Behavioral and Developmental Outcomes From Long Term Aripiprazole Treatment of Youth with Autism Spectrum Disorders

Background:  Only two medications (aripiprazole and risperidone) are approved for youth with autism.  Unfortunately studies to-date only address disruptive behaviors and suggest these drugs may have significant side effects.  It is not clear these medications are safe and effective for the chronic treatment of disruptive behaviors or provide any benefits for core features of this neurodevelopmental disorder affecting 1 in 110 children.

Objectives:  Assess long-term safety, tolerability and broad efficacy of aripiprazole in children and adolescents with autism spectrum disorders.

Methods:  Thirty youths with autism were enrolled in the study.  Twenty participated in open-label, flexible-dose treatment with aripiprazole (range 10 – 25mg/day).  Those who tolerated 12 weeks of aripiprazole treatment continued into a maintenance phase to assess efficacy and safety over a full year.  Ten youths participated as unmedicated controls.  All participants were evaluated at baseline, 12 weeks, 24 weeks and 52 weeks with a battery of cognitive and behavioral assessments.  The primary outcome was the change in overall functioning as assessed by the Clinical Global Impression – Improvement scale; CGI-I.  Secondary outcome measures included change in the severity of disruptive behaviors (Aberrant Behavior Checklist – ABC), parent-identified target symptoms, restrictive/repetitive behaviors (Repetitive Behavior Scale – Revised), social behaviors (Social Reciprocity Scale) and family stress, as well as objective standardized measures of cognition (Stanford-Binet-5) and language. Safety and tolerability were monitored throughout using surveillance labs and a semi-structured interview for adverse events.  All results are last observation carried forwards.

Results:  Participants reached their optimal dose within 12 weeks. Three children withdrew during the first 12 weeks: 1 adverse event (enuresis week 6), 1 lack of efficacy (week 4) and 1 lost to follow-up (week 8).  Twelve weeks of treatment coincided with a clinically significant mean CGI-I of 2.30±1.08.  25% (5) were rated very much improved, 50% (10) much improved, 15% (3) minimally improved and 10% (2) rated with no change.  Seventeen children continued into the maintenance phase.  Three subsequently discontinued: 1 adverse event (weight gain week 20), 1 loss of efficacy (week 18) and 1 lost to follow-up (week 24).   Improvement (CGI-I) was maintained through 52 weeks in all but one youth.  All ABC subscales improved ranging from 16% (inappropriate speech) to 43% (lethargy/social withdrawal).  Except for inappropriate speech, improvements persisted through week 52 and were statistically significant compared to baseline.  Stanford-Binet nonverbal fluid reasoning subscale increased by 9.3%, verbal knowledge 5.8% and abbreviated battery IQ by 2.3%.  Weight increased by 5.5% in the first 12 weeks. In the fourteen participants who completed one year of treatment, weight increased by 5.8% during the first 12 weeks and 16% over the full year.  No serious adverse events occurred.

Conclusions:  Aripiprazole appears to be safe and well-tolerated for the chronic treatment of autism.  Improvements were evident across multiple behavioral domains within 12 weeks and sustained with extended treatment.  Decrease in CGI-S and ABC suggest aripiprazole may reduce maladaptive behaviors and some core features of autism.  This pilot study highlights the practicality and necessity of long-term efficacy and safety trials as the standard for treating youth with serious pervasive neuropsychiatric illness.