Modafinil May Prevent Antipsychotic-Related Weight Gain

Janis Kelly

April 10, 2009

April 10, 2009 — A new brief-trial approach for candidate drugs to prevent weight gain associated with antipsychotics such as olanzapine (Zyprexa, Eli Lilly and Co.) has tagged the psychostimulant modafinil (Provigil, Cephalon) as a drug worth further study, researchers report in the April 1 issue of Biological Psychiatry.

"Half of the clinical studies of potential pharmacologic interventions to prevent olanzapine-associated weight gain have been negative, at huge expense. We hope that this approach will help identify drugs with a better chance of working," lead investigator James L. Roerig, PharmD, from the University of North Dakota School of Medicine, in Fargo, told Medscape Psychiatry.

The method developed by Dr. Roerig and colleagues uses brief placebo-controlled trials with normal volunteers to determine whether a prospective treatment drug deserves study in clinical trials.

The process starts with a brief trial to show that the main treatment agent will produce the target adverse effect in normal volunteers; it is followed by a short placebo-controlled study to see whether adding the candidate drug reduces the adverse effect enough in normal volunteers to signal that the test drug is likely to work and deserves further study.

"If you look at studies of atypical antipsychotic agents tested . . . for efficacy, olanzapine looks a little better than some of the other drugs, but clinicians worry about the associated risk of weight gain. We thought it would be useful to try to solve that problem," Dr. Roerig said.

Small but Significant Reduction

The researchers enrolled 50 normal volunteers in the study and randomized them to either 3 weeks of olanzapine plus placebo or 3 weeks of olanzapine plus modafinil titrated to 200 mg/day. The primary outcome variable was a change in body-mass index (BMI) over the 3 weeks of the trial.

Both groups had increases in BMI, but Dr. Roerig reported that analysis of covariance controlling for baseline BMI showed a significantly lower weight gain in the olanzapine/modafinil group (0.47 vs 0.89 kg/m2; < .05).

"The results of this trial should not be extrapolated to clinical practice at this time," Dr. Roerig warned. "But the data do support further clinical studies to determine if the effect of modafinil can be demonstrated over a longer period of time, and in relevant patient populations."

Guy Faulkner, PhD, associate professor at the University of Toronto's Faculty of Physical Education and Health, in Ontario, and lead author of a recent Cochrane review of interventions to reduce weight gain in schizophrenia, raised a different concern (Cochrane Database Syst Rev. 2007;1:CD005148).

"Many of these patients are already on elaborate cocktails of drugs, and this would add yet another drug to the mix. It would also increase the risk of drug interactions, many of which we do not yet know much about. The difference in weight gain in this study was small, and I am not sure it justifies further exploration," Dr. Faulkner told Medscape Psychiatry. "The greater focus should probably be on developing antipsychotics that are less likely to cause weight gain."

Dr. Faulkner reiterated the conclusion from his Cochrane review study: pharmacologic intervention should only be tried if behavioral and lifestyle interventions have failed to prevent or reverse weight gain in patients taking antipsychotics.

"The range of steps when beginning a patient on 1 of these drugs should include proper screening, warning the patient about this potential side effect, referring the patient for diet and physical-activity counseling where available, and monitoring the patient's weight regularly.

"Counseling should consider the patient's activity level and appetite, as well as the patient's insight into the effects of their activity level and of what they are eating. If there is a big weight increase, consider switching the patient to a different antipsychotic agent, since there is considerable heterogeneity in individual responses," Dr. Faulkner said.

This work was supported by Eli Lilly and Company. Dr. Roerig discloses having received research funding from Lilly Pharmaceuticals. Coauthor James E. Mitchell, MD, from the University of North Dakota School of Medicine and Health Sciences, in Fargo, discloses having received research funding from Lilly Pharmaceuticals, GlaxoSmithKline, and Pfizer.

Biol Psychiatry. 2009;65:607-613. Abstract

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