Aripiprazole for Irritability in Asian Children and Adolescents with Autistic Disorder: A 12-Week,Multinational,Multicenter,Prospective Open-Label Study

Abstract

Objectives:

We investigated the effectiveness and tolerability of aripiprazole in the treatment of irritability in Asian children and adolescents (6–17 years) with autistic disorder in a 12-week, multinational, multicenter, open-label study.

Methods:

Sixty-seven subjects (10.0 ± 3.1 years old, 52 boys) were enrolled and treated with flexibly dosed aripiprazole for 12 weeks (mean dose, 5.1 ± 2.5 mg; range 2–15 mg).

Results:

Aripiprazole significantly reduced the mean caregiver-rated scores for the Irritability, Lethargy/Social Withdrawal, Stereotypy, Hyperactivity, and Inappropriate Speech subscales of the Aberrant Behavior Checklist from baseline to week 12 (p < 0.001 for all subscales). Clinician-rated Clinical Global Impression Severity of Illness scale score also improved from baseline through week 12 (p < 0.001). The most common adverse event was weight gain and no serious adverse event related to aripiprazole treatment was noted.

Conclusion:

Our results suggest that aripiprazole is effective and generally tolerable in the treatment of irritability in Asian children and adolescents with autistic disorder. Further studies with larger sample sizes and longer treatment durations are required.

Introduction

Autistic disorder is a neurodevelopmental disorder characterized by deficits in social communication and social interaction as well as restricted, repetitive patterns of behavior, interests, or activities. In addition to core symptoms, subjects with autistic disorder frequently exhibit irritability such as aggression, tantrums, self-injurious behavior, tendencies to injure others, and quickly changing moods. These irritability symptoms can substantially affect subjects and their families and significantly impact their education and social development (McGuire et al. 2016).

Risperidone and aripiprazole are currently the only FDA-approved medications for treating irritability associated with autistic disorder. Although risperidone has been shown to be effective for reducing behavioral symptoms and impulsivity in several studies (McCracken et al. 2002; Shea et al. 2004; Nagaraj et al. 2006; Aman et al. 2015; McGuire et al. 2016), the drug is associated with adverse effects (AEs) such as increased appetite, weight gain, enuresis, sedation, and hyperprolactinemia. Aripiprazole has recently been reported to effectively decrease irritability in children with autistic disorder (Marcus et al. 2009; Owen et al. 2009), prevent relapse during long-term maintenance treatment (Findling et al. 2014), and carry lower risks of extrapyramidal symptom (EPS), sedation, and hyperprolactinemia (Fung et al. 2016).

However, most of the previous studies were randomized controlled trials from Western countries. Because the randomized controlled trials usually conducted in selected populations and in a highly controlled setting, the results are insufficient to be generalized to real-world clinical setting. Moreover, despite greater impact of behavioral problems associated with autistic disorder in Eastern countries than in Western countries (Freeth et al. 2013) and substantial ethnic differences in CYP2D6 and CYP3A4 metabolism (Xie et al. 2001), to the best of our knowledge, only one study has investigated the efficacy and safety of aripiprazole in an Asian population (Ichikawa et al. 2017). Thus, well-designed open-label studies from diverse ethnic groups are needed for generating real-world evidence.

We evaluated the effectiveness and safety of aripiprazole in reducing serious behavioral problems in Asian children and adolescents with autistic disorder in a multinational study. We hypothesized that aripiprazole would be effective and safe for serious behavioral problems in Asian youth, but side effect profile could be different from those from Western countries.

Methods

This was a 12-week, multinational, multicenter, open-label study. Children and adolescents with autistic disorder were recruited from eight hospitals: four hospitals in South Korea, one in Thailand, and three in the Philippines. This study was approved by the Institutional Review Boards of the participating institutions. All parents/guardians provided written informed consent, and subjects provided written informed assent when possible.

Subjects

The inclusion criteria were as follows: (1) age of 6–17 years; (2) diagnosis of autistic disorder defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR; American Psychiatric Association, 2000) and confirmed using the Autism Diagnostic Interview-Revised (ADI-R); (3) behavioral problems such as irritability, agitation, and/or self-injurious behavior; (4) a Clinical Global Impression Severity of Illness scale (CGI-S) score of ≥4 and an Aberrant Behavior Checklist Irritability (ABC-I) subscale score of ≥18 at screening and baseline; and (5) mental age of ≥24 months.

The exclusion criteria were as follows: (1) Rett's disorder, childhood disintegrative disorder, Asperger's disorder, or pervasive development disorder not otherwise specified according to the DSM-IV-TR; (2) schizophrenia, other psychosis, and mood disorders, including bipolar disorder and major depression according to the DSM-IV-TR criteria; (3) significant risk of committing suicide based on the subject's medical history or a routine mental status examination; (4) seizure in the past year; (5) history of severe head trauma or stroke; (6) history of neuroleptic malignant syndrome; (7) resistance to antipsychotic medication; and (8) presence of a significant comorbid medical illness.

Comorbid psychiatric disorders, including intellectual disability and attention-deficit/hyperactivity disorder (ADHD), were diagnosed based on the DSM-IV-TR. Intelligence quotient (IQ) was measured by one of the standardized methods.

Study design

Subjects received open-label aripiprazole treatment for 12 weeks. For the subjects who took other psychotropic medications and experienced intolerable side effects or whose behavioral problems were not controlled by that medication, all psychotropic medications (including antipsychotic, antidepressant, anxiolytic, mood-stabilizing, and neuroleptic agents) were washed out during the screening period. However, treatment for ADHD, such as methylphenidate, atomoxetine, and clonidine was allowed to continue if the drug had been administered for ≥12 weeks and the dose had been stable for ≥4 weeks.

The initial dose of aripiprazole was 2 mg/day, and dose escalation according to response to the target range of 5–15 mg/day (maximum dosage: 15 mg/day) and dose reduction according to tolerability were permitted. The dose adjustment schedule was managed by investigators, and it was planned to gradually occur at the weekly basis or each study visit. However, no adjustment was allowed after week 8 to ensure stable treatment during the final 4 weeks of analysis.

The use of all psychotropic medications was prohibited during the study, excluding lorazepam or alprazolam for anxiety related to medical or study procedures, hypnotics, and propranolol for akathisia. Benzodiazepine or propranolol was not administered within 12 hour before EPS assessments. The doses of ADHD medications were not increased during the study.

Assessment

The diagnosis of autistic disorder was confirmed using ADI-R (Lord et al. 1994), which was administered by an experienced interviewer who had been previously trained and approved as “research reliable” on ADI-R or who had successfully completed a 2-day rater training course conducted by a certified ADI-R trainer.

Effectiveness and safety assessments were performed at baseline, weeks 1, 2, 4, 8, and 12, and at the time of early termination when applicable. The primary outcome measure was the mean change in the caregiver-rated ABC-I subscale (Aman et al. 1985) score from baseline to week 12. The ABC-I subscale consist of 15 items such as “injures self,” “physical violence to self,” “aggressive to other children and adults,” “irritable,” “temper outbursts,” “depressed mood,” “mood change,” and “yells” or “screams.” Individual items are rated from 0 (never a problem) to 3 (severe problem). The validity of the Korean version of the ABC was previously studied (Moon et al. 2013). The Thai-translated version of the ABC and its back-translation into English were approved by Dr. Michael Aman, who originally developed this scale.

The secondary outcome measures included the clinician-rated mean changes in CGI-S score, other ABC subscale scores (Lethargy/Social Withdrawal, Stereotypy, Hyperactivity, and Inappropriate Speech), the Child Yale–Brown Obsessive-Compulsive Scale (CY-BOCS) (Scahill et al. 1997), the Vineland Adaptive Behavior Scale (VABS) (Sparrow et al. 2005), and the Parenting Stress Index-Short Form (PSI-SF) (Abidin 1995). The ABC and CGI-S were assessed at baseline and at weeks 1, 2, 4, 8, and 12. The Clinical Global Impression Global Improvement scale (CGI-I) was assessed at weeks 1, 2, 4, 8, and 12. The CY-BOCS, VABS, and PSI-SF were assessed at baseline and at week 12. Treatment response was defined as follows: ≥25% decrease from baseline in the caregiver-rated ABC-I and a rating of 1 or 2 (“very much improved” or “much improved”) on the clinician-rated CGI-I (Guy 1978).

Safety assessments, including AEs, vital signs, body weight, and the Columbia Suicide Severity Rating Scale, were collected at each visit. In addition, the presence and severity of EPSs were assessed at each visit using the Simpson-Angus Scale (SAS), Abnormal Involuntary Movement Scale (AIMS), and Barnes Akathisia Rating Scale (BARS). Twelve-lead electrocardiography and laboratory tests were performed at baseline and the end of treatment.

Statistical analyses

The safety sample included all subjects who received at least one dose of the study medication, and the effectiveness sample included all subjects in the safety sample who completed at least one follow-up effectiveness evaluation and had a corresponding baseline value. The difference in ABC-I score between baseline and week 12 was analyzed using a Wilcoxon signed-rank test. For secondary outcome measures and safety assessments, paired t-test or Wilcoxon's signed-rank test with Bonferroni's correction for multiple comparisons (p < 0.05/number of comparisons). Statistical significance for all other comparisons was defined as p < 0.05; all comparisons were two-tailed. The last-observation-carried-forward imputation was used for subjects who did not complete the treatment period.

The repeated measures analysis of variance was used to analyze the effects of the time and previous risperidone treatment and their interactions on prolactin level and AIMS Facial and Oral Movements subscale score. All statistical analyses were performed using SAS software (version 9.2; SAS Institute, Inc.).

Results

Sixty-seven subjects were enrolled and included in the safety analysis. Among them, 66 subjects completed baseline and at least 1 follow-up assessment and were included in the effectiveness sample. Of 67 subjects, 7 subjects discontinued treatment before 12 weeks due to loss of follow-up (6 subjects) and protocol violation (1 subject). No subjects withdrew due to AEs. No significant differences were observed regarding age (p = 0.088), gender (p = 0.070), and baseline ABC-I (p = 0.603), CGI-S (p = 0.276), and VABS scores (p = 0.464) between those who completed and did not complete the study.

Demographic and other baseline characteristics

The demographic and clinical characteristics of the subjects at baseline are shown in Table 1. The mean subject age was 10.0 ± 3.1 years, and most subjects were boys (n = 52, 77.6%) and younger than 12 years (n = 46, 68.7%). In total, 48 subjects (71.6%) had intellectual disabilities. Thirteen subjects (19.4%) had comorbid ADHD.

Table 1.

Demographic and Clinical Characteristics of the Subjects

	n = 67
Age, years, mean ± SD	10.0 ± 3.1
6–11 years, n (%)	46 (68.7)
12–17 years, n (%)	21 (31.3)
Gender
Boys, n (%)	52 (77.6)
Height, cm, mean ± SD	141.8 (16.5)
Weight, kg, mean ± SD	41.3 (14.2)
Body mass index, kg/m², mean ± SD	19.9 (4.1)
ABC-irritability subscale score, mean ± SD	25.1 (7.6)
CGI-S^a, mean ± SD	4.8 (0.8)
VABS adaptive behavior composite, mean ± SD	58.3 (7.3)
Comorbid psychiatric and genetic disorders
ADHD, n (%)	13 (19.4)
Intellectual disability, n (%)	48 (71.6)
Noonan syndrome, n (%)	1 (1.5)
Thalassemia alpha, n (%)	1 (1.5)

CGI-S is scored as following: 1 (Normal, not at all ill), 2 (Borderline mentally ill), 3 (Mildly ill), 4 (Moderately ill), 5 (Markedly ill), 6 (Severely ill), and 7 (Among the most extremely ill patients).

ABC, Aberrant Behavior Checklist; ADHD, attention-deficit/hyperactivity disorder; CGI-S, Clinical Global Impression-Severity; SD, standard deviation; VABS, Vineland Adaptive Behavior Scale.

The mean weight and height of the subjects at baseline were 41.3 ± 14.2 kg and 141.8 ± 16.5 cm, respectively. Forty-two subjects were naive to antipsychotics, 17 changed from risperidone, and 9 previously received aripiprazole. The caregivers were the mother, father, and grandparents for 80.7%, 14.5%, and 4.8% of the subjects, respectively.

Study medication

The mean daily dose of aripiprazole was 5.1 ± 2.5 mg (range 2–15 mg). Hypnotic/sedative/anxiolytic agents (n = 2, 3.0%), antiparkinsonian agents (n = 2, 3.0%), and methylphenidate (n = 9, 13.4%) were concomitantly used during the study.

Effectiveness outcomes

The mean ABC-I score significantly decreased during 12-week treatment (p < 0.001) (Fig. 1). The changes in secondary outcome measures over the 12-week are displayed in Table 2. Scores for the ABC Lethargy/Social Withdrawal, Stereotypy, and Hyperactivity subscales also significantly improved from week 1 through week 12 compared to baseline (p < 0.001 for all subscales). For ABC Inappropriate Speech subscale, significant improvement was observed from week 2 through week 12 compared to baseline when adjusted for multiple comparisons (p < 0.001 for week 2, 4, 8, and 12). The CGI-S score also significantly decreased during treatment (p < 0.001 for week 1, 2, 4, 8, and 12). Among 60 subjects who completed 12-week treatment, 51 subjects (85%) were responders to aripiprazole.

FIG. 1.

Mean change from baseline in the ABC Irritability subscale score (LOCF, efficacy sample). ***p < 0.001. Data are expressed as mean ± SD. ABC, Aberrant Behavior Checklist; LOCF, last-observation-carried-forward.

Table 2.

Results of Secondary Outcome Measures (Last Observation Carried Forward, Effectiveness Sample)

		Week 1		Week 2		Week 4		Week 8		Week 12
	Baseline Mean	Mean change from baseline	p	Mean change from baseline	P	Mean change from baseline	p	Mean change from baseline	p	Mean change from baseline	p
Aberrant Behavior Checklist
Irritability^a	25.1 ± 7.6	−8.7 ± 8.8	<0.001	−11.2 ± 8.1	<0.001	−13.4 ± 9.3	<0.001	−13.4 ± 8.9	<0.001	−15.1 ± 9.1	<0.001
Lethargy/social withdrawal^a	18.8 ± 9.3	−3.2 ± 6.9	<0.001	−5.9 ± 7.2	<0.001	−6.0 ± 9.2	<0.001	−7.3 ± 9.2	<0.001	−8.8 ± 8.9	<0.001
Stereotypy^a	9.7 ± 5.4	−2.5 ± 3.5	<0.001	−3.1 ± 3.8	<0.001	−4.1 ± 4.2	<0.001	−4.2 ± 4.3	<0.001	−4.8 ± 4.3	<0.001
Hyperactivity^a	27.1 ± 9.9	−6.8 ± 8.0	<0.001	−9.1 ± 7.7	<0.001	−12.0 ± 9.3	<0.001	−12.8 ± 9.2	<0.001	−14.2 ± 9.8	<0.001
Inappropriate speech^a	5.9 ± 3.8	−0.9 ± 2.7	0.016	−1.7 ± 3.3	<0.001	−1.8 ± 3.3	<0.001	−2.4 ± 3.4	<0.001	−2.4 ± 3.3	<0.001
CGI-S^a	4.8 ± 0.8	−0.2 ± 0.5	0.001	−0.5 ± 0.7	<0.001	−0.8 ± 0.9	<0.001	−1.0 ± 1.0	<0.001	−1.3 ± 1.2	<0.001
CY-BOCS
Obsession	3.2 ± 4.8									−1.2 ± 3.2	0.001
Compulsion	6.6 ± 5.9									−2.1 ± 3.0	<0.001
Vineland Adaptive Behavior Scale
Adaptive behavior composite	66.0 ± 27.7									−2.3 ± 24.5	0.004
Parenting Stress Index
Parental Distress	35.6 ± 8.4									−4.0 ± 7.7	<0.001
Parent–Child Dysfunctional	33.4 ± 7.2									−3.2 ± 7.3	0.001
Difficult Child	35.6 ± 12.2									−6.2 ± 8.7	<0.001

Data are expressed as mean ± SD.

Multiple-comparison adjusted significance level: p < 0.01.

CGI-S, Clinical Global Impression-Severity; CY-BOCS, Children's Yale–Brown Obsessive-Compulsive Scale; SD, standard deviation.

The mean Obsession and Compulsion subscale scores of the CY-BOCS also significantly declined from baseline to week 12 (Obsession, p = 0.001; Compulsion, p < 0.001). The adaptive behavior composite score of the VABS significantly increased from baseline to week 12 (p = 0.004). Three subscale scores of the PSI, namely Parental Distress, Parent–Child Dysfunctional Interaction, and Difficult Child, significantly decreased from baseline to week 12 (p < 0.001, p = 0.001, and p < 0.001, respectively).

Safety outcomes

During the study, 55 (82.3%) subjects experienced at least one AE. AEs that occurred in more than 5% of the subjects are listed in Table 3. The most common AE was weight gain, which was reported in 15 subjects (22.4%), followed by somnolence, sedation, nasopharyngitis, and pyrexia. All AEs were mild to moderate in severity, excluding one case of tonsillitis that was not related to the study medication.

Table 3.

Treatment-Emergent Adverse Events That Occurred in ≥5% of Subjects

Adverse event	(n = 67)
Weight increased	15 (22.4)
Somnolence	13 (19.4)
Sedation	12 (18.0
Nasopharyngitis	13 (19.4)
Pyrexia	8 (11.9)
Vomiting	5 (7.5)
Increased appetite	5 (7.5)
Headache	4 (6.0)
Rhinorrhea	4 (6.0)

Data are expressed as number (%).

The mean weight change during the 12-week aripiprazole treatment period was 2.1 ± 2.3 kg. Although 91.0% of subjects gained weight after aripiprazole administration, a greater-than-expected weight gain based on the subjects' normal growth patterns, was observed in only 15 subjects (22.4%). Blood LDL cholesterol levels decreased (p = 0.005) and blood triglyceride levels increased (p = 0.002) during treatment. Serum prolactin levels significantly decreased during treatment (p < 0.001), and the decrease was greater in subjects previously exposed to risperidone (group-by-time interaction, p = 0.040; partial η ² = 0.073). No subject experienced an increase in prolactin levels. No clinically significant changes were found in vital signs or electrocardiograms.

EPS-related AEs were not found in our study, and the SAS, BARS, and AIMS scores did not change during treatment, excluding the significant decrease of the AIMS Facial and Oral Movements subscale score. For the Facial and Oral Movement subscale of the AIMS, the effects of aripiprazole treatment (p = 0.050) and previous risperidone treatment (p = 0.089) were only marginally significant. Treatment-related suicidal ideation and behavior did not occur.

Discussion

This 12-week, multinational, multicenter, open-label study demonstrated that flexible-dose aripiprazole can effectively reduce irritability in Asian children and adolescents with autistic disorder. Furthermore, aripiprazole significantly improved social withdrawal, stereotypy, inappropriate behavior, and hyperactivity as measured by the ABC and adaptive behavior as measured by the VABS and decreased parental stress as measured by the PSI-SF. No serious AEs related to aripiprazole use were observed. These results suggest that aripiprazole was effective, generally safe, and well tolerated for the treatment of irritability associated with autistic disorder in Asian children and adolescents. To our knowledge, this is the only study to demonstrate the effectiveness and tolerability of aripiprazole in an Asian-focused multinational study.

Our finding that aripiprazole effectively controls irritability associated with autistic disorder is consistent with previous results. Aripiprazole has been reported to significantly reduce ASD-associated irritability in an 8-week, double-blind, randomized controlled trial using a fixed or flexible dosing schedule (Marcus et al. 2009; Owen et al. 2009). A 52-week open-label study (Marcus et al. 2011) illustrated that the response to aripiprazole was maintained with continued treatment, supporting the long-term effectiveness of this therapy. Findling et al. (2014) also reported that aripiprazole maintenance treatment can be helpful for preventing relapse. In a 2-month, randomized, double-blind, head-to-head comparison trial of aripiprazole and risperidone (Ghanizadeh et al. 2014), the effectiveness of the drugs in controlling irritability in subjects with ASD was similar. The results of a double-blind, placebo-controlled study from Japan were in line with our findings, indicating that aripiprazole was superior to placebo in reducing irritability in Asian pediatric patients with ASD (Ichikawa et al. 2017).

The dose of aripiprazole in this study was 5.1 mg/day, lower than those from Owen et al.'s flexible-dose placebo-controlled study (2009), in which 62% of the subjects took more than 10 mg/day of aripiprazole. However, the mean dose of aripiprazole in previous studies varies in a wide range. In a placebo-controlled (Ichikawa et al. 2017) and risperidone-comparison studies (Ghanizadeh et al. 2014), the mean dose of aripiprazole were 8.2 and 5.5 mg/day, respectively. In Findling et al.'s long-term maintenance study (2014), the mean aripiprazole dose was 9.7 mg/day. The factors associated with aripiprazole dose in autistic disorder are not studied yet, but low aripiprazole dose in our study could be related to the fact that a stable dose of ADHD medication was allowed. Further studies on aripiprazole dosing in autistic disorder are needed.

In our study, social withdrawal, stereotypy, inappropriate speech, and hyperactivity as measured by the ABC; adaptive skills as measured by the VABS; and the Obsession and Compulsion subscale scores of the CY-BOCS were significantly improved by aripiprazole treatment. These results are consistent with previous findings that aripiprazole significantly improved ABC Stereotypy and Inappropriate Speech subscale scores (Marcus et al. 2009; Owen et al. 2009; Findling et al. 2014) as well as ABC Hyperactivity subscale and CY-BOCS Compulsion scale scores (Marcus et al. 2009), implying that aripiprazole had a positive influence on core symptoms or adaptive function in ASD. The impact of aripiprazole or other antipsychotics on core symptoms or adaptive function in ASD is controversial.

Several double-blind, placebo-controlled studies have supported the influence of risperidone on improvements in general ASD severity (Luby et al. 2006; Nagaraj et al. 2006) as well as specific ASD symptoms of communication (Shea et al. 2004; Nagaraj et al. 2006), socialization (Shea et al. 2004; Nagaraj et al. 2006; Pandina et al. 2007), and/or stereotyped, repetitive behavior (Shea et al. 2004; Nagaraj et al. 2006). Several open-label (Williams et al. 2006; Gencer et al. 2008) and naturalistic (Masi et al. 2003; Capone et al. 2008) studies have also illustrated the ability of risperidone to improve social functioning and autistic severity. However, the largest randomized, placebo-controlled trial on risperidone (McDougle et al. 2005), Research Units on Pediatric Psychopharmacology Network, and a naturalistic longitudinal study (Marrus et al. 2014) failed to confirm the beneficial effect of risperidone on core ASD symptoms. Moreover, a recent systematic review of risperidone provided moderate evidence that the drug ameliorated stereotyped behaviors, but no evidence of improvements of social or communicative function (McPheeters et al. 2011).

Previous studies also found that aripiprazole improved quality of life (Varni et al. 2012), global functioning (Ichikawa et al. 2017), or sensory abnormalities (Fung et al. 2012). Our study also provides preliminary evidence that aripiprazole can improve core symptoms or adaptive function in ASD. However, whether this improvement is a direct effect of aripiprazole or is mediated by improvements in behavioral problems remains uncertain. Reducing serious maladaptive behavior promotes improvements in adaptive behavior (Scahill et al. 2012). Thus, further studies addressing these issues are needed.

Irritability is clearly associated with negative outcomes for caregivers of children with ASD, including increased parental stress, financial problems, a lack of support services, and negative impacts on day-to-day family life and well being (Powers et al. 2011; Hodgetts et al. 2013). Thus, addressing irritability or aggressive behavior is pivotal for improving outcomes for individuals with ASD and their caregivers. In our study, scores for the Parental Distress, Parent–Child Dysfunctional Interaction, and Difficult Child subscales of the PSI-SF significantly improved during aripiprazole treatment. These results suggest that aripiprazole improves the parental stress of caregivers and positively influences the parent–child relationship of subjects with autistic disorder.

Aripiprazole is generally tolerable, and no subject withdrew from this study due to AEs. In our study, weight gain was the most commonly reported AE, and the mean weight increase during the treatment period was 2.1 ± 2.3 kg. Increased appetite was reported in 7.5% of the subjects in our study. Our results are consistent with previous findings that aripiprazole treatment was associated with greater weight gain than placebo treatment (Marcus et al. 2009, 2011; Ichikawa et al. 2017), and increased appetite and weight gain were less frequent during aripiprazole treatment than during risperidone treatment (McCracken et al. 2002). In addition, the frequency of increased appetite was lower than that in previous studies from the United States (Marcus et al. 2009, 2011), but similar to that in a study from Japan (Ichikawa et al. 2017). However, weight and BMI increases were observed in both Asian and American children (Marcus et al. 2009, 2011). Thus, clinicians who treat children and adolescents with aripiprazole should be aware of the potential for weight gain and monitor weight even if patients or their parents do not report increased appetite.

The decline in serum prolactin levels observed in our trial has been previously reported (Marcus et al. 2009, 2011; Deb et al. 2014), although its clinical consequences are unknown (Safer et al. 2013). Because aripiprazole is a partial dopamine agonist that primarily acts at D2 and 5-HT1A receptors, its dopamine agonist activity could explain the reduction in serum prolactin levels (Safer et al. 2013). Moreover, in our study, greater decreases in serum prolactin levels were observed in subjects previously exposed to the dopamine antagonist risperidone. This result suggests that clinicians should consider previous treatment history when interpreting prolactin levels during aripiprazole treatment. Although we are unaware of the clinical significance of decreases in prolactin levels during aripiprazole treatment, drug-induced reductions in serum prolactin levels are more frequent in adolescents than in adults and are more prominent at higher aripiprazole doses and longer treatment durations (Safer et al. 2013).

Several limitations should be considered when interpreting our findings. First, the number of subjects in this study was relatively small. Second, this was an open-label study; thus, the effectiveness of aripiprazole could have been overestimated, and the evaluation of AEs and tolerability was limited by the lack of a placebo comparator. Third, our study included 17 subjects changed from risperidone and 9 subjects who previously received aripiprazole. Because the subjects who stopped risperidone and participated in this study were likely to have poor response or significant adverse events to risperidone and the subjects with previous aripiprazole exposure were less likely to have poor response or adverse events, there could be a selection bias. Further research using larger samples and a controlled design is warranted.

Despite these caveats, this study has the following strengths: (1) this was the first multinational, multicenter study in Asia to evaluate the effectiveness of aripiprazole on the irritability of autistic children and adolescents; (2) standardized instruments were used to diagnose autistic disorder; and (3) adaptive functions and parental stress were measured.

Conclusion

Aripiprazole treatment significantly improved irritability, social withdrawal, other behavioral problems, obsessive-compulsive symptoms, and adaptive function in Asian children with autistic disorder. Moreover, 12-week aripiprazole treatment was generally safe and tolerable.

Clinical Significance

Our results demonstrated a statistically significant improvement in irritability in children and adolescents with autistic disorder. Aripiprazole was also safe and generally tolerable. Aripiprazole could be an effective and safe option for Asian children and adolescents with autistic disorder and irritability. It is also important to be aware of the potential for weight gain and monitor weight even if Asian patients or their parents do not report increased appetite.

Footnotes

Acknowledgment

We thank Dr. Kim Seon-Woo at Statistics and Data Center, Samsung Medical Center for her statistical support.

Disclosures

This study was supported by Korea Otsuka International Asia Arab. Dr. Kim is supported by the National Research Foundation of Korea. No competing financial interests exist for other authors.

References

Abidin

: Parenting Stress Index (Short Form). Odessa, TX, Psychological Assessment Resource, 1995.

Aman

, Rettiganti

, Nagaraja

, Hollway

, McCracken

, McDougle

, Tierney

, Scahill

, Arnold

, Hellings

, Posey

, Swiezy

, Ghuman

, Grados

, Shah

, Vitiello

: Tolerability, safety, and benefits of risperidone in children and adolescents with autism: 21-Month follow-up after 8-week placebo-controlled trial. J Child Adolesc Psychopharmacol, 25:482–493, 2015.

Aman

, Singh

, Stewart

, Field

: The aberrant behavior checklist: A behavior rating scale for the assessment of treatment effects. Am J Ment Defic, 89:485–491, 1985.

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision. Washington, DC: American Psychiatric Association; 2000.

Capone

, Goyal

, Grados

, Smith

, Kammann

: Risperidone use in children with Down syndrome, severe intellectual disability, and comorbid autistic spectrum disorders: A naturalistic study. J Dev Behav Pediatr, 29:106–116, 2008.

Deb

, Farmah

, Arshad

, Deb

, Roy

, Unwin

: The effectiveness of aripiprazole in the management of problem behaviour in people with intellectual disabilities, developmental disabilities and/or autistic spectrum disorder—A systematic review. Res Dev Disabil, 35:711–725, 2014.

Findling

, Mankoski

, Timko

, Lears

, McCartney

, McQuade

, Eudicone

, Amatniek

, Marcus

, Sheehan

: A randomized controlled trial investigating the safety and efficacy of aripiprazole in the long-term maintenance treatment of pediatric patients with irritability associated with autistic disorder. J Clin Psychiatry, 75:22–30, 2014.

Freeth

, Sheppard

, Ramachandran

, Milne

: A cross-cultural comparison of autistic traits in the UK, India and Malaysia. J Autism Dev Disord, 43:2569–2583, 2013.

Fung

, Chahal

, Libove

, Bivas

, Hardan

: A retrospective review of the effectiveness of aripiprazole in the treatment of sensory abnormalities in autism. J Child Adolesc Psychopharmacol, 22:245–248, 2012.

10.

Fung

, Mahajan

, Nozzolillo

, Bernal

, Krasner

, Jo

, Coury

, Whitaker

, Veenstra-Vanderweele

, Hardan

: Pharmacologic treatment of severe irritability and problem behaviors in autism: A systematic review and meta-analysis. Pediatrics, 137 Suppl 2:S124–S135, 2016.

11.

Gencer

, Emiroglu

, Miral

, Baykara

, Dirik

: Comparison of long-term efficacy and safety of risperidone and haloperidol in children and adolescents with autistic disorder. An open label maintenance study. Eur Child Adolesc Psychiatry, 17:217–225, 2008.

12.

Ghanizadeh

, Sahraeizadeh

, Berk

: A head-to-head comparison of aripiprazole and risperidone for safety and treating autistic disorders, a randomized double blind clinical trial. Child Psychiatry Hum Dev, 45:185–192, 2014.

13.

Guy

(ed): ECDEU Assessment Manual for Psychopharmacology, Revised. US Department of Health, Education, and Welfare Publication (ADM). Rockville, MD, National Institute of Mental Health, 1978.

14.

Hodgetts

, Nicholas

, Zwaigenbaum

, Hodgetts

, Nicholas

, Zwaigenbaum

: Home sweet home? Families' experiences with aggression in children with autism spectrum disorders. Focus Autism Dev Disabil, 28:166–174, 2013.

15.

Ichikawa

, Mikami

, Okada

, Yamashita

, Ishizaki

, Tomoda

, Ono

, Usuki

, Tadori

: Aripiprazole in the treatment of irritability in children and adolescents with autism spectrum disorder in Japan: A randomized, double-blind, placebo-controlled study. Child Psychiatry Hum Dev, 48:796–806, 2017.

16.

Lord

, Rutter

, Le Couteur

: Autism Diagnostic Interview-Revised: A revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord, 24:659–685, 1994.

17.

Luby

, Mrakotsky

, Stalets

, Belden

, Heffelfinger

, Williams

, Spitznagel

: Risperidone in preschool children with autistic spectrum disorders: An investigation of safety and efficacy. J Child Adolesc Psychopharmacol, 16:575–587, 2006.

18.

Marcus

, Owen

, Kamen

, Manos

, McQuade

, Carson

, Aman

: A placebo-controlled, fixed-dose study of aripiprazole in children and adolescents with irritability associated with autistic disorder. J Am Acad Child Adolesc Psychiatry, 48:1110–1119, 2009.

19.

Marcus

, Owen

, Manos

, Mankoski

, Kamen

, McQuade

, Carson

, Corey-Lisle

, Aman

: Aripiprazole in the treatment of irritability in pediatric patients (aged 6–17 years) with autistic disorder: Results from a 52-week, open-label study. J Child Adolesc Psychopharmacol, 21:229–236, 2011.

20.

Marrus

, Underwood-Riordan

, Randall

, Zhang

, Constantino

: Lack of effect of risperidone on core autistic symptoms: Data from a longitudinal study. J Child Adolesc Psychopharmacol, 24:513–518, 2014.

21.

Masi

, Cosenza

, Mucci

, Brovedani

: A 3-year naturalistic study of 53 preschool children with pervasive developmental disorders treated with risperidone. J Clin Psychiatry, 64:1039–1047, 2003.

22.

McCracken

, McGough

, Shah

, Cronin

, Hong

, Aman

, Arnold

, Lindsay

, Nash

, Hollway

, McDougle

, Posey

, Swiezy

, Kohn

, Scahill

, Martin

, Koenig

, Volkmar

, Carroll

, Lancor

, Tierney

, Ghuman

, Gonzalez

, Grados

, Vitiello

, Ritz

, Davies

, Robinson

, McMahon

; Research Units on Pediatric Psychopharmacology Autism Network: Risperidone in children with autism and serious behavioral problems. N Engl J Med, 347:314–321, 2002.

23.

McDougle

, Scahill

, Aman

, McCracken

, Tierney

, Davies

, Arnold

, Posey

, Martin

, Ghuman

, Shah

, Chuang

, Swiezy

, Gonzalez

, Hollway

, Koenig

, McGough

, Ritz

, Vitiello

: Risperidone for the core symptom domains of autism: Results from the study by the autism network of the research units on pediatric psychopharmacology. Am J Psychiatry, 162:1142–1148, 2005.

24.

McGuire

, Fung

, Hagopian

, Vasa

, Mahajan

, Bernal

, Silberman

, Wolfe

, Coury

, Hardan

, Veenstra-VanderWeele

, Whitaker

: Irritability and problem behavior in autism spectrum disorder: A practice pathway for pediatric primary care. Pediatrics, 137 Suppl 2:S136–S148, 2016.

25.

McPheeters

, Warren

, Sathe

, Bruzek

, Krishnaswami

, Jerome

, Veenstra-Vanderweele

: A systematic review of medical treatments for children with autism spectrum disorders. Pediatrics, 127:e1312–e1321, 2011.

26.

Moon

, Chung

, Jung

, Cho

, Bahn

: A preliminary study for the rating of pharmacological effect with Aberrant Behavior Checklist in children with autistic disorder. J Korean Acad Child Adolesc Psychiatry, 24:164–169, 2013.

27.

Nagaraj

, Singhi

, Malhi

: Risperidone in children with autism: Randomized, placebo-controlled, double-blind study. J Child Neurol, 21:450–455, 2006.

28.

Owen

, Sikich

, Marcus

, Corey-Lisle

, Manos

, McQuade

, Carson

, Findling

: Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder. Pediatrics, 124:1533–1540, 2009.

29.

Pandina

, Bossie

, Youssef

, Zhu

, Dunbar

: Risperidone improves behavioral symptoms in children with autism in a randomized, double-blind, placebo-controlled trial. J Autism Dev Disord, 37:367–373, 2007.

30.

Powers

, Palmieri

, D'Eramo

, Powers

: Evidence-based treatment of behavioral excesses and deficits for individuals with autism spectrum disorders. In: Evidence-Based Practices and Treatments for Children with Autism. New York, NY, Springer, 2011, pp. 55–92.

31.

Safer

, Calarge

, Safer

: Prolactin serum concentrations during aripiprazole treatment in youth. J Child Adolesc Psychopharmacol, 23:282–289, 2013.

32.

Scahill

, McDougle

, Aman

, Johnson

, Handen

, Bearss

, Dziura

, Butter

, Swiezy

, Arnold

, Stigler

, Sukhodolsky

, Lecavalier

, Pozdol

, Nikolov

, Hollway

, Korzekwa

, Gavaletz

, Kohn

, Koenig

, Grinnon

, Mulick

, Yu

, Vitiello

; Research Units on Pediatric Psychopharmacology Autism Network: Effects of risperidone and parent training on adaptive functioning in children with pervasive developmental disorders and serious behavioral problems. J Am Acad Child Adolesc Psychiatry, 51:136–146, 2012.

33.

Scahill

, Riddle

, McSwiggin-Hardin

, Ort

, King

, Goodman

, Cicchetti

, Leckman

: Children's Yale-Brown Obsessive Compulsive Scale: Reliability and validity. J Am Acad Child Adolesc Psychiatry, 36:844–852, 1997.

34.

Shea

, Turgay

, Carroll

, Schulz

, Orlik

, Smith

, Dunbar

: Risperidone in the treatment of disruptive behavioral symptoms in children with autistic and other pervasive developmental disorders. Pediatrics, 114:e634–e641, 2004.

35.

Sparrow

, Cicchetti

, Balla

: Vineland Adaptive Behavior Scales, 2nd edition. Circle Pines, MN, American Guidance Service, 2005.

36.

Varni

, Handen

, Corey-Lisle

, Guo

, Manos

, Ammerman

, Marcus

, Owen

, McQuade

, Carson

, Mathew

, Mankoski

: Effect of aripiprazole 2 to 15 mg/d on health-related quality of life in the treatment of irritability associated with autistic disorder in children: A post hoc analysis of two controlled trials. Clin Ther, 34:980–992, 2012.

37.

Williams

, Scahill

, Vitiello

, Aman

, Arnold

, McDougle

, McCracken

, Tierney

, Ritz

, Posey

, Swiezy

, Hollway

, Cronin

, Ghuman

, Wheeler

, Cicchetti

, Sparrow

: Risperidone and adaptive behavior in children with autism. J Am Acad Child Adolesc Psychiatry, 45:431–439, 2006.

38.

Xie

, Kim

, Wood

, Stein

: Molecular basis of ethnic differences in drug disposition and response. Annu Rev Pharmacol Toxicol, 41:815–850, 2001.