The Prevention of Recurrent Episodes of Depression With Venlafaxine for Two Years (PREVENT) Study: Outcomes From the 2-Year and Combined Maintenance Phases

Martin B. Keller, M.D.; Madhukar H. Trivedi, M.D.; Michael E. Thase, M.D.; Richard C. Shelton, M.D.; Susan G. Kornstein, M.D.; Charles B. Nemeroff, M.D., Ph.D.; Edward S. Friedman, M.D.; Alan J. Gelenberg, M.D.; James H. Kocsis, M.D.; David L. Dunner, M.D.; Robert M. A. Hirschfeld, M.D.; Anthony J. Rothschild, M.D.; James M. Ferguson, M.D.; Alan F. Schatzberg, M.D.; John M. Zajecka, M.D.; Ronald D. Pedersen, M.S.; Bing Yan, M.D.; Saeeduddin Ahmed, M.D.; Jeff Musgnung, M.T.; and Philip T. Ninan, M.D.

Objective: To report second-year results from the 2-year maintenance phase of a long-term study to evaluate the efficacy and safety of venlafaxine extended release (ER) in preventing recurrence of depression.

Method: Outpatients with recurrent unipolar depression (DSM-IV criteria; N = 1096) were randomly assigned in a 3:1 ratio to 10 weeks of treatment with venlafaxine ER or fluoxetine. Responders (17-item Hamilton Rating Scale for Depression [HAM-D₁₇] total score <= 12 and >= 50% decrease from baseline) entered a 6-month, double-blind continuation phase on the same medication. Continuation-phase responders were enrolled into maintenance treatment consisting of 2 consecutive 12-month phases. At the start of each maintenance phase, venlafaxine ER responders were randomly assigned to receive double-blind treatment with venlafaxine ER or placebo, and fluoxetine responders were continued for each period. The second 12-month maintenance phase compared the time to recurrence of depression with venlafaxine ER (75 to 300 mg/day) versus placebo as the primary efficacy measure. The primary definition of recurrence was a HAM-D₁₇ total score > 12 and < 50% reduction from baseline (acute phase) at 2 consecutive visits or at the last valid visit prior to discontinuation. The time to recurrence was evaluated using Kaplan-Meier methods and compared between the venlafaxine ER and placebo groups using log-rank tests. Secondary outcome measures included rates of response and remission (defined as HAM-D₁₇ <= 7). The study was conducted from December 2000 through July 2005.

Results: The cumulative probabilities of recurrence through 12 months in the venlafaxine ER (N = 43) and placebo (N = 40) groups were 8.0% (95% CI = 0.0 to 16.8) and 44.8% (95% CI = 27.6 to 62.0), respectively (p < .001). At month 12, using last-observation-carried-forward analysis, the rate of response or remission was significantly higher in the venlafaxine ER group (93%) than in the placebo group (63%; p = .002). Overall discontinuation rates were 28% and 63% in the venlafaxine ER and placebo groups, respectively. Adverse events were the primary reason for discontinuation for 1 patient (2%) in the venlafaxine ER group and 4 (10%) in the placebo group. An analysis of the combined maintenance phases, which compared the risk of recurrence over 24 months for patients assigned to venlafaxine ER (N = 129) or placebo (N = 129) for the first maintenance phase, showed a significantly greater cumulative probability of recurrence through 24 months for the placebo group (47.3% [95% CI = 36.4 to 58.2]) than for the venlafaxine ER group (28.5% [95% CI = 18.3 to 38.7]; p = .005).

Conclusion: In this study, an additional 12 months of maintenance therapy with venlafaxine ER was effective in preventing recurrence of depression in patients who had been responders to venlafaxine ER after acute (10 weeks), continuation (6 months), and initial maintenance (12 months) therapy.

Trial Registration: ClinicalTrials.gov identifier NCT00046020 (http://www.clinicaltrials.gov).

(J Clin Psychiatry 2007;68:1246-1256)

Received March 30, 2007; accepted May 15, 2007. From the Department of Psychiatry and Human Behavior, Brown University, Providence, R.I. (Dr. Keller); Department of Psychiatry, University of Texas Southwestern Medical School, Dallas (Dr. Trivedi); Department of Psychiatry, University of Pennsylvania, Philadelphia (Dr. Thase); Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pa. (Dr. Friedman); Departments of Psychiatry and Psychopharmacology, Vanderbilt University, Nashville, Tenn. (Dr. Shelton); Institute for Women's Health, Departments of Psychiatry and Obstetrics and Gynecology, and Mood Disorders Institute, Virginia Commonwealth University Medical Center, Richmond (Dr. Kornstein); Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Ga. (Dr. Nemeroff); Department of Psychiatry, University of Arizona, Tucson (Dr. Gelenberg); Department of Psychiatry, Weill Cornell Medical College, New York, N.Y. (Dr. Kocsis); the Center for Anxiety and Depression, University of Washington-Seattle, Mercer Island (Dr. Dunner); Department of Psychiatry, University of Texas Medical Branch, Galveston (Dr. Hirschfeld); Department of Psychiatry and Center for Psychopharmacologic Research and Treatment, University of Massachusetts Medical School and UMass Memorial Health Care, Worcester (Dr. Rothschild); Department of Psychiatry, University of Utah, Salt Lake City (Dr. Ferguson); Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, Calif. (Dr. Schatzberg); Department of Psychiatry, Rush University Medical Center, Chicago, Ill. (Dr. Zajecka); and Wyeth Pharmaceuticals, Collegeville, Pa. (Drs. Yan, Ahmed, and Ninan and Messrs. Pedersen and Musgnung).

This clinical trial and analysis were sponsored by Wyeth Research, Collegeville, Pa. Funding for the development of this scientific article was provided by Wyeth Pharmaceuticals.

Data presented as a poster at the 159th annual meeting of the American Psychiatric Association, May 20-25, 2006, Toronto, Ontario, Canada; the 46th annual meeting of the New Clinical Drug Evaluation Unit, June 12-15, 2006, Boca Raton, Fla.; the 29th annual meeting of the Collegium Internationale Neuro-Psychopharmacoligicum, July 9-13, 2006, Chicago, Ill.; the 19th annual congress of the European College of Neuropsychopharmacology, Sept. 16-20, 2006, Paris, France; the 111th annual meeting of the American Osteopathic Association, October 1-20, 2006, Las Vegas, Nev.; the 24th Congress of the Latin American Psychiatric Association, Nov. 1-4, 2006, Santo Domingo, Dominican Republic; the 56th annual meeting of the Canadian Psychiatric Association, Nov. 9-12, 2006, Toronto, Ontario, Canada; and the 19th annual meeting of the U.S. Psychiatric and Mental Health Congress, Nov. 2006, New Orleans, La.

The authors wish to thank Sherri D. Jones, Pharm.D., Jennifer B. Hutcheson, and Lorraine M. Sweeney of Advogent for their writing and editorial assistance.

Financial disclosure appears at the end of the article.

Corresponding author and reprints: Martin Keller, M.D., Brown University, Box G-BH, Sawyer Building, 345 Blackstone Blvd., Providence, RI 02906 (e-mail: martin_keller@brown.edu).