Acomplia May Cause Depression by Blocking TRPV1 Receptor in the Brain

Diet drug rimonabant (Acomplia / Zimulti), in addition to promoting weight loss by blocking the body’s CB-1 receptors, may also block a receptor in the brain called TRPV1, possibly explaining why the diet pill produces depression, anxiety and suicidal thoughts in some patients, according to researchers. Rimonabant is a CB-1 receptor antagonist that reduces appetite by blocking the body’s cannebinoid receptors.

Rimonabant is widely available outside the United States, including in Eurolpe, but Sanofi Aventis pulled it back from consideration by the U.S. Food and Drug Administration last summer after an agency advisory panel unanimously expressed concern over the drug’s psychiatric side-effects.

Now, in a study published in the March 13 issue of the journal Neuron, researcher Julie Kauer of Brown University and her colleagues report that the TRPV1 receptor — a pain receptor that is central to learning and memory — may also be blocked by large doses of rimonabant.

“It’s possible that when the patient takes the drug, and the dose range is correct, it may not affect TRPV1 at all,” Kauer said. “However, in some patients, Acomplia could be hitting TRPV1 and may well have an effect on activating this receptor.”

In experiments with rat brains, Kauer and her fellow researchers found that TRPV1 controls a brain mechanism called long-term depression, which may relate to the psychiatric side effects seen with Acomplia.

“A large percentage of patients stop taking this drug as a result of psychiatric side effects, and our findings suggest the possibility that some of the central effects of [Acomplia] result from the antagonism of TRPV1 receptors …,” the researchers conclude.

Diet Drug Acomplia (Rimonabant) Still Seen as a Winner by Sanofi

Sanofi-Aventis said on April 3rd it still has high hopes for diet drug rimonabant (Acomplia / Zimulti), even though it was rejected by a U.S. FDA advisory panel last year and recent clinical trial news has been less than wildly encouraging. Marc Cluzel, Sanofi’s head of research, said in a round of interviews in London that he continues to believe Acomplia can be a winner.

Acomplia, which was to have been marketed in the United States as Zimulti, was withdrawn from FDA consideration last June after an expert panel unanimously recommended against approval out of concern over depressive and suicidal side-effects.

Data from a new clinical trial of possible use of Acomplia in slowing progression of coronary artery disease was reported this week along with news that 43.4 percent of patients who got rimonabant in this trial suffered psychiatric side effects such as anxiety and depression.

While the results of the heart trial were ambiguous at best, Cluzel put a positive face on it — and reiterated that Sanofi intends to resubmit rimonabant to the FDA and regulators worldwide in 2009 for approval as a treatment for type 2 diabetes.

He noted that the Acomplia development program — involving clinical trials for a variety of conditions in addition to obesity — is only one-third completed.

“It’s very difficult before 2011 to know exactly what will be the full benefits of the product,” Cluzel told the news agency Reuters.

Another Sanofi executive, Belen Garijo, also expressed confidence that sales of Acomplia — which have been disappointing to date — will grow in Europe and other countries where it is on the market.

“We are very confident that Acomplia will grow in Europe,” Garijo told Reuters, noting that it is being reimbursed by insurance in a growing number of markets