Pharmacogenomics in Autism Treatment
Condition: Autism
MeSH terms: Autistic Disorder
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      Autism is a complex neurodevelopmental disorder that is thought to involve an interaction
      between multiple and variable susceptibility genes, environmental factors, and epigenetic
      effects. Great concern has been raised about the marked increase in the prevalence of autism
      spectrum disorders in the last decade. Risperidone, the most studied atypical antipsychotic
      used in children, has been shown to improve severe behavioral difficulties in over half of
      children with autism who have these difficulties. However, not all children with autism and
      severe behavioral problems respond to risperidone, and for a few, it has significant side
      effects.

      Two controlled studies and numerous open-label and long term studies in children with autism
      spectrum disorders using the atypical antipsychotic risperidone show a significant decrease
      of associated serious behavioral problems. The use of atypical antipsychotics is of great
      concern, however, because of their significant side effects and the fact that only two-thirds
      of children positively respond. Ways to predict response, appropriate dosage and serious side
      effects are needed.
    

Detailed description: 
      For this study, we will identify 40 children (4 to 18 years old) with autism who also have
      serious behavioral problems. We will then treat them with risperidone. Blood samples will be
      obtained prior to treatment and at eight weeks of treatment or study exit. At that time,
      efficacy will be assessed using the Clinical Global Impression-Improvement scale (CGI-I) and
      the Irritability subscale of the Aberrant Behavior Checklist (ABC). Blood genomic profiles
      before and after risperidone treatment will be determined using Affymetrix oligonucleotide
      microarrays combined with RT-PCR.

      Blood genomic profiles are shown to predict medication response for disorders such as cancer
      and epilepsy. This exploratory or discovery study will use blood genomic profiles before and
      after risperidone treatment in children with autism and severe behavioral difficulties to
      determine if the profiles can predict response to treatment. The ultimate goal of this line
      of research is to develop methods to predict which medications work for which child before
      initiating treatment, to predict which child might develop particular side effects, and to
      identify new treatment targets for future medication development.

      Risperidone will be started at 0.5 mg at bedtime for 4 days and, if the current dosage is
      tolerated as evidenced by no more than mild sedation, no EPS or other moderate to severe AEs,
      and if there are continued behavioral symptoms, the dose will be increased to 1 mg at bedtime
      for an additional 4 days. If tolerated and indicated, 0.5 mg will be added in the AM for a
      daily total of 1.5 mg. After that, dosages may be increased if there does not appear to be an
      adequate clinical response. Dosage will not be increased if there are side effects (e.g.
      excessive sedation, salivation, EPS, lactation) and may be decreased if it is not tolerated.
      If the investigator determines that a significant adverse reaction occurs or if the subject
      or his or her family wants to stop the study, the medication will be tapered or stopped
      depending on the dose and reason for stopping and the subject will be offered alternative
      treatment at the M.I.N.D. Institute Clinic or referred elsewhere. This dosing schedule
      mirrors that used in the two recent positive trials of risperidone for treating severe
      behavioral problems in autism (McCracken et al., 2002; Shea et al., 2004).
    

Intervention name(s): Risperidone
Intervention type(s): Drug
Intervention description(s): Dose will start at 0.5 mg and may be increased throughout the course of the study if no adverse events occur
Other intervention name(s): Risperdal
Intervention MeSH terms: Risperidone
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment