New Hope For Treating Obesity

Norman Sussman, MD, DFAPA

Editor, Primary Psychiatry and Psychiatry Weekly, Professor of Psychiatry, New York University School of Medicine

We are constantly being reminded of the related epidemics of obesity and diabetes affecting millions of Americans. For many individuals, a combination of dietary restraint and exercise is effective in overcoming the consequences of portion creep and a sedentary lifestyle. Nevertheless, for many others, weight loss is virtually impossible. In contrast to the statins, which are highly effective in counteracting hyperlipidemia, and the various hypoglycemic agents that treat diabetes mellitus, no currently available drugs are consistently effective in combating obesity, often the underlying problem beneath both hyperlipidemia and diabetes. Although several weight loss medications are available, only two drugs are approved for long-term treatment of obesity. They are the lipase inhibitor orlistat and norepinephrine-serotonin reuptake inhibitor sibutramine. This paucity of effective long-term treatments may soon be rectified. On June 21, 2006 the European Union approved a new agent, rimonabant (Acomplia, Sanofi-Aventis) as an adjunct to diet and exercise for the treatment of obese patients, or overweight patients with associated risk factors, such as type 2 diabetes or dyslipidemia. Rimonabant is the first of a class of drugs known as selective cannabinoid-1 receptor blockers. It has been shown to reduce appetite and promote weight loss in patients who are obese or overweight. It is the only endocannabinoid receptor antagonist in clinical development.

Activation of cannabinoid-1 receptors by endogenous cannabinoids, as found in marijuana and hashish, is known to increase appetite, causing the “munchies.” This led Sanofi-Aventis to investigate whether blocking cannabinoid receptors in the brain might reduce appetite. Compounds with potential inhibitory activity against these receptors were screened for inhibitory activity, leading to the identification of rimonabant as a potent CB1 receptor antagonist. Preclinical animal studies subsequently showed that it could reduce consumption of fats and sugars, which contribute to weight gain. The drug also has potential as a treatment for smoking cessation because the endocannabinoid system is involved in the body’s response to tobacco dependence.

Thus far, over 6,000 obese subjects in the US and Europe have been studied. Positive effects such as weight reduction and prevention of weight gain were seen after a year’s treatment were sustained over the full two-year trial period. Overweight and obese patients taking rimonabant achieved significant reductions in body weight, waist circumference and improved lipid and glycemic profiles compared with placebo recipients.

Although it has not been studied in this role, rimonabant may be a potential antidote to the weight gain caused by commonly used psychotropics such asthe SSRIs and the atypical antipsychotic agents. However, patients in clinical trials to have been reported to experience higher rates of psychiatric side effects, such as anxiety and depression, than those taking placebo

When rimonabant will be available for clinical use in the US remains unclear. Rimonabant is approved for treatment of obesity in Europe, but the FDA has deferred final approval in the US pending further information from Sanofi-Aventis.

Disclosure: Dr. Sussman reports no affiliation with or financial interests in any organization that may pose a conflict of interest.