Weight-Loss Drug Rimonabant Increases Risk for Adverse Psychiatric Effects

Marlene Busko

November 21, 2007

To read this article for CME, click here.

November 21, 2007 — A meta-analysis of 4 randomized controlled trials of the weight-loss drug rimonabant concurs with Food and Drug Administration (FDA) findings of increased risk for serious adverse psychiatric effects — depressed mood disorders and anxiety — although depressed mood was an exclusion criteria.

These findings, based on data from the 4 clinical trials in the Rimonabant in Obesity (RIO)
program — RIO-Europe, RIO-Lipids, RIO-North America, and RIO-Diabetes — are published in a
November 17 article in The Lancet by Robin Christensen, MSc, and colleagues at the University of Copenhagen in Denmark.

Rimonabant ( Acomplia, Sanofi Aventis) was approved by the European Agency for the Evaluation of Medicinal Products in June 2006 and is available in Argentina, Austria, Denmark, Finland, Germany, Ireland, Norway, Sweden, Greece, and the United Kingdom. In June of 2007, coinciding with the submission of this Lancet article, the Advisory Committee of the US FDA unanimously concluded that more detailed safety information about rimonabant was needed before the drug could be approved for use in the United States, and subsequent to that decision, Sanofi Aventis withdrew its new drug application in the United States.

First Do No Harm

"There's no doubt that this is a serious matter because one should remember that the treatment must never be more harmful than the disease, for weight-loss compounds," study author Arne Astrup, MD, said in a podcast available on the Lancet Web site.

Rimonabant, a selective antagonist for the cannabinoid type 1 (CB1) receptor, is the first drug being marketed in this class of drugs that are involved in inhibiting the effect of food, cannabis, and tobacco on the central nervous system reward system.

The 4 RIO trails showed that rimonabant results in a weight loss that is 4 to 6 kg (8.8 - 13.2 pounds) greater than that with placebo, in 6 to 12 months, which is about the same as for the 2 other weight-loss drugs on the market, orlistat ( Xenical, Roche) and sibutramine ( Meridia, Abbott), the authors write. Although rimonabant was generally well tolerated, individual trials showed trends to increases in depressed mood disorders, depression, and severe adverse effects.

The group aimed to perform a meta-analysis to obtain more robust data to determine the drug's efficacy and safety, especially adverse psychiatric events. Only double-blind, randomized controlled trials using rimonabant for weight loss in patients with a body mass index of 30 kg/m2 or greater or 27 kg/m2 or greater with one or more obesity-related comorbidities were eligible.

The 4 large, multicenter, double-blind RIO trials met the study requirements. These trials included 4105 participants who received 20 mg/day of rimonabant or placebo.

High Study Drop-Out Due to Depression, Anxiety

Compared with patients in the placebo group, patients taking rimonabant had a 4.7-kg greater weight reduction at 1 year, and they were 5 times more likely to achieve at least 10% weight loss.

Compared with patients receiving placebo, those in the rimonabant study groups had a higher risk of developing a serious adverse event (5.9% vs 4.2%) and a greater risk of discontinuing the study because of developing a depressive mood disorder (3% vs 1.4%) or anxiety (1% vs 0.3%).

Table. Risk for Adverse Events in 4 RIO Studies, Rimonabant 20 mg/day vs Placebo*

Risk



Odds Ratio (95% CI)




P




Number Needed
to Harm


Developing a serious adverse event

1.4 (1.0 - 2.0)

.03



59


Study discontinuation due to depressive mood disorder

2.5 (1.2 - 5.1)

.01



49


Study discontinuation due to anxiety

3.0 (1.1 - 8.4)

.03



166


*RIO indicates Rimonabant in Obesity; CI, confidence interval.

Higher Risk in Clinical Practice

In countries where rimonabant is being prescribed, clinicians need to be really aware that patients have an increased risk of developing depression or anxiety, said Dr. Astrup. It is also important to note that the clinical trials excluded patients who had existing or past depression or were taking therapies for depression. "We think the risk will be higher in clinical practice," he cautioned. Another reason these findings are important is that 4 or 5 major pharmaceutical companies are developing similar CB 1 compounds that they are moving from phase 2 to phase 3, he added. "It is quite important for them to be aware of this problem with depression and anxiety so they will have a chance to do a better job of monitoring all these psychiatric symptoms. . . so we will have a much better idea of the severity of the problem."

Editorialists Agree

"Up to this point in time, there has been controversy over the rates and severity of psychiatric adverse effects with rimonabant," Phillip B. Mitchell, MD, who with Margaret J. Morris, PhD, both at the University of New South Wales, Australia, coauthored an accompanying editorial, told Medscape Psychiatry. "This is the first meta-analysis to examine rates of. . . symptoms severe enough to lead to patients discontinuing treatment."

The findings are significant because they "raise major questions about the safety of rimonabant in obese people, who are already at increased risk of depression. . . and suggest that phase III studies of CB1 antagonists should monitor psychiatric complications very carefully," they write, echoing the words of the study authors. In addition, they note that the link between depression and this CB1 blocker raises theoretical questions about a potential central role for the endocannabinoid system in normal and clinical mood states.

Robin Christensen was the statistical expert/consultant in the Lantus medical expert panel for Sanofi-Aventis (Denmark) in 2006. Arne Astrup participated in several advisory boards for biotechnology and pharmaceutical companies, some of which are developing CB1 antagonists for the treatment of obesity. He is president of the international society of the Study of Obesity (IASO), which had received funding from Sanofi Aventis when he was president-elect. He also participated in the Danish rimonabant advisory board for Sanofi-Aventis, until the board closed in June 2006.

Dr. Mitchell has received payments for lectures or advisory board membership from AstraZeneca, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, and Lundbeck in the past 3 years. Dr. Morris has disclosed no financial relationships.

Lancet. 2007;370:1671-1672, 1706-1713.

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