Evaluating the Effectiveness of Aripiprazole and D-Cycloserine to Treat Symptoms Associated With Autism

• Aberrant Behavior Checklist (ABC) Irritability Subscale [ Time Frame: Measured at Week 8 ] [ Designated as safety issue: No ]
• Clinical Global Impression (CGI) Scale [ Time Frame: Measured at Weeks 8 and 16 ] [ Designated as safety issue: No ]

• - Irritability subscale of the Aberrant Behavior Checklist (ABC) after 8 weeks of Double-Blind Treatment and after Open-Label Treatment
• - Clinical Global Impression (CGI)-global improvement item (CGI-I) after 8 weeks of Double-Blind Treatment and after Open-Label Treatment

• ABC Subscales [ Time Frame: Measured at Weeks 8 and 16 ] [ Designated as safety issue: No ]
• Vineland Maladaptive Behavior Subscales [ Time Frame: Measured at Weeks 8 and 16 ] [ Designated as safety issue: No ]
• A modified version of the Compulsion Subscale of the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) [ Time Frame: Measured at Weeks 8 and 16 ] [ Designated as safety issue: No ]
• Autism Diagnostic Observation Schedule (ADOS) [ Time Frame: Measured at Weeks 8 and 16 ] [ Designated as safety issue: No ]
• Social Reciprocity Scale (SRS) [ Time Frame: Measured at Weeks 8 and 16 ] [ Designated as safety issue: No ]

• - The ABC subscales other than the Irritability subscale after 8 weeks of Double-Blind Treatment and after Open-Label Treatment
• - Vineland Maladaptive Behavior Subscales which are part of the Vineland Adaptive Behavior Scales after 8 weeks of Double-Blind Treatment and after Open-Label Treatment
• - A Modified version of the “compulsion” subscale of the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) after 8 weeks of Double-Blind Treatment and after Open-Label Treatment
• - Autism Diagnostic Observation Schedule (ADOS) after 8 weeks of Double-Blind Treatment and after Open-Label Treatment
• - Social Reciprocity Scale (SRS) after 8 weeks of Double-Blind Treatment and after Open-Label Treatment

This study will determine the effectiveness of aripiprazole and D-Cycloserine in treating symptoms associated with autism in children.

Autism is a developmental disability that affects every child differently. A wide range of symptoms accompany autism, including self-injurious behavior, severe aggression, and irritability. Despite an improved ability to reduce these symptoms, existing drug treatments continue to be associated with adverse side effects. Also, there is no existing drug treatment that reliably improves social behavior, the core deficit in autism. Studies on drug treatment combinations that are designed to reduce self-injurious behavior, aggression, and irritability and improve social behavior in children with autism have yet to be conducted. This study will address the above-mentioned limitations by evaluating aripiprazole in reducing self-injurious behavior, aggression, and irritability and by evaluating the addition of D-Cycloserine in improving social behavior among children with autism.

This study will include three phases and an add-on component for some children. Participants will be randomly assigned to receive either aripiprazole or a placebo treatment for 8 weeks. Assessments measuring irritability, behavior, and social skills will be conducted at the end of this first phase. Those patients who respond well to aripiprazole will continue to receive aripiprazole treatment for another 16 weeks. This second phase will determine whether aripiprazole is associated with long-term maintenance of symptomatic improvement in patients who respond well to short-term treatment. Assessments will again be conducted at the end of this 16-week period. Those patients whose symptoms have stabilized and continue to improve while on aripiprazole will be asked to participate in the final phase of this study. During the last phase, D-Cycloserine will be added to the treatment regimen. Patients will take both aripiprazole and D-Cycloserine for an additional 8 weeks to determine if this combination of drug treatments results in improved social behavior once patients' aggression and self-injurious behavior have been stabilized with aripiprazole. At the end of this 8-week period, participants will be assessed for any changes in behavior, irritability, or social skills. Results from this study may aid in developing safer and more effective drug treatments for children and adolescents with autism.

Add-study: The Effects of Aripiprazole on Brain Circuitry in Children and Adolescents with Autism

The purpose of this added phase is to conduct a double-blind, placebo-controlled fMRI study of brain activation and connectivity patterns before and after aripiprazole treatment with 20 subjects who enter Study phase A. Children must be able to comply with the fMRI scan and a facial affect processing task. The child must have the ability to lie still during the scanning procedures and to comply with instructions. The aim is to determine the effects of aripiprazole treatment on amygdalar activation in response to a negative facial emotional task vs. a neutral (control) task. We that hypothesize that compared to placebo, aripiprazole treatment will increase amygdalar activation in response to a negative facial emotion task. In addition we hypothesize that increases in amygdalar activation will positively correlate with improvement on behavioral rating scales.

• Drug: Aripiprazole
  Participants will receive 8 weeks of initial treatment with aripiprazole. If responsive to treatment, participants may be assigned to an additional 16 weeks of aripiprazole and then an additional 8 more weeks of aripiprazole with D-cycloserine. Dosing schedule for participants less than 50 mg maximum dose will be 10 mg per day. Dosing schedule for participants greater than 50 kg maximum dose will be 15 mg.
  Other Name: Abilify
• Drug: Placebo
  Participants assigned to placebo will take a placebo pill for the initial 8 weeks of treatment.
• Drug: D-cycloserine
  D-cycloserine will be dosed in the range of 25 to 200 mg daily for the final 8 weeks of treatment.
• Other: fMRI
  Subjects will undergo an fMRI and a facial affect processing task.

• Placebo Comparator: 1
  Participants will take placebo
  Intervention: Drug: Placebo
• Active Comparator: 2
  Participants will take aripiprazole
  Intervention: Drug: Aripiprazole
• Active Comparator: 3
  Participants first will take aripiprazole then will also take D-cycloserine
  Interventions:

  • Drug: Aripiprazole
  • Drug: D-cycloserine
• Add-on Study
  To conduct a double-blind, placebo-controlled fMRI study of brain activation and connectivity patterns before and after aripiprazole with 20 subjects who enter the Study A Phase.
  Intervention: Other: fMRI

Inclusion Criteria:

• Weight of at least 15 kg (33.75 lbs)
• Meets DSM-IV criteria for autistic disorder
• Outpatient
• Medication-free for at least 2 weeks prior to baseline for all psychotropic medications. More information about this criterion, including exceptions, can be found in the protocol.
• Clinical Global Impression Scale Severity score (CGI-S) of at least 4
• Irritability subscale of the Aberrant Behavior Checklist (ABC) score of at least 18
• An IQ of at least 35 or a mental age of at least 18 months
• In good physical health

Exclusion Criteria:

• Meets DSM-IV criteria for Asperger's disorder, Rett's disorder, childhood disintegrative disorder, any other pervasive developmental disorder (PDD), schizophrenia, psychotic disorder, or bipolar disorder
• Current or past history of alcohol or other substance abuse within 6 months of study entry
• Comorbid neurodevelopmental disorder with possible association to autism (e.g., fragile-X syndrome, tuberous sclerosis)
• A significant medical condition such as heart, liver, kidney, or lung disease, or a seizure disorder
• Pregnant
• Prior adequate use of aripiprazole. More information about this criterion can be found in the protocol.
• Evidence of hypersensitivity to aripiprazole
• History of neuroleptic malignant syndrome