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Expert Opinion on Pharmacotherapy

ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: http://www.tandfonline.com/loi/ieop20

Using antipsychotics for behavioral problems in


children

Samreen Shafiq & Tamara Pringsheim

To cite this article: Samreen Shafiq & Tamara Pringsheim (2018): Using antipsychotics
for behavioral problems in children, Expert Opinion on Pharmacotherapy, DOI:
10.1080/14656566.2018.1509069

To link to this article: https://doi.org/10.1080/14656566.2018.1509069

Published online: 13 Aug 2018.

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EXPERT OPINION ON PHARMACOTHERAPY
https://doi.org/10.1080/14656566.2018.1509069

REVIEW

Using antipsychotics for behavioral problems in children


Samreen Shafiqa and Tamara Pringsheimb
a
Clinical Pharmacist and Research Assistant, Mathison Centre for Mental Health Research & Education, University of Calgary, Calgary, Canada;
b
Department of Clinical Neurosciences, Psychiatry, Pediatrics and Community Health Sciences, University of Calgary, Calgary, Canada

ABSTRACT ARTICLE HISTORY


Introduction: Antipsychotic use in children has increased over the past two decades. Randomized Received 20 April 2018
controlled trials have evaluated the efficacy of antipsychotics in autism spectrum disorder (ASD) and Accepted 3 August 2018
disruptive behavior disorders (DBD). KEYWORDS
Areas covered: The authors systematically analyze the results of randomized controlled trials of second Atypical antipsychotics;
and third generation antipsychotics for irritability in ASD and aggressive and disruptive behavior in DBD aripiprazole; risperidone;
with or without low IQ and ADHD. The aim of the review is to assist healthcare professionals to optimize lurasidone; quetiapine;
therapy in this population. autism spectrum disorder;
Expert opinion: There is evidence to support the short-term efficacy of risperidone and aripiprazole for disruptive behavior
irritability in ASD, and short-term efficacy of risperidone for aggressive and disruptive behavior in DBD, disorders; oppositional
although the benefits are closely balanced with an increased risk of metabolic, hormonal and extra- defiant disorder; conduct
disorder; aggression;
pyramidal adverse effects. The use of antipsychotics in children with these disorders should be reserved
irritability; children;
for those refractory to first and second-line therapies, and in whom there is a persistent and serious risk adolescents
of harm to self or others. Antipsychotics should be considered a short-term strategy while psychosocial
and behavioral therapies are continuously employed.

1. Introduction goal of the review is to analyze the growing evidence in


regards to clinical efficacy and the safety profile of antipsycho-
The prescribing of antipsychotics in children and adoles-
tics for these disorders. In addition, we aim to explore the
cents has steadily increased worldwide over the past
pathophysiology of ASD and DBD and the corresponding
15 years [1–8]. Antipsychotics are most frequently used in
neurobiological effects of second and third generation
children for aggressive and disruptive behavior associated
antipsychotics.
with attention-deficit/hyperactivity disorder (ADHD), opposi-
tional defiant and conduct disorder(CD), and adolescents
with mood and anxiety disorders [9]. Prescribing trends 2. Methodology
also reveal diminishing use of first generation antipsychotics
Several strategies were applied to identify controlled trials of
in comparison to second and third generation antipsycho-
antipsychotics in children and youth with autism and DBD.
tics [1–9]. The increased utilization may be due to expand-
Three recently published systematic reviews on the use of
ing evidence on antipsychotic efficacy in various pediatric
antipsychotic medications for the treatment of autism and
mental health conditions and the availability of newer anti-
DBD were identified and reviewed in detail [10–12]. To identify
psychotics. Traditionally, antipsychotics were mainly used in
any trials published after these systematic reviews were per-
children and adolescents with schizophrenia and bipolar
formed, we re-ran the searches described in these reviews
disorder. Several randomized controlled trials with second
from the last dates mentioned in the search strategies until
and third generation antipsychotics in children have been
March 2018. Two reviewers assessed the abstracts for rele-
conducted in the past 20 years, leading to US Food and
vance and further reviewed the selected full articles consid-
Drug Adminstration approval of risperidone and aripiprazole
ered to be pertinent to the review. Some studies were
in the treatment of irritability in autism spectrum disorder
identified through reference review of the full articles. The
(ASD), and aripiprazole for the treatment of tics in Tourette
inclusion criteria for relevant studies on the efficacy and safety
syndrome. While risperidone has not been approved for the
of second and third generation antipsychotics included the
use of disruptive and aggressive behavior, it is frequently
following: double-blind, randomized, placebo controlled trials,
used off-label for this purpose.
comparing the efficacy and safety of second and third gen-
The purpose of this article is to review the use of second
eration antipsychotics in ASD and DBD. We performed ran-
and third generation antipsychotics for children and adoles-
dom-effects meta-analyses of efficacy data from the identified
cents with irritability in ASD and aggressive and disruptive
trials by drug and disorder using Review Manager software.
behavior in disruptive behavior disorders (DBD). The primary

CONTACT Tamara Pringsheim tmprings@ucalgary.ca Department of Clinical Neurosciences, Psychiatry, Pediatrics and Community Health Sciences,
University of Calgary, 3280 Hospital Drive NW, AB T2N 4Z6 Calgary, Canada
© 2018 Informa UK Limited, trading as Taylor & Francis Group
2 S. SHAFIQ AND T. PRINGSHEIM

however microanatomical changes persist. This abnormal neu-


Article highlights rodevelopmental growth pattern results in smaller neural net-
● Evidence for the use of antipsychotics in the treatment of aggression
works which are less synchronized. Cortical thinning and
and irritability in children with ASD and DBDs has steadily increased inconsistency in the number and size of Purkinje cells are
over the past few years. observed, with the long-range functional connectivity of tem-
● Risperidone and aripiprazole have demonstrated efficacy for the
treatment of irritability in ASD.
poral and frontal cortex most impacted. The temporal and
● Currently, only risperidone is supported with evidence for the treat- frontal cortex in the normal brain are responsible for social,
ment of aggression in DBDs. communicative and self-regulation functions [16].
● Psychosocial and cognitive behavioral therapy is the mainstay of
treatment for mild to moderate case presentations. Antipsychotics
Current studies are exploring the roles of neurotransmitters
are reserved for short-duration therapy for severe case presentations. in the manifestation of symptoms in ASD. Considering the
● ADR must be anticipated and monitored delingently through avail- genetic etiology of ASD, most studies are observing the
able evidence-based guidelines.
● In order to optimize therapy, future investigations should focus on
genetic disposition related to neurotransmitter synthesis in
individual factors which may effect the efficacy and safety of ASD and established genetic disorders with autism-like symp-
antipsychotics. toms. Investigations of serotonin (5-HT), dopamine (D) and
This box summarizes key points contained in the article. glutamyl amino butyric acid (GABA) are the most promising.
Individuals with ASD are well documented to have a high
concentration of serotonin in platelets, however, this observa-
tion has not been associated with increased synthesis or
exposure of 5-HT in plasma. Although, it is well established
3. Autism spectrum disorder
that reduced serotonergic function may contribute to autism-
(ASD) is a neurodevelopmental disorder characterized by like symptoms, the direct correlation of hyperserotonemia in
impaired social interaction and repetitive and restricted beha- ASD is unclear [17].
vior which may limit everyday functioning [13] In 2013, the Additionally, dysregulation in dopaminergic function in the
Diagnostic and Statistical Manual of Mental Disorders, 5th forebrain has been associated with movement, perception,
Edition (DSM-V) updated ASD to encompass autistic disorder, and social behavior. Individuals with ASD have not been
Asperger’s disorder, pervasive developmental disorders – not found to exhibit impairment in dopamine synthesis and meta-
otherwise specified (PDD-NOS) and childhood disintegrative bolism [18]. Investigations evaluating certain genetic condi-
disorder. A review conducted on the global prevalence of ASD tions which effect dopamine synthesis and metabolism and
estimates a prevalence of autism of 17 per 10,000 individuals feature some of the core symptoms of ASD (ie. phenylketo-
and a prevalence of PDD of 62 per 10,000 individuals [14]. nuria) have not been able to associate a specific mutation in
The diagnosis, monitoring and treatment of ASD is directed an enzyme or gene to ASD [19]. The reduction in the size and
by a cluster of core symptoms. These core symptoms include; number of Purkinje cells in individuals with ASD has been
irritability, aggression and social withdrawal due to deficits in theorized to decrease GABA activity in this population. It has
forming relationships, patterns of repetitive behavior and pre- been proposed that this pathology may be associated with a
ferences resulting in hyperactivity or hypoactivity, and verbal increased predisposition to seizure disorders in individuals
and/or nonverbal communication impairment [13]. There are with autism [20].
various diagnostic tools available to diagnose and monitor
symptom severity of ASD. For the purpose of this review, we
3.1. Risperidone for treatment of irritability in ASD
will focus on the Aberrant Behavior Checklist (ABC), as the
RCTs analyzed in this review utilized the ABC scale to assess We conducted a meta-analysis of three RCTs which investi-
the effect of the study intervention. The ABC is a parent/ gated the effects of risperidone on irritability in children with
caregiver focused questionnaire which includes a set of 58 ASD[21–23] (see Table 1 for study details). These studies
questions based on core symptoms such as irritability, hyper- investigated the short term effects of risperidone compared
activity, stereotypy, social withdrawal and speech impair- to placebo in a double-blinded, randomized controlled trial.
ment [15]. The study subjects were individuals diagnosed with ASD (as
Individuals with ASD present with a widespread distribu- defined by DSM-IV) between the ages of 5 and 17 years, with a
tion of social and behavioral impairments. This heterogeneity Childhood Autism Rating Scale (CARS) of 30 or more or ABC-
is also consistent with findings of morphological studies con- Irritability Subscale score of 18 or more. The trials ranged from
ducted to investigate the differences in the central nervous 6 to 8 weeks in duration and risperidone was administered at
system of individuals with ASD. The usual existence of comor- the dose of 1.25–1.8 mg per day. Kent et al. investigated the
bidities further complicates the categorization of anatomical treatment with risperidone in both low (0.125–0.175 mg) and
differences in ASD patients. Generally, most studies indicate high (1.25–1.75 mg) doses over 6 weeks, while the other
that individuals with ASD have accelerated neurodevelopmen- studies examined the effect of risperidone in variable doses
tal processes in early life (prenatal to two years). This results in (according to body weight) over 8 weeks. We included the
an overall large brain volume, with the most evident enlarge- results of the higher dose of risperidone from the Kent study
ments of the frontal, temporal and parietal lobes. Subcortical in our meta-analysis. The primary outcomes were the changes
structures such as the brainstem, thalamus, and hippocampus from baseline to end of treatment for the core symptoms on
show reduced size. The neurodevelopmental growth pattern the ABC scale, the Nisonger Child Behavior Rating form (N-
eventually stabilizes to show a near normal brain size, CBRF) and Clinical Global Impression Scale (CGI). In addition,
Table 1. Included studies, risperidone, irritability in autism spectrum disorder.
Study, date, location, population
Intervention and length of Rx Behavioral outcome Adverse effects Risk of bias
RUPP Network 2002 Risperidone 0.5–3.5 mg/day Aberrant Behavior Checklist- Significantly greater mean increase in weight with risperidone (2.7 kg) than placebo (0.8 kg). Allocation concealment
United States Placebo Irritability Subscale Fatigue and drowsiness were significantly more common in risperidone group than placebo. unclear
Child and adolescents 5 to 8 weeks Mean change from baseline No difference between groups in extrapyramidal symptoms as measured with the Abnormal
17 years meeting criteria for Risperidone −14.9 SD 10.82 Involuntary Movement Scale or Simpson-Angus Scale. Tremor was more common in the
autistic disorder Placebo −3.6 SD 11.5 risperidone group.
N = 101 Mean difference −11.3 (−15.66,
−6.94)
Shea 2004 Risperidone 0.01 to 0.06 mg/ Aberrant Behavior Checklist- Somnolence Allocation concealment
Canada kg/day Irritability Subscale Risperidone 29/40; Placebo 3/39 unclear
Children 5 to 12 years with PDD Placebo Mean change from baseline URTI
with disruptive behavioral 8 weeks Risperidone −12.1 SD 5.8 Risperidone 15/40; Placebo 6/39
symptoms Placebo −6.5 SD 8.4 Tremor
N = 80 Mean difference −5.6 (−8.83, Risperidone 4/40; Placebo 0/39
−2.37) Weight gain
Risperidone 2.7 kg; Placebo 1.0 kg p < 0.001
Kent 2013 Risperidone low dose 0.125 Aberrant Behavior Checklist- The most common adverse events in the combined low and high dose groups of risperidone
United States to 0.175 mg/day (based Irritability Subscale were increased appetite (26%), sedation (15%), somnolence (11%) and weight gain (11%).
Children 5 to 17 years with on weight) Mean change from baseline Extrapyramidal symptom related adverse events were most frequent in the risperidone high-
autistic disorder Risperidone high dose 1.25 Placebo −3.5 SD 10.67 dose group (16%) and were mostly akathisia (13%).
N = 96 to 1.75 mg/day (based on Risperidone low dose −7.4 SD 8.12 Mean change from baseline in serum prolactin levels was greater in the risperidone high
weight) Mean difference −3.0 (−7.36, 1.27) dose group (20.23 ng/ml) than in the low dose group (2.58 ng/ml) or placebo (1.27 ng/
Placebo Risperidone high dose −12.4 SD ml).
6 weeks 6.52 Mean weight increase
Mean difference −7.9 (−12.19, Placebo 0.7 kg SD 1.19
−3.52) Risperidone low dose 1.2 kg SD 1.13
Risperidone high dose 2.4 kg SD 2.07
EXPERT OPINION ON PHARMACOTHERAPY
3
4 S. SHAFIQ AND T. PRINGSHEIM

the safety and tolerability of risperidone were also reported. substitution to placebo. Relapse rate was defined as a 25%
Meta-analysis of the results of the three trials demonstrated a increase in the ABC-Irritability Subscale. The relapse rate for
mean difference on the ABC-Irritability Subscale of −8.34 irritability after the discontinuation of risperidone was signifi-
points for the risperidone group compared to placebo after cantly higher in the placebo-treated group (62.5%) compared
6–8 weeks of treatment (95% CI −11.72 to −4.96, tau2 = 4.49, to the group receiving continued risperidone (12.5%) [25].
I2 = 55%, P value < 0.00001) (see Figure 1). This change from Similar results were observed by Troost et al, in which study
the baseline after 6–8 weeks of treatment is considered clini- subject selection, length, protocol and primary outcomes
cally important. In fact, Shea et al. reported a statistically were identical to the RUPP discontinuation study. The study
significant change in irritability for the risperidone group demonstrated that 67.0% of the children in the placebo
after 2 weeks of treatment. group of the discontinuation phase relapsed on the ABC
irritability scale compared to 25.0% in the risperidone group
[26]. Both studies also reported weight increase for the entire
3.2. Adverse drug reactions related to risperidone in ASD
subject population over the 6 months of treatment, with
The three studies above also investigated the occurrence of RUPP reporting a 5.1 kg increase and Troost et al. reporting
adverse drug reactions (ADR) in both the risperidone and a 5.7 kg increase from the baseline.
control group. The most common ADR was somnolence,
upper respiratory tract infection and weight gain.
Risperidone was associated with somnolence and sedation in
3.4. Pharmacodynamic, pharmacokinetic and
72.5% compared to 7.7% of the placebo group in Shea et al.
pharmacogenomic properties of risperidone
and 49.0% vs. 12.0% in RUPP 2002. Kent et al. reported that
the high-dose risperidone group experienced sedation (26.0%) Risperidone is a selective antagonist, which has a high
and somnolence (23.0%) compared to placebo (6.0% for both affinity for 5-HT2, D2, alpha (α1) and α2 adrenergic, and
sedation and somnolence). Upper respiratory tract infections histamine (H1) histaminergic receptors. It also has low to
occurred in 37.5% of the risperidone group compared to moderate affinity for 5-HT1C, 5-HT1D, and 5-HT1A receptors
15.4% in the placebo group in Shea et al. study. Moreover, a [27]. Although the role of serotonin and dopamine has not
systematic review meta-analyzed the results of weight gain in been established in the pathology of ASD and DBD, clinical
the RUPP trial and Shea et al. Children who gained weight in studies demonstrate the efficacy of risperidone in improving
the risperidone group gained an average of 2.7 kg compared irritability [11,21,22,24,28–37]., and this efficacy has been
to 1.0 kg in the control group[24]. Kent et al. report a mean attributed to risperidone’s activity on these pathways [38].
increase of 2.4 kg in individuals receiving high dose risperi- Risperidone is quickly absorbed and distributed in the
done, 1.2 kg receiving low dose risperidone and 0.7 kg receiv- plasma, with a protein binding of 99%. It is extensively
ing placebo. Shea et al. further reports extrapyramidal side- metabolized by cytochrome P450 (CYP 2D6) in to two
effects (EPS) in 27.5% of children in the risperidone group enantiomers of 9-hydroxyrisperidone. The overall clinical
compared to 12.8% in the placebo group. The RUPP trial effect is exhibited by the combined effect of risperidone
reported the occurrence of EPS with risperidone compared and 9-hydrorisperidone [38]. Certain pharmacogenomics
to placebo as dyskinesia (12.0% vs. 6.0%), tremors (14.0% vs. studies indicate that various genes may influence the clin-
2.0%) and muscle rigidity (10.0% vs. 2.0%). ical efficacy and safety of risperidone. Among these are
HTR2A (code for 5-HT2A), DRD3 (code for D2), HTR2C (code
for 5-HT2c), ABCB1 (code for P-glycoprotein) and CYP2D6
3.3. Long-term treatment with risperidone in ASD
(various alleles). Current studies have resulted in contradict-
Discontinuation studies of risperidone in ASD further evalu- ing outcomes, thus further research in this area is necessary
ate the effectiveness and safety of long-term therapy with [39,40]. Another mediator to clinical response and safety is
risperidone for the treatment of various behavioral symptoms the dose. One study examined the effect low dose of ris-
[25,26]. A study conducted by RUPP examined relapse rates peridone (0.125–0.175 mg/day) compared to high dose
after discontinuing risperidone gradually from responders (1.25–1.75 mg/day). The result indicated that high dose of
after 4 months of treatment. Individuals were initially pro- risperidone significantly improves response on the ABC-
vided with open label treatment with risperidone for Irritability Subscale, however, also increases the incidence
4 months. Responders were randomly allotted to an 8-week of ADR, such increased appetite, weight gain and somno-
trial of either continued risperidone treatment or gradual lence [22].

Figure 1. Risperidone for irritability in autism spectrum disorder.


EXPERT OPINION ON PHARMACOTHERAPY 5

3.5. Aripiprazole for the treatment of irritability in ASD The responders (≥ 25% improvement in ABC-irritability
Subscale and ≤2 on CGI scale over 12 weeks of treatment)
There are three published RCTs examining the short-term
from phase 1 were enrolled into phase 2. In phase 2, 85
efficacy of aripiprazole on irritability in ASD [41–43] (see
responders were randomly allocated to placebo or aripiprazole
Table 2 for study details). These studies were double-blinded,
in a double-blinded trial for 16 weeks or until relapse. The
randomized-controlled trials, which investigated the efficacy
primary end point was time from randomization to relapse
of aripiprazole for irritability in ASD compared to placebo. The
and the mean change in the ABC-Irritability Subscale. After
study subjects were individuals diagnosed with ASD (as
16 weeks of treatment with aripiprazole or placebo, relapse
defined by DSM-IV) between the ages of 6 and 17 years,
occurred in 35% and 52%, respectively, with a hazard ratio of
with a CGI score of 4 or more or ABC irritability score of 18
0.57 (95% CI, 0.28–1.12). The time to relapse for the aripipra-
or more. The trials were 8 weeks in duration and aripiprazole
zole group was 56 days (95% CI 31 to undefined) and 29 days
was administered at the dose of 1–15 mg per day. Owen et al.
(95% CI 25–45) for the placebo group. Additionally, an overall
further stratified the aripiprazole group according to dosing of
mean increase was reported for the ABC-Irritability Subscale
5, 10 and 15 mg. The primary outcomes studied were the
for both the placebo and aripiprazole group. The mean differ-
mean changes from baseline to endpoint for irritability on
ence between the two groups was −4.40 (95% CI −8.82–0.02),
the ABC scale. The safety and tolerability of aripiprazole were
favoring aripiprazole. The difference in the time to relapse
also reported. Meta-analysis of the three trials resulted in the
(P = 0.097) and mean changes in the irritability ABC subscale
mean difference on the ABC-Irritability Subscale of −5.47
(P = 0.051) were not statistically significant.
points for the aripiprazole group compared to placebo after
Findling et al. also reported ADRs. In the first phase, the
8 weeks of treatment (95% CI −7.66 to −3.28, tau2 = 0.63,
most common ADRs were weight gain (25.2%), somnolence
I2 = 17%, P value < 0.00001) (see Figure 2). This change from
(14.8%) and vomiting (14.2%). Extrapyramidal side-effects
the baseline after 8 weeks of treatment is considered clinically
occurred in 17.4% of individuals in the aripiprazole, of which
relevant.
tremor (6.5%) was most common. During the 16 weeks pla-
cebo discontinuation phase, the most common ADR reported
3.6. Adverse drug reaction related to aripiprazole in ASD in the aripiprazole group compared to placebo were upper
respiratory tract infections (10.3% vs. 2.3%, respectively), con-
A systematic review analyzed the cumulative results from stipation (5.1% vs. 0%, respectively) and movement disorders
Marcus et al. and Owen et al. on the ADRs associated with (5.1% vs. 0%, respectively). Extrapyramidal side-effects
aripiprazole compared to placebo [10]. The most common occurred in 7.7% of patients on aripiprazole and 7.0% of the
side-effects from the two studies were sedation, drooling, patients in the placebo group. Additionally, weight gain in the
and tremor. Individuals in the aripiprazole group were more aripiprazole group was 2.2 kg at the end of phase 2 compared
likely to experience sedation, compared to the placebo group to 0.6 kg for the control group.
(RR 4.28, 95% CI 1.58 to 11.6, tau2 = 0.00, I2 = 0%, P
value = 0.0043). Drooling was also more likely to occur in
the aripiprazole group (RR 9.64, 95% CI 1.29–72.10, tau2 = 0.00, 3.8. Pharmacodynamic, pharmacokinetic and
I2 = 0%, P value = 0.027). Tremor was more likely to occur with pharmacogenomic properties of aripiprazole
aripiprazole (RR 10.26, 95% CI 1.37–76.63, tau2 = 0.00, I2 = 0%, Aripiprazole is a partial agonist of 5-HT1A and D2 and an
P value = 0.023). As for other EPS-related side-effects, the antagonist for 5-HT2A. As a partial agonist, aripiprazole has
systematic review reported there was no difference between high affinity to the receptors, however, exhibits limited activity
aripiprazole and the control group for other EPS-related side [45]. The partial agonism of D2 results in reduced upregulation
effects. Additionally, greater weight gain occurred in indivi- of the receptor while antagonism of 5-HT2A increases dopa-
duals in the aripiprazole group compared to the placebo mine release. In addition, the partial agonism of 5-HT1A exerts
group, with a mean difference of 1.13 kg (95% CI 0.71–1.54, an anxiolytic effect [45]. Although, the role of dopamine and
tau2 = 0.00, I2 = 0%, P value < 0.00001). Ichikawa et al reported serotonin has not been established in the manifestation of the
somnolence as the most common ADR in the aripiprazole core symptoms of ASD, aripiprazole has demonstrated clinical
group (51.1%) compared to placebo group (8.9%). Salivary efficacy in irritability, hyperactivity, stereotypy and inappropri-
hypersecretion was observed in 4.3% of the aripiprazole ate speech [10,41–44]. Aripiprazole reaches maximum concen-
group compared to 2.2% with placebo. Extrapyramidal side- tration within 2 h of administration. The half-life is between 48
effects were noted in 2.1% of the aripiprazole group and none and 68 h in both children and adults. It is extensively protein
in the placebo group. Weight gain was not considered signifi- bound and metabolized by CYP 2D6 and CYP 3A4 to aripipra-
cant between the aripiprazole and placebo group (1.24 kg vs. zole and dehydroaripiprazole. Some studies indicate that poor
0.58 kg, P value = 0.085). metabolizers of CYP 2D6 and 3A4 are hypothetically linked to
increased adverse events [45].
3.7. Long-term treatment with aripiprazole in ASD
3.9. Use of lurasidone for the treatment of irritability in
One placebo discontinuation study of aripiprazole has been
ASD
conducted in children and youth with ASD [44]. This study was
performed in two phases. In phase 1, all subjects were treated Currently, one double-blinded RCT has investigated the short-
with aripiprazole for 13–26 weeks in a single-blinded setting. term clinical efficacy of lurasidone in ASD [46] (see Table 3).
6
S. SHAFIQ AND T. PRINGSHEIM

Table 2. Included studies, aripiprazole for irritability in autism spectrum disorder.


Study, date, location, population Intervention and length of Rx Behavioral outcome Adverse effects Risk of bias
Marcus 2009 Aripiprazole 5, 10 or 15 mg/day versus placebo Aberrant Behavior Checklist- Irritability Subscale Any extrapyramidal symptom Allocation concealment
United States 8 weeks Score (ABC-I) Aripiprazole 37/165; Placebo 6/51 unclear
Children and adolescents 6 to 17 years with Mean change from baseline to end point RR 1.91 (0.85, 4.26)
ASD and serious behavioral problems Aripiprazole −13.3 SD 9.4 Weight gain
N = 218 Placebo −8.4 SD 9.4 Aripiprazole 1.4 kg (SD 1.5) Placebo 0.3 (SD
Mean difference −4.9 (−7.90, −1.90) 1.5), mean difference 1.10 (0.62, 1.58)
Sedation
Aripiprazole 39/165; Placebo 3/51
RR 4.02 (1.30, 12.46)
Owen 2009 Aripiprazole 5, 10 or 15 mg/day -flexible dose Aberrant Behavior Checklist- Irritability Subscale Any extrapyramidal symptom
United States versus placebo Score (ABC-I) Aripiprazole 7/47; Placebo 4/50
Children and adolescents 6 to 17 years with 8 weeks Mean change from baseline to end point RR 1.86 (0.58, 5.95)
ASD and serious behavioral problems Aripiprazole −12.9 SD 9.4 Weight gain
N = 98 Placebo −5.0 SD 9.4 Aripiprazole 2.0 kg (SD 2.9) Placebo 0.8 kg (SD
Mean difference −7.9 (−11.68, −4.12) 2.0), mean difference 1.20 (0.40, 2.00)
Sedation
Aripiprazole 5/47 Placebo 1/50
RR 5.32 (0.65, 43.86)
Ichikawa 2017 Aripiprazole 1 to 15 mg/day -flexible dose versus Aberrant behavior Checklist- Irritability Subscale Somnolence
Japan placebo Score (ABC-I) Aripiprazole 24/47; Placebo 4/45
Children and adolescents 6 to 17 years with 8 weeks Mean change from baseline to end point Extrapyramidal symptoms
autistic disorder and behavioral problems Aripiprazole −11.4 SD 8.9 Aripiprazole 3/47; Placebo 1/45
such as irritability, agitation, self-injurious Placebo −7.5 SD 9.39 Increase in body weight of > 7% from
behavior Mean difference −3.9 (−7.77, −0.12) baseline was seen in 6.7% of the placebo
N = 92 group and 27.7% of the aripiprazole group
EXPERT OPINION ON PHARMACOTHERAPY 7

Figure 2. Aripiprazole for irritability in autism spectrum disorder.

The study subjects were diagnosed with ASD and required an Many investigations have explored neurobiological path-
ABC-Irritability Subscale score ≥18 and CGI score of ≥4. The ways in the manifestation of aggression and callousness in
subjects were randomly allocated to placebo (n = 50), lurasi- ODD and CD. Research indicates the role of amygdala reactiv-
done 20 mg (n = 49) and lurasidone 60 mg (n = 51). The ity in the processing of stressful situations. Individuals with CD
primary outcome was the mean change on the ABC-Irritability and high callousness have demonstrated hyporeactivity of
Subscale score from baseline to the end of 6 weeks treatment. amygdala when exposed to fearful faces. These individuals
The mean difference in change scores between lurasidone appear to process stressful situations with unemotional ten-
20 mg and placebo was −1.3 (95% CI −5.6–3.0, p = 0.55). dencies. In contrast, hyperreactivity of the amygdala is evident
Similarly, the mean difference between lurasidone 60 mg in individuals with CD and low callousness, accounting for
and placebo was −1.9 (95% CI −6.1–2.2, p = 0.36). The most inclination toward aggressiveness in perceived stressful situa-
common treatment-emergent adverse event was vomiting tions [53]. The hypothalamus-pituitary-adrenal (HPA) axis also
(28.0% in lurasidone 60 mg, 8.0% in lurasidone 20 mg, and regulates biological responses to stress. Studies have demon-
4.0% in placebo). Somnolence occurred in 18.0% of the lura- strated varying levels of cortisol in individuals with CD. Low
sidone 60 mg group, 6.0% of the lurasidone 20 mg group and levels of cortisol has been associated with callousness, while
4.0% of placebo. Weight gain occurred in 8.0% of the lurasi- high levels may be involved in exhibition of anxiety and
done group compared to 2.0% of placebo group. The mean aggressive behavior [53]. The reactivity of limbic system (i.e.
weight gain in lurasidone was 1.2 kg compared to 0.4 kg of amygdala, hypothalamus) is postulated to stimulate the upper
the placebo group (p = 0.015) [46]. brainstem and subsequent regulation of neurotransmitters
Lurasidone is an antagonist of 5-HT2A, 5-HT7 and D2 recep- release. Dopamine, 5-HT and noradrenergic hormones may
tors and a partial agonist for 5-HT1A receptors [47]. Although, be involved in the manifestation of aggression. Investigations
risperidone has similar pharmacodynamic activity as lurasi- have linked both high and low levels of serotonin to aggres-
done, comparatively, lurasidone has not demonstrated clinical sion. However, low levels of serotonin is also associated with
efficacy in ASD [46]. Lurasidone is rapidly absorbed and increased dopaminergic and noradrenergic activity, via sys-
reaches maximum concentration in 1–3 h. The administration temic imbalance. This increased activity is associated with
of lurasidone with food increases the area under the curve impulsivity and irritability [54].
(AUC) and maximum concentration by 2–3 fold. Additionally, it
is extensively protein bound and metabolized primarily by CYP
3A4 into 3 active metabolites [48]. 4.1. Risperidone for ODD/CD in individuals with
subaverage IQ
To date, five RCTs have studied the effect of risperidone on
4. Disruptive behavior disorders
ODD/CD in individuals with subaverage IQ [30–34] (see
DBD are a set of disorders which include oppositional defiant Table 4). These studies investigated the short and long term
disorder (ODD), CD and DBD not otherwise defined (DBD-NOS) effects of risperidone compared to placebo in a double-
[13]. Generally, these disorders are characterized by persistent blinded, randomized setting. The study subjects were indivi-
lack of inhibition and constraints over emotions and behavior. duals diagnosed with ODD or CD (as defined by DSM-IV) with
Emotional dysregulation is a key feature of ODD, which is or without ADHD between the ages of 5 and 18 years, with IQ
usually expressed through anger/irritable mood, defiant and between 36–85. The trials ranged from 4 weeks to 6 months in
argumentative behavior, or vindictiveness. CD is manifested as duration and risperidone was administered at the dose of 0.4–
aggression and callousness toward society that usually results 3.8 mg per day. The primary outcomes were the mean
in the violation of rights of others [49]. In 2010, a systematic changes from the baseline to end point in conduct problems,
analysis investigated the worldwide prevalence of CD and as measured by N-CBRF, Overt Aggression Scale (OAS-M), ABC
ODD to be 3.2% and 3.3%, respectively [50]. and CGI. A systematic review analyzed the standardized mean
Comorbidity of ODD and CD may occur, with ODD usually difference (SMD) between risperidone and placebo for con-
preceding CD in childhood [51]. Up to 60% of the individuals duct problems and aggression in a meta-analysis of study data
with ADHD have co-occurring ODD and 15% have CD [52]. from the three trials which provided data on end point or
Poor outcomes in overall childhood development and prog- change scores [11]. These results are demonstrated in Figure 3.
nosis of ADHD have been associated with the presence of The SMD was 0.98 (95% CI 0.57 to 1.38, I2 = 55%, P < 0.00001)
ODD or CD [52]. for the risperidone group compared to the placebo group
8 S. SHAFIQ AND T. PRINGSHEIM

after 6 weeks of treatment. In fact, Aman et al and Snyder et al.

bias
Risk
of
observed a significant decrease in the mean score of NCBRF
scale after 1 week of treatment. The ADR most commonly

small mean changes at Week 6 in the Barnes Akathisia Rating Scale total score
Treatment with lurasidone (20 and 60 mg/day vs. placebo) was associated with

(0.08 and −0.12 vs. 0.00) and the Simpson Angus Scale 10-item mean score

triglycerides (median change, 13.0 vs. −4.0 mg/dL) and cholesterol (median
There was an increase for the lurasidone 60 mg/day group versus placebo in
Increased weight was observed in all three treatment groups at Week 6. The
reported in the three trials was somnolence for risperidone

placebo, but a greater increase was noted for the lurasidone 60 mg/day
increased weight was similar for lurasidone 20 mg/day compared with
compared to placebo (Aman et al. reported 51% vs. 10%,
Snyder et al. reported 41.5% vs. 14.0%, Buitelaar et al reported
10.5% vs. 0%). Increase in appetite was also observed (Aman
et al. reported 15.0% vs 2.0%, Snyder et al. reported 15.1% vs.
3.5%). Although, Aman et al. and Snyder et al. indicate that the
incidence of EPS was not significantly different between pla-
cebo and risperidone, prolactin was significantly higher in the
Adverse effects

risperidone group compared to placebo.

4.2. Long-term treatment of with risperidone in DBD


change, 8.0 vs. −5.0 mg/dL).
(−0.01 and −0.05 vs. −0.01).

In a long-term discontinuation study, the efficacy of risperi-


done on conduct problems and aggression was studied for
6 months [34]. Children aged 5–17 years were included in the
study, with a diagnosis of ODD or CD (DSM-IV) with or without
ADHD. The subjects first received open-label treatment with
group.

risperidone for 6 weeks, then single-blinded treatment with


risperidone for 6 weeks, and then finally entered a 6-month
double-blinded, randomized-controlled study during which
The mean improvement in the ABC-I was not significantly different
for the lurasidone 20 mg/day group (−8.8), and the 60 mg/day

participants were randomized to placebo or continued risper-


idone treatment. The primary end point for the study was time
to symptom reoccurrence represented by CGI severity scale of
group (−9.4) compared with placebo (−7.5) at week 6

≥2 and change in NCBRF conduct problem subscale of ≥7


points. By the end of 6 months treatment, 27.3% in the
risperidone group relapsed compared to 42.3% of placebo
Behavioral outcome

group (P < 0.001). The mean weight increase after 6 months


of treatment was 2.1 kg in risperidone group compared to
ABC-Irritability Subscale Score (ABC-I)

−0.2 kg in the placebo group.

4.3. Risperidone for ODD/CD in individuals with average


IQ
Table 3. Included studies lurasidone for irritability in autism spectrum disorder.

For this review, we conducted a meta-analysis of three RCTs


which compared risperidone to placebo for oppositional beha-
vior or conduct problems in children and youth with average
IQ [[35–37]] (see Table 5). One study was conducted in indivi-
duals with ODD or CD without moderate to severe ADHD [35].
Lurasidone 20 mg/
Intervention and

day, Lurasidone
60 mg/day, or
length of Rx

The other two studies included individuals with severe symp-


toms of aggression and ADHD, with all study subjects receiv-
placebo

ing prior and concurrent treatment with stimulants and parent


6 weeks

training [36,37]. The trials ranged from 8 to 10 weeks in


duration and risperidone was administered at a dose of 0.5–
4.0 mg per day. The primary outcomes were the mean
changes from baseline to end point in oppositional or conduct
irritability, agitation, and/or self-
Children 6–17 years with autistic
Study, date, location, population

problems, as measured by NCBRF typical IQ Disruptive beha-


disorder who demonstrated

vior total, Rating of Aggression Against People and Property


(RAAPP) and Conners’ Parent Rating Scale Revised – Long
injurious behaviors

Version (CPRS-L). The cumulative results of the three trials


demonstrated a SMD of −0.64 (95% CI −0.89 to −0.40,
I2 = 0%, P < 0.00001) (see Figure 4) for the risperidone group
Loebel 2016

compared to the control group after 8–10 weeks of treatment.


N = 150

Jahangard et al. observed a weight gain of 4.2 kg for the


US

risperidone group compared to 0.74 kg for the placebo


Table 4. Included studies risperidone, conduct problems in children with disruptive behaviour disorders and low IQ.
Study, Date, location, population Intervention and length of Rx Behavioral outcome Adverse effects Risk of bias
Snyder 2002 Risperidone 0.98mg/d vs. Nisonger Child behavior Rating Form No discontinuations due to side effects. Method of randomization
Canada, USA, South Africa placebo (NCBRF) EPS 7 risperidone subjects; 3 placebo subjects not stated in methods.
Children 5–12 with CD, ODD, 6 weeks NCBRF-Conduct Problem: Change in score Significant increase in weight and BMI in risperidone group
DBD & sub average IQ from baseline to end point: Significant increase in prolactin in risperidone group
N = 110 Risperidone = 33.4 ± 0.86 to 17.6 ± 1.64
ADHD 76% Change = 15.8 ± 11.2 (95%CI 12.7, 18.9)
Placebo = 32.6 ± 0.83 to 25.8 ± 1.77
Change = 6.8 ± 11.2 (95%CI 3.8, 9.8)
p < 0.001
Effect size 0.81
Aman 2002 Risperidone 1.16 mg/d vs. NCBRF-Conduct Problem: Change in score No significant difference between groups in ESRS Method of randomization
USA placebo from baseline to end point: Risperidone mean weight gain 2.2 kg vs. placebo 0.9 kg not stated in methods,
Children 5–12 with sub average 6 weeks Risperidone = −15.2 ± 10.6 (95%CI 12.2, Significant increase in prolactin in risperidone group. There were 2 dropouts minor differences between
intelligence & severe DBD 18.2) in the risperidone group due to somnolence. groups at baseline.
N = 118 Placebo = −6.2 ± 11.2 p < 0.001 (95% CI
ADHD 59% 3.4, 9.0)
Effect size 0.83
Buitelaar 2001 Risperidone 2.9 mg/d vs. Clinical Global Impression-Severity (CGI-S) Significant increase in ESRS parkinsonism score at end point in risperidone Allocation concealment
Netherlands placebo CGI-S: Mean change from baseline to end group vs. placebo unclear.
Adolescents 12–18 with DBDs, 6 weeks point: Mean weight gain 2.3 kg in risperidone group vs. 0.6 kg in placebo group
sub average intelligence & Risperidone = 4.3 ± 1.4 to 2.7 ± 1.2 Significant increase in prolactin in risperidone group vs. placebo. There was
aggression Change = 1.6 ± 1.2 discontinuation in 1 participant in the risperidone group due to adverse
N = 38 Placebo = 4.2 ± 0.9 to 4.4 ± 1.0 effects.
ADHD 68% Change = -0.2 ± 0.9
p < 0.001
Effect size 1.2
Risperidone group showed significant
worsening on CGI-S scale during 2-week
washout.
EXPERT OPINION ON PHARMACOTHERAPY
9
10 S. SHAFIQ AND T. PRINGSHEIM

Figure 3. Risperidone for ODD/CD in individuals with subaverage IQ.

group. Aman et al. reported a 1.8 kg weight gain in the effects and drug induced movement disorders. One small RCT
risperidone group compared to −1.2 kg in the placebo group. of quetiapine for conduct problems in youth with CD suggests
some benefit compared to placebo. One long-term placebo
discontinuation study of risperidone in DBD demonstrated a
4.4. Quetiapine in individuals with CD lower risk of relapse with continued risperidone treatment.
One double blind randomized controlled trial investigated the
effects of quetiapine in adolescents with CD [55](see Table 5).
Subjects included were diagnosed with CD as per the overt 6. Expert opinion
aggression scale score of ≥25 and CGI score of ≥4. The trial Irritability and aggression are potentially debilitating conse-
was of 6 weeks duration and quetiapine was administered at a
quences of ASD and DBD. The presence of aggression in DBD
dose of 200–600 mg per day. Nine individuals were rando- and irritability in ASD is associated with poor quality of life for
mized to quetiapine and 10 to placebo. The primary outcome patients and their families [52,57,58]. For healthcare providers,
was improvement in CGI severity scores. After 6 weeks of
the management for behavioral symptoms in children across
treatment, CGI severity scores were lower by 1.80 units (95% diagnostic categories must be individualized to the patient,
CI −0.53 to −3.10, P = 0.007) in the quetiapine group com- with a focus on the identification of environmental triggers
pared to the placebo group. In this study, the occurrence of
and the implementation of behavioral strategies. It is recom-
drug related side-effects were not considered significantly mended that management begin with parent/caretaker train-
different between quetiapine and placebo. ing and counseling sessions [59,60]. The use of antipsychotics
Quetiapine is an antagonist for 5-HT2A and D2 receptors.
should be reserved for severe cases, where harm to self or
The exact mechanism of antipsychotic effect is unknown, others is present or imminent.
however may involve down-regulation of 5-HT2A and partial Current treatment guidelines on the management and sup-
agonism of 5-HTIA. Quetiapine is quickly absorbed after oral port of children and young people with ASD make recommen-
ingestion and is 83.0% protein bound. It is primarily metabo- dations on behavior that challenges [61]. First and foremost,
lized by CYP 3A4 [56]. factors that increase the risk of challenging behaviors should
be assessed and addressed, including impairments in commu-
nication, coexisting physical and mental health disorders, the
5. Conclusion
environment, changes in routine, onset of puberty, the
For the treatment of irritability in ASD, there are three short- absence of structure, and inadvertent reinforcement of beha-
term RCTs of risperidone and three short-term RCTs of aripi- vioral problems. If no trigger is identified, psychosocial inter-
prazole, all demonstrating superiority to placebo for this out- ventions should be offered as first-line treatments.
come. Adverse effects also have been demonstrated with Antipsychotics are only to be considered when psychosocial
treatment, including a higher risk of upper respiratory tract or other interventions are insufficient or cannot be delivered
infections, sedation, metabolic effects, increased prolactin (for due to the severity of behavioral problems. A recent systema-
risperidone) and drug-induced movement disorders. One RCT tic review of pharmacological treatments for severe irritability
of lurasidone for irritability in ASD did not demonstrate super- and problem behaviors found that only one other medication
iority over placebo. Two long-term placebo discontinuation (besides risperidone and aripiprazole) showed a moderate to
studies of risperidone in ASD have shown higher rates of large effect for treating irritability in ASD – N-acetylcysteine
relapse of symptoms in individuals randomized to placebo [12]. N-acetylcysteine is an antioxidant/glutamatergic modula-
after four months of successful treatment with risperidone. tor for which one small trial of 33 children demonstrated an
One long-term placebo discontinuation study of aripiprazole improvement on the ABC-Irritability Subscale after 12 weeks of
in ASD did not demonstrate a difference in symptom relapse treatment [62].
rates between children randomized to continued aripiprazole The initial treatment of children and youth with ADHD with
treatment versus placebo. disruptive and aggressive behavior includes the use of psy-
For the treatment of aggression and disruptive behavior chosocial interventions and psychostimulants to treat core
associated with ADHD, ODD, CD with and without low IQ, six ADHD symptoms [63]. Psychostimulants have demonstrated
of seven short-term RCTs demonstrate superiority of risperi- efficacy for overt and covert aggression, as well as opposi-
done to placebo for this outcome. Again, adverse effects are tional behavior and conduct problems in children with ADHD
demonstrated, including sedation, metabolic effects, hormonal [11]. If these strategies are ineffective, there is evidence to
Table 5. Included studies risperidone and quetiapine, disruptive behaviour disorders and normal IQ.
Study, date, location,
population Intervention and length of Rx Behavioral outcome Adverse effects Risk of bias
Risperidone, Aggressive behavior and conduct problems in children with disruptive Behavior disorders and normal IQ
Armenteros 2007 Risperidone 1.08 mg/d vs. placebo Children’s aggression scale – parent (CAS-P) Abdominal pain and vomiting were experienced by more Allocation concealment unclear.
USA 4 weeks CAS-P: % of subjects in each group improving by more than than 10% of the risperidone-treated subjects. There was
Children 7–12 with 30% from baseline to end point: no significant difference between groups in average
ADHD & aggression Risperidone = 100% weight change. There were no dropouts due to adverse
N = 25 Placebo = 77% p < 0.05 effects.
ODD/CD 76% Children’s aggression scale – teacher (CAS-T)
CAS-T: Showed no significant difference between groups.
Findling 2000 Risperidone 0.028 ± 0.004 mg/kg/d Rating of Aggression Against People or Property Scale No subjects experienced parkinsonian symptoms, an acute More than 20% did not finish
USA 10 weeks (RAAPP) dystonic reaction, or any abnormal involuntary trial.
Youth 5–15 with conduct RAAPP: Difference from baseline to week 10: movements. The mean predicted end-of-study weight
disorder Risperidone = −1.65 ± 0.40 (SE) gain was 4.2 ± 0.7 kg for the risperidone group
N = 20 Placebo = −0.16 ± 0.54 (SE) compared to 0.74 ± 0.9 kg for the placebo group. There
Excluded youth with p = 0.03 was discontinuation in 1 participant in the risperidone
moderate to severe Effect size 1.05 group due to adverse effects.
ADHD
Aman 2014 Risperidone 1.7 ± 0.75 mg/day vs. Nisonger Child Behavior Rating Form Disruptive behavior Gastrointestinal upset
USA placebo, added to parent Total (NCBRF D-Total) Risperidone 16.4%
Children 6–12 with ODD/ training in behavior NCBRF D-Total at baseline, after openly titrated stimulant Placebo 5.0% p = 0.03
CD, ADHD, serious management and openly titrated (3 weeks), and after augmentation with risperidone or Prolactin level
physical aggression, stimulant therapy placebo (9 weeks): Risperidone 36.0 ± 27.5 μg/L
and seriously 6 weeks Risperidone: 42.1 ± 10.4, 25.9 ± 15.2, 10.7 ± 9.0 Placebo 7.1 ± 9.3 μg/L, p < 0.001
disruptive behavior Placebo: 43.5 ± 10.3, 24.9 ± 15.3, 17.8 ± 15.4 Significantly greater weight gain with risperidone vs.
N = 168 p = 0.01 at week 9, ES = 0.43 from baseline to week 9, placebo (p < 0.0001).
ODD/CD 100% ES = 0.50 from week 3 to 9 There were 2 dropouts in the risperidione augmented
Estimate for comparison of therapies at week 9 (based on group and 1 dropout in the placebo group due to
results of linear mixed-model): 0.67 (95%CI = 0.14, 1.20) adverse effects.
Jahangard 2017 Risperidone 0.5 mg/day vs placebo, Conners’ Parent Rating Scale Revised Long Version, Weight gain
Iran added to methylphenidate and Oppositional Problems subscale Placebo −0.62 kg
Children 7–10 with family therapy Baseline Risperidone 2.34 (SD 0.31) Risperidone + 1.4 kg
ADHD and ODD 8 weeks End point Risperidone 1.71 (SD 0.29) Waist circumference increased significantly with risperidone
N = 84 Baseline Placebo 2.39 (SD 0.32) compared to placebo
End point Placebo 1.92 (SD 0.27) Significant increase in prolactin observed with risperidone
Effect size 0.75 (0.31, 1.19)
Quetiapine, adolescents with conduct disorder
Connor 2008 Quetiapine 294 mg/d ± 78 mg vs. CGI-S: Baseline to end point: The quetiapine group had an average weight gain of 2.3 kg Allocation concealment unclear;
USA placebo Quetiapine = 5.9 ± 0.6 to 3.4 ± 1.1 compared to 1.1 kg in the placebo group, but this method of randomization not
Adolescents 12–17 with 6 weeks Placebo = 5.5 ± 1.2 to 5.0 ± 0.6 p < 0.01 difference was not significant. stated in methods; major
conduct disorder CGI-S scores were estimated (based on regression results Neither group reported any neurological abnormalities as differences between groups at
N = 19 from mixed-effects models) to decline by 1.80 units (95% rated by the Neurological Rating scale or the Abnormal baseline.
CI = −0.53, −3.10) more with quetiapine compared to Involuntary Movement Scale. Discontinuation due to
placebo, corresponding to an effect size of 1.6 (95% adverse events occurred in 1/9 of the quetiapine group,
CI = 0.9, 3.0) 0/10 in the placebo group.
CGI-I ≥ 2 improvement:
Quetiapine = 8/9 patients
EXPERT OPINION ON PHARMACOTHERAPY

Placebo = 1/10 patients p = 0.0006


11
12 S. SHAFIQ AND T. PRINGSHEIM

Figure 4. Risperidone for ODD/CD in individuals with average IQ.

support the use of atomoxetine, guanfacine and clonidine for gain, manifesting as an increase in body mass index and waist
oppositional behavior and conduct problems associated with circumference percentiles.
ADHD [63]. As the side effect burden of these medications is Health care professionals advising families with children
lower than with antipsychotics, their use is preferable over and youth with behavioral problems about treatment options
risperidone. If adequate symptom control is not achieved should participate in shared decision-making. It is essential
with the use of atomoxetine, guanfacine or clonidine, or they that patients are aware of all treatment options, both medical
are contraindicated or intolerable, a trial of risperidone may be and behavioral, their benefits and risks, and that their values
attempted. If risperidone is ineffective, there is very little and beliefs are incorporated into treatment decisions. Making
evidence to support the use of other antipsychotics. decisions about the treatment of behavioral symptoms in
If antipsychotics are prescribed for behavioral problems, children is stressful and difficult for parents, due to the variety
short-term treatment (less than 3 months) at the lowest effec- of potential management strategies, the diversity of health
tive dose is recommended due to the accumulation of adverse care professionals involved, and feelings of guilt and inade-
effects with continued treatment, and evidence to suggest quacy with respect to parenting. Providing excellent decisio-
some waning of clinical efficacy with prolonged treatment. If nal support should be the goal of all practitioners in this area.
no improvement in targeted behaviors is observed after trial Future research on the use of antipsychotics for behavioral
at an adequate dose for six weeks, medication should be problems in children should focus on the identification of
tapered and discontinued. Antipsychotics should only be pre- individual factors associated with adverse effects, and strate-
scribed for this purpose by physicians with expertise in the gies to mitigate or prevent them. Health systems should focus
assessment and treatment of behavioral problems in children, on providing greater accessibility to psychosocial and beha-
which includes developmental pediatricians, psychiatrists and vioral treatments for children and families.
neurologists. Antipsychotic medications should be considered
a temporary solution for very severe irritability or aggression
Funding
while behavioral strategies are employed for long-term man-
agement. Gradual tapering of antipsychotic medication over Funding for this article was provided by the Owerko Centre, Alberta
several weeks to months can be attempted after sustained Children’s Hospital Research Institute.
improvement of behavioral symptoms. Some children with
severe disability related to irritability in ASD or aggressive
and disruptive behavior in the context of ADHD, ODD, and Declaration of interest
CD require longer courses of therapy and have difficulty wean- The authors have no relevant affiliations or financial involvement with any
ing off medication. In these situations, the need for drug organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
safety monitoring is crucial so patients and families can
employment, consultancies, honoraria, stock ownership or options, expert
make informed choices regarding the benefits and risks of testimony, grants or patents received or pending, or royalties
treatment.
Drug safety monitoring of second and third generation
antipsychotics includes assessment for metabolic, hormonal Reviewer disclosures
and extrapyramidal adverse effects. The occurrence of these
Peer reviewers on this manuscript have no relevant financial or other
side-effects are evident in children across numerous pediatric relationships to disclose.
psychiatric conditions [64,65]. Evidence-based guidelines are
available on the routine assessment for these adverse effects.
The CAMESA (Canadian Alliance for Monitoring Effectiveness References
and Safety of Antipsychotic medications in children) [66]
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