New meta-analysis demonstrates significant incidence of psychiatric side effects of the weight loss medication rimonabant

November 20, 2007 By Benjamin A. Olenchock, M.D. Ph.D. [mailto:bolenchock@partners.org]

A new meta-analysis has pooled data from the randomized controlled trials of rimonabant. Their findings, published online in the journal Lancet demonstrate significant incidence of depression and anxiety among patients taking rimonabant in the clinical trial setting.

Rimonabant is a cannabinoid receptor antagonist which is approved for use in Europe as a weight loss medication. The cannabinoid receptors are involved in the reward & pleasure responses in the brain that accompany activities such as eating and smoking. Rimonabant works by blocking the reward response, leading to less food intake. Sanofi-Aventis submitted a new drug application for rimonabant (brand name Acomplia) to the FDA in April 2005. Studies have consistently demonstrated a benefit to rimonabant for weight reduction, however the FDA did not approve the drug because of concerns regarding psychiatric side effects, specifically suicidality.

The four Rimonabant in Obesity (RIO) randomized controlled trials were included in the meta-analysis. Patients had a body mass index greater than 30 kg/m^2 or greater than 27 kg/m^2 with obesity-related co-morbidities such as dyslipidemia or type II diabetes. They found that compared to patients taking placebo, patients taking 20 mg rinonabant for 1 year had an average weight loss of 4.7 kg (~10 lb; p<0.0001). Over that same time period, however, they were 1.4 times more likely to experience a serious adverse event, and 2.5 times more likely to discontinue the medication because of symptoms of depression (3% in rimonabant vs. 1.4% in placebo). These numbers translate into 1 in 49 patients who developed depression serious enough to discontinue the medication. Patients were also 3 times more likely to experience anxiety on rimonabant (p<0.01). The number needed to harm was 25 for any adverse event and 57 for a serious adverse event.

By pooling data from the clinical trials, the meta-analysis was powered to demonstrate risk that was not noted in the individual RIO reports. Their findings were quite similar to those of the FDA advisory committee, which had access to additionally unpublished data as well. The recent FDA briefing document can be found at: http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4306b1-fda-backgrounder.pdf. At the time of the FDA publication, unblinded data were available for 11 subjects with suicidality who were randomized to rimonabant and 6 subjects in the placebo group. Patients with a history of mental illness were excluded from the randomized controlled trials, and the FDA was concerned that the real-world psychiatric risk might be even greater.

The risk of serious psychiatric adverse events will likely keep this drug from the US market. Post-approval studies in Europe will be informative regarding the real world risks and benefits of this medication. The market for a safe, effective weight loss medication is quite large, as is the public health need for such a medication. The risk profile of rimonabant has been disappointing to many physicians and patients, as the beneficial effects on obesity, metabolic syndrome, and smoking cessation were quite impressive.

This work was funded by grants from the Center for Pharmacogenomics, University of Copenhagen, The Oak Foundation, the H:S Research Foundation and Diabesity EC-FP6

1. Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Robin Christensen MSc, Pernelle Kruse Kristensen BSc, Else Marie Bartels DSc, Prof Henning Bliddal MD and Prof Arne Astrup MD. ''The Lancet 2007; 370:1706-1713 DOI:10.1016/S0140-6736(07)61721-8''