JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY

Volume 28, Number 9, 2018 Review Articles

ª Mary Ann Liebert, Inc.
Pp. 582–605
DOI: 10.1089/cap.2018.0037

A Focused Review on the Treatment of Pediatric

Patients with Atypical Antipsychotics

Esther S. Lee, MD, Carol Vidal, MD, MPH, and Robert L. Findling, MD, MBA

Abstract
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Objectives: The use of atypical antipsychotic medications in pediatric patients has become more prevalent in recent years. The
purpose of this review is to provide a clinically relevant update of recent selected key publications regarding the use of
atypical antipsychotics in this population.
Methods: Studies reviewed included randomized, double-blind, placebo-controlled medication trials conducted within the
past 5 years. A PubMed search was conducted for each of the 11 second-generation antipsychotic medications currently
approved by the Food and Drug Administration for use in the United States: clozapine, risperidone, olanzapine, quetiapine,
aripiprazole, ziprasidone, paliperidone, asenapine, iloperidone, lurasidone, and cariprazine. Trials published in English with
subjects 18 years of age and younger were included in this review. Additional studies, chosen for their significance to clinical
practice, were also included at the discretion of the authors.
Results: This review demonstrates that more empiric data are available regarding both the acute efficacy and, to a lesser
extent, the longer-term efficacy and tolerability for several of the considered antipsychotic medications. The clinical con-
ditions for which these medications have been studied include schizophrenia, bipolar disorder, Tourette’s disorder, and
autism spectrum disorder. They have also been used as an adjunctive treatment for disruptive behavior disorders with
aggression, which have not responded to treatment with stimulants.
Conclusion: Evidence regarding the efficacy and tolerability of antipsychotic medications for mental health disorders in
children and adolescents has expanded exponentially in recent years. However, more information is needed so that evidence-
based comparisons between medications can be made. In the future, data enabling the selection of medications based upon
individual patient characteristics could potentially lead to greater efficacy and efficiency in treating what are frequently
debilitating medical conditions. Maladaptive aggression in children, often treated with antipsychotics, is one such area in
which there is a dearth of actual information available to the clinician. It is to be hoped that additional, longer-term studies of
these medications will further inform evidence-based practice in clinical settings.

Keywords: antipsychotics, psychotic disorders, attention-deficit/hyperactivity disorder, mood disorders, psychopharma-

cology, children and adolescents

Introduction years, given their comparable clinical efficacy and relatively fa-
vorable side effect profile, with antipsychotic treatment visits

A ntipsychotic medications were first introduced during the

early 1950s in the form of chlorpromazine in adults. Many
additional antipsychotic medications were developed in the fol-
lowing decades with the first ‘‘atypical’’ antipsychotic, clozapine,
being developed as a therapeutic option for those patients who were
resistant to or unable to tolerate the side effects from other available
treatments. Since the introduction of clozapine to the U.S. market in
1990, other atypical antipsychotics with a reduced propensity for
causing extrapyramidal side effects (EPS) have been developed and
tested (Shen 1999). The use of atypical antipsychotic medications
in all patient populations has become more prevalent in recent
shifting from typical agents (84% of antipsychotics in 1995) to
atypical agents (93% in 2008) (Alexander et al. 2011).
In addition to the increasing use of antipsychotic medications in
general, there is evidence that their use is increasing specifically
among children and adolescents. Data obtained from the National
Ambulatory Medical Care Survey (NAMCS) between 1993 and
2009 show a significant increase in overall antipsychotic use by
youths, treated by both psychiatrists and nonpsychiatric physicians.
During the 2005–2009 period, almost one-third of outpatient visits
for a diagnosis of mood disorder (31.3%) involved the pre-
scribing of an antipsychotic medication. Also during this period, a

Division of Child and Adolescent Psychiatry, Department of Psychiatry and Behavioral Sciences, Johns Hopkins Hospital School of Medicine,
Baltimore, Maryland.

582
 UPDATES ON THE USE OF ANTIPSYCHOTICS IN CHILDREN AND ADOLESCENTS
significant number of child and adolescent outpatient visits in-
volving antipsychotic medication did not actually include a Food
and Drug Administration (FDA) clinical indication, with a dis-
ruptive behavior disorder (DBD) diagnosis being among the most
frequent diagnoses given. The most commonly prescribed anti-
psychotic medications during outpatient child visits were risper-
idone (42.1%), aripiprazole (28.0%), quetiapine (19.2%), and
olanzapine (4.4%) (Olfson et al. 2012).
Presently, several members of the atypical antipsychotic class of
medications have at least one FDA-approved indication in pediatric
patients. Diagnoses for which there is an FDA approval include
schizophrenia, bipolar disorder, irritability associated with autistic
disorder, and Tourette’s disorder (TD) (Table 1). The purpose of
this review is to provide an update of recent selected key publica-
tions regarding the use of atypical antipsychotics in children and
adolescents. A particular focus of this work will be to describe the
clinical salience of these new data so that this information can be
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incorporated into clinical practice.
Methods
This review focuses on primary analyses of randomized, double-
blind, placebo-controlled medication trials that have occurred
within the past 5 years. A PubMed search for each of the 11 second-
generation antipsychotic medications currently approved by the
FDA for use in the United States was completed between No-
vember 29, 2017, and March 20, 2018, with the purpose of finding
recent medication trials conducted against placebo with filtering for
the following terms: clinical trial, 5 years, humans, English, and
child: birth to 18 years of age. Search results were reviewed by all
three authors and articles selected for their relevance to the clinical
practice of child and adolescent psychiatry. Additional articles
were added and reviewed at the discretion of the authors. The
agents that will be considered are clozapine, risperidone, olanza-
pine, quetiapine, aripiprazole, ziprasidone, paliperidone, asena-
pine, iloperidone, lurasidone, and cariprazine.
Table 1. FDA-Approved Pediatric Age Ranges and Indications for Atypical Antipsychotics, Modified Chart
from Centers for Medicare & Medicaid Services Medicaid Program Integrity Education
5 6 7 8 9 10
Clozapine
Risperidone
Olanzapine
Quetiapine
Aripiprazole
Ziprasidone
Paliperidone
Asenapine
Iloperidone
Lurasidone
Cariprazine
Schizophrenia Bipolar type I disorder: manic or mixed
Tourette’s disorder Bipolar I disorder: depressive episodes
583
Results
Clozapine
Clozapine is the gold standard for efficacy in treatment-resistant
schizophrenia, oftentimes effective when other agents have failed,
and potentially helpful in treating aggression and suicide risk in
schizophrenia. It is a second-generation antipsychotic with binding
affinity to serotonin 5HT2A and dopamine D2 receptors. Clozapine
also binds to many other receptors (Meltzer 1994). It is not cur-
rently FDA approved for treatment in children and adolescents and
we have not been able to identify any randomized or blinded studies
regarding clozapine’s use that have been published within the past 5
years. However, prior work has demonstrated that clozapine has a
role in the treatment of children and adolescents with refractory
early-onset schizophrenia. Clozapine is superior to haloperidol for
both negative and positive symptoms of schizophrenia (Kumra
et al. 1996) and it has also been shown to be more efficacious than
olanzapine in treatment-refractory patients (Shaw et al. 2006;
Kumra et al. 2008).
Clozapine presents a side effect profile with apparently more
adverse effects than other drugs. Some of the side effects include
nocturnal enuresis, tachycardia, hypertension, and weight gain
(Shaw et al. 2006), as well as hypertriglyceridemia and a higher
incidence of ‘‘pre-diabetes’’ (Kumra et al. 2008). Clozapine also
has an increased risk for agranulocytosis, seizures, and sedation. It
can cause excessive salivation and increase the risk for myocarditis
(Gogtay and Rapoport 2008; Stahl 2013). Due to its risk for adverse
events and the need for hematological monitoring, given its risk of
agranulocytosis, clozapine’s use is restricted to patients with
treatment-resistant conditions.
Risperidone
Risperidone is a second-generation antipsychotic with high an-
tagonistic affinity for 5-HT2A receptors and a moderately high
affinity for D2, a-1, a-2, and H1 receptors. It was approved by the
Age Range (Years)
11 12 13 14 15 16 17
Irritability with autistic disorder
 584
FDA for the treatment of schizophrenia in adults in 1993, and is
currently FDA approved for schizophrenia in adolescents 13–17
years of age, bipolar mania in children and adolescents 10–17 years
of age, and irritability associated with autistic disorder in children
older than 5 years of age. Although initially synthesized in an
attempt to replicate clozapine’s effectiveness and lower risk profile
for EPS due to its high 5-HT2A/D2 ratio, risperidone can cause EPS
at higher doses. Nonetheless, its risk for EPS at low and moderate
doses appears to be lower than the risk with first-generation anti-
psychotic drugs (Tasman et al. 2008).
Risperidone is metabolized by the enzyme cytochrome P450
2D6 (CYP2D6), which catalyzes hydroxylation of risperidone into
its metabolite, 9-hydroxyrisperidone. Risperidone and 9-
hydroxyrisperidone have similar pharmacological activity. The
oral formulations of risperidone, which are the ones used in the
studies reviewed here, are rapidly absorbed after oral administra-
tion, achieve peak plasma levels within 1 hour, and have linear
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pharmacokinetics. There is no food effect for risperidone, which
can be administered with or without meals. See Table 2 for selected
recent risperidone intervention trials in pediatric populations.
Disruptive behavior disorders. Risperidone had demon-
strated efficacy in the treatment of disruptive behaviors in children
of low intellect both in the short term (Aman et al. 2002) and long
term (Turgay et al. 2002; Findling et al. 2004; Croonenberghs et al.
2005), as well as in children of normal intellect (Reyes et al. 2006).
More recently, the use of risperidone to reduce aggression in dis-
ruptive behaviors has been explored in the Treatment of Severe
Childhood Aggression Study (TOSCA), in which the children
carried a diagnosis of a DBD (Aman et al. 2014). This study con-
sisted of a 3-week open-label trial of methylphenidate combined
with a behavioral intervention that enrolled children 6–12 years of
age with severe aggression, including physical harm. For those who
did not respond to these two treatments in combination, participants
were then eligible to enter a 6-week double-blind placebo-
controlled study in which patients were randomized to receive
adjunctive treatment with either risperidone or placebo. The mean
final dose of risperidone was 1.7 – 0.75 mg/day.
When compared to the placebo group, risperidone provided
moderate, but variable improvement in aggression and other dis-
ruptive behaviors when added to the basic treatment with parent
training and stimulant medication, as measured by the Nisonger
Child Behavior Rating Form (NCBRF) Disruptive–Total subscale,
the NCBRF Social Competence subscale, and Antisocial Behavior
Scale Reactive Aggression subscale. Adverse events included
prolactin level elevations and gastrointestinal upset, which oc-
curred more frequently in the group augmented with risperidone.
Weight gain in this group was relatively modest.
Following the initial study, Findling et al. (2017a) conducted a
study looking at clinical responders of the 9-week TOSCA trial, who
had presented with improvement in the Clinical Global Impressions-
Improvement (CGI-I) scale plus substantial reduction in parent
ratings of disruptiveness. This study observed the patients for an-
other 12 weeks (21 weeks in total), while they remained on blinded
treatment. The main purpose was to check the durability of the acute
phase positive responses at week 21 and the accumulation of side
effects. The findings indicated that those children who responded at
week 9 continued to respond over the following 12 weeks regardless
of what treatment arm they were originally assigned. The 103 ex-
tension participants showed no significant between-treatment group
outcome differences. This may have been because participants in the
extension were selected for good response.
LEE ET AL.
Finally, Gadow et al. (2016) conducted a prospective follow-up
study of the TOSCA trial 12 months after the initial baseline
evaluation. This study compared placebo group and the group
augmented with risperidone. Both randomized groups improved
from baseline to follow-up, but the parent-reported behavioral
outcomes showed no significant differences between groups.
Nonetheless, exploratory findings for secondary outcomes sug-
gested that there was a greater benefit from augmentation with
risperidone. Prolactin levels were significantly higher in the group
treated with risperidone.
Secondary analyses of the TOSCA study have indicated that
risperidone might be useful in reducing context-specific severity of
attention-deficit/hyperactivity disorder (ADHD) and oppositional
defiant disorder (ODD) symptoms, peer aggression, and symptom-
induced impairment (Gadow et al. 2014). In addition, greater
baseline severity has been associated with better treatment re-
sponse, either with stimulant and parent training or in their com-
bination with risperidone in a subsequent study on predictors and
moderators (Farmer et al. 2015).
Arnold et al. (2015) examined the effect of augmented treatment
on the severity of anxiety, mood, autism spectrum disorder (ASD),
and schizophrenia spectrum disorder (SSD) symptoms, and found
that the addition of risperidone improved symptoms and func-
tioning in these areas. The SSD symptoms did not include hallu-
cinations or delusions, but social withdrawal and disorganized
impulsiveness. Therefore, the improved symptoms were consid-
ered to fall into the group of anxiety-social avoidance rather than
the psychotic symptom spectrum. Anxiety also mediated im-
provement in DBD, suggesting an anxiety-driven fight or flight
response in DBD with aggression.
A study conducted by Jahangard et al. (2017), using a similar
design to the TOSCA trial, studied subjects with ADHD and ODD
diagnoses who failed to have adequate clinical improvement after a
standard treatment with methylphenidate (15–20 mg/day) and fam-
ily therapy. The study was an 8-week double-blind, placebo-
controlled randomized trial in which risperidone at doses of 0.5 mg/
day was used as an adjuvant treatment to methylphenidate in chil-
dren 7–10 years of age. Symptoms of ADHD rated by both parents
and experts decreased over time, but more so in the group augmented
with risperidone. However, the effect sizes for symptom improve-
ment with risperidone were small to medium. Adverse effects in-
cluded weight gain and higher prolactin levels. Overall, side effects
increased over time in the group augmented with risperidone.
Autism spectrum disorder. The efficacy of risperidone for
the treatment of ASD symptoms such as irritability and aggression
has been demonstrated in the past (McCracken et al. 2002; Shea et al.
2004; Sharma and Shaw 2012). More recently, Kent et al. (2013)
examined the efficacy and safety of two different risperidone doses
in children and adolescents 5–17 years of age, with a diagnosis of
ASD. This 6-week double-blind, placebo-controlled multicenter
study randomized participants to one of two fixed weight-based
doses of risperidone or placebo: risperidone low dose was 0.125 or
0.175 mg/day depending on the subject’s weight (< or ‡45 kg) and
high dose was 1.25 mg/day (20 to <45 kg) or 1.75 mg/day (‡45 kg).
Irritability scores as measured by the Aberrant Behavior
Checklist-Irritability (ABC-I) as well as global functioning, ob-
sessive compulsive symptoms, and hyperactivity improved in the
high-dose risperidone group and separation from placebo was ob-
served from day 8. The low-dose group showed improvements in
stereotypic behavior when compared to placebo. A higher per-
centage of patients in the placebo group were treated with
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Table 2. Selected Recent Primary Risperidone Intervention Trials in Pediatric Populations

Study design, Age Primary efficacy Noteworthy adverse
Publication Study target duration N (years) Dose measures Response rate Effect sizea Findings/comments events (%)b

Aman et al. ADHD with average Open label (3 weeks) 168 6–12 1.7 – 0.75 mg/day NCBRF D-total 42% (defined as a 0.43 ( p = 0.143) Risperidone provided Prolactin elevations
(2014) IQ and ODD or followed by decline in moderate, but (65) and
(TOSCA) CD, significant RDBPCT NCBRF-D scores variable gastrointestinal
physical or (6 weeks) by week 9) improvement in upset (16.4% in
property aggression and augmented vs.
aggression other disruptive 5.0% in basic);
behaviors when moderate weight
added to parent gain (mean of 0.38
training and BMI)
stimulants.
Findling ADHD with average Extended blinded 103 6–12 1.56 – 0.73 mg/day NCBRF D-Total 87% in augmented 0.8780 Minimal worsening of Delayed sleep onset in
et al. IQ and ODD treatment initially, vs. 80% in basic behavior from the both groups (27),
(2017a) or CD, significant (12 weeks) in 1.55 – 0.72 mg/ ( p = 0.56) end of the 9-week elevated prolactin
physical or property clinical day at conclusion acute trial, but (46% in
aggression, positive responders to improved Augmented vs. 3%
response to the initial acute outcomes at the in Basic)
acute TOSCA TOSCA trial extension endpoint
intervention. (9 weeks) compared with
acute study
baseline.

585
Gadow ADHD and Prospective, multisite 168 6–12 Variable NCBRF D-total Augmented obtained 0.34 ( p = 0.08) Both randomized Elevated prolactin
et al. co-occurring follow-up TOSCA a lower score on groups improved levels in both
(2016) ODD or CD, trial (12 months NCBRF D-total from baseline to groups,
serious physical after baseline follow-up, but significantly higher
aggression. evaluation), parent-reported in the risperidone
9 weeks behavioral augmentation
outcomes showed group (36% vs.
no significant 15% in basic;
between-group p = 0.03)
differences.
Secondary
outcomes
suggested greater
benefit from
augmentation
Jahangard ADHD and ODD RDBPCT, 8 weeks 84 7–10 MPH 1 mg/kg/day Conners’ Parent Decrease in ADHD/ 0.45–0.67 ADHD/ Symptoms of ADHD Weight gain of
et al. who failed standard plus RISP Rating Scale ODD symptoms ODD symptoms decreased over ‡5.7%, higher
(2017) treatment with 0.5 mg/day Revised-Long 0.30–0.67 symptom time, MPH + RISP prolactin levels
methylphenidate Version; CGI severity. > MPH only. Small
(15–20 mg/day) 0.6–0.9 in symptom to medium effect
and family therapy. improvement in sizes for symptom
the CGI. improvement.
(continued)
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Table 2. (Continued)

Study design, Age Primary efficacy Noteworthy adverse

Publication Study target duration N (years) Dose measures Response rate Effect sizea Findings/comments events (%)b

Kowatch BP-I disorder, mixed RDBPCT, 6 weeks 46 3–7 RISP mean dose of YMRS total 88% for RISP and 3.58 for RISP, YMRS total scores RISP: Increased
et al. or manic episode 0.5 mg/day at scores 50% for VPA 1.66 for VPA, were improved in prolactin levels,
(2015) endpoint, VPA (defined as ‡50% 0.56 for placebo. RISP-treated liver functions,
mean dose of YMRS total score subjects with metabolic
300 mg/day from baseline significant measures, and
improvement) differences BMI.
between RISP- and VPA: Increased
VPA-treated BMI, decrease in
subjects. albumin, RBC, Hb,
and Htc. Increase in
mood lability (28).
Kent Autistic disorder RDBPCT, 6 weeks 96 5–17 Low dose: 0.125 or ABC-I 83% ( p = 0.004) in the 0.36 with low dose Irritability scores, Adverse effects were
et al. 0.175 mg/day. high-dose group; ( p = 0.164), 0.94 CGI-S and C- higher in RISP
(2013) High dose: 1.25 52% ( p = 0.817) with high dose YBOCS improved high-dose group
or 1.75 mg/day in the low-dose ( p < 0.001) in the in the high-dose (87) vs. the low-
(depending on group. ABC. 0.08 with RISP, but not the dose (60) and
weight) 41% in the placebo low dose (0.769) low-dose RISP. placebo (80).
group (defined as and 1.02 (<0.001) High-dose group RISP (combined
‡25% with high dose. also showed high- and low-dose
improvement in improvement on groups): increased
ABC-I subscale hyperactivity. Low- appetite (26),
score) dose group showed sedation (15),
improvement in somnolence (11),

586
stereotypic weight increase,
behavior. and akathisia,
prolactin and
insulin level
increases were most
frequent in the
high-dose group.
McGorry Clinical phenotype RDBPCT (3 115 14–30 Starting dose of Transition to 10.7% CBT + RISP No statistically Fatigue, depression,
et al. of at ultra-high alternatives: 0.5 mg/day, full-threshold 9.6% CBT + significant concentration
(2013) risk for psychosis low-dose RISP + increased up to psychosis, as placebo differences in difficulties, and
CBT, CBT + 2 mg/day frank symptoms 21.8% ST + transition to full- orthostatic
placebo, and daily for at placebo ( p = 0.60) threshold psychosis dizziness.
supportive least a week between the three
therapy + placebo), or more, using groups. All groups
12 months CAARMS improved,
particularly in terms
of negative
symptoms and
overall functioning.
a
Effect sizes are reported as Cohen’s d.
b
Percentages reflect adverse events observed in active medication/treatment groups.
ABC-I, Aberrant Behavior Checklist-Irritability; ADHD, attention-deficit/hyperactivity disorder; BMI, body mass index; CAARMS, Comprehensive Assessment of At-Risk Mental States; CBT, cognitive behavioral
therapy; CD, conduct disorder; CGI, Clinical Global Impressions; CGI-S, Clinical Global Impressions-Severity; C-YBOCS, Children’s Yale-Brown Obsessive Compulsive Scale; Hb, hemoglobin; Htc, hematocrit; MPH,
methylphenidate; NCBRF D, Nisonger Child Behavior Rating Form Disruptive Behavior; ODD, oppositional defiant disorder; RBC, red blood cells; RDBPCT, randomized double-blind placebo-controlled trial; RISP,
risperidone; ST, supportive therapy; TOSCA, Treatment of Severe Child Aggression; VPA, valproic acid; YMRS, Young Mania Rating Scale.
 UPDATES ON THE USE OF ANTIPSYCHOTICS IN CHILDREN AND ADOLESCENTS
antihistaminic drugs. Adverse effects included somnolence, seda-
tion, increased appetite, and increased weight, and were more
frequent in the high-dose versus the low-dose or placebo groups.
Extrapyramidal symptoms (akathisia) and changes in mean pro-
lactin and insulin levels were greater in the high-dose group.
Other updates include an uncontrolled follow-up reassessment
21.4 months (1.8 years) after initial entry into the 8-week placebo-
controlled randomized trial conducted by the Research Units
on Pediatric Psychopharmacology (RUPP) Autism Network
(McCracken et al. 2002) to assess the safety and tolerability of
risperidone in children and adolescents 5–17 years of age with
autism and severe irritability (Aman et al. 2015). The mean ris-
peridone dose used was 2.47 mg/day (SD = 1.29 mg). The study
found that the risperidone group presented with improvement in
social skills and other maladaptive behaviors such as aggression,
self-injury, hyperactivity, and agitation, as well as a decrease in
irritability and sensory problems. Noteworthy adverse effects in-
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cluded enuresis, increased appetite, and weight gain.
Another study, based on data collected through the RUPP mul-
tisite study, explored the role of baseline symptom severity in the
efficacy of risperidone (Levine et al. 2016). Symptom reduction
increased with moderate through severe baseline severity. Those
with moderate to severe baseline ASD symptoms demonstrated
decreased irritability and lethargy on the ABC parent ratings with
risperidone. There were no changes in clinician ratings of irrita-
bility or CGI, nor were there any changes on parent ratings of
stereotypic behaviors, hyperactivity, or inappropriate speech.
Bipolar disorder. In the area of mood disorders, previous
research showed risperidone monotherapy to be effective in the
acute treatment of mania in children and adolescents with bipolar
disorder (Haas et al. 2009a). More recently, Kowatch et al. (2015)
conducted a study with younger children 3–7 years of age with a
diagnosis of bipolar I (BP-I) disorder during a mixed or manic
episode, psychotic or nonpsychotic, and a score of ‡20 on the
Young Mania Rating Scale (YMRS) at the time of randomization.
The study had three arms comparing risperidone, valproic acid
(VPA), and placebo. The mean dose of risperidone at endpoint was
0.5 mg/day (range of 0.5–0.75 mg/day) and the mean dose of VPA
was 300 mg/day. YMRS total scores improved in risperidone-
treated subjects versus placebo, but not in VPA versus placebo-
treated subjects. Adverse effects for those treated with risperidone
included increased prolactin levels and elevated unconjugated
bilirubin, GGT, and body mass index (BMI). There were also de-
creases in albumin and total protein, and elevations in cholesterol
and insulin. In the group treated with VPA, there was an increase in
cholesterol and weight/BMI, a decrease in albumin, total RBC,
hemoglobin, and hematocrit, and an increase in mood lability.
Schizophrenia/psychosis. Risperidone is efficacious in the
treatment of symptoms of schizophrenia in adolescents (Haas et al.
2009b, 2009c). More recently, to study its potential role as a pre-
ventive intervention for psychosis, McGorry et al. (2013) studied
subjects with a clinical phenotype at ultra-high risk for psychosis,
between 14 and 30 years of age. This 12-month double-blind, placebo-
controlled randomized trial presented three alternatives: low-dose
risperidone and cognitive behavioral therapy (CBT), CBT and pla-
cebo, and supportive therapy and placebo. Risperidone was started at
0.5 mg/day and increased over 4 weeks up to 2 mg/day, if tolerated.
There were no statistically significant differences between the three
groups in the rates of transition to full-threshold psychosis over 12
months. All groups improved, particularly in terms of negative
587
symptoms and overall functioning. These results failed to provide
support for the first-line use of antipsychotic medications in patients at
ultra-high risk of psychosis, suggesting that an initial approach with
supportive therapy is likely to be effective with fewer risks.
Olanzapine
Olanzapine is currently FDA approved in children and adoles-
cents for use in the treatment of schizophrenia (Kryzhanovskaya
2009), manic or mixed episodes as both monotherapy and in
combination with lithium or valproate (Tohen et al. 2007), and
bipolar depression (Detke et al. 2015). However, due to its risk for
weight gain, (Olanzapine Package Insert 2009) it is recommended
that prescribers carefully consider olanzapine’s risks, while also
considering other medications for the treatment of their teenage
patients. The pharmacokinetic profile of olanzapine has been found
to be similar to that described in adults, with no adjustments needed
in dosing (Lobo et al. 2010). A study by Theisen et al. (2006) found
that, consistent with other studies, olanzapine concentrations were
lower in smokers than in nonsmokers, suggesting a higher rate of
clearance. See Table 3 for selected recent primary olanzapine in-
tervention trials in pediatric populations.
Bipolar depression. A study by Detke et al. (2015) investi-
gated the effect of olanzapine/fluoxetine combination (OFC)
treatment for BP-I depression and found that, after 8 weeks of
randomization to either OFC (flexible dosing, target dose 12/50 mg)
or placebo, OFC was statistically superior to placebo, with more
patients achieving response (78.2% vs. 59.2%) at a faster rate
(median of *3 weeks vs. *5 weeks), as well as remission (59.0%
vs. 43.4%). The OFC group also demonstrated greater improve-
ment on all secondary measures of depressive symptomatology and
overall illness severity. The authors concluded that for this study,
OFC was superior to placebo in the acute treatment of BP-I de-
pressive episodes. However, it should be noted that the weight gain
seen with OFC was 4.4 kg, whereas the weight gain observed with
placebo was 0.5 kg during the course of study participation.
Posthoc analyses. Of the three posthoc analyses that are
included herein, two studies looked into whether early treatment
response was predictive of treatment outcome in youth being
treated with olanzapine.
The first study by Stentebjerg-Olesen et al. (2015) found that
early response (ER) at week 3 had slightly better predictive power
than ER at week 2 for both ultimate response (UR) and remission in
adolescents with schizophrenia, although both were significant, and
a threshold for ER of ‡20% reduction on the Brief Psychiatric
Rating Scale for children (BPRS-C) had the best predictive validity
for UR. It was also noted that most patients who were ultimate
nonresponders failed to demonstrate a response at week 2 or 3.
The second analysis by Xiao et al. (2017) found that significantly
more patients with BP-I disorder who achieved ER status by week 1
went on to achieve UR at week 3 and remission at study endpoint.
Receiver operating characteristic (ROC) curves determined that a
cutoff threshold of 35.5% reduction in YMRS total score at week 1
showed the highest accuracy (70.2%) and the greatest area under
the curve (0.75) in predicting UR.
Finally, the third posthoc analysis by Kemp et al. (2013) ex-
amined the associations between obesity, acute weight gain, and
response to treatment with olanzapine in adolescent schizophrenia.
In addition to significantly more olanzapine-treated patients
gaining ‡7% of their body weight at any time (45.8% vs.
 588 LEE ET AL.

and hepatic analysts somewhat

14.7%), the BPRS-C total scores demonstrated significant

higher, and glucose somewhat

improvement for olanzapine-treated patients compared to placebo

tremor (8.8), sedation (6.5);

changes in lipids, prolactin,
(15.9), somnolence (15.9),
Weight gain (20.0), appetite
increase (16.5), headache
and were decreased by a greater percentage in those with significant

adverse events (%)b

weight gain compared to those without in both the olanzapine group

lower than in adults

Noteworthy
(45.6% vs. 31.9%) and the placebo group (34.1% vs. 16.8%). Despite
this significant inverse correlation, the authors found that the rela-
tionship became nonsignificant when the analyses were controlled

BP-I, bipolar I disorder; CDRS-R, Children’s Depression Rating Scale-Revised; RDBPCT, Randomized Double-Blind Placebo-Controlled Trial; YMRS, Young Mania Rating Scale.
for treatment duration, which was itself significantly related to in-
creased weight and improvement in symptoms. It was suggested that
patients who experience improvement with olanzapine may be more
likely to continue treatment and experience weight gain secondarily.
from placebo

Quetiapine
in the acute

depressive
comments
Findings/
Table 3. Selected Recent Primary Olanzapine Intervention Trials in Pediatric Populations

treatment

episodes Quetiapine is FDA approved for use in children/adolescents with

Separation

of BP-I

schizophrenia (Findling et al. 2012a) and acute mania (Pathak et al.

2013) as both monotherapy and adjunct to lithium or divalproex.
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The binding profile for quetiapine differs slightly from other

atypical antipsychotics, in that, it has weaker antagonistic effects at
Effect
sizea

0.46

dopamine D2 and serotonin 5-HT2 receptors, stronger antagonistic

effects at a-1 receptors, and modest histaminergic effects (Nas-
rallah 2008). The pharmacokinetic profile has been described as
score and a YMRS
as ‡50% reduction
in CDRS-R total

item 1 score £2)

being similar to that of adults (McConville et al. 2000) with no

placebo (defined
78.2% vs. 59.2%

dosage adjustments required for pediatric patients (Winter et al.

Response

2008). See Table 4 for selected recent primary quetiapine inter-

rate

vention trials in pediatric populations.

Bipolar mania. As a treatment for children and adolescents

with BP-I mania, Pathak et al. (2013) found in their 3-week trial
in CDRS-R

that quetiapine (dosed at 400 or 600 mg/day) demonstrated sig-

Mean change

total score
measure
Primary

nificantly greater improvement over placebo in manic symptoms

efficacy

and equal efficacy in patients subcategorized by age (10–12 years

vs. 13–17 years), gender, ADHD status, and psychostimulant use.
Mean change in body weight was greater in the quetiapine groups
than with placebo, but there were few incidences of potentially
combination, flexible

clinically significant shifts in laboratory, hematologic, and vital

Olanzapine/fluoxetine

dose was 12/50 mg

between 6/25 and
12/50 mg. Dosing

sign measures. It was concluded that both quetiapine doses were

Percentages reflect adverse events observed in active medication/treatment groups.
was initiated at
dosing allowed

3/25 mg, target

significantly more effective for acute manic symptoms in youth

Dose

with BP-I disorder, and that the safety profile in children was
consistent with that of adults with bipolar disorder.

Bipolar mania/schizophrenia. Many of the individuals from

the previous study went on to participate in a continuation study by
Findling et al. (2013d) looking into the safety, tolerability, and
(years)

10–17
Age

efficacy of quetiapine in youth with both schizophrenia and BP-I

disorder. The 26-week treatment course was completed by 237
(62.2%) of the enrolled patients (71.0% schizophrenia and 54.6%
255
N

bipolar disorder) with the mean dose of quetiapine and duration of

time being 632 mg and 156 days in the schizophrenia subgroup, and
8 weeks
RDBPCT,
duration
design,

571 mg and 137 days in the bipolar disorder subgroup. The most
Effect sizes are reported as Cohen’s d.
Study

common adverse events, similar to the adult profile of bipolar

disorder patients, included somnolence, headache, sedation, and
vomiting. Weight increase (mean change in BMI of 0.9 kg/m2) and
depression

increased appetite were also seen in this pediatric population, and it

target
Study

was observed that a number of adverse events were more frequently

seen in patients from the prior-placebo rather than the prior-
BP-I

quetiapine group in the previous trials, possibly indicating im-

proved tolerability over time.
Publication

While patients treated with quetiapine during the acute studies

(2015)

continued to demonstrate significant improvement in symptoms

et al.
Detke

and functioning, improvement was generally greater in prior-placebo

b
a

patients. It was concluded that quetiapine at the aforementioned

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Table 4. Selected Recent Primary Quetiapine Intervention Trials in Pediatric Populations

Study design, Primary efficacy Noteworthy adverse
Publication Study target duration N Age (years) Dose measure Response rate Effect sizea Findings/comments events (%)b

Pathak et al. BP-I, mania RDBPCT, 284 10–17 400 and 600 mg/day. Mean change in 55% for 400 mg/day 0.539 for Separation from placebo at Somnolence (28.4/
(2013) 3 weeks Dosage was YMRS total score dose, 56% for 400 mg/day both quetiapine doses, 31.6), sedation
initiated at 50 600 mg/day dose, dose, 0.867 safety profile in children (23.2/25.5),
mg/day and 28% for for 600 consistent with that in dizziness (18.9/
placebo (defined as mg/day adults with bipolar 17.3), headache
‡50% reduction in dose disorder. (15.8/13.3), mean
YMRS score) change in weight
Percentages given
for quetiapine 400
and 600 mg/day
doses
Findling et al. Schizophrenia Open-label 381 13–17 years 400–800 mg/day, Safety and Schizophrenia: 17.4% Treatment is safe and Somnolence (24.0/
(2013d) and BP-I continuation (schizophrenia), flexible dosing. tolerability, (defined as ‡30% generally well tolerated 22.0), headache
study, 26 10–17 years Dosage was PANSS and CGI-I PANSS score in these pediatric (12.6/23.9),
weeks (BP-I) initiated at 50 mg/ and CGI-S of reduction from populations. Weight gain, sedation (6.9/20.5),
day, mean daily Illness scale open-label lipid profiles, and blood weight increase
doses of 632 mg (schizophrenia), baseline). Bipolar: pressure should be (9.1/17.1),
(schizophrenia) YMRS and CGI- 30.9% (defined as regularly monitored. vomiting (10.3/
and 571 mg (BP-I) BP Improvement ‡50% reduction in 11.2), dizziness

589
and Severity of YMRS score) (6.9/10.2), fatigue
Illness scale (BP-I) (4.0/11.7), nausea
(6.3/12.2),
increased
triglyceride levels
(8.4/11.9)
Percentages given
for schizophrenia
and bipolar
disorder subgroups
Findling et al. Bipolar RDBPCT, 193 10–17 150–300 mg/day of Mean change in 63.0% vs. 55.0% with No separation from placebo Headache (21.7),
(2014b) (I or II) 8 weeks quetiapine XR, CDRS-R total placebo (defined as in treatment of depression sedation (7.6),
depression flexible dosing. score ‡50% reduction in associated with bipolar I or dizziness (6.5),
Dosage was adjusted CDRS-R II disorder. Fasting blood somnolence (6.5),
initiated at 50 total score) lipid levels, glucose, and diarrhea (5.4),
mg/day with a BP should be monitored fatigue (5.4),
mean modal dose appropriately nausea (5.4), and
of 204.9 mg/day weight increase
(12.5)
a
Effect sizes are reported as Cohen’s d.
b
Percentages reflect adverse events observed in active medication/treatment groups.
BP, blood pressure; CDRS-R, Children’s Depression Rating Scale-Revised; CGI-BP, Clinical Global Impressions-Bipolar; CGI-I, Clinical Global Impressions-Improvement; PANSS, Positive and Negative Syndrome
Scale; RDBPCT, Randomized Double-Blind Placebo-Controlled Trial; YMRS, Young Mania Rating Scale.
 590
dosage and duration is safe and generally well tolerated in these
pediatric populations.
Bipolar depression. Findling et al. (2014b) also studied the
efficacy and safety of extended-release quetiapine fumarate for
bipolar depression in children 10–17 years of age. When flexibly
dosed between 150 and 300 mg/day, improvement was seen in both
quetiapine XR and placebo groups, with subgroup analyses
showing consistency for patients with or without rapid cycling,
with BP-I or BP-II disorder, and in children 10–12 or 13–17 years
of age. Rates of response and remission from baseline were 63.0%
and 45.7% for quetiapine XR and 55.0% and 34.0% for placebo. It
was concluded that quetiapine XR did not demonstrate efficacy
relative to placebo in this study, but that the medication in this dose
range was generally safe and well tolerated.
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Aripiprazole
Aripiprazole is currently FDA approved in children and/or ad-
olescents as a treatment for schizophrenia (Findling et al. 2008a),
acute treatment of manic and mixed episodes associated with BP-I
disorder (Findling et al. 2009), irritability associated with autistic
disorder (Marcus 2009; Owen et al. 2009), and TD. It has a strong
affinity for the dopamine D2 and D3 receptors and moderate af-
finity for D4 receptors, with partial agonism occurring with the D2
receptors (Whitney et al. 2015). At similar doses, the maximum
plasma concentrations at steady state were found to be higher in the
pediatric population compared to adults and also required less time
to achieve (Mallikaarjun et al. 2004). The safety profile has been
found to be similar to that of adults (Findling et al. 2008b). See
Table 5 for selected recent primary aripiprazole intervention trials
in pediatric populations.
Tourette’s disorder. There were two studies investigating
aripiprazole as a treatment for TD. The first by Yoo et al. (2013),
studying the effect of aripiprazole dosed up to 20 mg/day in chil-
dren 6–18 years of age, demonstrated a significant reduction in tics
compared to placebo. Mean decreases in the phonic tic score and
the Tourette’s Syndrome CGI-Severity (CGI-S) of Illness score
were larger in the active medication group compared to placebo,
with no difference being found on the motor tic score between both
groups. The active treatment group had an endpoint response rate of
65.6% versus 44.8% with placebo. The data suggest that fairly rapid
symptom improvement might be achieved at relatively low doses,
as nearly 80% of the total efficacy response was achieved within 6
weeks at doses of 10 mg/day or less.
The second study by Sallee et al. (2017) investigated the effects
of both low-dose (<50 kg at baseline, 5 mg/day; ‡50 kg at baseline,
10 mg/day) and high-dose (<50 kg at baseline, 10 mg/day; ‡50 kg at
baseline, 20 mg/day) aripiprazole in children 7–17 years of age and
demonstrated statistically significant improvement in tics for both
low-dose and high-dose aripiprazole groups (45.9% and 54.2%
decrease from baseline scores, respectively) compared to placebo.
The magnitude of improvement for most efficacy endpoints was
generally greater with high-dose versus low-dose aripiprazole. The
medication was frequently well tolerated and the study concluded
that aripiprazole might provide an effective and safe treatment
option for those with tolerability concerns.
Autism spectrum disorder. Findling et al. (2014a) sought to
expand on previous medication trials of aripiprazole as a treatment
for irritability associated with autistic disorder by studying its
LEE ET AL.
safety and efficacy for maintenance purposes in 157 children be-
tween 6 and 17 years of age. After a stabilization phase (13–26
weeks of single-blind aripiprazole treatment, flexibly dosed be-
tween 2 and 15 mg/day), those participants demonstrating a 12-
week period of stable response to medication then entered a ran-
domization phase (up to 16 weeks of double-blind treatment with
continued aripiprazole or placebo). The mean time to relapse for
25% of the group occurred at 56 and 29 days for aripiprazole and
placebo respectively, which was not found to be statistically sig-
nificant. Of note, a posthoc analysis found a clinically relevant
number needed to treat six to prevent one additional relapse.
Bipolar disorder. A study that examined the postacute effi-
cacy of aripiprazole in the treatment of pediatric bipolar disorder
examined participants who continued blinded treatment after
completing an acute 4-week, double-blind placebo-controlled
study (Findling et al. 2009, 2012b). The authors found that for
patients between 10 and 17 years of age, treated with 10 or 30 mg/
day for up to 30 weeks, aripiprazole demonstrated statistically
significant greater improvement in manic symptoms when com-
pared to placebo over this period of time. The aripiprazole 10 and
30 mg/day treatment groups had a significantly longer median time
to discontinuation from the point of randomization (15.6 and 9.5
weeks, respectively, vs. 5.3 weeks with placebo), as well as being
significantly superior in terms of response rates (58.7% and 64.8%
vs. 29.7% in placebo) and Children’s Global Assessment Scale
(CGAS) and CGI-bipolar severity of overall and mania scores than
those who received placebo.
A second study (Findling et al. 2017b) investigated the use of
aripiprazole in treating symptomatic youth at familial high risk for
bipolar disorder (parent diagnosis of bipolar disorder and another
first- or second-degree relative with a mood disorder), who had
failed to respond to psychotherapy. These symptomatic, at-risk
patients had been previously described as having ‘‘cyclotaxia.’’
Participants 5–17 years of age were treated with up to 15 mg/day of
aripiprazole (mean total daily dose 7.1 mg/day) and demonstrated
significantly greater improvement in manic symptoms, overall bi-
polar symptom severity, and functioning scores compared to pla-
cebo. The study found that aripiprazole was generally well
tolerated and demonstrated significant efficacy in reducing sub-
syndromal symptoms of bipolar disorder in children and adoles-
cents with cyclotaxia.
Schizophrenia. There was one study addressing aripiprazole
as a maintenance treatment in adolescent schizophrenia by Correll
et al. (2017). After being stabilized on 10–30 mg/day of ar-
ipiprazole, participants between 13 and 17 years of age were ran-
domized to receive medication or placebo for up to 52 weeks.
Aripiprazole treatment was associated with a significantly longer
time to (hazard ratio = 0.46) and fewer participants (19.4% vs.
37.5% with placebo) meeting criteria for exacerbation of symp-
toms/impending relapse. Time to discontinuation was significantly
longer and tolerability in the active treatment group was consistent
with the known profile of aripiprazole. It was concluded that the
medication was a safe and effective maintenance treatment option
for this population.
Posthoc analyses. One posthoc analysis article studied the
relationship between prior antipsychotic exposure (PAE), weight
change, and adverse events in pediatric patients receiving ar-
ipiprazole for the treatment of irritability in autism (Mankoski et al.
2013). That study found that compared with those having had PAE,
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Table 5. Selected Recent Primary Aripiprazole Intervention Trials in Pediatric Populations

Study design, Age Primary efficacy Effect Noteworthy adverse
Publication Study target duration N (years) Dose measure Response rate sizea Findings/comments events (%)b

Yoo et al. Tourette’s RDBPCT, 10 weeks 61 6–18 Up to 20 mg/day, Mean change on Separation from Nausea (18.8),
(2013) disorder (Korea) flexible dosing. YGTSS-TTS placebo in total headache (15.6),
Dosage was tic score, sedation (12.5),
initiated at improvement in somnolence (12.5),
2 mg/day, phonic tics and nasopharyngitis
mean dose Tourette’s (12.5), increased
of 11.0 mg/day Syndrome CGI-S weight, decreased
of Illness scores, prolactin levels
but not motor tics
Sallee et al. Tourette’s RDBPCT, 8 weeks 133 7–17 Low dose (<50 kg Mean change on 73.8% (low dose) and Separation from Sedation (18.2/8.9),
(2017) disorder at baseline, YGTSS-TTS 88.6% (high dose) placebo for both somnolence (11.4/
5 mg/day; ‡50 kg vs. 54.8% placebo low-dose and high- 15.6), increased
at baseline, (defined as >25% dose groups in appetite (9.1/6.7),
10 mg/day) improvement in treatment of tic and fatigue (6.8/
and high dose YGTSS-TTS or a severity, 15.6); prolactin
(<50 kg at baseline, CGI-TS improvement medication was levels were noted
10 mg/day; ‡50 kg score of 1 or 2) generally well to be lower with
at baseline, tolerated aripiprazole
20 mg/day). treatment
Dosage was Percentages given
initiated at 2 mg/day for low-dose and
high-dose groups
Findling, Irritability RDBPCT with 157 6–17 Phase 1: flexibly Time from No separation from Phase 1: weight

591
et al associated stabilization dosed between randomization placebo for mean increase (25.2),
(2014a) with Autistic phase (13–26 2 and 15 mg/day to relapse time to relapse for somnolence (14.8),
Disorder weeks) followed (initiated at 25% of the group, and vomiting
by randomization 2 mg/day) although (14.2).
phase (up to Phase 2: flexibly statistically Phase 2: upper
16 weeks) dosed between 2 significant lower respiratory tract
and 15 mg/day relapse rate seen in infection (10.3),
(initially continued white patients with constipation (5.1),
at phase 1 dose) med. Posthoc and vomiting (5.1).
analysis Lower prolactin
demonstrated levels observed
clinically relevant with med
NNT of 6.
Findling, BP-I, current RDBPCT with acute 296 10–17 10 and 30 mg/day, Change in 58.7% (10 mg/day) and Separation from Headache (24.0/26.8),
et al. manic or treatment phase dosage initiated YMRS total 64.8% (30 mg/day) placebo at both somnolence
(2013c) mixed episode (4 weeks) and at 2 mg/day score vs. 29.7% placebo doses in (28.0/28.2), and
extension phase (defined as ‡50% improvement of extrapyramidal
(26 weeks) reduction in manic symptoms disorder (13.3/25.4).
YMRS total score) and longer median Medication groups
time to demonstrated higher
discontinuation rates of low
prolactin levels and
increased weight
Percentages given
for 10 and 30 mg
doses overall
(continued)
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Table 5. (Continued)

Study design, Age Primary efficacy Effect Noteworthy adverse

Publication Study target duration N (years) Dose measure Response rate sizea Findings/comments events (%)b

Findling et al. Bipolar Disorder, RDBPCT, 12 weeks 62 5–17 Up to 15 mg/day, Mean change in 1.16 Separation from Headaches (48.4),
(2017b) familial high flexible dosing, YMRS total score placebo in stomachache
risk mean total daily dose treatment of manic (35.5), sedation
7.1 mg. Dosage symptoms in high- (22.6), increased
initiated at risk youth with appetite (22.6),
0.1 mg/kg/day cyclothymic emesis (22.6), and
disorder or BP- coughing (12.9%);
NOS decreased prolactin
levels and
increased weight
Correll et al. Schizophrenia RDBPCT with three 146 13–17 10–30 mg/day, mean Time from Separation from Psychotic disorder
(2017) treatment phases: daily dose was randomization placebo in (9.2), insomnia
cross-titration to 19.2 – 6.7 mg to exacerbation extending time to (5.1), weight

592
med (4–6 weeks), of psychotic and fewer increase (8.2),
stabilization on med symptoms/impending participants headache (6.1), and
(7–21 weeks), and relapse in the double-blind meeting criteria for nasopharyngitis
randomized maintenance phase exacerbation of (7.1)
double-blind psychotic Observed during
maintenance symptoms/ double-blind
treatment phase impending relapse, maintenance phase
(up to 52 weeks) with time to
discontinuation
being significantly
longer
a
Effect sizes are reported as Cohen’s d.
b
Percentages reflect adverse events observed in active medication/treatment groups.
BP-NOS, bipolar disorder not otherwise specified; CGI-S, Clinical Global Impressions-Severity; CGI-TS, Clinical Global Impressions-Tourette Syndrome; NNT, number needed to treat; RDBPCT, Randomized Double-
Blind Placebo-Controlled Trial; YGTSS-TTS, Yale Global Tic Severity Scale–Total Tic Score; YMRS, Young Mania Rating Scale.
 UPDATES ON THE USE OF ANTIPSYCHOTICS IN CHILDREN AND ADOLESCENTS
antipsychotic-naive (AN) patients had greater mean changes in
weight compared to placebo (treatment difference of 1.2 kg with
AN vs. 0.9 kg with PAE). The trend suggested that younger subjects
with higher baseline weight z-scores were at greatest risk of weight
gain and AN patients were at higher risk of a new-onset event
related to somnolence.
Two of the studies addressed how to better assess treatment
response with aripiprazole in the treatment of pediatric BP-I dis-
order. Findling et al. (2013c) found that the effect sizes on the 10-
item parent General Behavior Inventory Mania (GBI-M10) total
score were similar to those of the clinician-rated scales, indicating
the possible value of this parent-completed scale in detecting
symptom change in both research and clinical settings. The same
data set was also used by Youngstrom et al. (2013) to compare
multiple outcomes measures using a range of definitions of re-
sponse to evaluate which might be most clinically relevant. The
authors concluded that clinically meaningful definitions included
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‡50% reduction in YMRS total score and a composite measure of
response (YMRS <12.5, Children’s Depression Rating Scale-
Revised (CDRS-R) £40, and CGAS ‡51), with parent-reported
measures being better indicators of symptom change than those
based on subject self-report.
Finally, Correll et al. (2013) investigated whether early response
(ER) or nonresponse (ENR) at week 2 or 3 of treatment with ar-
ipiprazole in adolescents with schizophrenia predicts clinical out-
come. This analysis found that ER/ENR status at week 3 provided
the best overall sensitivity, specificity, and accuracy in predicting a
decrease of at least 30% in Positive and Negative Syndrome Scale
(PANSS) total score by week 6. The authors noted that if a different
dosing/titration schedule was used, this could change the predictive
time point in actual clinical practice.
Ziprasidone
Ziprasidone is a second-generation antipsychotic approved for
adults in the treatment of schizophrenia and BP-I disorder, but with
no current FDA-approved indications for children and adolescents.
Ziprasidone is a serotonin 5-HT2A and dopamine D2 antagonist
with a higher 5-HT2A/D2 receptor affinity in vitro than other
atypical antipsychotic agents. It exhibits potent interactions with 5-
HT2C, 5-HT1D, and 5-HT1A receptors. Ziprasidone has low
affinity for a-1adrenoceptors, histamine H1, and muscarinic M1
receptors (Stahl and Shayegan 2003). Its oral form reaches peak
plasma concentrations at 6–8 hours and its absorption increases
with food up to twofold (Miceli et al. 2007). As such, ziprasidone
should be taken with food. The major CYP contributor to the oxi-
dative metabolism of ziprasidone is CYP3A4. Ziprasidone has a
higher risk and a label warning for QTc prolongation (Orsolini et al.
2016) and Torsade de pointes (Kelly and Love 2001). Prior research
has reported ziprasidone to be effective for the treatment of tics in
adolescents with Tourette’s syndrome (Sallee et al. 2000). See
Table 6 for selected primary ziprasidone intervention trials in pe-
diatric populations.
Schizophrenia. Findling et al. (2013b) evaluated the short- and
long-term efficacy, safety, and tolerability of ziprasidone in adoles-
cents 12–17 years of age with schizophrenia in a 6-week interna-
tional, double-blind, multicenter, randomized placebo-controlled
trial followed by a 26-week open-label extension (OLE). Subjects
were randomized in a 2:1 ratio to flexible-dose oral ziprasidone (40–
160 mg/day, based on weight) or placebo. The starting dose was
20 mg/day and it was increased by 20 mg every 2 days to a target dose
593
of 120–160 mg/day (weight ‡45 kg) or 60–80 mg/day (£45 kg). After
reaching the target dose, ziprasidone could be flexibly dosed at 80–
160 mg/day (40–80 mg/day for subjects £45 kg).
Ziprasidone failed to separate from placebo in the treatment of
schizophrenia in adolescents and both studies were terminated after
the randomized controlled trial (RCT) demonstrated futility. The
failure of the RCT to demonstrate ziprasidone’s efficacy over
placebo may have been due to the higher placebo response ob-
served in some countries, which accounted for 27% of the study
population. The most common treatment-emergent adverse events
(‡10%) during the RCT were somnolence and extrapyramidal
disorders, and somnolence only during the OLE. Overall, ziprasi-
done was often well tolerated with an overall neutral weight and
metabolic profile.
Bipolar manic or mixed. Findling et al. (2013a) assessed the
short- and long-term efficacy and safety of ziprasidone in children
and adolescents 10–17 years of age with a manic or mixed episode
associated with BP-I disorder in a 4-week, double-blind, multi-
center, randomized placebo-controlled trial followed by a 26-week
OLE. Subjects were randomized 2:1 to initially receive flexible-
dose ziprasidone (40–160 mg/day) or placebo. Ziprasidone was
administered with meals and titrated over a 1–2 week period from a
starting dose of 20 mg/day up to a target dose of 120–160 mg/day
(‡45 kg) or 60–80 mg/day (£45 kg) by day 14. Following titration,
further dosing adjustments were made if necessary within the range
of 80–160 mg/day (subjects ‡45 kg), or between 40 and 80 mg/day
(‡45 kg). The estimated least squares mean changes in YMRS total
were -13.83 (ziprasidone) and -8.61 (placebo; p = 0.0005) at RCT
endpoint.
In the OLE, 162 subjects were enrolled and the median duration
of treatment was 98 days. The mean change in YMRS score from
the end of the RCT to the end of the OLE was -3.3. Posthoc
efficacy analyses for the RCT took into consideration the presence
of key mania symptoms (grandiosity or elation/euphoria), parental
history of bipolar disorder, and ADHD comorbidity, and ziprasi-
done was efficacious when compared to placebo in all of these
analyses. The most common adverse events in the ziprasidone
group during the RCT were sedation, somnolence, headache,
fatigue, and nausea. Subjects in the OLE also presented with in-
somnia. One subject on ziprasidone in the RCT had Fridericia-
corrected QT interval (QTcF) ‡460 mseconds. Elevated blood
prolactin occurred more frequently in the ziprasidone group, while
the incidence of all other frequently occurring abnormal laboratory
findings (>10% in any group) was either similar in both groups or
higher in the placebo group.
There were challenges in the conduct of this multisite study,
which included dosing errors at three of the trial sites. It is possible
that as a result of these challenges, ziprasidone was not FDA ap-
proved for the treatment of bipolar mania in pediatric patients,
despite its observed positive effect for manic or mixed states.
Another multisite RCT of a similar study design examining zi-
prasidone’s acute efficacy and tolerability in pediatric BP-I disor-
der is currently ongoing (NCT02075047; clinicaltrials.gov).
Paliperidone
Paliperidone extended release (ER) currently has FDA approval
for the treatment of adolescents 12–17 years of age with schizo-
phrenia (Singh et al. 2011) and comes with weight-based dosing
recommendations, specifically a starting dose of 3 mg/day with
subsequent dosing between 3 and 6 mg/day for adolescents <51 kg
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Table 6. Selected Recent Primary Ziprasidone Intervention Trials in Pediatric Populations

Study Age Primary efficacy Effect Noteworthy adverse
Publication Study target design, duration N (years) Dose measure Response rate sizea Findings/comments events (%)b

Findling Schizophrenia RDBPCT 283 in RDBPCT, 12–17 40 or 80 mg/day BPRS-A total score Ziprasidone failed to Somnolence and
et al. (6 weeks) 221 in OLE depending on weight. separate from extrapyramidal
(2013a) followed by After reaching target placebo in symptoms (‡10%
OLE study dose, ziprasidone treatment of in the treatment
(26 weeks) could be dosed at schizophrenia in group)
40–80 or 80–160 adolescents and
mg/day depending both studies were
on weight terminated for
futility.
Findling BP-I RDBPCT 237 in the RDBPCT, 10–17 Target dose: 60–80 or RDBPCT: YMRS 53% of ziprasidone 0.50 Statistically RDBPCT: sedation
et al. (4 weeks) 162 in the OLE 120–160 mg/day scores from subjects vs. 22% significant (32.9), somnolence
(2013b) followed depending on body baseline, CGI-S reduction of estimated least (24.8), headache
by OLE weight. Following score, CGI-I, subjects in the squares mean (22.1), fatigue
(26 weeks) titration, further CGAS placebo group at changes in YMRS (15.4), nausea
dosing adjustments OLE: YMRS and week 4 (defined as total for (14.1)
between 40–80 and CGI-S scales ‡50% reduction in ziprasidone OLE: sedation
80–160 mg/day YMRS score) (-13.83) vs. (26.5), somnolence

594
depending on body placebo (23.5), headache
weight (-8.61) at (22.2), insomnia
RDBPCT endpoint. (13.6)
The YMRS score Elevated blood
from the end of the prolactin occurred
RDBPCT to the more frequently in
end of the OLE the ziprasidone
was -3.3. Posthoc (12) vs. placebo (3)
efficacy analyses groups.
showed similar
effects in subjects
with key elation/
euphoria or
grandiosity, with
parental BP history
and comorbid
ADHD
a
Effect sizes are reported as Cohen’s d.
b
Percentages reflect adverse events observed in active medication/treatment groups.
ADHD, attention-deficit/hyperactivity disorder; BP-I, bipolar I disorder; BPRS-A, Brief Psychiatric Rating Scale-Anchored; CGAS, Children’s Global Assessment Scale; CGI-I, Clinical Global Impressions-Improvement;
CGI-S, Clinical Global Impressions-Severity; OLE, open label extension; RDBPCT, Randomized Double-Blind Placebo-Controlled Trial; YMRS, Young Mania Rating Scale.
 UPDATES ON THE USE OF ANTIPSYCHOTICS IN CHILDREN AND ADOLESCENTS
and 3–12 mg/day for those ‡51 kg (Younis et al. 2013). Paliperidone
is an active metabolite of its parent compound risperidone (Har-
rington and English 2010) and the ER formulation provides con-
sistent plasma concentrations over 24 hours (Boom et al. 2009),
allowing for once-daily dosing. It is eliminated primarily through
renal excretion (Vermeir et al. 2008). See Table 7 for selected recent
primary paliperidone intervention trials in pediatric populations.
Schizophrenia. Savitz et al. (2015a) directly compared the
efficacy, safety, and tolerability of paliperidone ER in adolescents
with schizophrenia to that of aripiprazole. This randomized double-
blind trial assigned participants to either paliperidone ER (3–9 mg/
day, flexible dosing) or aripiprazole (5–15 mg/day, flexible dosing)
for an 8-week double-blind acute treatment period followed by an
18-week double-blind maintenance phase. The study was com-
pleted by 76% of participants (75% of paliperidone ER group and
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77% of aripiprazole group) and demonstrated no significant dif-
ference in PANSS total scores between the two treatment groups,
with both sets of patients demonstrating clinically meaningful
improvement at endpoint (day 56) and a continued decrease in
scores up to day 182. Adverse events, including weight gain, were
observed more frequently with paliperidone ER (77% vs. 66.7%). It
was concluded that both medications provided clinically mean-
ingful symptomatic and functional improvement in this population.
Savitz et al. (2015b) also investigated the medication’s long-
term safety in adolescents with schizophrenia in a 2-year open-label
study. Patients 12–17 years of age were flexibly dosed between 1.5
and 12 mg/day and, after completion of the study by 220 partici-
pants (184 completed the 2 years, 36 completed a 6-month study
before trial extension), the results showed an improvement in
schizophrenia symptoms (as measured by PANSS total score)
within the first 3 months. Patients were generally able to sustain
improvement until the endpoint with 41.7% achieving remission,
thus supporting the clinical recommendation for long-term anti-
psychotic treatment. The safety profile was consistent with estab-
lished information regarding paliperidone ER in adults and
risperidone in adolescents, although it was additionally noted that
patients ‡51 kg had a higher incidence of adverse events compared
to those <51 kg (88.0% vs. 77.2%). The authors concluded that
paliperidone demonstrated efficacy and general tolerability as a
maintenance treatment option in this population.
Asenapine
Asenapine is a second-generation atypical antipsychotic ad-
ministered sublingually. In the United States, asenapine was ap-
proved in adults as monotherapy in 2009 and as adjunctive therapy
with lithium or valproate in 2010 for manic or mixed episodes
associated with BP-I disorder. Asenapine became FDA approved in
2015 for patients aged 10–17 years with an acute manic or mixed
episode associated with BP-I disorder. The pharmacokinetic profile
of asenapine is similar among adolescents and adults. In the pedi-
atric population, asenapine is rapidly absorbed with maximum
plasma concentrations achieved within 1.5 hours. Asenapine
exposure increases in a dose-proportional manner over the range
of 1–10 mg. Clearance and volume of distribution are linear with
respect to time and dose. Steady state is achieved within 6–8 days of
twice-daily (BID) dosing, consistent with a terminal elimination
half-life of *20 hours (Findling et al. 2015c). The pharmacologic
profile of asenapine is characterized by high affinity and antago-
nism of serotonergic receptors and potent dopamine, adrenergic,
and histamine antagonism with low cholinergic activity (McIntyre
595
and Wong 2012). See Table 8 for selected recent primary asenapine
intervention trials in pediatric populations.
BP-I manic/mixed. Findling et al. (2015c) studied adoles-
cents 10–17 years of age with BP-I disorder currently in manic or
mixed episodes in a 3-week double-blind, randomized placebo-
controlled trial, with patients randomized 1:1:1:1 to placebo, ase-
napine 2.5, 5, or 10 mg BID. The starting dose was 2.5 mg BID,
which was increased every 3 days to the dose target for the
group. All asenapine doses were superior based on change in
YMRS, with significantly higher 50% YMRS responder rates
(42%–54%) compared to placebo (28%) on day 21. Asenapine was
generally well tolerated. There was a higher incidence of somno-
lence, sedation, and hypersomnia in the asenapine treatment groups
versus placebo. There was also a higher incidence of oral hy-
poesthesia with dysgeusia in the treatment groups versus placebo.
Oral hypoesthesia and paresthesia are unique to asenapine and re-
sult from the local anesthetic properties of the sublingual formu-
lation. The asenapine groups also had a higher incidence of weight
gain and fasting insulin, cholesterol, triglycerides, low-density li-
poprotein, and glucose changes than the placebo group.
Findling et al. (2016) conducted the first long-term safety and
tolerability study with patients 10–17 years of age with an acute
manic or mixed episode associated with BP-I disorder. Following
the above-mentioned study (Findling et al. 2015c), patients could
enroll in this flexible-dose (2.5–10 mg BID) OLE study for an ad-
ditional 50 weeks. Open-label asenapine was started at 2.5 mg BID
on day 1 and increased to 5 mg BID on day 4. At the day 7 visit, the
asenapine dose was increased to 10 mg BID if tolerated, after which
asenapine dosing was flexible based upon tolerability and/or
symptomatology.
In terms of efficacy, the improvement in mania as measured by
the YMRS total score from baseline was maintained over the course
of the extension trial. In addition, patients who transitioned to
asenapine in the OLE after receiving placebo during the acute
phase achieved the same level of response as the asenapine/ase-
napine group by the end of the extension study. After 26 weeks of
open-label asenapine treatment, the majority of patients achieved
clinically meaningful symptom improvement.
Long-term flexible dose administration of sublingual asenapine
was generally well tolerated. Somnolence, weight gain, sedation,
and headache were the adverse effects most commonly reported.
Among the predefined treatment-emergent adverse events of in-
terest, the combination of somnolence, sedation, and hypersomnia
was most frequent (42.4% of the total treatment group) followed by
oral hypoesthesia/dysgeusia, EPS, and dizziness. Significant weight
gain (‡7% increase) was experienced by 34.8% of the patients. Even
though asenapine was overall well tolerated, 56.4% of patients
discontinued from the total number, 15% due to adverse effects.
Schizophrenia. Findling et al. (2015b) evaluated the safety
and efficacy of asenapine in adolescents 12–17 years of age, who
met DSM-IV-TR criteria for schizophrenia in an 8-week random-
ized placebo-controlled trial that randomized 1:1:1 to placebo,
asenapine 2.5 mg BID, and asenapine 5 mg BID, plus a 26-week
OLE with flexible dosing of asenapine. The starting dose was
2.5 mg BID with an increase to 5 mg BID on day 4 for those in the
5 mg BID group. In the OLE, the participants started on day 1 with
asenapine 2.5 mg BID, and on day 4, the dose was increased to 5 mg
BID. From day 5, dosing was adjusted to 2.5 or 5 mg BID based
upon tolerability and/or symptomatology. The mean average dose
was 8.7 mg/day.
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Table 7. Selected Recent Primary Paliperidone Intervention Trials in Pediatric Populations

Study design, Age Primary efficacy Effect Noteworthy

Publication Study target duration N (years) Dose measure Response rate sizea Findings/comments adverse events (%)b

Younis Schizophrenia RDBPCT, 6 weeks, 201 12–17 Patients weighing Change in PANSS Separation from
et al. three phases, 29–50 kg: total score placebo in
(2013) including 1.5 mg/day improvement of
screening, DB (low), 3 mg/day symptoms for the
treatment phase (med), and 6 mg/ medium-dose
(6 weeks), and day (high). group (3 mg/day
follow-up vs. Patients for those <51 kg,
enrollment in a weighing ‡51 kg: 6 mg/day for
long-term, open- 1.5 mg/day those ‡51 kg)
label safety study (low), 6 mg/day
(med), and
12 mg/day (high)
Savitz Schizophrenia RDBT, 228 12–17 Paliperidone ER: Mean change in 67.9% vs. 76.3% No separation from Akathisia (11.5/7.9),
et al. paliperidone ER 3–9 mg/day PANSS total aripiprazole on aripiprazole in headache (10.6/
(2015a) compared to flexibly dosed, score day 56, 76.8% treatment 4.4), somnolence
aripiprazole, 8- starting dose of vs. 81.6% efficacy– (10.6/10.5),
week DB acute 6 mg/day, aripiprazole on clinically tremor (10.6/9.6),
treatment phase median mode day 182 (defined meaningful weight gain (10.6/
followed by 18- dose 6 mg/day as ‡20% improvement in 6.1), mean
week DB Aripiprazole: 5– reduction in symptoms and increases in serum

596
maintenance 15 mg/day PANSS total functionality prolactin levels
phase flexibly dosed, score) seen with both (for paliperidone
starting dose of meds ER group)
2 mg/day, Percentages given
median mode for paliperidone
dose 15 mg ER and
aripiprazole
Savitz Schizophrenia Open label, 2 years 400 12–17 1.5–12 mg/day, Evaluate long-term 66.7% (defined as Improvement seen Somnolence (18.3),
et al. flexibly dosed. (2-year) safety ‡20% in schizophrenic weight increase
(2015b) Dosage initiated and tolerability improvement in symptoms (-19.1 (18.3), headache
at 6 mg/day, PANSS total on PANSS total (14.8), insomnia
most common score) score) from (14.5),
dose was 6 mg/ baseline to study nasopharyngitis
day endpoint (13.3), akathisia
(13.0),
schizophrenia
(12.5), tremors
(11.0), and
increased
prolactin levels.
Higher incidence
of adverse events
noted in patients
‡51 kg
(continued)
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Table 7. (Continued)

Study design, Age Primary efficacy Effect Noteworthy

Publication Study target duration N (years) Dose measure Response rate sizea Findings/comments adverse events (%)b

Joshi Bipolar Open label, 8 15 6–17 Patients ‡20 kg: Mean change in 73% (defined as Statistically Decreased energy
et al. spectrum weeks 3 mg/day YMRS or CGI-I ‡30% reduction significant (27.0), cold/
(2013) disorders Patients 12 years scores in YMRS score improvement in infection/allergy
of age and older or CGI-I £2) manic symptoms symptoms (27.0),
with weight after 8 weeks of increased appetite
>45 kg: up to treatment (20.0), headache
6 mg/day (20.0), weight
Dosage initiated gain
at 3 mg/day

597
Stigler Irritability Open label, 8 25 12–21 3–12 mg/day, Mean change in 84% (defined as CGI-I: 2.4 Marked Excessive appetite
et al. associated weeks flexibly dosed. CGI-I and ABC- CGI-I score of 1 ABC-I: 2.2 improvement in (36.0), weight
(2012) with autistic Dosage was I scores or 2 and a ‡25% CGI-I (endpoint gain (36.0),
disorder initiated at 3 mg/ improvement on score of tiredness (24.0),
day, mean final ABC-I subscale 1.8 – 1.3) and rhinitis (16.0),
dosage was score) ABC-I subscale increases in mean
7.1 mg/day scores (decrease HDL and
from 30.3 – 6.5 prolactin levels
to 12.6 – 9.1)
a
Effect sizes are reported as Cohen’s d.
b
Percentages reflect adverse events observed in active medication/treatment groups.
ABC-I, Aberrant Behavior Checklist-Irritability; CGI-I, Clinical Global Impressions-Improvement; DB, double blind; HDL, high-density lipoproteins; PANSS, Positive and Negative Syndrome Scale; RDBPCT,
Randomized Double-Blind Placebo-Controlled Trial; YMRS, Young Mania Rating Scale.
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Table 8. Selected Recent Primary Asenapine Intervention Trials in Pediatric Populations

Primary
Study design, Age efficacy Noteworthy adverse
Publication Study target duration N (years) Dose measure Response rate Effect sizea Findings/comments events (%)b

Findling BP-I, manic or RDBPCT, 3 403 10–17 1:1:1:1 randomization YMRS at 50% (range, 42%– All asenapine doses Worsening bipolar
et al. (2015a) mixed weeks to placebo and day 21 54%) in all three were superior to disorder (0–3/4).
episode asenapine 2.5, 5, or doses of asenapine placebo based on Somnolence,
10 mg BID. Dose vs. 28% response change in YMRS sedation,
initiated at 2.5 mg rate in the placebo on day 21 and other hypersomnia
BID on day 1 and group (defined as secondary 2.5 mg (47.1/11.9),
increased every reduction of mania, measures. 5 mg (52.5/11.9),
3 days to target as measured by and 10 mg b.i.d.
dose for group change from (48.55/11.9).
baseline in YMRS Hypoesthesia with
total score on dysgeusia
day 21) (20.2–25.3/4). ‡7%
weight gain
(8.0–12.0/1.1).
Percentages given
for asenapine vs.
placebo groups
Findling Schizophrenia RPCT (8 weeks) 306 in the RCT, 12–17 1:1:1 randomization PANSS 8-week phase: 50% 0.30 for asenapine Nonsignificant mean Somnolence,

598
et al. (2015b) followed by 196 in the to placebo and for asenapine 2 mg 2.5 mg BID and differences sedation, and
OLE with OLE either asenapine BID ( p = 0.028), 0.35 for asenapine between asenapine hypersomnia
flexible dosing 2.5 or 5 mg BID. In 49% for asenapine 5 mg BID and placebo (24–29/9%.
(26 weeks) the OLE, all started 5 mg BID symptoms on day Dizziness (7/1) and
with asenapine at ( p = 0.048) 36% in 56. In the OLE, akathisia (7/1).
2.5 mg BID and the placebo group symptoms ‡7% increased
increased to 5 mg (clinically decreased more in weight gain from
BID, after which significant change the placebo/ baseline (9–13/3).
dosing was defined as -0.5 SD asenapine group Dose–response
adjusted. Mean change in the than with insulin
average dose was PANSS total score asenapine/ concentration
8.7 mg/day in adults, or eight asenapine. increase in
points on the scale) asenapine.
26th week OLE: Higher prolactin
Overall, 48% concentrations
(19–23/13).
Percentages given
for asenapine vs.
placebo groups
a
Effect sizes are reported as Cohen’s d.
b
Percentages reflect adverse events observed in active medication/treatment groups.
BID, bis in die (twice a day); BP-I, bipolar I disorder; OLE, open-label extension; PANSS, Positive and Negative Syndrome Scale; RDBPCT, Randomized Double-Blind Placebo-Controlled Trial; RPCT, Randomized
Placebo-Controlled Trial; SD, standard deviation; YMRS, Young Mania Rating Scale.
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Table 9. Selected Recent Primary Lurasidone Intervention Trials in Pediatric Populations

Primary
Study design, Age efficacy Noteworthy adverse
Publication Study target duration N (years) Dose measure Response rate Effect sizea Findings/comments events (%)b

Findling Pharmacokinetics, Open-label, 105 6–17 Sequentially escalated Lurasidone exposure Somnolence (42.0),
et al. tolerability single and doses (20, 40, 80, similar to that sedation (18.0),
(2015a) multiple 120, and 160 mg/ observed in adults, nausea (17.0), and
ascending- day); all groups, slightly higher vomiting (15.0)
dose trial, except 120 and exposure levels in
10–12 days 160 mg/day were 6–9-year cohort at
started at assigned some doses, linear
dose dose effect on drug
exposure with
20–80 mg/day on
day 1 and also
at steady state for
20–160 mg/day
Loebel Irritability RDBPCT, 6 150 6–17 20 or 60 mg/day. ABC-I 54.2% for 20 mg/day, No separation from Vomiting (8.0/28.0)
et al. in ASD weeks Dosage initiated at subscale 52.9% for 60 mg/ placebo at either and somnolence
(2016) 20 mg/day score day, 57.1% for dose in treating (6.0/18.0);
placebo (defined irritability increased effect
as ‡25% on weight, lipids,
improvement in and prolactin at
ABC-I score) higher dose

599
Percentages given
for 20 and 60 mg/
day doses
Goldman Schizophrenia RDBPCT, 6 326 13–17 40 or 80 mg/day. Change in (defined as ‡20% 0.51 for 40 mg/ Separation from Nausea (12.7/14.4),
et al. weeks Dosage initiated at PANSS reduction in day dose, placebo for both anxiety (10.0/2.9),
(2017) 40 mg total PANSS total 0.48 for doses in somnolence (9.1/
score score–30pts 80 mg/day improvement of 11.5), akathisia
subtracted to dose symptoms (9.1/8.7), vomiting
account for scale (8.2/6.7), and
range) sedation (5.5/1.9)
Percentages given
for 40 and 80 mg/
day doses
DelBello Bipolar-I RDBPCT, 6 347 10–17 20–80 mg/day, Mean 59.5% vs. 36.5% 0.45 Separation from Nausea (16),
et al. depression weeks flexible dosing. change in placebo (defined as placebo in somnolence (11.4)
(2017) Dosage initiated at CDRS-R ‡50% reduction in improving
20 mg/day total CDRS-R total depressive
score score–17 pts symptoms
subtracted to adjust
for scale range)
a
Effect sizes are reported as Cohen’s d.
b
Percentages reflect adverse events observed in active medication/treatment groups.
ABC-I, Aberrant Behavior Checklist-Irritability; ASD, autism spectrum disorder; CDRS-R, Children’s Depression Rating Scale-Revised; PANSS, Positive and Negative Syndrome Scale; RDBPCT, Randomized Double-
Blind Placebo-Controlled Trial.
 600
Mean differences between asenapine and placebo on the PANSS
total score on day 56 were not significant. Significant improvement in
the CGI-S score was observed in the 5 mg BID group vs placebo on
day 56. In the OLE, PANSS total scores decreased by -16.1 points in
the group previously treated with placebo and -11.2 points in the
continuous asenapine group from OLE baseline to week 26. In the
acute phase, weight gain and the composite event of somnolence,
sedation, and hypersomnia were more common in both asenapine
groups than in the placebo group. Akathisia, fasting glucose eleva-
tion, and extrapyramidal syndrome were also more common in the
5 mg BID group than in the placebo group. There were no unexpected
adverse events in the OLE. The mean change from baseline to end-
point of fasting insulin was greater for the 2.5 and 5 mg BID doses of
asenapine compared to placebo, with a dose–response for asenapine.
Iloperidone
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As with other second-generation antipsychotics, iloperidone acts
through a combination of dopamine D2 and serotonin 5-HT2 an-
tagonism (Citrome 2010; Meltzer and Massey 2011). It is approved
for the treatment of schizophrenia in adults, but has no FDA-
approved indications in children. Iloperidone has high binding af-
finity to serotonin 5-HT2A, dopamine D2 and D3 (Kalkman et al.
2003), and norepinephrine NE a-1 receptors (Richelson and Souder
2000). Its elimination is through hepatic metabolism involving
CYP2D6 and CYP3A4 isozymes of the cytochrome P450
group. Iloperidone is associated with QTc interval prolongation
comparable to ziprasidone and haloperidol (Caccia et al. 2010) in
adults with schizophrenia. No published prospective studies were
found in children and adolescents over the past 5 years.
Lurasidone
Lurasidone has FDA approval for adolescents with schizophre-
nia (13–17 years) and very recently received an indication for BP-I
depression (10–17 years). It is characterized by high-affinity
binding to D2 (antagonist), 5-HT2A (antagonist), 5-HT7 (antago-
nist), and 5-HT1A (partial agonist) receptors, but has also dem-
onstrated moderate affinity for noradrenergic a2C and a2A
receptors, and a weak affinity for 5-HT2C receptors (Ishibashi et al.
2010). It is recommended that lurasidone be taken with at least a
350-Kcal meal as Cmax and AUC were found to be substantially
higher (threefold and twofold, respectively) when administered
with food (Preskorn et al. 2013).
When looking at the pharmacokinetic profile of lurasidone in
children (6–17 years of age) dosed between 20 and 160 mg/day,
Findling et al. (2015a) found general similarity to that seen in adults
with the exception of slightly higher exposure levels seen in
younger children at some doses (e.g., 120 mg). A linear dose effect
on drug exposure was observed on day 1 (20–80 mg/day) and at
steady state (20–160 mg/day) on day 10/12, with similar linear
effects seen for all three active metabolites.
The adverse event profile demonstrated a higher frequency of
somnolence in the study sample when compared with adults, but
few adverse events related to movement disorders. Patients at
higher doses (120 and 160 mg/day), especially younger partici-
pants, were found to have a higher likelihood of experiencing an
adverse event, and it was concluded that a dose range of 20–80 mg/
day provided adequate serum concentrations along with more ac-
ceptable tolerability. For that reason, this dose range was subse-
quently used in several key studies of lurasidone in youths. See
table 9 for selected recent primary lurasidone intervention trials in
pediatric populations.
LEE ET AL.
Autism spectrum disorder. Lurasidone’s potential as a
treatment for irritability associated with ASD in children between 6
and 17 years of age was investigated by Loebel et al. (2016) who,
after 6 weeks of treatment with either fixed, once-daily doses of
lurasidone (20 or 60 mg/day) or matching placebo, found no sig-
nificant difference in endpoint irritability as measured by the ABC-
I subscale scores. Although improvement by endpoint on the CGI-I
score was significant for the lurasidone 20 mg/day group, with the
60 mg/day group showing numerical improvement, there were no
significant differences observed on additional secondary efficacy
measures, including other ABC subscales (hyperactivity, stereo-
typic behavior, inappropriate speech, and lethargy/withdrawal), the
Children’s Yale-Brown Obsessive Compulsive Scales (CY-BOCS)
modified for pervasive developmental disorders, and the Caregiver
Strain Questionnaire (CGSQ). It was concluded that the results of
this study did not confirm the efficacy of lurasidone for this patient
population.
Schizophrenia. Goldman et al. (2017) studied the efficacy
and safety of lurasidone after 6 weeks in adolescents with schizo-
phrenia, 13–17 years of age, and found that fixed-dose lurasidone
(40 or 80 mg/day) brought about statistically significant and clini-
cally meaningful improvement in symptoms (-18.6 and -18.3 in
PANSS total score respectively) compared to placebo, with similar
improvement in both the 13–15 and 16–17 year groups. The lur-
asidone groups also demonstrated significant improvement in
clinical severity, functionality, and quality of life. The authors
concluded that lurasidone was a safe and effective option for short-
term treatment in this population.
Bipolar depression. A more recent study by DelBello et al.
(2017) looked into the efficacy and safety of lurasidone in children
and adolescents 10–17 years of age with BP-I depression. When
flexibly dosed from 20 to 80 mg/day with mean daily doses of
31.5 mg/day in the 10–14-year-old group, 33.8 mg/day in the
15–17-year-old group, and 32.5 mg/day in the combined age
groups, the lurasidone-treated patients demonstrated statistically
significant and clinical meaningful improvement in depressive
symptoms (CDRS-R total score mean change of -21.0 vs. -15.3 in
placebo; effect size 0.45) after 6 weeks, in addition to significant
improvement in anxiety, quality of life, and global functioning.
Effect sizes were observed to be larger for the older participant
group (0.68) compared to the younger (0.13), which was accounted
for, in part, by the greater improvement on placebo in the younger
group. It was concluded that lurasidone monotherapy significantly
improved depressive symptoms in this pediatric population and was
generally well tolerated.
Cariprazine
Another second-generation antipsychotic, cariprazine, acts
through a combination of partial agonist activity with high binding
affinity at central dopamine D2 and serotonin 5-HT1A receptors,
and antagonist activity with high to moderate affinity at serotonin
5-HT2A receptors (Kiss et al. 2010; Agai-Csongor et al. 2012). It is
approved for the treatment of schizophrenia and the treatment of
acute manic or mixed episodes associated with BP-I disorder in
adults, but has no FDA-approved indications in children (Federal
Drug Administration 2015). Cariprazine has two major active
metabolites, desmethyl cariprazine and didesmethyl cariprazine,
which are pharmacologically equipotent to cariprazine. It is me-
tabolized by CYP3A4 and to a lesser extent by CYP2D6 (Kirschner
 UPDATES ON THE USE OF ANTIPSYCHOTICS IN CHILDREN AND ADOLESCENTS
et al. 2008). Cariprazine should not be given concomitantly with
CYP3A4 inducers and its dosing should be reduced by half when
co-administered with strong CYP3A4 inhibitors.
Cariprazine’s half-life is 2–6 days, while one of its metabolites
(didesmethyl cariprazine) has a half-life of 14–21 days. Due to its
long half-life, patients need to be monitored for treatment response
and late-occurring adverse reactions for several weeks after starting
and with each dosage change. Cariprazine is generally well toler-
ated when given to adults with schizophrenia and bipolar disorders.
It is associated with adverse effects such as insomnia, EPS, seda-
tion, akathisia, nausea, dizziness, vomiting, and constipation when
given to adults with schizophrenia (Citrome 2013a, 2013b). No
published prospective studies were found in children and adoles-
cents over the past 5 years.
Clinical Significance
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Antipsychotics are commonly prescribed medications for chil-
dren and adolescents. Historically, there has been a paucity of data
on the efficacy and tolerability of these agents in pediatric popu-
lations. However, as shown in this review, a number of methodo-
logically rigorous clinical trials have been completed over the past
5 years, the results of which can meaningfully inform clinical
practice. An ever-increasing body of knowledge is now available
for the clinical practitioner considering the use of an antipsychotic
agent as treatment in a child or adolescent. This review of recent
clinical trials shows that more data are available in regard to both
the acute efficacy and, to a lesser extent, the postacute efficacy and
tolerability for several of the considered antipsychotic medications.
Conditions that have been studied include monotherapy in
schizophrenia, bipolar disorder, and autism, as well as adjunctive
treatment of DBDs with aggression.
The atypical antipsychotic class of medications has more re-
cently been used preferentially over the typicals for a variety of
clinical situations due to their putative reduced propensity to cause
EPS when compared to first-generation ‘‘neuroleptics.’’ Despite
the concerns for weight gain and obesity-related health outcomes,
such as cardiovascular disease and diabetes, the incidence of dys-
kinesias and other EPS tends to be comparatively lower for the
newer agents.
The atypical antipsychotics have been shown to be effective and
generally well tolerated when used to treat psychotic symptoms,
although their utility in treating symptoms of prodromal schizo-
phrenia in at-risk patients is less clear (McGorry et al. 2013). For
the treatment of nonpsychotic disorders, these medications are
frequently used as adjunct treatment in disruptive behaviors, es-
pecially for ADHD with aggression not responding to optimized
doses of stimulants, and for the irritability and behavioral problems
frequently seen with ASD. Specific agents are usually selected for a
given patient population based upon what is known about their
efficacy and tolerability. When considering the durability of the
therapeutic effect and how long these medications should continue
to be administered, there are many issues relating to their impact on
maturation, physical growth, and possible development of reduced
effectiveness that are relevant for long-term efficacy (Lemmon
et al. 2011; Marcus et al. 2011).
Some of the limitations discussed in the above studies include
relatively small sample sizes, lack of comorbidity inclusions, short-
term use of medication, and use of concomitant medications. The
generalizability of findings to other clinical situations is therefore
restricted and, given that most studies do not extend beyond a few
months or a year, there is often little available information regarding
601
the long-term effects of these medications. For some antipsychotic
agents, despite being approved for use in children, the tested dosage
ranges are frequently lower than what is prescribed in the adult pop-
ulation, and the effects at higher dosages have yet to be determined.
When considering the direction of future research, there is a need
for studies that evaluate expanded treatment lengths, dosage, co-
administration with other agents, and age. The lack of psycho-
pharmacological studies in very young children limits the treatment
options available to that population. There is sometimes reticence
in families to enroll their children and adolescents in clinical trials,
and longer-term studies may selectively involve families with a
substantive commitment to study participation. This, in turn, may
result in a possible bias toward more positive outcomes (Findling
et al. 2017a).
Another consideration is the difficulty of diagnostic precision,
particularly in early presentations of psychosis or mood distur-
bance. Furthermore, there are few methodologically rigorous
blinded, head-to-head studies involving active controls available to
inform medication selection for specific individual patients. In
addition to the need for longer-term studies to assess efficacy and
safety as well as remission and relapse rates, it may be that future
research will identify a means by which medications can be se-
lected in a more patient-specific way. Considering that aggression
is oftentimes a key target symptom for which antipsychotics are
prescribed (USDHHS 2009), the role of these medications in ad-
dressing dysfunctional and maladaptive aggression within the
context of DBDs is one such area that warrants further study.
Conclusion
In summary, although evidence is mounting regarding the efficacy
and tolerability of antipsychotic medications for mental health dis-
orders in children and adolescents, more research is needed so that
evidence-based comparisons between medications can be made in
patients across developmental status, psychiatric comorbidities, and
all socioeconomic groups. The atypical antipsychotics have shown
tremendous potential in treating myriad psychiatric illnesses in
younger patients, and the functional knowledge pertaining to this
diverse class of medications will only grow in the upcoming years. It
is to be hoped that future research will better enable informed
treatment choices that take into account individual patient charac-
teristics when selecting psychopharmacological agents, and that
these data can be incorporated into evidence-based practices in
clinical settings.
Disclosures
Dr. Findling receives or has received research support, acted as
a consultant and/or served on a speaker’s bureau for Aevi, Akili,
Alcobra, Amerex, American Academy of Child & Adolescent
Psychiatry, American Psychiatric Press, Bracket, Epharma Solu-
tions, Forest, Genentech, Guilford Press, Ironshore, Johns Hopkins
University Press, KemPharm, Lundbeck, Merck, NIH, Neurim,
Nuvelution, Otsuka, PCORI, Pfizer, Physicians Postgraduate Press,
Purdue, Roche, Sage, Shire, Sunovion, Supernus Pharmaceuticals,
Syneurx, Teva, Tris, TouchPoint, Validus, and WebMD.
Dr. Lee and Dr. Vidal have no competing financial interests.
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Address correspondence to:
Carol Vidal, MD, MPH
Division of Child and Adolescent Psychiatry
Department of Psychiatry and Behavioral Sciences
Johns Hopkins Hospital School of Medicine
1800 Orleans Street
Baltimore, MD 21287
E-mail: cvidal2@jhmi.edu