically, medications undergo first an enzymaticoxidative or hydrolytic transformation (phase I), and then are conjugated withglucuronic acid, sulfate, glutathione, or acetate to form products that are eliminated
via the kidneys or bile.
The phase I oxidative processes are mediated by cytochrome 450 (CYP450)
microsomal enzymes, which are concentrated primarily in the liver. The CYP450
system is immature at birth, but its metabolizing capacity increases rapidly, so thatby one month of age it is already about 20% of the mature level, which is achievedby three years of age. Because children have proportionally more liver parenchyma
than adults, they have greater weight-adjusted metabolic capacity.
The two most important CYP450 enzymes in pediatric psychopharmacology
Table A.7.5 Pharmacokinetic characteristics in children relative
to adults
Liver & kidney mass adjusted for body weight

Greater

Metabolism and elimination

FasterDosingHigherElimination half-life

Shorter

Plasma steady-state

SoonerWithdrawal symptoms

More likely

DosingMore FrequentPrinciples of pharmacotherapy A.7

9IACAPAP Textbook of Child and Adolescent Mental Healthare the CYP3A4 and the CYP2D6, which are involved in the metabolism of
most psychotropics, as well as CYP2C9 and CYP2C19. For example, the 3A4
system metabolizes sertraline, citalopram, escitalopram, bupropion, mirtazapine,
aripiprazole, quetiapine, ziprasidone, lurasidone, cariprazine, alprazolam, zolpidem,
and oral contraceptives. The 2D6 system metabolizes fluoxetine, trazodone,
atomoxetine, tricyclic antidepressants, risperidone, olanzapine, chlorpromazine,
and haloperidol.
Some psychotropics can also act as inhibitors of these enzymes so that
concurrent administration of another drug that is a substrate for the enzyme results
in reduced metabolism and higher medication concentration in the body. For
example, 3A4 metabolized enzymes can be inhibited by fluoxetine or fluvoxamine.
Concomitant administration of fluvoxamine (inhibitor of 3A4) and quetiapine
or aripiprazole (metabolized by 3A4) could lead to higher levels of quetiapine or
aripiprazole and prolongation of the QTc interval.
An additional complexity is that some medications, such as carbamazepine
and phenobarbital, can induce CYP3A4 activity, thus potentiating its metabolizing
capacity. The concomitant administration of carbamazepine and a medication
metabolized by CYP3A4 can result in lower blood levels of many anticonvulsants,
antipsychotics, tricyclic antidepressants, clonazepam, and oral contraceptives. In
females, use of oral contraceptives can also induce CYP enzymes and thus increase
lamotrigine metabolism and elimination resulting in decreased lamotrigine serum
concentration.
Genetic polymorphisms have been identified for CYP 450 enzymes.
About 7-10% of Caucasians, 1-8% of Africans, and 1-3% of East Asians are poorCYP2D6 metabolizers of specific medications. Poor metabolizers have higher
drug concentrations in plasma and other body tissues. For example, the meanelimination half-life of atomoxetine is about 5 hours in children or adults who are
fast metabolizers, but 22 hours in poor metabolizers (Sauer et al, 2005). While thesemetabolic differences do not appear to be clinically significant for atomoxetine,some cases of toxicity have been reported with other psychotropics. For example,
one case of death in a child with a 2D6 genetic deficiency was associated withunusually high plasma levels of fluoxetine (Sallee et al, 2000).
Technological advances in the 2010’s have enabled affordable testing ofgenetic variants potentially relevant to medication metabolism and response.
With direct-to-consumer advertising of commercially available pharmacogenomic
testing. Many parents ask to use such tests for decision-making about prescription.
While future advances are promising, the evidence to support this practice isinsufficient at this time.
On November 1, 2018, the FDA published the following warning: “The FDA
has become aware of genetic tests with claims to predict how a person will respondto specific medications in cases where the relationship between genetic (DNA)variations and the medication’s effects has not been determined. For example, the
FDA is aware of genetic tests that claim results can be used to help physicians
identify which antidepressant medication would have increased effectiveness or side
effects compared to other antidepressant medications. However, the relationshipbetween DNA variations and the effectiveness of antidepressant medication has
never been established. Patients and health care providers should not make changes

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IACAPAP Textbook of Child and Adolescent Mental Healthto a patient’s medication regimen based on the results from genetic tests that claim
to predict a patient’s response to specific medications, but are not supported bysufficient scientific or clinical evidence to support this use, because doing so may put
the patient at risk for potentially serious health consequences. There are a limited
number of cases for which at least some evidence does exist to support a correlation
between a genetic variant and drug levels within the body, and this is described in thelabeling of FDA cleared or approved genetic tests and FDA approved medications.”
While testing for genetic polymorphism is not routinely done in current childpsychiatry practice, it may be considered for individual patients who do notrespond to adequate doses of medication, or present with unusual reactions to
medications metabolized by enzymes with genetic polymorphism (e.g., 2D6 and2C19).
The main route of drug elimination is through the kidneys. Absolute
clearance is usually lower in children than in adults, but weight-adjusted clearance
is greater. Because of the faster elimination, the drug plasma half-life can be shorterin children than in adults (Daviss et al, 2005). A shorter elimination half-lifemeans that plasma steady-state is reached sooner during repeated administration,and that withdrawal symptoms upon discontinuation are more likely. In thesecases, a more frequent administration is needed to maintain consistent therapeuticlevels and prevent withdrawal symptoms between doses.

Assessing and monitoring
medication effects ismore complex and time
consuming in children thanin adults because cliniciansmust collect and integrate
information from multiple
sources.

For some medications, the dose and duration of treatment can influencepharmacokinetics. After a single dose of sertraline 50 mg in adolescents, the mean
half-life is about 27 hours but after repeated administration it decreased to about
15 hours (Axelson et al, 2002). Moreover, the steady-state half-life is longer (about
20 hours) after administration of higher doses (100-150 mg). Based on these
data, lower doses (50 mg/day) of sertraline should be given twice a day to ensure
consistent treatment and prevent withdrawal, while higher (100-150 mg) doses
can be given once a day.
The pharmacokinetics of many psychotropics has been studied in children
and adolescents. For escitalopram, aripiprazole, quetiapine, risperidone, andlithium, pharmacokinetics was found to be similar in youth and adults (Rao,2007; Findling et al, 2008; Thyssen et al, 2010; Findling et al, 2010). However,considerable inter-subject variability was observed, so that major individual
differences in the time-course of pharmacological effects can occur in clinicalpractice. For methylphenidate and amphetamines, whose short half-life results inshort duration of action and in the need for multiple daily administrations, a variety
of extended release formulations have been developed and require prescribers tocontinue to keep up their learning.

PHARMACODYNAMICS
Most psychotropics act through neurotransmitters, such as dopamine,
serotonin, glutamate, GABA, and norepinephrine, whose receptors undergo
major changes during development. Receptor density peaks in the preschool years
and then gradually declines toward adult levels in late adolescence (Chugani etal, 2001). The impact of these developmental changes on drug activity, efficacy,
and safety are still not well understood. However, observed differences between
children and adults in efficacy and safety suggest that development can significantly

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IACAPAP Textbook of Child and Adolescent Mental Health

Table A.7.6 Psychotropic drug groups: pharmacodynamic differences between
children and adults
Drug groupChildren

AdultsTricyclic antidepressantsNot effective for pediatricdepression

Effective for adult depression

Serotonergic antidepressantsIncrease the risk of suicidal
ideation

Do not increase the risk after age
25

Antipsychotics

Relatively greater metabolic side Relatively lower metabolic side
effects
effects

Amphetamine-basedstimulants

Less likely to induce euphoria

More likely to induce euphoria

Methylphenidate

Lower tolerability and efficacy inchildren with ADHD aged 3 to 5
years

Higher tolerability and efficacy inadults and children with ADHD
above the age of 5 years

influence the effects of psychotropics (summarized in Table A.7.6). For example,
tricyclic antidepressants, though proven effective in adult depression, have nodemonstrable antidepressant effect in children (Hazell et al, 1995); amphetaminebased stimulants are more likely to induce euphoria in adults than in children;
antipsychotics have stronger metabolic effects in youth than in adults (Correll etal, 2009); and serotonergic antidepressants increase the risk for suicidal ideation inchildren, adolescents, and young adults, but not in the middle-aged or the elderly(Hammad et al, 2006; Stone et al, 2009).
The developmental stage influences the response to a number of psychotropics.
This is evident also in the lower tolerability and efficacy of methylphenidate inchildren with ADHD between 3 and 5 years of age as compared with older children(Greenhill et al, 2006). Abnormal brain development, such as in autism, impacts
medication response, as shown by the lack of benefit from SSRIs for compulsive
and repetitive behaviors in autism (King et al, 2009). Thus, information derived
from adolescents may not be applicable to younger children or to those who sufferfrom pervasive disorders of development. This underscores the need for research in
specific patient populations.

EFFICACY

Some adverse effects canbe anticipated based on
the mechanism of actionof the medication, whileothers are completely
unexpected, such asincreased suicidality withantidepressant treatment.

The term efficacy is used to describe treatments with a demonstrated
therapeutic benefit when tested under controlled experimental conditions, usually
involving carefully selected samples of patients. Effectiveness refers to treatmentsthat have demonstrated benefit in non-experimental clinical settings with patients
broadly representative of the population likely to receive the treatment. Often,
however, these two terms are used interchangeably.
Double-blind trials are methodologically more persuasive than open studies
because they control for placebo effects. A number of well-designed placebocontrolled clinical trials have been conducted in pediatric psychopharmacology. The
results of these studies provide the foundation for evidence-based pharmacotherapy

Principles of pharmacotherapy A.7

12IACAPAP Textbook of Child and Adolescent Mental Healthin child psychiatry, summarized in evolving practice guidelines and treatment
algorithms (e.g., National Institute for Health and Clinical Excellence, 2005 and2008; Pliszka et al, 2007; Birmaher & Brent, 2007; McClellan et al, 2007). One
critical element in evaluating the efficacy of a treatment is the chosen outcome. A
treatment can be effective at:• Decreasing symptoms (improvement)• Eliminating the key manifestations of the disorder (remission, in the
short-term, and recovery, if sustained over time)• Restoring functioning (functional recovery)• Decreasing the risk for relapse or recurrence of the symptoms.
Thus, when stating that a certain treatment is effective, one should also
specify the particular outcome. Typically, medications are approved for clinical use
based on studies showing that they decrease symptoms. Proving treatment effects
on remission, recovery, or functioning requires longer-term controlled trials, which
are more difficult and expensive to conduct.

Efficacy
A term used to indicatethat a treatment has ademonstrated therapeutic
benefit when tested in
rigorous conditions, usually
involving carefully selected
samples of patients.
EffectivenessTypically means that thetreatment has shown to bebeneficial in usual clinicalsettings for patients broadly
representative of the
population likely to receivethat treatment.

There are, however, studies supporting efficacy and effectiveness for remission
and recovery in some medications, such as stimulants in ADHD (Swanson et al,2001) and serotonergic antidepressants in adolescent depression (Kennard et al,
2009; Vitiello & Davico, 2018).
The need to document symptom reduction and remission highlights theimportance of measuring the behavioral, emotional, and functional manifestationsof mental dysfunction. In the absence of direct biological markers of disease andtreatment effects, clinicians must rely on symptoms and indirect signs to gauge
treatment response. Rating scales have been developed for all of the conditions inchild mental health (see Chapter A.5).
These scales can be divided into those that are completed by the clinician
based on both direct observation and informants (clinician-rated), and thosethat are completed directly by informants (self, parent, teacher). A distinctive
characteristic of pediatric psychopharmacology is that, in addition to the child,clinical information is usually derived from parents and teachers. Since cliniciansmust collect and integrate information from multiple sources, assessing andmonitoring medication effects is more complex and time consuming in children.
When comparing treatments, it is useful to quantify the size of the treatment
effect (see also Chapter A.6). Using data from controlled trials, the magnitude of
the treatment effect relative to a control can be expressed in standard deviation
units. The most commonly used ways of computing effect size are Cohen’s d or
Hedges’ g—the difference in the means of the outcome measure between the study
groups (active treatment and control) divided by the pooled standard deviation(Rosenthal et al, 2000).
Compared with placebo, stimulants have a large effect size (0.8 and above),
while non-stimulants (clonidine, guanfacine, atomoxetine) have small to moderate
effect sizes (0.25-0.5) in decreasing symptoms of ADHD (Greenhill et al, 2001).
In trials that have detected a separation between SSRI and placebo, the SSRIs had
a moderate effect size (0.5-0.7) in the treatment of major depression (TADS Team,
2004) or obsessive-compulsive disorder (Pediatric OCD Treatment Study, 2004).
However, meta-analyses of all available clinical trials in pediatric depression (bothpositive and negative) indicated that the effect size of antidepressant medication vs.

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IACAPAP Textbook of Child and Adolescent Mental Healthplacebo was small (0.25, 95% C.I. 0.16-0.34) (Bridge at al, 2007).
Effect size can also be used to quantify pre-post treatment difference within
the same group of patients, rather than the difference between treatment andcontrol groups. However, due to the lack of a parallel control group, the effect due
to the treatment cannot be separated from the effect of the mere passage of time
as well as of patient’s expectations, classical conditioning, and other non-specificcomponents of the placebo effect. For this reason, a within-group pre-post effectsize is expected to over-estimate the effect of treatment and reflect the combined
effects of placebo and specific treatment.
It is also useful to quantify the therapeutic benefit using the number needed
to treat (NNT)—the number of patients who need to receive the treatment inorder to add one more improved patient to those who improve in the control
condition. NNT is a type of effect size and is the inverse of the absolute risk
reduction (ARR). ARR is the difference between outcome incidence in the treatedand control groups. Thus, in the Treatment for Adolescents with Depression Study(TADS), 61% of patients treated with fluoxetine improved at the at 12 weeks,compared with 35% of the placebo patients (TADS Team, 2004). Based on theabsolute difference of 26% (ie, 61- 35) observed, the NNT for fluoxetine is 4 (i.e.,
100/26 = 3.9), which indicates that one needs to treat on average 4 patients toimprove one patient more than the placebo condition.
The smaller the NNT the greater the efficacy of the treatment. The NNTs of
psychotropic medications, though variable among studies, are often quite favorable
when compared with other non-psychiatric drugs used in pediatrics. For example,
NNT for antibiotics for pain reduction in case of acute otitis media in children
is 16 (Sanders et al, 2004). Most of what is currently known about the effectsof treatments is limited to the short- (i.e., weeks) and intermediate-term (i.e.,months) (see also Chapter A.6).
Relatively few studies have addressed the long-term effectiveness ofpharmacotherapy in childhood mental disorders (MTA Cooperative Group, 2004;
TADS Team, 2007; Vitiello et al, 2011; Findling et al. 2010). More research isneeded to determine whether reduction of symptoms leads to better prognosis. For
example, it would be important to know if improved ADHD symptoms translate
into a lower risk for motor vehicle accidents, higher academic and occupational
achievement, and better social adjustment, in the same way that the control ofhypertension has been found to decrease cardiovascular morbidity and mortality.
Unfortunately, we have yet to obtain data to answer these questions. Studying
the long-term effects of treatments poses many challenges from practical andmethodological perspectives. Long-term randomized controlled trials are difficult
to implement, while observational studies are insufficient to prove causality.

SAFETY
Ensuring safety is especially important when treating children.
Pharmacological treatment during human development may result in toxicities thatare not seen in adults. A general concern is that agents acting on neurotransmitter
systems during rapid development may interfere with normal processes and resultin unwanted long-lasting changes.

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IACAPAP Textbook of Child and Adolescent Mental HealthStudies in developing animals have been informative. For example,
fluoxetine given to newborn mice transiently inhibits the serotonin transporter
during early development; this is associated with behavioral abnormalities suchas reduced exploratory behavior and slower adaptation to novel environments or
stimuli in adult age (Ansorge et al, 2004). Even though the relevance of these data
to children is unclear, a high level of concern is warranted when treating children
with medication, especially when the treatment is at an early age (under age 6) or
long-term.
Medications may cause a variety of adverse effects (Vitiello et al, 2003a).
Some, such as dystonias with anti-dopaminergic agents or appetite suppression
with stimulants, become evident after hours to days, while others, such as tardive
dyskinesia or metabolic syndrome with antipsychotics, emerge slowly withtreatment over months to years. Some adverse effects are related to elevated plasma
concentrations, such as lithium-induced tremor, while others emerge after drug
discontinuation, such as antipsychotic withdrawal dyskinesias. Some adverse
effects can be anticipated based on the mechanism of action of the medication(e.g., sedation with antipsychotics). Other adverse effects are paradoxical, such asincreased suicidality with antidepressant treatment.
Assessment of safety largely relies on monitoring and reporting by
responsible adults. Identification of adverse effects is contingent on a thoroughevaluation by a clinician. In recent years, more information has become available
on the long-term safety of several psychotropics in children. For example, it is
now recognized that stimulants, such methylphenidate and amphetamines, cancause a dose-related delay in physical growth, in both weight and height. After 14months of treatment, children treated with stimulant medication for ADHD grewon average 1.4 cm less in height than peers treated with behavior therapy (MTA
Cooperative Group, 2004). A growth deficit was found to persist in future years
in children who were medicated for three years (Swanson et al, 2007). The effecton height appears to be more evident in children who started stimulant treatment
before the onset of puberty (Díez-Suárez et al, 2017). The mechanism underlying
the interference of stimulants with skeletal growth is still unclear.
Because stimulants have adrenergic activity, concern has been raised about
unwanted cardiovascular outcomes, including sudden death (Gould et al, 2009).
However, analyses of large patient population data have not identified an association
between therapeutic use of stimulants and increased cardiac death or cardiac events
leading to emergency department visits (Cooper et al, 2011; Schelleman et al,2011). Moreover, a prospective study of children treated for up to 10 years did not
find an increased risk for hypertension, although stimulants have a small detectable
acute effect on heart rate and blood pressure (Vitiello et al, 2012).
As stimulants have abuse potential, concerns have also been raised about thepossibility that treatment in childhood may sensitize the brain and thus increase therisk of substance abuse in adulthood (Vitiello, 2001). The feasibility of mounting
randomized, well-controlled studies to address this issue is questionable, andresearchers have relied on naturalistically treated samples. Available prospective
studies have not found increased risk of adult substance abuse associated withchildhood treatment with stimulants (Volkow & Swanson, 2008; Biederman et al,2008; Wilens et al, 2008).

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IACAPAP Textbook of Child and Adolescent Mental Health

Table A.7.7 Key steps in implementing pharmacotherapy in child andadolescent psychiatry
1. Complete a comprehensive diagnostic evaluation documenting thepresence of a condition for which medication is indicated
2. Inform parents and child (to the extent allowed by developmental
level and cognitive functioning) of the potential benefits and risks of
medication as compared with alternative options
3. If the medication does not have a regulatory-approved indication foruse in children with the condition, inform parents and child that the
medication is being used “off-label”
4. Identify and measure the target symptoms and functions that
medication is expected to improve
5. Based on the medication, obtain baseline clinical or laboratory
parameters (e.g., weight, height, blood pressure, pulse rate, cholesterollevel, renal function)
6. Start medication at a dose in the lower end of the usually effective dose
range aiming at identifying the lowest possible dose that produces thedesired outcome
7. Monitor effects, side effects and, if appropriate, plasma levels (e.g.,lithium levels) in the first few weeks of treatment, and adjust the dose
as appropriate
8. If there is improvement, optimize the dose aiming at maximum
resolution of symptoms and improvement in functioning
9. Determine the maintenance dose and, based on the condition andmedication, establish a tentative duration of treatment
10. As appropriate, periodically consider the need for continuous treatment
vs. discontinuation
11. When discontinuing treatment, examine the need for gradualtaper, which is recommended for most medications after chronic
treatment (e.g., antidepressants, lithium, antipsychotics), vs. abrupt
discontinuation, which can be appropriate for some medications (e.g.,
methylphenidate)

Differences in tolerability have been observed across age and type ofdevelopment. Preschoolers with ADHD show lower tolerability to methylphenidate
than older children (Greenhill et al, 2006; Wigal et al, 2006). Likewise, children
with autism spectrum disorder and comorbid ADHD symptoms were moresensitive to the adverse effects of methylphenidate as indicated by an 18%
treatment discontinuation due to adverse events (most commonly irritability) as
compared with less than 5% in children with ADHD without ASD (Research
Units on Pediatric Psychopharmacology Autism Network, 2005b).
Youth exposed to second generation antipsychotics are more prone togaining weight than adults (Correll et al, 2009). Antidepressants have been foundto increase the risk for suicide-related events, such as thoughts about suicideand suicidal behaviors, although an effect on completed suicide has not been
determined (Hammad et al, 2006). In a meta-analysis including 13 placebocontrolled trials in children and adolescents with major depression, the suicidality

Principles of pharmacotherapy A.7

Preschoolers with ADHD
show lower tolerability tomethylphenidate than older
children. Likewise, children
with autism or otherpervasive developmental
disorders with ADHD
symptoms are moresensitive to the adverse
effects of methylphenidate.

16

IACAPAP Textbook of Child and Adolescent Mental Healthrate (thoughts, attempts, and self-harm) was 3% on antidepressant and 2% on
placebo (Bridge et al, 2007). A similar meta-analysis in adults documented aninteraction between age and risk of suicidality with antidepressant use: risk wasincreased for individuals under age 25, not affected between 25 and 64 years,
and actually decreased in patients over 64 (Stone et al, 2009). These data provide
an example of interaction between development and pharmacological effect, eventhough the biological underpinning of this interaction remains unknown.
The mechanism through which antidepressants may trigger suicidality
remains a matter of speculation. It is possible that some youth become abnormally
activated by the antidepressant, with akathisia, agitation, anxiety, insomnia, andimpulsivity. However, this explanation, based on anecdotal reports, remains atheory as systematic analyses of treated patients have not confirmed it (Vitielloet al, 2009b). A related explanation includes unmasking or triggering a bipolar
disorder, but this also lacks experimental evidence.
Safety is a relative concept and the risks of pharmacotherapy must be weighedagainst the risks of an untreated illness. Decisions about prescribing medicationmust also take into account the availability of effective nonpharmacologicalinterventions. Though generally found less effective at decreasing acute and severe
symptoms in most conditions, psychotherapy should always be considered in lieu
of, or in combination with medication. Psychotherapy, used either sequentially(i.e., start first with psychotherapy, then add medication if insufficient) or in
combination (i.e., start both psychotherapy and medication concurrently), may beable to shorten time to recovery and reduce the total dose of medication needed tocontrol symptoms (TADS Team 2007; MTA Cooperative Group, 1999).

ETHICAL AND REGULATORY CONSIDERATIONSChildren should be able to learn about their condition and the possible
treatments to the extent allowed by their cognitive and emotional development.
However, before the age of 14, 16, or 18 years (the legal age for consent to treatment
varies according to country; see Chapter A.1), they cannot give legal permission
for treatment, which must come from their guardians. It is the responsibility of theprescribing clinician to inform the parents of the expected benefits and risks of the
medication. Parents are also instrumental for implementing pharmacotherapy byensuring appropriate administration of prescribed medication and for reporting
treatment-emergent adverse effects.

Research in children
Progress in pediatric psychopharmacology depends on the participation ofchildren in research (see also Chapter J.7). In the US and some other countries,
research involving children is subject to special regulations in addition to those
for adults participating in research (United States Department of Health andHuman Services; Food and Drug Administration, 2001). Only scientifically soundresearch that utilizes valid methodology and is posited to add new knowledge about
important health issues may be ethically acceptable (Vitiello, 2003b).

A number of public andprivate websites provide
detailed information
about child participationin research and theprocess of determining
if a particular project is
ethically acceptable. Clickon the picture below toaccess the website of the
Office for Human ResearchProtection.

Pediatric research can be divided into two broad categories based on whether
it does or does not have the prospect of direct benefit to the individual participant.
“Prospect of direct benefit” means that each participant has the potential of

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IACAPAP Textbook of Child and Adolescent Mental Healthderiving a health benefit from participation. General acquisition of knowledge
relevant to the child’s condition does not satisfy the requirement of direct benefit.
To be ethically acceptable, research with prospect of direct benefit must also havea favorable balance between anticipated benefits and foreseeable harms. Usually,studies of treatment efficacy have potential for direct benefit to the research
participants. In these cases, the main criterion for determining ethical acceptability
is the risk/benefit ratio. The inclusion of a placebo arm in randomized clinical trial
is usually considered acceptable. Placebo does not necessarily mean absence oftreatment and has been associated with substantial improvement, especially in thecase of mood and anxiety disorders.
Pharmacological research that does not offer a prospect of direct benefit
includes pharmacokinetic and pharmacodynamic studies. In order to be acceptable,
such research must have potential for generating essential knowledge relevant to
the disorder or condition of the participant. If the information is not relevant tothe child’s disorder or condition (e.g., a pharmacokinetic study in healthy children
at no increased risk for the condition being targeted by the treatment), the research
can be conducted only if it entails no more than minimal risk.

Children and youth whocome to the attention of
the child welfare systemhave disproportionately
high rates of emotionaland mental healthchallenges and areprescribed high rates ofpsychotropic medications.
Click here to access the
Recommendations about
the Use of Psychotropic
Medications for Children
and Adolescents Involvedin Child-Serving Systems
by the AACAP

Minimal risk is defined as “risk for harm not greater than ordinarily
encountered in daily life, or during routine physical or psychological examinations
or tests” (section 46.102(i) in U.S. Department of Health and Human Subjects
1991). The prevailing interpretation is that the daily life exams and tests of a normalchild is to be used as reference, but a precise quantification of risk in ordinary daily
life is not easy and remains a matter of discussion.
If the study aims to acquire information relevant to the child’s condition(e.g., pharmacokinetics of a medication for ADHD being studied in children withADHD), the research risk cannot be greater than a minor increase of minimal risk.
The process of informing parents and children about the aims, procedures,
potential risks and benefits of research participation, existence of alternative
treatments, and the rights of research participants is critical for obtaining theirinformed consent and assent. In general, children age 7 and above are able to provide
assent, which is often documented in writing within an appropriate “research
participation assent form.” By age 16, adolescents have a level of understanding
similar to that of their parents (Vitiello et al, 2007).

PEDIATRIC PSYCHOPHARMACOLOGY IN CLINICALPRACTICE
Practicing evidence-based pharmacotherapy in child and adolescent
psychiatry requires the integration of knowledge and expertise at different levels,
including developmental psychopathology, pharmacology, current regulatory
policies for prescribing—that vary from country to country—bioethics relevant tovulnerable patients, and at least enough familiarity with psychosocial interventions
to allow an informed and balanced decision-making process.

Click on the image to viewa short clip (2:30) abouttalking to children about
psychotropic medication

Research typically provides information at the group level. This is certainly
useful for preparing general practice guidelines and algorithms, but the informationneeds to be interpreted and adapted to the needs of the individual child, a processthat relies on the skills of the clinician.

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IACAPAP Textbook of Child and Adolescent Mental Health

The first few weeks of treatment are devoted to determining if and at which
dose the medication is effective and tolerated. During this phase (acute treatment),
frequent monitoring is needed in order to titrate the dose based on clinical response(Table A.7.7). Depending on the type of medication, clinical response can take justa few days to emerge or may require several weeks. As previously discussed, the useof standardized rating scales is especially useful in this phase.
Even for the most effective medications, such as stimulants in ADHD, thechance that an individual patient will derive a clinically significant benefit is about
70%, thus leaving about a third of patients without sufficient improvement. Thismeans that the clinician must be ready to recognize non-response and change
the treatment plan accordingly. In many cases, a second-step medication should
be considered. For example, if a child with ADHD has not improved frommethylphenidate, an amphetamine product may be effective. Likewise, depressedadolescents who have not improved on one antidepressant have about a 50%
chance to respond to another antidepressant (Brent et al, 2008).
Once a medication has been found to be of benefit and well tolerated by
the patient, the treatment continues with the goals of optimizing it, achieving
remission and functional recovery (continuation phase). After achieving recovery,
the treatment typically continues with the purpose of maintaining improvement
and preventing relapse or recurrence (maintenance phase). The duration ofmaintenance treatment depends on the condition being treated and the history ofillness of the individual patient. For example, ADHD is a chronic condition, so that
long-term treatment is usually indicated. However, the phenotypic manifestationsof ADHD may change with time, as hyperactivity tends to decrease in adolescenceor young adulthood, so that periodic reassessment of the need for pharmacologicaltreatment is advisable on an annual basis or so.
In the case of MDD, it is recommended that effective treatment be continued
for 6 to12 months after reaching remission, after which a gradual tapering off ofthe medication over a 2-3 months period can be considered (Hughes et al, 2007).
For patients who had had recurrent episodes of depression, a proportionately
prolonged treatment is usually advisable.

CHALLENGES
While insufficient access to competent prescribers and integrated systems ofcare is virtually universal, countries across the globe also face great region-specificchallenges. In high income countries, such as the US, polypharmacy practice has
become increasingly prevalent even though evidence for its efficacy and safety islagging. Shortage of prescribers and excessive reliance on medications in the absenceof effective psychosocial interventions exacerbate this problem. There is a concernthat insufficient training and team integration of “mid-level physician extenders”
may lead to “over-prescribing.” Responsible approaches to deprescribing are still inearly stages of development.
Another emerging challenge in high income countries has to do withthe growing commercial use of pharmacogenomic testing before it has gatheredsufficient scientific evidence. Conversely, low- and middle-income countries arefacing a severe dearth of both medications and prescribers. Medications that areconsidered to be the standard of care in high income countries may not be available

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IACAPAP Textbook of Child and Adolescent Mental Healthin low- and middle-income countries.
Some countries have less than ten or no child psychiatrists at all. Other
countries have questioned the need for child psychiatry as a specialty altogether.
The growing practice of conducting clinical trials in low- and middle-income
countries that will disproportionately benefit patients on high income countries
presents both ethical and cross-cultural validity challenges. Finally, in the absenceof effective public education in both high- and low- and middle-income countries,
the use of sham treatments that have not been scientifically studied continues tobe on the rise.

CONCLUSIONS••

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When properly used, medications have an important role in the treatmentof youth with severe mental disorders. There is evidence that some medications canhelp not only manage symptoms, but also improve functioning and hasten recovery.
A thorough and complete diagnostic evaluation before considering medicationis critical, as well as the need for consistent monitoring during treatment. The
therapeutic value of a number of psychotropics is now well documented in both theshort and intermediate-term, while more research is needed to better understandthe long-term impact of pharmacotherapy. Pediatric psychopharmacology
continues to develop rapidly, and clinicians must remain informed as new data
become available.

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IACAPAP Textbook of Child and Adolescent Mental HealthAppendix A.7.1
SELF-ASSESSMENT EXERCISES
A.7.1 Discontinuing risperidone inchildren with autism and severe
behavioral disturbances:
A
B
C
D
E

Increases the risk of recurrence
Results in an improvement of
behavior
Does not make any difference
Lessens self-harming behaviors
Improves learning

A.7.2

Psychotropic medications weretypically introduced to treat adult
disorders and then extended tothe pediatric population, with the
exception of:

A
B
C
D
E

Chlorpromazine
Psychostimulants
SSRIs
Lithium carbonate
Clozapine

A.7.3

When compared with adults andadjusted for body weight, therelative mass of children’s liverand kidney tissue is:

A
B
C
D
E

Smaller
Similar
Greater
Much greater
Of no clinical relevance

Principles of pharmacotherapy A.7

A.7.4

Using a medication “off label”
means that it:A
B

Lacks evidence of effectivenessHas not received approval for thatindication by a regulatory agency(e.g., FDA)
Has significant side effects
Is not recommended by the WHO
Is not recommended by clinicalpractice guidelines

C
D
E

A.7.5

Some medications are includedin the WHO list of essential
medicines for mental andbehavioral disorders in spite of:

A
B
C
D

Their price
Their availability
Being “of label”
Lacking evidence of effectiveness inchildrenSignificant side effects

E

A.7.6

Which one of the CYP450
enzymes listed bleow ismost relevant in pediatric
psychopharmacology?

A
B
C
D
E

CYP2C9CYP2C19
CYP2B6
CYP3B7CYP3A423

IACAPAP Textbook of Child and Adolescent Mental Health

A.7.7 When treating children, decreasing
adult target dosage based on thechild’s weight:
A
B
C
D
E

Is a good practice
Reflects pharmacodynamic principles
Reduces side effects
May result in under-treatment
May result in over-treatment

A.7.10Which statements listed below
are true or false:A

The higher the number needed
to treat (NNT) the lower theeffectiveness of a treatment
Even for the most effective
medications, such as stimulants in
ADHD, the chance that an individual
child will derive a clinically significant
benefit is about 70%
Nowadays psychotropic medication
should not be prescribed unlessgenetic testing has been carried out
Psychotherapy should not be usedconcurrently with medication
Antipsychotic drugs are better
tolerated by children than by adults

B

C
A.7.8

Tricyclic antidepressants fordepression in children:

A
B
C
D
E

Should not be used
Are effective
Are better tolerated than in adults
Require lower doses than adults
Require higher doses than adults

A.7.9

Effect size is the difference in theoutcome measure between the
study groups…

A

Multiplied by the pooled standard
deviation at the end of treatment
Divided by the pooled standard
deviation at the end of treatment
Subtracted from the pooled standard
deviation at the end of treatment
Added to the pooled standard
deviation at the end of treatment
Divided by the square of the pooled
standard deviation at the end oftreatment

B
C
D
E

Principles of pharmacotherapy A.7

D
E

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IACAPAP Textbook of Child and Adolescent Mental HealthANSWERS•

A.7.1

Answer: A

•

A.7.2

Answer: B

•

A.7.3

Answer: C

•

A.7.4

Answer: B

•

A.7.5

Answer: D

•

A.7.6

Answer: E

•

A.7.7

Answer: D

•

A.7.8

Answer: A

•

A.7.9

Answer: B•

A.7.10

Answer: A, true; B, true; C, false; D, false; E, false

Principles of pharmacotherapy A.7

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