Psychiatric adverse effects of rimonobant in adults with Prader Willi syndrome.
BACKGROUND
Prader Willi syndrome (PWS) without strict environmental modifications can lead to obesity associated with significant morbidity and mortality. In addition to increased appetite, these individuals have decreased energy expenditure with lower insulin like growth factor 1 (IGF1), which contributes to adiposity. No effective treatment is available for this condition. Endocannabinoid receptor CB1 antagonist, rimonobant, has been effective for treatment of obesity in adult subjects. Rimonabant promotes weight loss by multiple proposed mechanisms, including decreased appetite and lipogenesis, and increased energy expenditure. Therefore, we conducted this pilot study to evaluate the effect of rimonabant on body weight and composition of adults with PWS.


METHODS
This was a double blind placebo controlled study. Body weight, total fat mass, fasting ghrelin, leptin, IGF1 and insulin like growth factor binding protein (IGFBP-3) were collected at baseline, and after 90 and 180 days of treatment with placebo or 20 mg of rimonabant.


RESULTS
Due to psychiatric adverse effects, 50% of subjects in the rimonabant group withdrew, and the study was terminated early (N=10) for safety concerns. There was a trend for weight loss, lower fat mass and higher IGF1 level at the end of study in this group. Leptin followed the fat mass and decreased with rimonabant treatment.


CONCLUSIONS
Rimonabant administration may be efficacious for weight loss in adults with PWS; unfortunately it is associated with an unacceptably high risk of psychiatric side effects. Future CB1 antagonists will need a better psychiatric profile before considered in the treatment of obesity in this genetic condition.
Department of Pediatrics, Weill Cornell Medical College, 525 East 68th Street, New York, NY 10065, USA. rojamotaghedi@gmail.com
Roja
R
Motaghedi
Elizabeth G
EG
Lipman
Jeannette E
JE
Hogg
Paul J
PJ
Christos
Maria G
MG
Vogiatzi
Moris A
MA
Angulo
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D001835:Body Weight / Q000187:drug effects; D063387:Cannabinoid Receptor Antagonists; D004311:Double-Blind Method; D005215:Fasting / Q000097:blood; D005260:Female; D054439:Ghrelin / Q000097:blood; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D020738:Leptin / Q000097:blood; D008297:Male; D010259:Paranoid Disorders / Q000139:chemically induced; D010865:Pilot Projects; D010880:Piperidines / Q000009:adverse effects / Q000627:therapeutic use*; D011218:Prader-Willi Syndrome / Q000188:drug therapy*; D011618:Psychotic Disorders / Q000209:etiology; D011720:Pyrazoles / Q000009:adverse effects / Q000627:therapeutic use*; D011863:Radioimmunoassay; D000077285:Rimonabant; D016896:Treatment Outcome; D055815:Young Adult
D063387:Cannabinoid Receptor Antagonists; D054439:Ghrelin; D018972:Insulin-Like Growth Factor Binding Protein 3; D020738:Leptin; D010880:Piperidines; D011720:Pyrazoles; D007334:Insulin-Like Growth Factor I; D000077285:Rimonabant