Following the first wave of excitement over the latest trial data showing that obese and overweight people lose four times as much weight on Acomplia as on a placebo, an undercurrent of unease has emerged over side effects that the researchers described as "mainly minor and short-lived."

The concern is fueled by the trial results suggesting that long-term use of Acomplia will be required to maintain the significant weight loss that occurs mainly in the first year. Participants in the trial who were switched after a year from Acomplia to a placebo tended in the second year to regain the weight they had lost.

Thus, proof of safety and tolerability over an unlimited treatment period seems likely to be a major consideration if Sanofi-Aventis, as expected, asks the U.S. Food and Drug Administration in mid-2005 to approve Acomplia for long-term use.

The RIO-North America trial was the first to produce two-year safety and efficacy data for Acomplia, and concern over possible side effects has focused on the noticeable rate of withdrawal from the trial due to depression.

Some 2.9 percent on the optimal higher dose of Acomplia had to drop out of the trial because they developed depression, compared with only 1.5 percent of those taking placebos, according to Dr. Douglas Greene, vice president for corporate and regulatory affairs for Sanofi-Aventis, developer of the drug.

“Perhaps we’ve uncovered some latent cases of depression. Perhaps people who are depressed treat their depression by eating. We’re in the process of figuring all that out,” Greene said.

But since Acomplia is part of an entirely new class of drugs that affects the cannabinoid receptor, a pleasure receptor in the brain, any neuropsychiatric side effects seem likely to get particular attention from regulators.

Dr. Xavier Pi-Sunyer, the lead researcher, noted that the neuropsychiatric symptons did not result in any measurable difference on the Hospital Anxiety Depression scale between those taking Acomplia and those taking a placebo.

But earlier this fall, European researchers reporting on results of a quality of life study among patients receiving either Acomplia or placebo said two patients suffered amnesia while taking Acomplia -- a condition that apparently cleared up after the drug was stopped.

They also reported mood disorders (such as depression) were higher among patients taking Acomplia.

These trial results suggest that while most patients do well on Acomplia, there are likely to be some who do not. And if a side effect like depression shows up in only one in 100 patients, that could translate into a huge number of people if millions of people are taking the drug.

Dr. George Bakris, vice chairman of the department of preventive medicine at Rush University Medical Center in Chicago, was among those voicing concern about this issue.

"When you start interfering with that part of the brain, things can happen," Bakris said.

Given the not-all-that-distant memories of Fen-Phen and current climate of increased regulatory focus on the safety of new drugs after the recent Vioxx controversy, the FDA seems certain to want a lot of data on any potential risk factors in the use of a new drug that affects the brain.

While Sanofi-Aventis is hoping the drug can be on the market in the United States in 2006, some experts think FDA concern over side effects may make this timetable a bit optimistic.

Updated November 16, 2004

For more details on results of the RIO-North America study, please CLICK HERE.