The first placebo-controlled trial of any psychiatric medication for behavioral symptoms in Prader-Willi syndrome shows promising results
STUDY: Singh D et al, Am J Med Genet B Neuropsychiatr Genet 2025;0:e33032
STUDY TYPE: Small, randomized, double-blind, placebo-controlled trial
FUNDING: Foundation for Prader-Willi Research and Maimonides Research and Development Foundation
Background
Prader-Willi syndrome is a rare genetic disorder marked by hyperphagia, aggression, skin-picking, and hyperactivity. Despite over 65% of adults with the condition taking at least one psychotropic medication, no randomized controlled trial had ever tested any of them for behavioral symptoms. This study, though small, changes that.
The Study
Fourteen children and adults aged 6–35 with genetically confirmed Prader-Willi syndrome and moderate-to-severe aggression or self-injury were randomized to guanfacine extended-release or placebo for 8 weeks, followed by an 8-week open-label extension. Guanfacine was titrated to a mean stable dose of 2.75mg daily.
Guanfacine reduced overall aberrant behavior (Aberrant Behavior Checklist score down 9.96 points, p=0.03), with the strongest effect on hyperactivity and noncompliance (down 5.27 points, p=0.01). Aggression also improved (Modified Overt Aggression Scale down 3.65 points, p=0.02). Clinicians rated participants as significantly improved on the global impression scale (p=0.002). Skin-picking trended toward improvement but didn’t reach significance versus placebo.
Side Effects
Fatigue was the main side effect, occurring in 93% of the guanfacine group versus 29% on placebo, though overall daytime sleepiness on the Epworth Sleepiness Scale didn’t differ between groups.
No serious adverse events occurred. Weight, heart rate, blood pressure, and cardiac rhythm were unchanged, which matters in a population already prone to obesity.
Limitations: just 14 subjects were randomized, which limits confidence in any subgroup or safety conclusions. There is a lack of large RCTs in this population.
Practice Implications
- Antipsychotics are often used in Prader-Willi syndrome, but they carry metabolic risks in a population already fighting obesity.
- Guanfacine is a safer option for aggression or hyperactivity.
— Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
