Ramy A. Mahmoud, MD, MPH; Gahan J. Pandina, PhD; Ibrahim Turkoz, MS; Colette Kosik-Gonzalez, MS; Carla M. Canuso, MD; Mary J. Kujawa, MD, PhD; Georges M. Gharabawi-Garibaldi, MD
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, email@example.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.
Mahmoud R., Pandina G., Turkoz I., Kosik-Gonzalez C., Canuso C., Kujawa M., Gharabawi-Garibaldi G.; Risperidone for Treatment-Refractory Major Depressive Disorder: A Randomized Trial. Ann Intern Med. 2007;147:593-602. doi: 10.7326/0003-4819-147-9-200711060-00003
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Published: Ann Intern Med. 2007;147(9):593-602.
Major depressive disorder is the leading cause of disability worldwide (1), affecting nearly 121 million people. It is associated with increased overall mortality (2, 3); premature cardiovascular-related death (4, 5); and morbidity, including disability, lost productivity, and decreased wages, compared with individuals without depression (6). Selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors are generally considered first-line treatments for depression.
Despite a sufficient dose and duration of antidepressant treatment, symptoms do not resolve in 30% to 40% of patients with major depressive disorder (7–10). Remission, defined as the virtual absence of depressive symptoms, is important because it is associated with improved patient prognosis and functioning relative to response (generally defined as ≥50% reduction in symptoms) (11, 12). In an effort to improve the therapeutic efficacy of antidepressant monotherapy, several pharmacologic strategies to modulate different or additional neurotransmitters (13–15) are commonly used, despite a paucity of evidence from randomized clinical trials. These strategies include switching monotherapy within (10, 16–18) or between antidepressant classes (10, 19–21), combination regimens consisting of 2 antidepressants (22–26), and “augmentation” of antidepressants with nonstandard treatments—for example, thyroid hormone (27); S-adenosyl-l-methionine (28); lithium (29); cyclooxygenase-2 inhibitors (30); or an atypical antipsychotic (31–33), such as risperidone.
November 6, 2007
Risperidone as antidepressant
We are very interested in risperidone's effect on depression published by Mahmoud and colleagues (1). We are particularly interested in the rapid onset (within a week) of effect by low dosages of risperidone. Other antidepressants such as SSRIs usually take weeks for their efficacy.
Risperidone has a prolactin elevating effect more than other antipsychotic drugs such as olanzapine or quetiapine. Prolactin elevation is related to dopamine D2 receptor blockade at the level of the anterior pituitary lactotorphs, where dopamine exerts an inhibitory effect on prolactin secretion. The anterior pituitary lies outside the blood brain barrier (BBB). Risperidone have a higher peripheral (pituitary) D2 receptor occupancy than central (striatum) at low dosages (2), which easily elevates prolactin.
Recently prolactin is proved to have an anti-stress effect in rodents(3). It is possible that prolactin play an important role in coping with stress in humans too.
We know a similar augmentive effect of sulpiride in depression treatment with rapid onset of efficacy (4). In Japan sulpiride as low dosages is very widely used for treatment of depression. Sulpiride is also known as its poor penetration through the BBB (5).
The anti-depressive mechanisms of rispeidone and sulpiride could be explained by a peripheral (pituitary) dopamine D2 receptor blockade resulting in the elevation of prolactin. Low dosages of risperidone may not act in the brain, where it requires more time to exert anti-depressive effect.
(1) Mahmoud A, Pandina GJ, Turkoz I, Kosik-Gonzalez C, Canuso CM, Kujawa MJ, Gharabawi-Garibaldi GM. Risperidone for Treatment- Refractory Major Depressive Disorder:A Randomized Trial. Ann Intern Med. 2007; 147:593-602.
(2) Kapur S, Langlois X, Vinken P, Megens AA, De Coster R, Andrews JS. The differential effects of atypical antipsychotics on prolactin elevation are explained by their differential blood-brain disposition: a pharmacological analysis in rats. J Pharmacol Exp Ther. 2002 ;302:1129-34.
(3) Fujikawa T, Soya H, Tamashiro KL, Sakai RR, McEwen BS, Nakai N, Ogata M, Suzuki I, Nakashima K. Prolactin prevents acute stress-induced hypocalcemia and ulcerogenesis by acting in the brain of rat. Endocrinology. 2004 ;145:2006-13.
(4) Uchida H, Takeuchi H, Suzuki T, Nomura K, Watanabe K, Kashima H. Combined treatment with sulpiride and paroxetine for accelerated response in patients with major depressive disorder. J Clin Psychopharmacol. 2005 ;25:545-51.
(5) Takano A, Suhara T, Yasuno F, Suzuki K, Takahashi H, Morimoto T, Lee YJ, Kusuhara H, Sugiyama Y, Okubo Y. The antipsychotic sultopride is overdosed--a PET study of drug-induced receptor occupancy in comparison with sulpiride. Int J Neuropsychopharmacol. 2006 ;9:539-45.
Ralph J. Koek
Dept. of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles
December 26, 2007
Risperidone for Depression?
TO THE EDITOR: Mahmoud et al (1) reported that "risperidone augmentation offered great benefit" to patients showing "suboptimal response to standard antidepressant monotherapy." This report has methodologic shortcomings and the presentation of the data is biased.
Regarding internal validity, the authors did not describe the method of initial diagnosis, or any measure of diagnostic reliability. Depressive disorder course, number of prior episodes, or mood disorder subtype (e.g., bipolar disorder or psychotic depression or atypical depression or melancholic depression) were not stated. No data were provided on co-morbid Axis II disorders or on screening for actively co-morbid substance abuse. No data were provided on adequacy of treatment for the index episode. Each of these variables is standard in the assessment of antidepressant treatment and treatment-refractoriness (2, 3). There is no description of whether the risperidone and placebo groups were comparable on any of these potentially confounding variables. The choice of an inactive placebo rather than an active placebo also should be questioned, given that risperidone, even in the low doses used, induced significant somnolence and fatigue. The authors did not address the issue of unblinding.
As to external validity, the authors point out that "The fact that we enrolled patients receiving a wide variety of antidepressants from both primary care and psychiatry centers may increase the generalizability of our findings." (p. 599). But some study participants were recruited from media advertisements (p. 594) and at least 38 of the 75 participating sites were contract research organizations (CROs) rather than clinical care settings (www.clinicaltrials.gov #NCT00095314). Thus the study findings may not be generalizable to clinical practice.
As to bias, in presenting the efficacy data, the authors switched without explanation from intent to treat (ITT) data (Study Flow Diagram Figure 1) to completer data (Figure 2, Figure 3 and Results). This change was not justified, though it creates the appearance of greater therapeutic benefit. For instance, by ITT data the Number Needed to Treat (NNT) to remission is 15.6 at 4 weeks and 10.2 at 6 weeks. These NNTs are considerably higher than the value of 7.25 ("approximately 7") reported at 6 weeks for the completers. In the present context, an NNT of 10.2 does not signify compelling clinical benefit. The favorable-appearing NNT comparisons cited by the authors (references 46-48) are misleading because they mostly concern prevention, where NNT tends to be higher than in the acute treatment context. A more appropriate comparison would be with augmentation by lithium. In a meta- analysis of 9 trials of lithium augmentation (4) the NNT for response is 4, compared with an NNT for response of 9.5 for risperidone at 6 weeks using the authors' ITT data. Thus, risperidone augmentation is clearly inferior to "the best established augmentation strategy" (5).
Risperidone failed to achieve the de minimis goal of a mean drug- placebo difference of 3 points on the primary outcome measure. What little advantage was found for risperidone might well have occurred with any agent that has mildly sedative properties (hence the need for an active placebo).
The risks of augmentation with risperidone were understated. The authors report that 6/137 risperidone patients and 2/131 placebo recipients had treatment-emergent weight gain. Here the authors have reverted to ITT data, which tends to minimize the apparent frequency of weight gain. The authors should explain why they biased their reporting by using completer data for efficacy but ITT data for toxicity. Moreover, they gave no operational definition of "weight gain." In other reports (6, 7) from Janssen Pharmaceutica on use of risperidone for refractory depression, "weight gain" was defined as a 7% increase in body weight. In a footnote to Table 3, they note a highly significant (p <0.001) difference in mean weight gain between risperidone and placebo groups after 6 weeks on 1-2 mg daily. This salient difference did not find its way into the Abstract or the "Summaries for Patients" posting (p. I-34). No monitoring of glucose or lipids, now standard when prescribing atypical antipsychotics, was documented. It is also clear that augmentation with risperidone results in markedly elevated serum prolactin levels and impaired sexual functioning in depressed women during treatment beyond 6 weeks (7).
In summary, this trial suffers from problems of internal validity, external validity, and bias. Efficacy was reported using the biased completer data set whereas the reporting of metabolic toxicity was biased through use of the more favorable ITT data set. When the ITT data set is used consistently, the NNT for remission (15.6 at 4 weeks and 10.2 at 6 weeks) does not suggest compelling clinical benefit for augmentation with risperidone. The risk- benefit ratio also appears to be less favorable than the authors implied. Although the authors, who all work for the sponsor, did their best to present the results in the most positive light, overall the data do not suggest that augmentation with risperidone in non-responding depressed patients is a clinically justifiable strategy.
1. Mahmoud RA, Pandina GJ, Turkoz I, Kosik-Gonzalez C, Canuso CM, Kujawa MJ, Gharabawi-Garibaldi GM. Risperidone for treatment-refractory major depressive disorder. A randomized trial. Ann Intern Med 2007;147:593-602. PMID: 17975181.
2. Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 2003;53:649-659. PMID: 12706951
3. Salzman C. A 60-Year-Old Woman Who Has Felt Sad for Much of Her Life JAMA 2006 295: 318-323. PMID: 16418468
4. Lithium augmentation for treatment-resistant depression. Bandolier. July 2000:77-3. Accessed at www.ebandolier.com on 21 December 2007.
5. Nelson JC. Augmentation strategies in depression 2000. J Clin Psychiatry 2000; 61(suppl. 2):13-19. PMID: 10714619
6. Rapaport MH, Gharabawi GM, Canuso CM, Mahmoud RA, Keller MB, Bossie CA, Turkoz I, Lasser RA, Loescher A, Bouhours P, Dunbar F, Nemeroff CB. Effects of risperidone augmentation in patients with treatment-resistant depression: results of open-label treatment followed by double-blind continuation. Neuropsychopharmacology 2006; 31: 2505-13. PMID: 16760927
7. Janssen (2005) Janssen Pharmaceutica Products, LP. A study of the effectiveness and safety of risperidone to augment SSRI therapy in patients with treatment-resistant depression. ClinicalTrials.gov identifier NCT00044681. http://www.clinicaltrials.gov/ct/show/NCT00044681? order=11 14 February, 2005 (accessed 11/02/2006).
Ralph J. Koek, MD Clinical Professor Psychiatry and Biobehavioral Sciences David Geffen School of Medicine at University of California, Los Angeles Staff Psychiatrist, Sepulveda Ambulatory Care Center, VA Greater Los Angeles Healthcare System 16111 Plummer St. (116A-11) North Hills, CA 91343 Tel 818-891-7711, x7547 FAX 818-895-9588 firstname.lastname@example.org
Bernard J. Carroll MBBS, PhD. Pacific Behavioral Research Foundation P.O. Box 223040 Carmel, CA 93922-3040
In the past 2 years, Dr. Koek has participated in a research study partly funded by Abbott Laboratories. Bernard J. Carroll reports the following in the past 2 years. Consultant: University of Washington; University of Michigan; St. Louis University; Lundbeck, Copenhagen; AstraZeneca; GlaxoSmithKline. Royalty: Multi-Health Systems, Toronto, Canada (Carroll Depression Scales). Travel support: Lundbeck, Copenhagen (indirect travel support to melancholia symposium May 2006). Speaker honoraria: Wyeth. Patent pending: Genetic screening for predicting antidepressant drug response. US Patent Office # 11-867400 October 4, 2007.
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