Aripiprazole for Treatment-Resistant Schizophrenia: Results of a Multicenter, Randomized, Double-Blind, Comparison Study Versus Perphenazine

John M. Kane, M.D.; Herbert Y. Meltzer, M.D.; William H. Carson, Jr., M.D.; Robert D. McQuade, Ph.D.; Ronald N. Marcus, M.D.; and Raymond Sanchez, M.D.; for the Aripiprazole Study Group

Objective: Treatment-resistant schizophrenia poses a major therapeutic challenge. This multicenter, double-blind, randomized study compared the efficacy and safety of aripiprazole and perphenazine in treatment-resistant patients with schizophrenia.

Method: Schizophrenia patients (DSM-IV diagnosis) with a history of antipsychotic resistance underwent 4 to 6 weeks of open-label treatment with olanzapine or risperidone to confirm treatment resistance. Only patients who completed this open-label period and failed to respond (< 20% improvement in Positive and Negative Syndrome Scale [PANSS] total score or a Clinical Global Impressions-Severity of Illness score >= 4) entered the 6-week, double-blind treatment phase. In all, 300 patients with confirmed treatment resistance were randomly assigned to aripiprazole (15-30 mg/day) or perphenazine (8-64 mg/day). The primary outcome measure was change in PANSS score from baseline. The study was conducted between August 30, 2000, and March 18, 2002.

Results: Both aripiprazole and perphenazine treatment were associated with clinically relevant improvements in PANSS total scores from baseline. After 6 weeks, 27% of aripiprazole-treated patients and 25% of perphenazine-treated patients were responders (>= 30% decrease in PANSS total score or a Clinical Global Impressions-Improvement score of 1 or 2). Perphenazine-treated patients had a higher incidence of extrapyramidal symptom-related adverse events, mean increases (i.e., worsening) in extrapyramidal symptom rating scale scores, and a higher rate of elevated prolactin levels than aripiprazole (57.7% vs. 4.4%, p < .001). Improvements in quality of life considered to be clinically relevant (>= 20% improvement in Quality of Life Scale score) occurred in 36% of the aripiprazole-treated patients and in 21% of those treated with perphenazine (p = .052).

Conclusions: Aripiprazole and perphenazine, at the doses used here, can improve the symptoms of schizophrenia in treatment-resistant patients who have failed to respond to olanzapine or risperidone.

(J Clin Psychiatry 2007;68:213-223)

Received June 20, 2006; accepted Dec. 13, 2006. From the Zucker Hillside Hospital and The Albert Einstein College of Medicine, Glen Oaks, N.Y. (Dr. Kane); the Division of Psychopharmacology, Psychiatric Hospital at Vanderbilt, Nashville, Tenn. (Dr. Meltzer); Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, N.J. (Drs. Carson and McQuade); Bristol-Myers Squibb Co., Wallingford, Conn. (Dr. Marcus); and Bristol-Myers Squibb Co., Paris, France (Dr. Sanchez).

This study was supported by Bristol-Myers Squibb Co. and Otsuka Pharmaceutical Development & Commercialization, Inc.

Various analyses of these data have been presented at the 24th meeting of the Collegium Internationale Neuro-Psychopharmacologicum, June 20-24, 2004, Paris, France; 17th annual congress of the European College of Neuropsychopharmacology, October 9-13, 2004, Stockholm, Sweden; 157th annual meeting of the American Psychiatric Association, May 1-6, 2004, New York, N.Y.; 12th Biennial Winter Workshop on Schizophrenia, February 7-13, 2004, Davos, Switzerland; 16th annual congress of the European College of Neuropsychopharmacology, Sept. 20-24, 2003, Prague, Czech Republic; and 156th annual meeting of the American Psychiatric Association, May 17-22, 2003, San Francisco, Calif.

Dr. Kane is a consultant to Abbott, Bristol-Myers Squibb, Janssen, Eli Lilly, Pfizer, Wyeth, and AstraZeneca; has received honoraria from Bristol-Myers Squibb and Janssen; and is on the speakers bureaus of AstraZeneca, Abbott, Bristol-Myers Squibb, and Janssen. Dr. Meltzer is a consultant to and has received grant support from ACADIA, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Pfizer, Sanofi, and Solvay; has received grant support from Sepracor and Organon; has received honoraria from Janssen, Pfizer, Bristol-Myers Squibb, Eli Lilly, and AstraZeneca; and is a consultant to Alamo and Merck. Drs. Carson and McQuade are employees of Otsuka, and Dr. McQuade is a stock shareholder in and former employee of Bristol-Myers Squibb. Drs. Marcus and Sanchez are employees of Bristol-Myers Squibb, and Dr. Sanchez is a stock shareholder in Bristol-Myers Squibb.

Study investigators are listed at the end of the article.

Corresponding author and reprints: John M. Kane, M.D., Zucker Hillside Hospital and The Albert Einstein College of Medicine, 75-59 263rd St., Glen Oaks, NY 11004 (e-mail: psychiatry@lij.edu).