Meta-Analysis Links Diet Drug to Significant Risk of Depression and Anxiety

COPENHAGEN, Nov. 16 -- The investigational diet drug, rimonabant (Zimulti, Acomplia) appears to trigger depression and anxiety in patients with no previous history of mood disorders, researchers here found.
Action Points
Explain to interested patients that rimonabant is not approved by the FDA.
Explain, too, that this study reports findings of a meta-analysis, so the results should not be given the same weight as findings of randomized trials.
In randomized, controlled trials patients taking 20 mg of rimonabant were 2.5 times more likely to discontinue treatment because of depression and three times more likely to stop treatment because of anxiety than patients randomized to placebo, said Arne Astrup, M.D., of the University of Copenhagen, and colleagues reported in the Nov. 17 issue of The Lancet.
Moreover, depression and anxiety dogged rimonabant users even though patients taking the drug lost an average of 4.7 kg more than patients in the placebo group (P<0.0001).
The authors concluded that these findings combined with a recent FDA finding of increased risk of suicide during treatment with rimonabant, "suggest that the potential of rimonabant to induce depressive symptoms and depression in overweight persons needs greater attention."
Rimonabant, a selective antagonist of the cannabinoid type 1 receptor, works by targeting a central nervous system reward system -- the endocannabinoid system. Theoretically, the drug takes away the pleasure associated with food intake. By limiting pleasure, food consumption declines.
In an editorial in the same issue, Philip B. Mitchell, M.D., and Margaret Morris, M.D., of the University of New South Wales, wrote that several other companies are developing drugs that target the endocannabinoid system. Given the findings of the meta-analysis, "phase III studies of such CB1 antagonists should monitor psychiatric complications very carefully," they wrote.
Moreover, the editorialists suggested that the "link between depression and this CB1 -receptor blocker raises theoretical questions about a potential central role for the endocannabinoid system in both normal and clinical mood states."
The researchers conducted a meta-analysis based on data collected in the four RIO (Rimonabant in Obesity) trials -- RIO-Europe, RIO-Lipids, RIO-North America, and RIO-Diabetes. The RIO protocol required only a modest reduction in calories consumed -- participants were asked to reduce their daily caloric intake by 600 calories. There was no maximum calorie limit and no exercise component.
The trials enrolled 4,105 adults with BMIs ranging from 34 to 37, and glucose averaging 5.11 mmol/L to 8.35 mmol/L. Participants were also likely to have elevated triglycerides, low HDL, and central adiposity -- all components of the metabolic syndrome.
Patients with a history of depression or mood disorders were excluded from the trials.
Among the findings:
Rimonabant was associated with a 40% increase in risk for adverse events compared with placebo (OR: 1.4, P=0.0007).
The number needed to harm was 24 in the rimonabant arm.
The odds ratio for depression in the rimonabant arm was 2.5 (P=0.01) and for anxiety the OR was 3.0 (P=0.03).
Last June an FDA advisory panel unanimously agreed that the drug's risk/benefit profile did not warrant approval for weight management. The FDA panel asked the manufacturer, sanofi-aventis, to gather more detailed information about the long-term safety of the drug.
Rimonabant is available in Argentina, Austria, Denmark, England, Germany, Greece, Ireland, Norway, and Sweden.
The meta-analysis was supported by grants from the Center for Pharmacogenomics, University of Copenhagen, the Oak Foundation, the H.S. Research Foundation, and Diabesity ED-FP6.
Dr. Astrup disclosed that he "participates in several advisory boards for biotechnology and pharmaceutical companies, some of which are developing CB-1 antagonists for treatment of obesity." Dr. Astrup also disclosed that he is president of the International Association for the Study of Obesity, which has received funding from sanofi-aventis, and that he served on the advisory board of a sanofi-aventis-funded Danish rimonabant study.Primary source: The LancetSource reference: Christensen R, et al "Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomized trials"The Lancet 2007; 370: 1706-13. Additional source: The LancetSource reference: Mitchell PB, Morris MJ, "Depression and anxiety with rimonabant" The Lancet 2007; 370: 1671-72.