Eur Child Adolesc Psychiatry (2007)

16:104–120 DOI 10.1007/s00787-006-0580-1 ORIGINAL CONTRIBUTION

Peter S. Jensen Management of psychiatric disorders in

Jan Buitelaar
Gahan J. Pandina children and adolescents with atypical
Carin Binder
Magali Haas antipsychotics
A systematic review of published clinical trials

j Abstract We aimed to provide a endocrine effects. The review of

Accepted: 3 July 2006
Published online: 30 October 2006 descriptive review of treatment published scientific data suggests
studies of atypical antipsychotics that most of the atypical antipsy-
Supported by funding from Janssen, L.P. in paediatric psychiatric disorders. chotics, excluding clozapine, have
A systematic review of the litera- a favourable risk/benefit profile
P.S. Jensen ture used Medline and EMBASE and effectively reduce disabling
Center for the Advancement of Children’s databases to identify clinical trials behaviours in paediatric psychiat-
Mental Health
Columbia University of atypical antipsychotics in chil- ric patients. While there is a body
New York State Psychiatric Institute dren and adolescents between of evidence published of treatment
New York, NY, USA 1994 and 2006. Trials were limited of DBDs and PDDs, there is a lack
J. Buitelaar to double-blind studies and open- of controlled data to guide clinical
Department of Psychiatry, and Karakter label studies of ‡8 weeks duration practice for the use of atypical
University Center for Child and that included ‡20 patients. Nine- antipsychotics for paediatric psy-
Adolescent Psychiatry teen double-blind and 22 open- chotic disorders and bipolar dis-
Radboud University
Nijmegen Medical Center label studies were identified. order. While there have been
Nijmegen, The Netherlands Studies included use of clozapine, studies with duration up to
olanzapine, quetiapine, risperi- 2 years, no definitive data are
G.J. Pandina, PhD (&)
Janssen Pharmaceutica Inc. done, and ziprasidone in the available that suggest long-term
1125 Trenton-Harbourton Rd treatment of disruptive behavio- safety; additional studies are war-
Titusville, NJ 08560, USA ural disorders (DBDs), pervasive ranted.
Tel.: +1-609/730-2324 developmental disorders (PDDs),
Fax: +1-609/730-3125
E-Mail: gpandina@janus.jnj.com tic disorder, psychotic disorders,
and mania. These medications
C. Binder generally reduced the severity of a
Janssen-Ortho Inc. j Key words atypical antipsy-
Toronto, Canada variety of psychiatric symptoms in chotics – paediatric psychiatric
children and adolescents. Less disorders – clozapine –
M. Haas frequent adverse events included
Johnson & Johnson Pharmaceutical olanzapine – quetiapine –
Research and Development extrapyramidal symptoms, hyper- risperidone – ziprasidone
Titusville, NJ, USA glycaemia and diabetes, and

psychotics include disruptive behavioural disorders

Introduction
Atypical antipsychotics have been used to treat a
variety of psychiatric disorders, many of which also
affect the paediatric population. Common disabling
ECAP 580
(DBDs), pervasive developmental disorders (PDDs),
tic disorders, schizophrenia, and bipolar disorder.
These disorders include disturbing and disruptive
behavioural symptoms that have a significant and

psychiatric disorders in children and adolescents that often long-lasting negative effect on the quality of life
have been targeted for treatment with atypical anti- of both the patients and their caregivers [29, 53, 61].
 P. Jenson et al.
Paediatric Atypical Review
Paediatric psychiatric disorders typically require a
combination of psychoeducation, cognitive and
behavioural management strategies, and, where
appropriate, pharmacological agents. In schizophre-
nia and bipolar disorder, medication use is the first
line of treatment. However, in DBD, PDD, and tic
disorders, medications are typically reserved for those
patients whose moderate-to-severe symptoms have
not responded adequately to behavioural interven-
tions and who have continued impaired functioning.
Medication choice is often driven by side-effect pro-
files in paediatric patients and may influence com-
pliance, development, and educational performance.
Over the past few years, atypical antipsychotics have
been increasingly used in children and adolescents.
However, it appears that the use of these agents has
often surpassed the available evidence, especially with
regard to safety. While some guidelines suggest that
atypical antipsychotics may be preferred over typical
antipsychotics for selected indications [38, 48], recent
concerns about weight gain, diabetes, and elevated
prolactin levels indicate the need to re-examine the
evidence on true risk/benefit of these agents. This
review aims to systematically examine the published
evidence for treatment with atypical antipsychotics of
paediatric psychiatric disorders.
Methods
A systematic literature search using the Medline and
EMBASE databases was performed to identify all
paediatric clinical trials of atypical antipsychotics
whose results were published in the peer-reviewed
literature from January 1994 through March 2006.
Unpublished data or abstracts from conferences were
not considered in order to prevent any bias related to
the accessibility of the data. The keywords used were
[children or preschool or juvenile or youth* or ado-
lescent*] and [antipsychotic* or neuroleptic* or
quetiapine or risperidone or olanzapine or aripip-
razole or clozapine or ziprasidone] (* = wild-card
term). Search results were limited to publication type:
clinical trial. The search identified over 100 controlled
and open-label studies. Trials limited to double-blind
and open-label studies of ‡8 weeks duration with ‡20
patients were included in this review.
Results
Nineteen double-blind studies and 22 open-label
studies met the criteria for final review. These studies
and their findings are presented below by indication
(DBD, 12 studies; PDD, 10 studies; tics/Tourette’s
105
syndrome, four studies; schizophrenia, six studies;
mania/bipolar disorder, six studies; safety and toler-
ability, three studies). For each study, mean daily
doses of the medication are reported both as total
milligrams and, when available, milligrams per kilo-
gram. Because different efficacy endpoints were used
in the clinical trials for specified disorders, direct
comparisons across studies were difficult, but the data
were summarized and contrasted whenever possible.
In addition, where placebo-controlled double-blind
studies were conducted and available for review, we
report effect sizes (ES) for making comparisons of
efficacy (ES = mean active drug score—mean placebo
score/pooled standard deviation). Adverse events
noted in each study are also presented.
j Disruptive behavioural disorders (Table 1)
DBDs of childhood include conduct disorder
(destructiveness and violence), oppositional defiant
disorder (e.g. defiance of authority and rule-breaking
behaviour), and DBD-not otherwise specified. These
are among the most common reasons for psychiatric
referral in children.
When psychosocial interventions such as
behavioural therapy or family therapy are inadequate
to treat the symptoms of DBD, atypical antipsychotics
appear to be increasingly used. Short-term reductions
in DBD symptoms have been demonstrated with both
olanzapine and risperidone (Table 1). Double-blind
controlled studies are only available for risperidone
and show consistently superior efficacy versus pla-
cebo in reducing symptoms. Data were available to
calculate the ES of treatment with risperidone com-
pared with placebo on the primary measure of efficacy
for three of the double-blind studies reported in Ta-
ble 1. The ES ranged from )0.6 (medium) to )1.5
(very large). Global improvements in the patients’
condition were observed, as well as reduction in the
main symptoms of aggression and agitation. In the
double-blind and open-label risperidone (0.02–
0.06 mg/kg/day) trials and the one open-label trial
with olanzapine (0.15–0.20 mg/kg/day), significant
behavioural improvement was seen within the first 1–
2 weeks of treatment. Furthermore, a placebo-con-
trolled maintenance versus withdrawal trial showed
that patients who responded to initial treatment with
risperidone would benefit from continuous treatment
over the longer term [55]. Long-term maintenance of
efficacy in treating DBD has been demonstrated with
risperidone in open-label studies [15, 20, 55, 68].
Both risperidone and olanzapine were generally
well tolerated in children with DBD. There were either
no or mild extrapyramidal symptoms (EPS), and
sedation was typically mild and transient. Weight gain
Table 1 Atypical antipsychotics in the treatment of disruptive behaviour disorders in paediatric patients
106

Inclusion criteria
(mean age or
Study Duration Mean daily dose (n) age range) Efficacy Safety and tolerability Limitations

Double-blind studies
Findling et al. [19] 10 weeks Risperidone Conduct disorder of RAAPP score )1.7 risperidone No EPS. Sedation in 3 risperidone Short duration of treatment
0.03 mg/kg (10), at least moderate vs. )0.2 placebo (P < 0.05); patients vs. 2 placebo Small sample size
placebo (10) severity (9.2 years) ES = )1.0. Weight gain 4.2 kg risperidone vs. Different drop-out rates per
CGI )2.6 risperidone vs. )0.1 0.7 kg placebo (P < 0.01) treatment group
placebo (P < 0.01)
Buitelaar et al. 6 weeks Risperidone 2.9 mg DBD or ADHD with Risperidone > placebo after Risperidone: no or mild EPS; Short duration of treatment
[11] (0.04 mg/kg) (19), severe chronic 2 weeks transient tiredness in 58%. Behavioural changes were
placebo (19) aggression CGI score )1.6 risperidone vs. Weight gain 2.3 kg risperidone vs. evaluated by a number of nurses
requiring +0.2 placebo (P < 0.001); 0.6 kg placebo (P < 0.05) and teachers, which might have
hospitalization ES = )1.5. resulted in a measurement error
IQ 60–90 (14 years) ABC significantly improved with
risperidone (P < 0.05)
van Bellinghen 4 weeks Risperidone 1.2 mg Persistent ABC score improvement in 65% EPS similar with risperidone and Short duration of treatment
et al. [69] (0.05 mg/kg) (6), behavioural risperidone vs. 7% placebo placebo Results limited to borderline IQ
placebo (7) disturbance Weight gain 1.8 kg risperidone vs.
IQ 45–85 (6– 0.6 kg placebo (P = 0.319)
14 years)
Snyder et al. [64] 6 weeks Risperidone DBD with N-CBRF Risperidone > placebo after Hypertonia 8% risperidone vs. 2% Short duration of treatment
0.98 mg (0.03 mg/ conduct scale 1 week placebo; somnolence 42% vs. 14% Results limited to borderline IQ
kg) (53), placebo scores ‡24. N-CBRF conduct scale score placebo; increased appetite 15% vs. Lack of structured diagnostic
 Steinkopff Verlag 2006

(57) IQ 36–84 )15.8 risperidone vs. )6.8 8%; weight gain 2.2 kg vs. 0.2 kg interviews
(8.7 years) placebo (P < 0.001);
ES = )0.6.
CGI much improved in 38%
risperidone vs. 16% placebo
(P < 0.001)
Aman et al. [4] 6 weeks Risperidone 1.2 mg DBD with N-CBRF N-CBRF conduct scale score EPS low severity with risperidone Short duration of treatment
(0.04 mg/kg) (55), conduct scale )15.2 risperidone vs. )6.2 and placebo Results limited to borderline IQ
placebo (63) scores ‡24. placebo (P < 0.01); ES = )0.8. Mild/transient somnolence 51%
IQ 36–84 (5– BPI aggressive scale )6.8 risperidone vs. 10% placebo; weight
12 years) risperidone vs. )2.4 placebo gain 15% (2.2 kg) vs. 2% (0.9 kg)
European Child & Adolescent Psychiatry (2007) Vol. 16, No. 2

(P < 0.01)
CGI improvement in 77%
risperidone vs. 33% placebo
(P < 0.001)
Reyes et al. [55] 6 months Risperidone DBD with N-CBRF Symptom recurrence rate: Weight increased with risperidone Only patients who responded to
blinded 0.02 mg/kg (172); conduct scale 42.3% with placebo vs. 27.3% during the initial 12 weeks (weight initial treatment were randomized;
risperidone placebo (163) scores ‡24. with risperidone; HR 2.24 (95% z-score change = 0.3) and use of psychostimulants
withdrawal IQ ‡55 (11 years) CI = 1.54–3.28) stabilized afterwards
Somnolence (11.6%)
Infrequent EPS and prolactin
related adverse events
Open-label studies
Soderstrom et al. 2–10 months Olanzapine 0.15– Conduct disorder Five treatment responders Weight gain in 5 (mean Small sample size
[65] 0.20 mg/kg (6) with severe within 2 weeks gain = 10 kg); sedation in 4.
aggression (14–
19 years)
Table 1 Continued

Inclusion criteria
(mean age or
Study Duration Mean daily dose (n) age range) Efficacy Safety and tolerability Limitations

Buitelaar et al. 8 weeks Risperidone 2.1 mg Persistent 56% decrease in aggression Moderate akathisia and hand Short duration of treatment
[10] (26) aggression and CGI improved much/very much tremor 1; mild sedation 2; weight Lack of weekly outcome
subaverage intellect in 14 patients and moderate in gain 2 (8 and 10 kg). Two measurements
IQ 78 (15 years) 10. discontinued (sedation plus weight Results limited to borderline IQ
gain)
Findling et al. [20] 48 weeks Risperidone 1.5 mg Severe DBD Long-term improvements in No changes in ESRS Exclusion of patients who had
or 0.041 mg/kg (N-CBRF conduct N-CBRF problem behaviour and Somnolence 33%, headache 33%, experienced adverse events leading
(107) score ‡24). IQ prosocial scales (P < 0.001) weight gain 21% (mean = 5.5 kg) to discontinuation in a previous
36–84 (9 years) and CVLT and continuous double-blind study
performance task (P < 0.05) Unblinded
Results limited to borderline IQ
Turgay et al. [68] 48 weeks Risperidone 0.02– DBD with N-CBRF Stable improvement in N-CBRF No severe EPS Exclusion of patients who had
0.06 mg/kg (77) conduct score ‡24. conduct scale scores Weight gain more pronounced experienced adverse events leading
IQ 36–84 >50% reduction in VAS most during first months of treatment to discontinuation in a previous
(5–12 years) troublesome symptoms Two patients discontinued after 34 double-blind study
CGI severe ratings 68% at and 37 weeks (headache and Results limited to borderline IQ
P. Jenson et al.

baseline vs. 17% at endpoint dyspnea)

Croonenberghs 1 year Risperidone 0.02– DBD with N-CBRF Reductions in N-CBRF conduct Low incidence of EPS. ESRS scores Selective inclusion of children with
et al. [15] 0.06 mg/kg (504) conduct score ‡24. scores and other behaviour reduced over the 48 weeks subaverage intelligence and severe
IQ 36–84; subscales (P < 0.001) Two cases of tardive dyskinesia disruptive behaviours
Paediatric Atypical Review

(5–14 years) Improvements at week 1 Transient increase in prolactin, then

maintained to within normal levels
Reyes et al 2006 2 years Risperidone DBD with N-CBRF Improvement sustained over Three cases of involuntary muscle Small patient number
[55] extension study 1.92 mg or conduct score‡24. 2 years, CGI-S score of 3.1 at contractions Inclusion of patients who
0.046 mg/kg (35) IQ 36–84; end point BMI mean increase responded and showed good
(5–17 years) 1 year = 1.4 kg/m2; tolerance to risperidone
2 years = 1.1 kg/m2

ABC = Aberrant Behaviour Checklist; ADHD = attention-deficit/hyperactivity disorder; BMI = body mass index; BPI = Behaviour Problems Inventory; CGI = Clinical Global Impression; CI = confidence interval;
CVLT = California Verbal Learning Test; DBD = disruptive behavioural disorder; EPS = extrapyramidal symptoms; ES = effect size (risperidone vs. placebo); ESRS = Extrapyramidal Symptom Rating Scale;
HR = Hazard ratio; N-CBRF = Nisonger-Child Behaviour Rating Form; RAAPP = Rating of Aggression Against People and/or Property scale
107
108 European Child & Adolescent Psychiatry (2007) Vol. 16, No. 2
 Steinkopff Verlag 2006
was often significantly greater in children receiving an
atypical antipsychotic than placebo.
Methodological limitations
Overall, the double-blind studies were of short
duration and thus unlikely to report rare adverse
events. In addition, findings cannot be generalized to
long-term treatment of DBD, which is a chronic
condition. The only double-blind study of interme-
diate duration [55] followed patients with DBD who
had initially responded to risperidone treatment and,
therefore, results might have been prone to a selec-
tion bias. The majority of the studies were limited to
paediatric patients with borderline or subaverage
intelligence (IQ 36–85). One open-label study [55]
followed patients up to 2 years, but the findings
should be viewed against the limitations of a small
sample size and a selection of patients who had
shown good tolerability to risperidone in a previous
1-year open-label study.
j Pervasive developmental disorders (Table 2)
PDDs as defined here include autism, Asperger’s
syndrome, PDD, and PDD-not otherwise specified.
PDDs are often associated with disruptive behaviour,
including aggression, hyperactivity, screaming, and
self-injurious behaviour that adds to the burden of
care for these children [31].
Olanzapine (10.7 mg/day) and risperidone (0.49–
1.8 mg/day) have demonstrated efficacy in reducing
symptoms in children with PDD (Table 2). The only
double-blind studies available were with risperidone.
Data were available to calculate the ES of treatment
with risperidone versus placebo on the primary
measure of efficacy (change from baseline on the
Aberrant Behaviour Checklist [ABC]-Irritability sub-
scale score for both of these studies (McCracken et al.
[45] ES = )1.2; Shea et al. [62] ES = )0.8). Early, 2-
week efficacy was demonstrated by Shea et al. [62].
Conversely, gradual blinded risperidone discontinu-
ation after 6 months was associated with a rapid re-
turn of disruptive and aggressive behaviours in 62.5%
of placebo patients compared with 12.5% of those
who continued risperidone [58]. Comparable results
were obtained by Troost et al. [67].
In the open-label study of olanzapine [33], signif-
icant improvements in both ABC and Clinical Global
Impression (CGI) scores were reported. In 2 open-
label risperidone trials, significant improvements in
Childhood Autism Rating Scale scores were reported
[17, 44]. Maintenance of treatment benefits was re-
ported in 77–81% of children with PDD treated with
risperidone for 6–7 months [17, 42].
It is of interest that a secondary analysis of the
RUPP data [58] by McDougle et al. [46] showed that
risperidone treatment (1.8 mg/day) could lead to
significant improvement in core symptoms of autism
such as restricted, repetitive, and stereotyped patterns
of behaviour, interests, and activities in children with
severe autism. However, risperidone treatment did
not result in significant effects on deficits in social
interaction and communication.
The most common side-effects in children with
PDD receiving risperidone were mild transient som-
nolence and weight gain with short-term treatment.
One trial that followed with children with autism for
6 months showed that intermediate-duration risperi-
done treatment was associated with weight gain of
5.1 kg, a significantly greater increase than would be
expected from developmental norms [46]. No extra-
pyramidal or neurological symptoms were noted in
these children, except for caregiver-reported tremor
(P = 0.06 vs. placebo) [45] or ‘‘abnormal movements’’
[46]. EPS that resolved with dose adjustment were
reported in children receiving olanzapine.
Methodological limitations
The study by McCracken et al. [45] and the follow-
up study by McDougle et al. [46] were limited to
children with autism and severe behavioural prob-
lems. Due to small sample sizes, the open-label
studies were not able to detect rare adverse events.
The double-blind study by Troost et al. [67] and the
open-label study by Kemner et al. [33] were limited
to high-functioning patients. Overall, there is a need
for further standardization of tools to be used for
tracking changes in core and associated behavioural
symptoms of autism in children with autism and
other PDDs.
j Tic disorders (Table 3)
Tic disorders include Tourette’s syndrome, chronic
motor and vocal tic disorder, transient tic disorder,
and tic disorder-not otherwise specified [6]. Atypical
antipsychotics are often used when tic disorders are
accompanied with symptoms of aggression or rage.
The efficacy of risperidone and ziprasidone in the
treatment of tic disorders has been assessed in four
double-blind trials (Table 3). A crossover comparison
treating Tourette’s disorder with risperidone (2.5 mg/
day) and pimozide (2.4 mg/day; 4 weeks each)
showed greater improvements in tic severity with
risperidone (42% vs. 21% with pimozide; P = 0.05)
[27]. Tolerability was generally similar in the two
groups, with the exception of greater weight gain with
risperidone. Two other double-blind studies also
Table 2 Atypical antipsychotics in the treatment of pervasive developmental disorders

Inclusion criteria
Study Duration Mean daily dose (n) (mean age) Efficacy Safety and tolerability Limitations

Double-blind studies
McCracken et al. 8 weeks Risperidone 1.8 mg Autism with tantrums, ABC-I score )57% risperidone vs. Mild, transient drowsiness and Short duration of treatment
[45] (49), placebo (52) aggression, and/or self- )14% placebo; ES = )1.2. fatigue with risperidone Study limited to patients with
injurious behaviour CGI much/very much improved at Weight gain 2.7 kg risperidone vs. autistic disorders and severe
(8.8 years) 8 weeks: 76% risperidone vs. 12% 0.8 kg placebo behavioural problems
placebo
Shea et al. [62] 8 weeks Risperidone 1.2 mg PDD with or without Risperidone efficacious after Risperidone: no increase in EPS; Short duration of treatment
(0.04 mg/kg) (41), mental retardation 2 weeks transient somnolence
placebo (39) CARS score ‡30 Improvement in all ABC subscale Weight gain 2.7 kg risperidone vs.
(7.5 years) scores in 55–64% risperidone vs. 1.0 kg placebo
24–40% placebo (P £ 0.05) See McCracken et al. [45]
ES = )0.8 (ABC-Irritability)
McDougle et al. 8 weeks Risperidone 1.8 mg Autism with tantrums, Ritvo-Freeman Real Life Rating Study limited to patients with
[46] + 16 weeks OL (49); placebo (52) aggression, and/or self- Scale—significantly greater autistic disorders and severe
continuation injurious behaviour reduction with risperidone in total behavioural problems
(8.8 years) scores (ES = )1.08); subscales Rating diagnostic instruments not
scores for sensory motor behaviours validated
(ES = )0.45), Affectual Reactions
P. Jenson et al.

(ES = )1.10), Sensory Responses

(ES = )0.77)
RUPP Autism 4 months OL + Risperidone Subject with severe Relapse rate: 62.5% with placebo Weight gain 5.1 kg Inclusion of patients with severe
Network 2005 [58] 8 weeks DB 1.96 mg/day autism who responded vs. 12.5% with risperidone; median behavioural problems was an entry
Paediatric Atypical Review

risperidone (OL, 63; DB to risperidone during a time to relapse 34 and 57 days, criteria
withdrawal withdrawal, 32) previous short term trial respectively
[45]
Troost et al. [67] 6 mo OL + 8 wks Risperidone PDD with CGI-S Relapse rate: 67% with placebo vs. Weight gain of 5.7 kg. Two patients Findings are not generalizable for
DB risperidone 1.8 mg/day (OL 36; disruptive behaviour 25% with risperidone; median time discontinued due to unacceptable the impaired autism population,
withdrawal DB withdrawal 24) rating ‡ moderate; to relapse 42 and 49 days, weight gain because sample studied included
ABC-I score ‡18. respectively relatively high-functioning
(5–17 years) patients
Open-label studies
Kemner et al. [33] 12 weeks Olanzapine Autism or PDD-NOS ABC irritability, hyperactivity, EPS in three patients resolved with Small sample size. Findings are not
10.7 mg (25) (11.2 years) excessive speech scale scores dose adjustment generalizable for the impaired
reduced (P < 0.05) Weight gain in 56% (mean gain autism population, because sample
CGI-severity 13% reduction 4.7 kg) studied included relatively high-
Gestures and verbal actions reduced functioning patients
(P < 0.05)
Masi et al. [44] 16 weeks Risperidone PDD with CARS CPRS score improved 21%. Increase appetite in six; enuresis in Small sample size
0.49 mg (24) scores > 30 (4.6 years) Improvements of 22–34% three Evaluation of efficacy was based on
(P < 0.001) in 7 CARS scales, and Mean weight gain 1 kg only 2 ratings (CPRS and CARS)
CARS total (14%; P < 0.001) Two patients discontinued
Much/very much improvement on (sedation and hyporeflexia in one
CGI in 36%. and tachycardia in other)
Malone et al. [42] 7 months Risperidone 1.2 mg Autism with severely CPRS-14 score improved 21%. No EPS Small sample size
(22) disruptive symptoms CGI much/very much improvement Mild, transient sedation in 68%. Long-term efficacy was based on
(7.1 years) in 77% at 1 month and in 10/13 at Mean weight gain after 7 months CGI alone
6 months 3.3 kg
109
110 European Child & Adolescent Psychiatry (2007) Vol. 16, No. 2
 Steinkopff Verlag 2006

showed improvement with risperidone (1.5 and

Evaluation of efficacy was based on

Evaluation of efficacy was based on

ABC-I = Aberrant Behaviour Checklist, irritability subscale; CARS = Childhood Autism Rating Scale; CGI = Clinical Global Impression; CPRS = Children’s Psychiatric Rating Scale; DB = double-blind;
2.5 mg/day), with a reduction in obsessive-compul-
sive traits and a reduction in tic severity [24, 60].
Greater weight gain was noted in patients receiving
CGI-I and CARS only risperidone than either clonidine or placebo in these
Small sample size

Small sample size

CPRS ratings only

studies. A placebo-controlled study of ziprasidone
(28.2 mg/day) demonstrated a 39% reduction in tic
Limitations

severity after 8 weeks vs. 16% in the placebo group

(P < 0.05) [59]. Data were available to calculate ES for
treatment with active drug versus placebo on tic
severity reduction for two of these studies: Scahill
Weight gain >10% in two patients

et al. [60] (ES = )1.2) and Sallee et al. [59]

12 weeks and 3.7 kg at 24 weeks

EPS = extrapyramidal symptoms; ES = effect size (risperidone vs. placebo); OL = open-label; PDD-NOS = pervasive developmental disorder-not otherwise specified
(ES = )0.8). No weight gain was reported with zipr-
Mild sedation in four patients

Mild, transient sedation in six

Mean weight gain 2.6 kg at

asidone in this study, but mild, transient sedation was

reported in more children receiving ziprasidone than
Safety and tolerability

placebo. No open-label studies met our inclusion

criteria.
patients
No EPS

Methodological limitations
Studies were limited by short duration and small
sample sizes.
Reductions of 13–37% (P < 0.05)
CPRS-14 scores improved 17%.

in scores on 8 CPRS-14 scales

CGI improvement in 81%.
CARS total reduced 18%

j Schizophrenia and related disorders (Table 4)

Schizophrenia and bipolar disorder are typically

recognized in adolescents or young adults rather
(P = 0.001)

than children. Childhood-onset schizophrenia is re-

Efficacy

ported in about 0.01% of children aged <12 years,

with the incidence increasing during the teenage
years [51]. Few trials have been conducted in this
Autism (4.95 years)

Autism with CARS

age group.
Inclusion criteria

Kumra et al. [37] reported improvements (Brief

(mean age)

scores ‡30

Psychiatric Rating Scale scores) in significantly more

(6.0 years)

patients receiving clozapine (3.1 mg/kg/day) than

haloperidol (0.29 mg/kg/day) in a 6-week study (Ta-
ble 4). In an 8-week comparison of haloperidol, ris-
Mean daily dose (n)

1.53 mg (0.09 mg/

peridone, and olanzapine, Sikich et al. [63] reported

similar treatment benefits for all three treatments in
1.26 mg (20)
kg/day) (20)

50 children and adolescents with schizophrenia or

Risperidone

Risperidone

affective disorder with psychotic features. Mean daily

doses were 12.3 mg olanzapine, 4.0 mg risperidone,
and 5.0 mg haloperidol. Mean time to efficacy re-
sponse was about 2 weeks in all 3 groups. Severity of
EPS was similar in all treatment groups. Greater
weight gain was reported with the atypical antipsy-
6 months

24 weeks

chotics (olanzapine 7.1 kg; risperidone 4.9 kg; halo-

Duration

peridol 3.5 kg; P < 0.05). Open-label studies of

atypical antipsychotics in the treatment of schizo-
phrenia and related disorders have identified treat-
Table 2 Continued

ment responses occurring as early as 1–3 weeks after

Diler et al. [17]

Gagliano et al.

treatment initiation (Table 4). Preliminary data

showed that clozapine treatment (476 mg/day) is
Study

efficacious in adolescents with treatment refractory

[25]

schizophrenia and aggressive behaviour [36].

 P. Jenson et al. 111
Paediatric Atypical Review

Table 3 Atypical antipsychotics in Tourette’s syndrome and tic disorders

Mean daily Inclusion criteria

Study Duration dose (n) (mean age) Efficacy Safety and tolerability Limitations

Double-blind studies
Gaffney et al. [24] 8 weeks
Scahill et al. [60] 8 weeks
Gilbert et al. [27] 4 weeks
Sallee et al. [59] 8 weeks
Risperidone 1.5 mg Tourette’s Response similar in two Sedation in 1 Short duration of
(9), clonidine (11.4 years) groups risperidone patient and treatment
0.18 mg (12) Tics reduced 21% 5 clonidine patients Use of active
risperidone vs. 26% Weight gain 2.1 kg comparator
clonidine risperidone vs. 0.1 kg Small sample sizes
OCD traits reduced 42% clonidine
risperidone vs. 20%
clonidine
Risperidone 2.5 mg Tic disorder with IQ Tic severity reduced No EPS Short duration of
(12), placebo (14) ‡70; subanalysis of 36% risperidone vs. 9% Weight gain 2.8 kg treatment
paediatric patients placebo (P < 0.01); risperidone vs. 0 kg Small sample sizes
(11.1 years) ES = )1.2 placebo Patients ascertained
CGI much/very much from a specialty clinic
improvement in 9 Exclusion of patients
risperidone vs. 1 with obsessive-
placebo compulsive disorder
Crossover: Tourette’s Greater reduction in tic AEs similar in two Short duration of
risperidone 2.5 mg syndrome severity with groups treatment
and pimozide (11 years) risperidone (42%) vs. Weight gain 1.9 kg Small sample sizes
2.4 mg (9) pimozide (21%; risperidone vs. 1.0 kg
P = 0.05) pimozide
CGI improvement in 2
(much improved)
risperidone vs. 3
(minimally improved)
pimozide
Ziprasidone Tourette’s Tic severity )39% Severe akathisia in 1 Short duration of
28.2 mg (16), syndrome or ziprasidone vs. )16% ziprasidone patient treatment
placebo (12) chronic motor or placebo (P = 0.02); resolved with dose Small sample sizes
vocal tic disorder ES = )0.8. reduction
(11.5 years) CGI changes 30% Mild/transient sedation
ziprasidone vs. 16% in 11 ziprasidone vs. 5
placebo; ES = )0.5. placebo
Weight gain 0.7 kg
ziprasidone vs. 0.8 kg
placebo

AE = adverse event; CGI = Clinical Global Impressions; EPS = extrapyramidal symptoms; ES = effect size (atypical v2s. placebo); OCD = obsessive-compulsive
disorder

In these open-label studies, children and adoles-
cents receiving haloperidol had more severe EPS than
those receiving olanzapine or risperidone. In the
open-label study [53] with clozapine, six of the 36
patients discontinued owing to a variety of adverse
events.
Methodological limitations
Overall, the studies were limited by short duration,
small sample sizes, and use of adjunctive medication.
The study by Remschmidt et al. [53] is limited by its
retrospective character. Patients were not randomly
assigned to haloperidol, olanzapine, or risperidone in
the study by Gothelf et al. [28].
j Mania in bipolar disorder (Table 5)
Reductions in the severity of symptoms of mania,
psychosis, aggression, and depression in children or
adolescents with bipolar disorder have been shown in
open-label studies of olanzapine (9.6 mg/day) and
risperidone (1.7 mg/day), with improvement noted
during the first week of treatment (Table 5). Quetia-
pine (450 mg/day) produced superior control of
mania in adolescents in a double-blind study when
used as adjunctive therapy to valproate compared
with valproate plus placebo [14]. Sedation with que-
tiapine combination therapy was mild to moderate in
severity and did not result in drug discontinuation.
While no patients in either group discontinued be-
Table 4 Atypical antipsychotics in paediatric schizophrenia or other psychotic disorders
112

Study Duration Mean daily dose (n) Inclusion criteria (mean age) Efficacy Safety and tolerability Limitations

Double-blind studies
Kumra et al. [37] 6 weeks Clozapine 176 mg Schizophrenia BPRS improvement in 32% Drowsiness 9 clozapine vs. 3 Short duration of treatment
(3.1 mg/kg/day IQ ‡70 (14.0 years) clozapine vs. 15% haloperidol haloperidol
(10), haloperidol (P = 0.03) Tachycardia 7 clozapine vs. 5
16 mg (0.29 mg/ Significant improvements in haloperidol
kg/day (11) positive and negative Weight gain 0.9 kg clozapine
symptoms with clozapine and haloperidol
Sikich et al. [63] 8 weeks Risperidone 4.0 mg Psychotic disorder with ‡ 1 BPRS improvement 50% No difference in EPS among Short duration of treatment
(19), olanzapine positive psychotic symptom of risperidone, 56% olanzapine, groups Limited sample size
12.3 mg (16), moderate severity on BPRS and 33% haloperidol Weight gain 7.1 kg olanzapine, Differences in the diagnosis
haloperidol 5.0 mg IQ >69 (14.7 years) BPRS total reduced 47% 4.9 kg risperidone, 3.5 kg across the treatment groups
(15) risperidone, 50% olanzapine, haloperidol (P < 0.05) Adjunctive use of mood
36% haloperidol stabilizers and/or
CGI much/very much improved antidepressants
and ‡ 20% BPRS reduction
74% risperidone, 88%
olanzapine, 53% haloperidol
Open-label studies
Remschmidt et al. [53] 22 weeks Clozapine 330 mg Schizophrenia (18.3 years in Improvements in 27 patients; Discontinuation in six due to Retrospective study
(36) entire sample of 113 patients; complete remission in 4 AEs: stupor, leukopaenia (8%),
age of those receiving clozapine Positive symptoms improved in cardiovascular abnormalities
not given) 65%. (44%), or abnormal liver
enzymes
 Steinkopff Verlag 2006

Ross et al. [57] 1 year Olanzapine Schizophrenia or schizoaffective Symptom severity No significant change in EPS Small sample size
10.4 mg (20) disorder (10.5 years) reduced ‡ 20% and/or residual Weight gain at 1 year 12.8 kg Outcomes limited to symptom
mild symptoms in 68% at assessment
6 weeks and 74% at 1 year Concurrent medication use was
not controlled
Gothelf et al. [28] 8 weeks Olanzapine Schizophrenia (16.9 years) PANSS score reductions of More severe EPS and Short duration of treatment
12.9 mg (19), 11.3% (olanzapine), 24.1% depression with haloperidol Small sample sizes
risperidone 3.3 mg (risperidone), 39.5% (57%) than olanzapine (12%) or No randomization in the choice
(17), haloperidol (haloperidol) in positive risperidone (24%) groups of medication
8.3 mg (7) symptoms and 17.7% (P < 0.01)
(olanzapine), 14.0%
European Child & Adolescent Psychiatry (2007) Vol. 16, No. 2

(risperidone), 19.2%
(haloperidol) in negative
symptoms
Kranzler et al. [36] 6 months Clozapine 476 mg Schizophrenia/schizoaffective Decreased frequency of Not reported Unblinded
(20) disorder (14.2 years) administration of emergency Mirror-image design
oral/injectable medication and Use of adjunctive psychotropic
seclusion (P < 0.001 for each) medication

AE = adverse event; BPRS = Brief Psychiatric Rating Scale; CGI = Clinical Global Impression; EPS = extrapyramidal symptoms; PANSS = Positive and Negative Syndrome Scale
Table 5 Atypical antipsychotics in paediatric mania and bipolar disorder

Study Duration Mean daily dose (n) Inclusion criteria (mean age) Efficacy Safety and tolerability Limitations

Double-blind studies
Delbello et al. [16] 6 weeks
Open-label studies
Frazier et al. [23] 8 weeks
Frazier et al. [22] 6 months Risperidone 1.7 mg (28)
Divalproex plus quetiapine Bipolar I disorder, mixed or More patients showed YMRS No EPS Short duration of treatment
450 mg (maximum) (15) or manic, YMRS score ‡20 improvements with addition of Sedation: quetiapine 80% vs. Small sample sizes
placebo (15) (14.3 years) quetiapine (87%) than placebo placebo 33%. All patients were hospitalized
(53%) (P < 0.05) Nonresponders to valproate were
excluded from the study
Olanzapine 9.6 mg Bipolar disorder, YMRS score Improvements maintained for Somnolence in 10.
(0.21 mg/kg) (23) ‡15 (10.3 years) 8 weeks
YMRS & BPRS improved 62% Weight gain in seven patients
(P < 0.001) (mean 5 kg)
CGI-S reduced 38% bipolar 1 discontinuation (depression)
disorder, 40% mania, 37%
depression (P < 0.001)
Mixed or hypomanic bipolar CGI-S reduced 46% mania, 41% Sedation and weight gain each Retrospective study
disorder (10.4 years) aggression, 14% ADHD reported in 18%. Short duration of drug exposure
CGI improvement (£2) 82% Small sample size
mania and aggression, 69%
psychosis, 8% ADHD
P. Jenson et al.

Pavuluri et al. [49] 6 months Risperidone Mixed or manic episode with ‡50% reduction in YMRS scores Risperidone + lithium discontinued Small sample sizes
0.70 mg + divalproex YMRS >20 (12.1 years) in 80% of in 2 (enuresis and fatigue) Short wash-out period (3–4 days)
925 mg (106 lg/dl) (20), risperidone + divalproex Weight gain 6 kg Concomitant use of clonidine,
risperidone group, 82.4% of risperidone + lithium, 6.8 kg trazodone allowed
Paediatric Atypical Review

0.75 mg + lithium 750 mg
(0.9 mEq/l) (17)
Biederman et al. [8] 8 weeks Risperidone 1.25 mg (30)
Biederman et al. [8] 8 weeks Risperidone 1.4 mg (16)
Olanzapine 6.3 mg (15)
Mixed, manic or hypomanic
episode with YMRS ‡15 (6–
17 years)
Mixed or manic episode with
YMRS ‡15 (4–6 years)
risperidone + lithium group
Improvements (P < 0.001) in
YMRS, CGI-BP, and CDRS-R
scores in both groups with no
between-group differences
Response rate (CGI-
Improvement [£2]): 70%
Improvements (<0.001) in
YMRS, BPRS, CDRS
Response rate (30% reduction
in YMRS or CGI-Improvement
[£2]): 69% with risperidone vs.
53% with clozapine, NS
risperidone + divalproex Patients known to worsen on study
Sedation in 23.5% of lithium group medication were excluded
and 20% of divalproex group
Prolactin elevation in 4 resolved by
reducing risperidone dose
Weight gain 2.1 kg Short duration of treatment
4-fold increase in prolactin levels Unblinded treatment
from baseline Spontaneous reports of adverse
events
Increase in prolactin levels in both Short duration of treatment
groups, but significantly larger with Unblinded treatment
risperidone Spontaneous reports of adverse
Weight gain 2.2 kg risperidone, events
3.2 kg olanzapine

ADHD = attention-deficit/hyperactivity disorder; BPRS = Brief Psychiatric Rating Scale; CDRS-R = Child Depression Rating Scale-Revised; CGI-BP = Clinical Global Impression Scale for Bipolar Disorder; CGI-
S = Clinical Global Impression-Severity; EPS = extrapyramidal symptoms; NS = not significant; YMRS = Young Mania Rating Scale
113
114 European Child & Adolescent Psychiatry (2007) Vol. 16, No. 2
 Steinkopff Verlag 2006
cause of side-effects, the combination therapy group
experienced a much higher dropout rate than the
monotherapy group (7 vs. 1, respectively).
Biederman et al. [8] reported comparable response
rates in children aged 4–6 years treated with risperi-
done 1.4 mg/day (69%) or olanzapine 6.3 mg/day
(53%) for 8 weeks measured as £30% reduction in
scores of Young Mania Rating Scale or CGI-
Improvement (£2). The increase in prolactin levels
from baseline to endpoint was twofold larger with
risperidone, while weight gain associated with ola-
nzapine was 1.5-fold larger than with risperidone.
Significant improvement in mania symptoms was
observed in youths aged 6–17 years treated with ris-
peridone monotherapy (1.25 mg/day) for 8 weeks [8].
Six-month efficacy with risperidone was reported in a
retrospective chart review [22] and in a prospective
open-label trial of risperidone in combination with
either lithium or divalproex [49]. In the latter study,
neither combination demonstrated superiority over
the other. Both of these studies noted weight gain and
sedation with risperidone. Pavuluri et al. [49] also
reported prolactin elevation in four patients, which
resolved with dose reduction. Prospective, long-term
studies are needed to identify the long-term effects of
atypical antipsychotic in the treatment of manic epi-
sodes in adolescents.
Methodological limitations
The only double blind study [16] was limited by its
short duration, small sample sizes, and the inclusion
of hospitalized patients. The open-label study by
Frazier et al. [22] was a retrospective study. Patients
known to worsen on study medication were excluded
from the study by Pavuluri et al. [49], potentially
resulting in a selection bias. In the 2 open-label
studies by Biederman et al. [8], adverse events were
spontaneously reported, which might have resulted in
an underestimation.
Safety and tolerability of atypical antipsychotics
in paediatrics
In general, atypical antipsychotics are better tolerated
and show improved medication compliance than
typical antipsychotics [12]. In the studies reviewed,
risperidone, clozapine and olanzapine were generally
well tolerated, with few patients discontinuing treat-
ment as a result of adverse events (2.6% up to 8.3%
across the different studies). The most frequent sig-
nificant adverse events reported with these atypical
antipsychotics in a paediatric population were seda-
tion and weight gain. The maximum length of dura-
tion of the various studies was 1 year, and only one
study that followed children up to 2 years. There were
few studies with quetiapine and ziprasidone.
Somnolence was frequently reported with atypical
antipsychotics, although it was usually mild to mod-
erate in severity and infrequently resulted in treat-
ment discontinuation [52]. The impact of somnolence
was effectively reduced in studies with olanzapine and
risperidone by switching from morning to evening
dosing, using divided dosing, or reducing dosage [62,
65].
Weight gain is another important consideration in
the use of atypical antipsychotics in paediatric pa-
tients. The weight gain observed with atypical anti-
psychotics can range from 1 kg for 16 weeks [44] up
to 12.8 kg over a year of treatment [57]. A summary
of weight gain data with atypical antipsychotics in
studies meeting inclusion criteria for this review is
shown in Table 6. As with efficacy data, most studies
meeting inclusion criteria involved trials with ris-
peridone. Most weight gain with risperidone occurred
during the initial 2 months of treatment, with rela-
tively less additional weight gain during long-term
therapy [43]. In a follow-up study of 14 children with
DBD who discontinued treatment with risperidone
because of weight gain, a comparison of standardized
weight scores at termination and at 3, 9–12, and
24 months after termination suggested that weight
gain during treatment was reversible [41]. However,
the authors cautioned that more data were needed
before this could be asserted for all children. A more
recent study that followed 527 children with DBD over
a period of 6 months concluded that weight increased
over the initial 12 weeks of treatment, after which it
plateaued [55].
EPS were infrequently noted with atypical anti-
psychotics (Tables 1–5). A previous review of atyp-
ical antipsychotics in the treatment of psychosis [39]
identified a higher incidence of EPS in paediatric
patients than in adult patients. Therefore, it is
noteworthy that EPS occurred infrequently in the
current analysis of more recent studies treating a
broad range of psychiatric symptoms at lower doses.
A recent review of studies that included 2,769 pa-
tients treated with atypical antipsychotics identified a
weighted mean annual incidence of tardive dyski-
nesia of 2.1% across all age groups [14]. The use of
atypical antipsychotics may be associated with lower
dyskinesia risk compared with typical antipsychotics.
For example, a recent study that prospectively eval-
uated 102 children and adolescents receiving anti-
psychotics reported a rate of 5.9% for probable
tardive dyskinesia found to be significantly associ-
ated with the use of typical antipsychotics [13].
However, the duration of this study was only
3 months and this could have resulted in underes-
timation of the prevalence rates.
 P. Jenson et al. 115
Paediatric Atypical Review

No randomization of
Hyperglycaemia and diabetes have also been linked

Retrospective study
Small sample sizes

Small sample sizes

to the use of atypical antipsychotics, in particular
clozapine and olanzapine [40], but few data are
Limitations

available for the paediatric population. In 3 long-term

patients
open-label trials of risperidone that included a total of
688 children, only one case of a diabetes-associated
adverse event was reported, indicating that these are
not common adverse events with risperidone treat-

)1.01 kg/m2 no antipsychotic

ment [15, 20, 68].

Risperidone vs. neuroleptic,

+0.31 kg/m2 neuroleptic,
+3.67 kg/m2 risperidone,
Physical and sexual development should also be
Mean change in BMI

carefully studied in paediatric patients, particularly

when exposed to long-term therapy. A recent meta-
analysis assessed growth in 350 children and sexual
Not reported

Not reported
P = 0.001.
maturation in 222 children who participated in long-
term treatment of DBD with risperidone [18]. After
12 months, there was no inhibition of the expected
growth (National Health and Nutrition Examination
Survey data and growth velocity charts), nor was there
at 6 months, 8.2 kg at 12 months;

any delay in sexual maturation as assessed by Tanner

in patients aged 13–16, 4.2 and
in patients aged 8–12, 3.8 kg

staging, with risperidone. However, additional data

)1.04 kg no antipsychotic

are needed to confirm the long-term safety of the

Range )4.0 to + 15.3 kg
risperidone than placebo
Weight gain higher with

+2.8 kg after 2 months

+5.8 kg after 6 months

atypical antipsychotics during pubertal development.

+3.03 kg neuroleptic
+8.64 kg risperidone
8.4 kg, respectively

Antipsychotic treatment has also been linked to

Change in weight

hyperprolactinaemia. A survey of prolactin levels at

(P < 0.0001)

baseline and after 6 weeks of treatment in children

Mean gain

and adolescents (mean age 14.1 years) showed ele-

vations with both atypical and typical antipsychotics
[70]. Prolactin increase was significantly higher with
haloperidol (mean: 47.8 ng/ml) compared with ola-
nzapine (23.7 ng/ml) or clozapine (mean: 11.2 ng/ml;
agitation, or self-injurious
Autism with aggression,
or property destruction

P < 0.001). Prolactin levels with treatment exceeded

aggression, self-injury,

Adolescent inpatients

behaviour (8.6 years)

the upper limit of normal in 90% of the patients

PDD with severe
Inclusion criteria

treated with haloperidol, 70% treated with olanzapine,

(13.4 years)

(14.1 years)
(mean age)

and in none treated with clozapine. A follow-up

extension to this study similarly found significant
prolactin elevation after 6 weeks of treatment with
Table 6 Weight change with atypical antipsychotics in paediatric patients

haloperidol or olanzapine (P < 0.01), but not cloza-

pine [2]. Post-hoc analysis from five large prospective
BMI = body mass index; PDD = pervasive developmental disorder
no antipsychotic (19)

clinical trials including a total of 592 children with

Mean daily dose (n)

antipsychotics (23),

DBD and subaverage intelligence demonstrated that,

Risperidone (18),

Risperidone (63)
crossover study

despite hyperprolactinaemia associated with the first

placebo (15),
Risperidone
1 mg (11),

4–8 weeks of risperidone treatment, prolactin levels

tended to normalize by 1 year of treatment [21].
Adverse events potentially related to prolactin were
reported in 4.9% (most commonly gynaecomastia in
males, seen in 3.7%). One of the limitations of this
6 months

6 months
50 weeks
Duration

study, however, was that there was no long-term

control group to show the incidence of gynaecomastia
that would occur normally in such a population.
Interestingly, prolactin elevation did not correlate
Double-blind studies

with these side-effects, nor was there any correlation

Hellings et al. [30]

Open-label studies

Martin et al. [43]

between dose, prolactin level, and adverse events

Kelly et al. [32]

potentially related to prolactin. Although this post-

hoc analysis suggested that hyperprolactinaemia can
Study

be transitory, long-term awareness is required and

additional studies are warranted.
116 European Child & Adolescent Psychiatry (2007) Vol. 16, No. 2
 Steinkopff Verlag 2006
Cognitive adverse events were infrequently re-
ported with atypical antipsychotics. Although cogni-
tive deficits do not improve in adult patients with
schizophrenia receiving conventional antipsychotics,
it has been reported that they can improve with
atypical antipsychotics [47]. Verbal learning and
continuous performance tasks showed improvements
with risperidone in two large open-label studies of
children with DBD [15, 20]. Additional studies mea-
suring cognitive changes and academic performance
in paediatric patients are needed.
Serious adverse events have been reported with
atypicals, including clozapine, olanzapine and zipr-
asidone. Particularly troublesome are the haemato-
logical adverse events associated with clozapine
treatment. A recent retrospective study reported
neutropenia (absolute neutrophil count <1,500/mm)
in 13% (23/172) and agranulocytosis (absolute neu-
trophil count <500/mm) in 0.6% (1/172) of the hos-
pitalized psychiatrically ill children treated with
clozapine and observed for 8 months [26]. Similarly,
serious electrocardiographical changes have been re-
ported with low-dose ziprasidone (£40 mg/day)
among paediatric outpatients treated up to 6 months:
the mean QTc prolongation was 28 ± 26 ms, with
three patients reaching 450 ms and 1 subject experi-
encing a 114 ms prolongation [9].
Discussion
Ideally, children and adolescents with DBDs, PDDs, or
tic disorders would be managed with nonpharmaco-
logical therapy alone to minimize the occurrence of
adverse events. However, when symptoms are severe,
fail to respond to behavioural interventions, and
interfere with social, family, or academic functioning,
medications are often recommended. Thus, proper
diagnostic assessment is important in order to identify
an appropriate medication treatment course for pae-
diatric patients with DBDs, PDDs, or tic disorders.
However, for paediatric psychotic disorders or acute
mania in paediatric bipolar disorder, medication is the
first line strategy and early pharmacological interven-
tion is important with regard to prognosis. Atypical
antipsychotics might be considered because of their
documented efficacy in both double-blind and open-
label studies and low incidence of EPS. As noted above,
a number of double-blind and open-label studies have
demonstrated rapid efficacy in combination with
favourable short- and long-term tolerability of atypical
antipsychotics for treating a broad spectrum of psy-
chiatric disorders in children and adolescents.
Double-blind clinical trials have been conducted
with risperidone for DBD and PDD; with risperidone
and ziprasidone for tic disorders; with clozapine,
olanzapine, and risperidone for psychotic disorders;
and with quetiapine for mania. A recent international
expert panel recommended risperidone as the medi-
cation treatment of choice for conduct disorder be-
cause of demonstrated efficacy in this population and
good tolerability [38]. It has been reported that ris-
peridone has a favourable risk/benefit profile when
combined with methylphenidate for the treatment of
attention-deficit/hyperactivity disorder, which is fre-
quently comorbid with DBD [3, 38]. However, ris-
peridone is currently approved only for DBD
treatment in several countries and in few countries for
the treatment of autism. For the other indications
mentioned in this review, more data are needed. In
preliminary studies, however, atypical antipsychotics
have been shown in both double-blind and open-label
studies to reduce a variety of disabling psychiatric
symptoms in children and adolescents.
The most common adverse events in paediatric
patients documented for treatment with risperidone,
clozapine, or olanzapine in both short- and long-term
studies include somnolence and weight gain, whereas
there are few data for ziprasidone and quetiapine.
Serious haematalogical adverse events have been re-
ported with clozapine. There is evidence that treat-
ment with ziprasidone can result in serious
electrocardiographical changes that are known to be
associated with increased risk of arrhythmia and
sudden death. Data on rare adverse events should be
considered preliminary because of the lack of long-
term studies designed to systematically investigate all
possible adverse events that extend beyond 1 year.
Weight gain is regarded as a class effect, although a
recent review of the literature showed that it was more
substantial with clozapine or olanzapine, moderate
with risperidone or quetiapine, and low with zipr-
asidone [66]. Evaluating weight change in children
must take into account expected weight changes
associated with normal growth, and thus comparative
trials versus typical antipsychotics or placebo are
useful to understand the magnitude of weight change
associated with use of atypical antipsychotics. Limited
data are available in children and adolescents
regarding the risk of obesity and the associated
cluster of metabolic adverse events, e.g. the metabolic
syndrome and diabetes, when atypical antipsychotics
are given. However, the consensus on antipsychotic
drugs and obesity and diabetes recently published by
the American Diabetes Association in collaboration
with the American Psychiatric Association [5] rec-
ommends closely monitoring patients’ weight at reg-
ular intervals and providing nutrition and physical
activity counselling to both patients and caregivers. It
is recommended that if an adult patient gains ‡5% of
his/her initial weight, therapy should be re-evaluated
[5]. This value, however, is possibly not specific en-
 P. Jenson et al.
Paediatric Atypical Review
ough for the paediatric population. Current guidelines
indicate that children or adolescents who are over-
weight (body mass index 85th percentile for age and
sex) and have family history of diabetes in a first- or
second-degree relative are at increased risk to develop
diabetes [1]. An analysis of the cases of hyperglyca-
emia reported to the US Food and Drug Administra-
tion MedWatch drug surveillance system in patients
younger than 19 years identified an increased number
of cases (compared with the background rate) in pa-
tients treated with clozapine, but not olanzapine [34].
A more recent query of MedWatch relating to chil-
dren treated with risperidone identified 12 cases of
diabetes-associated adverse events between 1993 and
2002, but the relative rate was not reported [35].
Certain ethnic groups carry an increased risk of dia-
betes and metabolic adverse effects, e.g. African
American, Hispanic, Asian Islander, because of ge-
netic predisposition to insulin resistance [1]. These
patients may require extra caution when treated with
atypical antipsychotics.
Other, less frequent adverse events that should
nonetheless be closely monitored include EPS, hyper-
glycaemia and diabetes, and endocrine adverse events.
While the initial TRAAY recommendations did not
suggest monitoring for glucose and lipids in patients at
risk of development of diabetes [48], in light of the
recent American Diabetes Association and American
Psychiatric Association guidelines [5], it appears pru-
dent to consider that these same recommendations
might also apply to children and adolescents.
Several long-term studies (>6 months) indicate
that, at least with risperidone, there are no negative
effects of atypical antipsychotics on cognitive func-
tioning or growth and sexual maturation. In addition
to measuring cognitive development, future studies
using atypical antipsychotics in paediatric patients
should also measure long-term academic and social
development in treated children, as well as the need
for long-term maintenance therapy. Pharmacoeco-
nomic studies, measuring both treatment and societal
costs from paediatric psychiatric diseases, should also
be conducted.
The improved tolerability and safety profile com-
pared to their predecessors is one factor that has led
to the increased use of the atypical antipsychotics in
children and adolescents. However, caution is re-
quired because this population may be more suscep-
tible to EPS and hyperprolactinaemia-related adverse
events. While there have been some studies with
duration up to 2 years, no definitive data are available
that suggest long-term safety, and additional studies
are therefore warranted.
Although we aimed to provide an extensive review
of the available clinical trials with atypical antipsy-
chotics in children and adolescents, our search was
117
limited to the published peer-reviewed literature. A
more exhaustive review might have included unpub-
lished data or abstracts from conferences. However,
the inclusion of unpublished data could have biased
the findings, since not all published data are readily
accessible and such studies are not invariably of suf-
ficiently high quality to warrant publication. While
the inclusion of other databases (such as the Coch-
rane Reviews) could have been done, Medline and
EMBASE are principal sources for the world’s litera-
ture of controlled clinical trials in high quality peer-
reviewed journals, and would be unlikely to change
the findings reported here.
To allow for comparisons of efficacy, we report
effect sizes where placebo-controlled double-blind
studies were available for review. Caution is required,
however, when interpreting effect sizes across studies,
because differences in dosing, duration of studies, and
sample characteristics could have influenced the
medication vs. placebo differences.
Conclusion
Significant psychiatric illness occurs in about 20% of
children. These psychiatric disorders lead to impaired
academic and social development, as well as increased
societal costs. In patients with DBDs and PDD and
moderate-to-severe symptoms who have not ade-
quately responded to behavioural interventions or
primary disease therapies, it is apparent that atypical
antipsychotics can effectively reduce disabling
behaviours across a broad spectrum of common
paediatric psychiatric disorders, with a growing lit-
erature suggesting tolerability. Conversely, there is
unmet need of controlled data to guide clinical
practice with atypical antipsychotics for paediatric
psychotic disorders and mania.
There is growing evidence of the favourable risk/
benefit profile of risperidone, olanzapine, and quetia-
pine in both short- and long-term studies. Side-effects
such as weight gain and endocrine side-effects have
been elucidated in clinical studies, but additional data
are warranted to confirm the long-term safety of
atypical antipsychotics during pubertal development
and the risk of metabolic abnormalities. Therefore,
endocrine side-effects and weight gain should be
carefully managed by the treating physician. Properly
designed studies should systematically assess the risk
for rare adverse events and tardive dyskinesia. The use
of clozapine should be limited in children because of
the reported serious haematalogical adverse events.
Close electrographical monitoring is required when
prescribing ziprasidone to children because of harm-
ful cardiac rhythm disturbances.
118
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