Risperidone for Treatment-Refractory Major Depressive Disorder

A Randomized Trial

6 November 2007 | Volume 147 Issue 9 | Pages 593-602

Background: Major depressive disorder has high prevalence, morbidity, and mortality. Inadequate results with antidepressants have prompts addition of a nonstandard treatment (augmentation therapy).

Objective: To assess whether augmentation therapy with risperidone reduces symptoms and increases response to antidepressant therapy and remission of depression in adults.

Design: Multicenter, double-blind, placebo-controlled, randomized trial conducted from 19 October 2004 to 17 November 2005.

Setting: 75 primary care and psychiatric centers.

Patients: 274 outpatient adults with major depressive disorder that was suboptimally responsive to antidepressant therapy.

Intervention: After a 4-week run-in period to ensure insufficient response to standard antidepressants, patients were randomly assigned to receive risperidone, 1 mg/d, or placebo for 6 weeks. After 4 weeks, the dosage of risperidone was increased to 2 mg/d in some cases.

Measurements: Symptoms were measured by using the 17-item Hamilton Rating Scale for Depression (HRSD-17). Other outcomes were response to therapy, remission of depression, and various clinician- and patient-rated assessments.

Results: Of the intention-to-treat population (268 patients), 81% (111 of 137) who received risperidone and 87.8% (115 of 131) who received placebo completed 6 weeks of double-blind treatment. Mean (±SE) HRSD-17 scores improved more in the risperidone augmentation group than in the placebo group (13.4 ± 0.54 vs. 16.2 ± 0.53; difference, –2.8 ± 0.72 [95% CI, –4.2 to –1.4]; P <0.001). More risperidone recipients than placebo recipients experienced remission of depression (24.5% [26 of 106] vs. 10.7% [12 of 112]; P = 0.004) and had a response (46.2% [49 of 106] vs. 29.5% [33 of 112]; P = 0.004). Headache (8.8% of risperidone recipients vs. 14.5% of placebo recipients), somnolence (5.1% vs. 1.5%), and dry mouth (5.1% vs. 0.8%) were the most frequently reported adverse events.

Limitations: Patients were receiving many different antidepressants, and the duration of augmentation therapy was limited.

Conclusion: Risperidone augmentation produced a statistically significant mean reduction in depression symptoms, substantially increased remission and response, and improved other patient- and clinician-rated measures.

ClinicalTrials.gov registration number: NCT00095134.

Editors' Notes Context Does augmentation with an atypical antipsychotic improve symptoms in patients with major depression that is suboptimally responsive to antidepressant monotherapy? Contribution This double-blind randomized trial found that 6 weeks of treatment with risperidone improved symptoms more than placebo in 274 adults with major depression that was suboptimally responsive to antidepressant monotherapy. Risperidone, compared with placebo, resulted in more remissions (25% vs. 11%), as well as more cases of somnolence (5% vs. 2%) and dry mouth (5% vs. 1%). Caution The trial duration was short, and 19% of risperidone recipients did not complete treatment. Implication Risperidone augmentation may improve symptoms in some patients with suboptimal response to antidepressant monotherapy. —The Editors

 

Author and Article Information

From Ortho-McNeil Janssen Scientific Affairs, Titusville, New Jersey.

Note: The other principal investigators in this multicenter study were Mohammed A. Allaw, MD, Evansville, Indiana; Roy H. Autry, PhD, Atlanta, Georgia; Allan B. Aven, MD, Arlington Heights, Illinois; Leonard C. Bass, MD, Fort Lauderdale, Florida; Maria S. Blahey, MD, Beaumont, Texas; Benjamin I. Blank, DO, Glendora, New Jersey; Stephen A. Braden, MD, Bryan, Texas; Daniel H. Brune, MD, Peoria, Illinois; Stephen J. Bupp, MD, Tucson, Arizona; Geoffrey M. Burgess, MD, Downingtown, Pennsylvania; Michael F. Conlin, MD, Austell, Georgia; William R. Cox, MD, Cincinnati, Ohio; Henry F. Crabbe, PhD, MD, New London, Connecticut; Daniel J. Crable, MD, Jefferson Borough, Pennsylvania; Edward C. Cullen, MD, Medford, Oregon; James G. Cunnar, MD, Naperville, Illinois; Lori L. Davis, MD, Tuscaloosa, Alabama; Ronald G. Degarmo, DO, Greer, South Carolina; G. Michael Dempsey, MD, Albuquerque, New Mexico; Humam W. Farah, MD; St. Louis, Missouri; Matthew P. Finneran, MD, Wadsworth, Ohio; Bruce D. Forney, MD, Alliance, Nebraska; Jose E. Gamez, MD, Hialeah, Florida; John H. Gilliam, MD, Richmond, Virginia; Brian H. Goldman, MD, Raleigh, NC; Paras Harshawat, MD, Terre Haute, Indiana; Willis Holloway Jr., MD, Oklahoma City, Oklahoma; Waguih William Ishak, MD, Los Angeles, California; Rodney K. Ison, MD, Canal Fulton, Ohio; Michael R. Johnson, MD, Gainesville, Florida; Amy Kaissar, MD, Indianapolis, Indiana; Curtis Kaufman, MD, Johnson City, Tennessee; Roy S. Kiser Jr., MD, Richardson, Texas; Rebecca A. Knight, MD, Peoria, Illinois; Elly R. Lee, MD, Irvine, California; Roger J. Miller Jr., MD, Jacksonville, Florida; Julio E. Navarro, MD, Newark, Delaware; Richard A. Neiman, MD, Kirkland, Washington; Mahmoud S. Okasha, MD, Norwich, Connecticut; Gregory S. Paniccia, MD, San Diego, California; Robert J. Pearlstein, DO, Norristown, Pennsylvania; John H. Peniston, DO, Feasterville, Pennsylvania; Stephen J. Poland, MD, Cincinnati, Ohio; Alfredo N. Rivera, MD, Cincinnati, Ohio; Michael T. Robinson, DO, Medford, Oregon; Joseph M. Rybicki, DO, Philadelphia, Pennsylvania; Martin J. Schaer, MD, Dayton, Ohio; Michael R. Seidner, MD, Lansdale, Pennsylvania; Mary L. Stedman, MD, Tampa, Florida; Ronald K. Stegemoller, MD, Avon, Indiana; Brock H. Summers, MD; Burbank, California; H. Mikel Thomas, MD, Prairie Village, Kansas; Tanya Vapnik, PhD, RN, Los Angeles, California; Michael W. Warren, MD, Reading, Pennsylvania; Thomas R. Weiss, MD, San Antonio, Texas; David B. Wilhelm, MD, Birmingham, Alabama; Brian K. Wooten, MD, Shreveport, Louisiana; and Christine M. Zador-Silverman, DO, Levittown, Pennsylvania.

Acknowledgment: The authors thank Andrew Greenspan, MD, Titusville, New Jersey; John Greist, MD, Madison, Wisconsin; Charles Nemeroff, MD, PhD, Atlanta, Georgia; Mark H. Rapaport, MD, Los Angeles, California; and David Sheehan, MD, Tampa, Florida, for their contributions to the design of this study. Editorial assistance was provided by Susan Ruffalo, PharmD, MedWrite, Newport Coast, California.

Financial Support: By funding from Ortho-McNeil Janssen Scientific Affairs.

Potential Financial Conflicts of Interest: Employment: R.A. Mahmoud (Ortho-McNeil Janssen Scientific Affairs), G.J. Pandina (Ortho-McNeil Janssen Scientific Affairs), I. Turkoz (Ortho-McNeil Janssen Scientific Affairs), C. Kosik-Gonzalez (Ortho-McNeil Janssen Scientific Affairs), C.M. Canuso (Ortho-McNeil Janssen Scientific Affairs), M.J. Kujawa (Ortho-McNeil Janssen Scientific Affairs). Stock ownership or options (other than mutual funds): R.A. Mahmoud (Johnson & Johnson), G.J. Pandina (Johnson & Johnson), I. Turkoz (Johnson & Johnson), C. Kosik-Gonzalez (Johnson & Johnson), C.M. Canuso (Johnson & Johnson), M.J. Kujawa (Johnson & Johnson).

Requests for Single Reprints: Ramy A. Mahmoud, MD, MPH, ETHICON, Inc., PO Box 151, U.S. Highway 22 West, Room E314, Somerville, NJ 08876; e-mail, rmahmou{at}ethus.jnj.com.

Current Author Addresses: Dr. Mahmoud: ETHICON, Inc., PO Box 151, U.S. Highway 22 West, Room E314, Somerville, NJ 08876.

Drs. Pandina, Canuso, and Kujawa; Mr. Turkoz; and Ms. Kosik-Gonzalez: Ortho-McNeil Janssen Scientific Affairs, LLC, 1125 Trenton-Harbourton Road, PO Box 200, Titusville, NJ 08560-0200.

Dr. Gharabawi-Garibaldi: Hoffman-La Roche, Medical Affairs, 340 Kingsland Street, Building 721/F2-1139, Nutley, NJ 07110-1199.

Author Contributions: Conception and design: R.A. Mahmoud, G.J. Pandina, I. Turkoz, C. Canuso, G.M. Gharabawi-Garibaldi.

Analysis and interpretation of the data: R.A. Mahmoud, G. Pandina, I. Turkoz, C.M. Canuso, M.J. Kujawa, G.M. Gharabawi-Garibaldi.

Drafting of the article: R.A. Mahmoud, G.J. Pandina, I. Turkoz, C.M. Canuso, M.J. Kujawa, G.M. Gharabawi-Garibaldi.

Critical revision of the article for important intellectual content: R.A. Mahmoud, G.J. Pandina, I. Turkoz, M.J. Kujawa, G.M. Gharabawi-Garibaldi.

Final approval of the article: R.A. Mahmoud, G.J. Pandina, I. Turkoz, M. Kujawa, C. Kosik-Gonzalez, C.M. Canuso, G.M. Gharabawi-Garibaldi.

Provision of study materials or patients: G.J. Pandina.

Statistical expertise: I. Turkoz.

Obtaining of funding: R.A. Mahmoud, G.M. Gharabawi-Garibaldi.

Administrative, technical, or logistic support: R.A. Mahmoud, G.J. Pandina, C. Kosik-Gonzalez.

Collection and assembly of data: G.J. Pandina, I. Turkoz, C. Kosik-Gonzalez.

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