Treatment of Self-Injurious Behavior in Individuals With Prader-Willi Syndrome

PWS is a neurogenetic disorder resulting from a loss of the paternal-only expressed genes on
chromosome 15 (15 q11-13). PWS is characterized by a persistent pattern of SIB, most
notably skin picking, that results in frequent medical care and attention. SIB in mental
retardation and related developmental disabilities is often monitored by behavioral
observation methods. Direct evaluation of skin lesions has been reported to help
systematically follow wounds and wound healing. However, there are differences between the
type and body location of SIB in individuals with PWS as compared to those with mental
retardation. The goal of this study is to characterize SIB in PWS and to evaluate the
efficacy of topiramate versus placebo in attenuating SIB in individuals with PWS.

A preliminary 8-week open-label study conducted to evaluate topiramate for appetite and
weight in PWS has shown good tolerability and beneficial effects of topiramate. During that
study, an unexpected and serendipitous finding was that of the six participants, four
engaged in SIB and all four had noticeable symptom improvement during the 8 weeks of
treatment. Three of these four have continued on topiramate therapy long term with positive
results in terms of decreased self-injury.

Participants in the study will be randomized to receive either topiramate or a placebo for 6
weeks. All participants will be monitored for SIB by observation and photographic
recordings of the resultant skin lesions, by reports of group home staff, and by
standardized rating measurements of self-injury. At the end of 6 weeks, participants
receiving topiramate will receive decreasing doses of topiramate; participants receiving
placebo will continue to receive the placebo. At week 9, participants previously receiving
topiramate will be given placebo and participants previously receiving placebo will be given
topiramate. After 6 weeks, all participants will be entered into a 4-month open-label
extension phase. Safety and efficacy measurements will be assessed during the 15 study
visits; in the event of worsening SIB, the blind will be broken by the study’s medical
oversight physician and, if appropriate, the participant will be placed directly into the
4-month open-label extension phase.

Inclusion Criteria

- PWS due to deletion of 15 q11-13 or uniparental disomy

- Actively engaging skin picking behavior

- Individual with PWS or legal guardian able to provide full informed consent. If
legal guardian gives informed consent, then individual with PWS will give his/her
assent.

- Acceptable methods of contraception

Exclusion Criteria

- Pregnant or breastfeeding

- Clinically significant suicidality or homicidality

- DSM-IV diagnosis of substance abuse or dependence within 6 months of study entry

- Cardiovascular, hepatic, renal, gastrointestinal, pulmonary, metabolic, endocrine, or
other systemic disease which could interfere with treatment or assessment of PWS

- Treatment with any drug which might interact adversely with topiramate

- Medication or significant behavioral management change within 4 weeks of study entry

- Personal history or a first-degree family history of nephrolithiasis