title: Aripiprazole treatment of irritability associated with autistic disorder and the relationship between prior antipsychotic exposure, adverse events, and weight change. Aripiprazole in the Treatment of Irritability in Children and Adolescents with Autism Spectrum Disorder in Japan: A Randomized, Double-blind, Placebo-controlled Study Risperidone in Children With Autism: Randomized, Placebo-Controlled, Double-Blind Study Risperidone in the Treatment of Disruptive Behavioral Symptoms in Children With Autistic and Other Pervasive Developmental Disorders Risperidone in children with autism and serious behavioral problems. Aripiprazole in the Treatment of Irritability in Children and Adolescents With Autistic Disorder Risperidone versus haloperidol in children and adolescents with AD Haloperidol in the treatment of infantile autism: effects on learning and behavioral symptoms. Comparison of long-term efficacy and safety of risperidone and haloperidol in children and adolescents with autistic disorder. An open label maintenance study. The effects of haloperidol on learning and behavior in autistic children Psychometric characteristics of the aberrant behavior checklist. 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. A Head-to-Head Comparison of Aripiprazole and Risperidone for Safety and Treating Autistic Disorders, a Randomized Double Blind Clinical Trial A placebo-controlled, fixed-dose study of aripiprazole in children and adolescents with irritability associated with autistic disorder. The effects of haloperidol on discrimination learning and behavioral symptoms in autistic children Risperidone for children and adolescents with autism spectrum disorder: a systematic review
abstract: OBJECTIVE The purpose of this study was to evaluate the impact of prior antipsychotic exposure ( PAE ) on safety and tolerability outcomes in pediatric subjects receiving aripiprazole treatment . METHODS This study was a post-hoc analysis of pooled data from two 8-week , double-blind , r and omized , placebo-controlled studies evaluating aripiprazole for the treatment of irritability in pediatric subjects with autistic disorder , aged 6 - 17 years . Subjects were stratified by PAE ; adverse events ( AEs ) , and changes in weight , and metabolic measures were evaluated . For subjects receiving aripiprazole , regardless of PAE , baseline weight , age , gender , and symptom severity were evaluated in a regression model predicting body weight change . RESULTS Of 316 r and omized subjects , 259 ( 82.0 % ) were antipsychotic naïve ( AN ) and 57 ( 18.0 % ) had a PAE . Aripiprazole-treated AN subjects were more likely than PAE subjects to report somnolence ( 11.9 % vs. 2.8 % ) , sedation ( 22.7 % vs. 11.1 % ) , or fatigue ( 17.0 % vs. 13.9 % ) . Rates of extrapyramidal disorder and drooling , but not akathisia or tremor , were marginally higher in AN subjects . Overall , 10.8 % of aripiprazole-treated AN subjects had at least one AE leading to discontinuation compared with 8.3 % of aripiprazole-treated PAE subjects . AN subjects receiving aripiprazole had a larger change in weight from baseline to endpoint compared with those receiving placebo ( 1.9 vs. 0.7 kg ; treatment difference 1.2 kg , 95 % CI : 0.5 , 1.9 ) than PAE subjects receiving aripiprazole compared with subjects receiving placebo ( 0.4 vs. -0.4 kg ; treatment difference 0.9 kg , 95 % CI : -0.6 , 2.4 ) . Regression analysis identified that younger subjects with higher baseline weight z-score were at highest risk for weight gain . There were no significant changes in metabolic measures compared with placebo in either group . CONCLUSIONS Weight gain was more pronounced in AN subjects and more likely to occur in younger subjects with a higher baseline weight z-score . AN subjects were more likely to experience AEs related to somnolence . However , based on discontinuations rates from AEs , overall tolerability was good for both AN and PAE groups . CLINICAL TRIAL REGISTRATION Study of aripiprazole in the treatment of  children and adolescents with autistic disorder  . Registry : www . clinical trials.gov . Identifiers : NCT00332241 and NCT00337571 We evaluated the efficacy and safety of aripiprazole in the treatment of irritability in children and adolescents ( 6–17 years ) with autism spectrum disorder ( ASD ) in a r and omized , double-blind , placebo-controlled 8-week study in Japan . Patients received flexibly dosed aripiprazole ( 1–15 mg/day ) or placebo .  Ninety-two patients were r and omized to placebo ( n = 45 ) or aripiprazole ( n = 47 ) . Aripiprazole produced a significant improvement in the mean parent/caregiver-rated Aberrant Behavior Checklist Japanese Version irritability subscale score relative to placebo from week 3 through week 8 . Administration of aripiprazole provided significantly greater improvement in the mean clinician-rated Clinical Global Impression-Improvement scores than placebo from week 2 through week 8 . All patients r and omized to aripiprazole completed the study , and no serious adverse events were reported . Three patients in placebo group discontinued . Aripiprazole was effective and generally safe and well-tolerated in the treatment of irritability associated with ASD in Japanese children and adolescents Some open-label studies suggest that risperidone can be useful in the treatment of certain target symptoms in children with autism . We aim ed to study whether the use of risperidone in comparison with placebo improved functioning in children with autism with regard to behavior ( aggressiveness , hyperactivity , irritability ) , social and emotional responsiveness , and communication skills . We conducted a r and omized , double-blind , placebo-controlled trial with 40 consecutive children with autism , whose ages ranged from 2 to 9 years , who were receiving either risperidone or placebo given orally at a dose of 1 mg/day for 6 months . Autism symptoms were monitored periodically . The outcome variables were total scores on the Childhood Autism Rating Scale ( CARS ) and the Children 's Global Assessment Scale ( CGAS ) after 6 months . Of the 40 children enrolled , 39 completed the trial over a period of 18 months ; 19 received risperidone , and 20 received placebo . In the risperidone group , 12 of 19 children showed improvement in the total Childhood Autism Rating Scale score and 17 of 19 children in the Children 's Global Assessment Scale score compared with 0 of 20 children for the Childhood Autism Rating Scale score and 2 of 20 children for the Children 's Global Assessment Scale score in the placebo group ( P < .001 and P = .035 , respectively ) . Risperidone also improved social responsiveness and nonverbal communication and reduced the symptoms of hyperactivity and aggression .  Risperidone was associated with increased appetite and a mild weight gain , mild sedation in 20 % , and transient dyskinesias in three children . Risperidone improved global functioning and social responsiveness while reducing hyperactivity and aggression in children with autism and was well tolerated . ( J Child Neurol 2006;21:450—455 ; DOI 10.2310/7010.2006.00099 ) Objective . To investigate the efficacy and safety of risperidone for the treatment of disruptive behavioral symptoms in children with autism and other pervasive developmental disorders ( PDD ) . Methods . In this 8-week , r and omized , double-blind , placebo-controlled trial , risperidone/placebo solution ( 0.01–0.06 mg/kg/day ) was administered to 79 children who were aged 5 to 12 years and had PDD . Behavioral symptoms were assessed using the Aberrant Behavior Checklist ( ABC ) , Nisonger Child Behavior Rating Form , and Clinical Global Impression-Change . Safety assessment s included vital signs , electrocardiogram , extrapyramidal symptoms , adverse events , and laboratory tests . Results . Subjects who were taking risperidone ( mean dosage : 0.04 mg/kg/day ; 1.17 mg/day ) experienced a significantly greater mean decrease on the irritability subscale of the ABC ( primary endpoint ) compared with those who were taking placebo . By study endpoint , risperidone-treated subjects exhibited a 64 % improvement over baseline in the irritability score almost double that of placebo-treated subjects ( 31 % ) . Risperidone-treated subjects also exhibited significantly greater decreases on the other 4 subscales of the ABC ; on the conduct problem , insecure/anxious , hyperactive , and overly sensitive subscales of the Nisonger Child Behavior Rating Form ( parent version ) ; and on the Visual Analog Scale of the most troublesome symptom . More risperidone-treated subjects ( 87 % ) showed global improvement in their condition compared with the placebo group ( 40 % ) . Somnolence , the most frequently reported adverse event , was noted in 72.5 % versus 7.7 % of subjects ( risperidone vs placebo ) and seemed manageable with dose/dose-schedule modification . Risperidone-treated subjects experienced statistically significantly greater increases in weight ( 2.7 vs 1.0 kg ) , pulse rate , and systolic blood pressure . Extrapyramidal symptoms scores were comparable between groups . Conclusions . Risperidone was well tolerated and efficacious in treating behavioral symptoms associated with PDD in children BACKGROUND Atypical antipsychotic agents , which block postsynaptic dopamine and serotonin receptors , have advantages over traditional antipsychotic medications in the treatment of adults with schizophrenia and may be beneficial in children with autistic disorder who have serious behavioral disturbances . However , data on the safety and efficacy of atypical antipsychotic agents in children are limited . METHODS We conducted a multisite , r and omized , double-blind trial of risperidone as compared with placebo for the treatment of autistic disorder accompanied by severe tantrums , aggression , or self-injurious behavior in children 5 to 17 years old . The primary outcome measures were the score on the Irritability subscale of the Aberrant Behavior Checklist and the rating on the Clinical Global Impressions - Improvement ( CGI-I ) scale at eight weeks . RESULTS A total of 101 children ( 82 boys and 19 girls ; mean [ + /-SD ] age , 8.8+/-2.7 years ) were r and omly assigned to receive risperidone ( 49 children ) or placebo ( 52 ) . Treatment with risperidone for eight weeks ( dose range , 0.5 to 3.5 mg per day ) result ed in a 56.9 percent reduction in the Irritability score , as compared with a 14.1 percent decrease in the placebo group ( P<0.001 ) . The rate of a positive response , defined as at least a 25 percent decrease in the Irritability score and a rating of much improved or very much improved on the CGI-I scale , was 69 percent in the risperidone group ( 34 of 49 children had a positive response ) and 12 percent in the placebo group ( 6 of 52 , P<0.001 ) . Risperidone therapy was associated with an average weight gain of 2.7+/-2.9 kg , as compared with 0.8+/-2.2 kg with placebo ( P<0.001 ) . Increased appetite , fatigue , drowsiness , dizziness , and drooling were more common in the risperidone group than in the placebo group ( P<0.05 for each comparison ) . In two thirds of the children with a positive response to risperidone at eight weeks ( 23 of 34 ) , the benefit was maintained at six months . CONCLUSIONS Risperidone was effective and well tolerated for the treatment of tantrums , aggression , or self-injurious behavior in children with autistic disorder . The short period of this trial limits inferences about adverse effects such as tardive dyskinesia OBJECTIVE : The objective of this study was to evaluate short-term efficacy and safety of aripiprazole in the treatment of irritability in children and adolescents with autistic disorder who were manifesting behaviors such as tantrums , aggression , self-injurious behavior , or a combination of these . METHODS : This 8-week , double-blind , r and omized , placebo-controlled , parallel-group study was conducted of children and adolescents ( aged 6–17 years ) with autistic disorder . Patients were r and omly assigned ( 1:1 ) to flexibly dosed aripiprazole ( target dosage : 5 , 10 , or 15 mg/day ) or placebo . Efficacy outcome measures included the Aberrant Behavior Checklist irritability subscale and the Clinical Global Impression – Improvement score ( CGI-I ) . Safety and tolerability were also assessed . RESULTS : Ninety-eight patients were r and omly assigned to receive placebo ( n = 51 ) or aripiprazole ( n = 47 ) . Mean improvement in Aberrant Behavior Checklist irritability subscale score was significantly greater with aripiprazole than with placebo from week 1 through week 8 . Aripiprazole demonstrated significantly greater global improvements than placebo , as assessed by the mean CGI-I score from week 1 through week 8 ; however , clinical ly significant residual symptoms may still persist for some patients . Discontinuation rates as a result of adverse events ( AEs ) were 10.6 % for aripiprazole and 5.9 % for placebo . Extrapyramidal symptom-related AE rates were 14.9 % for aripiprazole and 8.0 % for placebo . No serious AEs were reported . Mean weight gain was 2.0 kg on aripiprazole and 0.8 kg on placebo at week 8 . CONCLUSIONS : Aripiprazole was efficacious in children and adolescents with irritability associated with autistic disorder and was generally safe and well tolerated Objective The aim of the study was to compare safety , efficacy and tolerability of risperidone with haloperidol in the treatment of Autistic Disorder ( AD ) . Method This study was design ed as a double-blind , prospect i ve , for a 12-week period . A total of 30 subjects , between the ages of 8 and 18 with AD based on DSM IV criteria , were included in the study . Behavioral Rating Scales were performed by the investigators and the parents . Safety assessment included vital signs , electrocardiogram , electroencephalogram , adverse events , laboratory tests , extrapyramidal symptoms and the side effects . Both treatments were applied in a once daily dosage regimen of 0.01–0.08 mg/kg/day . Results The reduction from baseline in Ritvo – Freeman Real Life Rating Scale ( RF-RLRS ) , sensory motor ( subscale I ) and language ( subscale V ) scores were significant in risperidone group ( P < 0.05 ) . Compared to haloperidol , risperidone led to a significantly greater reduction in the Aberrant Behavior Checklist ( ABC ) and Turgay DSM-IV Pervasive Developmental Disorder ( PDD ) scale scores ( P < 0.05 and P < 0.01 ) . There was a greater increase of prolactin in the risperidone group , while alanine amino transferase ( ALT ) had further increased in the haloperidol group . Sensory motor behaviors ( subscale I ) and language at the end of the 12th week , RF-RLRS sensory motor and language subscale scores decreased in the risperidone group further than the other group ( P < 0.05 ) . Conclusions Risperidone was found to be more effective than haloperidol in the treatment of behavioral symptoms , impulsivity , language skills , and impaired social relations in children with AD . These results demonstrated that both drugs were safe and well tolerated in the treatment of AD In this double-blind , placebo-controlled study the administration of haloperidol result ed in significant decreases in behavioral symptoms and in general clinical improvement in 40 autistic children ages 2.33 to 6.92 years .  Haloperidol also produced greater facilitation and retention of discrimination learning in the laboratory . No adverse effects were observed at therapeutic doses , which ranged from 0.5 to 3.0 mg/day or 0.019 to 0.217 mg/kg per day BACKGROUND The aim of the study was to investigate safety , efficacy and tolerability of risperidone in comparison with haloperidol in the long-term treatment of autistic disorder . METHODS This was an open-label continuation study of the r and omized , double-blind , controlled trial of risperidone and haloperidol study for 12 week in autistic children and adolescents . A total of 28 subjects between 8 and 18 ages with autistic disorder were enrolled to the open label phase of the study . Behavioral rating scales ( Clinical Global Impression Scale [ CGI-I ] , Ritvo-Freeman Real Life Rating Scale [ RF-RLRS ] ) , Aberrant Behavior Checklist [ ABC ] , Turgay DSM-IV Pervasive Developmental Disorder Rating Scale [ TPDDRS ] ) and safety assessment scales ( Extrapyramidal Symptoms Rating Scale [ ESRS ] , UKU-Side Effect Rating Scale ) were performed at 12 , 16 , 20 and 24 weeks , following the 12 week double-blind phase . Risperidone and haloperidol treatments were applied with a once daily dosage regimen as 0.01 - 0.08 mg/kg/day . RESULTS Risperidone led to a significant greater reduction on CGI scale . There was significant improvement on RF-RLRS sensory motor and language subscale and ABC scores in risperidone group . Weight gain was observed more frequently in the haloperidol group at week 24 . CONCLUSIONS These results demonstrate that risperidone is more efficacious and well tolerated than haloperidol in the long-term maintenance treatment of autistic disorder The effects of haloperidol on behavioral symptoms and learning were critically assessed in autistic children in an ongoing double-blind placebo-controlled clinical trial . Children were r and omly assigned to haloperidol-placebo-haloperidol or placebo-haloperidol-placebo treatment sequences . Statistically , haloperidol was significantly superior to placebo in reducing behavioral symptoms . In discrimination learning paradigm , children receiving haloperidol  learned the discrimination while those on placebo did not . Discrimination attained on haloperidol was retained when the children were switched to placebo Information was presented on the psychometric characteristics of the Aberrant Behavior Checklist . The internal consistency and test-retest reliability of the Checklist appeared to be very good . Interrater reliability tended to vary across raters and subscales and ranged from mediocre to good but was generally in the moderate range and acceptable for research purpose s. Validity was assessed by comparing Checklist scores for residents presenting with attributes thought to reflect varying degrees of social adaptation .  Validity was also evaluated by comparing Aberrant Behavior Checklist scores with ratings on adaptive behavior scales and with objective observations of behavior . In general , validity was established for most Aberrant Behavior Checklist subscales . Preliminary data from drug investigations suggested that the Checklist may provide a useful adjunct for the assessment of psychotropic drug effects OBJECTIVE To evaluate the efficacy and safety of aripiprazole versus placebo in preventing relapse of irritability symptoms associated with autistic disorder in pediatric patients . METHOD This multicenter , double-blind , r and omized , placebo-controlled , relapse-prevention trial enrolled patients ( 6 - 17 years ) who met the current Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition , Text Revision ( DMS-IV-TR ) criteria for autistic disorder and who also had serious behavioral problems ( ie , tantrums , aggression , self-injurious behavior , or a combination of these behavioral problems ) between March 2011 and June 2012 . In phase 1 , single-blind aripiprazole was flexibly dosed ( 2 - 15 mg/d ) for 13 - 26 weeks . Patients with a stable response ( ≥ 25 % decrease in Aberrant Behavior Checklist-irritability subscale score and a rating of " much improved " or " very much improved " on the Clinical Global Impressions-Improvement scale ) for 12 consecutive weeks were r and omized into phase 2 to continue aripiprazole or switch to placebo . Treatment was continued until relapse or up to 16 weeks . The primary end point was time from r and omization to relapse . RESULTS Eighty-five patients were r and omized in phase 2 . The difference in time to relapse  between aripiprazole and placebo was not statistically significant ( P = .097 ) . Kaplan-Meier relapse rates at week 16 were 35 % for aripiprazole and 52 % for placebo ( hazard ratio [ HR ] = 0.57 ; number needed to treat [ NNT ] = 6 ) . The most common adverse events during phase 1 were weight increase ( 25.2 % ) , somnolence ( 14.8 % ) , and vomiting ( 14.2 % ) ; and , during phase 2 ( aripiprazole vs placebo ) , they were upper respiratory tract infection ( 10.3 % vs 2.3 % ) , constipation ( 5.1 % vs 0 % ) , and movement disorder ( 5.1 % vs 0 % ) . CONCLUSIONS In this study , there was no statistically significant difference between aripiprazole and placebo in time to relapse during maintenance therapy . However , the HR and NNT suggest some patients will benefit from maintenance treatment . Patients receiving aripiprazole should be periodically reassessed to determine the continued need for treatment . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT01227668 Abstract Aripiprazole and risperidone are the only FDA approved medications for treating irritability in autistic disorder , however there are no head-to-head data comparing these agents . This is the first prospect i ve r and omized clinical trial comparing the safety and efficacy of these two medications in patients with autism spectrum disorders . Fifty nine children and adolescents with autism spectrum disorders were r and omized to receive either aripiprazole or risperidone for 2 months . The primary outcome measure was change in Aberrant Behavior Checklist ( ABC ) scores . Adverse events were assessed . Aripiprazole as well as risperidone lowered ABC scores during 2 months . The rates of adverse effects were not significantly different between the two groups . The safety and efficacy of aripiprazole ( mean dose 5.5 mg/day ) and risperidone ( mean dose 1.12 mg/day ) were comparable . The choice between these two medications should be on the basis of clinical equipoise considering the patient ’s preference and clinical profile OBJECTIVE To evaluate the short-term efficacy and safety of aripiprazole in the treatment of irritability in children and adolescents with autistic disorder . METHOD Two hundred eighteen children and adolescents ( aged 6 - 17 years ) with a diagnosis of autistic disorder , and with behaviors such as tantrums , aggression , self-injurious behavior , or a combination of these symptoms , were r and omized 1:1:1:1 to aripiprazole ( 5 , 10 , or 15 mg/day ) or placebo in this 8-week double-blind , r and omized , placebo-controlled , parallel-group study . Efficacy was evaluated using the caregiver-rated Aberrant Behavior Checklist Irritability subscale ( primary efficacy measure ) and the clinician-rated Clinical Global Impressions-Improvement score . Safety and tolerability were also assessed . RESULTS At week 8 , all aripiprazole doses produced significantly greater improvement than placebo in mean Aberrant Behavior Checklist Irritability subscale scores ( 5 mg/day , -12.4 ; 10 mg/day , -13.2 ; 15 mg/day , -14.4 ; versus placebo , -8.4 ; all p < .05 ) . All aripiprazole doses demonstrated significantly greater improvements in mean Clinical Global Impressions-Improvement score than placebo at week 8 . Discontinuation rates due to adverse events were as follows : placebo 7.7 % , aripiprazole 5 mg/day 9.4 % , 10 mg/day 13.6 % , and 15 mg/day 7.4 % . The most common adverse event leading to discontinuation was sedation . There were two serious adverse events : presyncope ( 5 mg/day ) and aggression ( 10 mg/day ) . At week 8 , mean weight change ( last observation carried forward ) was as follows : placebo + 0.3 kg , aripiprazole 5 mg/day + 1.3 kg , 10 mg/day + 1.3 kg , and 15 mg/day + 1.5 kg ; all p < .05 versus placebo . CONCLUSIONS Aripiprazole was efficacious and generally safe and well tolerated in the treatment of children and adolescents with irritability associated with autistic disorder This double-blind and placebo-controlled clinical trial in autistic children had three objectives : ( a ) to replicate earlier findings that haloperidol administration is associated with a significant reduction of behavioral symptoms ; ( b ) to further assess its safety when given on a short-term basis : and ( c ) to assess whether it has an effect on discrimination learning .  Forty-five children , 2.02 to 7.58 years old ( M=4.49 ) , completed this crossover design , with r and om assignment to treatment sequences . Haloperidol was shown to be a powerful therapeutic agent when administered for 4 weeks and free of side effects ; at doses ranging from 0.25 to 4.0 mg/day ( M=0.844 ) , there was a clinical ly and statistically significant reduction of a variety of symptoms . Under the given conditions , the children failed to learn on either haloperidol or placebo Background Various clinical trials suggested that risperidone was beneficial in the treatment of autism spectrum disorder ( ASD ) in children and adolescents . Objective The aim of this systematic review was to determine the efficacy , acceptability and tolerability of risperidone in the treatment of children and adolescents with ASD . Data sources The data bases of Scopus , PubMed , CINAHL and Cochrane Controlled Trials Register were search ed in February 2017 . Study eligibility criteria , participants and interventions Eligible RCTs of risperidone in the treatment of child and adolescent patients with ASD . Language s were not restricted . Study appraisal and synthesis methods The full-text versions of relevant studies were thoroughly assessed and extracted . The primary efficacy of outcome was the pooled response rate and the pooled mean changed scores of the st and ardized rating scales for ASD . Results A total of 372 r and omized subjects from seven RCTs were included in this review . In acute treatment , the pooled mean change score of the Aberrant Behavior Checklist for irritability subscale ( ABC-I ) and response rate for the risperidone-treated group had a greater significance than that of the placebo-treated group . In the long-term treatment , the pooled mean change score of the CARS in the risperidone-treated group was significantly greater than that in the placebo-treated group . According to the discontinuation phase , the overall pooled relapse rate of the risperidone-treated group was significantly less than that of the placebo-treated group . The rates of pooled overall discontinuation and discontinuation due to adverse events rates were not different between the two groups in acute and long-term treatments . Limitations A small study was included in the current review . Conclusion In relation to the current systematic review , risperidone is efficacious in the treatment of symptoms in children and adolescents with ASD . Although its acceptability is comparable to placebo , treatment with risperidone is well tolerated in children and adolescents with ASD
target: The pooled mean change scores in aripiprazole-treated group for the Aberrant Behavior Checklist (ABC)-Irritability , ABC-Hyperactivity/noncompliance , ABC-Inappropriate speech and ABC-Stereotypic behavior were significantly greater than those of the placebo-treated group .
  Unfortunately , the significant difference between two groups was not found for ABC-Lethargy/social withdrawal .
  The pooled overall discontinuation rate in aripiprazole-treated group was significantly better than that of placebo-treated group .
  Conclusion Aripiprazole has efficacy in the treatment of behavioral disturbances , including irritability , hyperactivity/noncompliance , inappropriate speech and stereotypic behavior found in ASD children and adolescents ; however , it could not improve the lethargy/social withdrawal in such patients .
  The present evidence also indicates that it is safe , acceptable and tolerable in such treatment .
background: Background Recent r and omized controlled trials indicated that aripiprazole was the effective treatment for children and adolescents with autism spectrum disorder ( ASD ) .
  Objective This study systematic ally review ed the efficacy , acceptability and tolerability of aripiprazole in treatment of ASD children and adolescents .