Baldessarini, Ross J.

Lau, Wai Keat

Sim, Jordan

Sim, Kang

Sum, Min Yi

The International Journal of Neuropsychopharmacology

Harvard University - DASH 

Suicidal Risks in Reports ofLong-Term Treatment Trialsfor Major Depressive DisorderThe Harvard community has made thisarticle openly available.  Please share  howthis access benefits you. Your story mattersCitation Baldessarini, Ross J., Wai Keat Lau, Jordan Sim, Min Yi Sum, andKang Sim. 2015. “Suicidal Risks in Reports of Long-Term TreatmentTrials for Major Depressive Disorder.” International Journal ofNeuropsychopharmacology 19 (3): pyv107. doi:10.1093/ijnp/pyv107.http://dx.doi.org/10.1093/ijnp/pyv107.Published Version doi:10.1093/ijnp/pyv107Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:26860116Terms of Use This article was downloaded from Harvard University’s DASHrepository, and is made available under the terms and conditionsapplicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAAInternational Journal of Neuropsychopharmacology, (2016) 19(3): 1–2doi:10.1093/ijnp/pyv107Advance Access Publication  September 13, 2015Letter to the Editor© The Author 2015. Published by Oxford University Press on behalf of CINP.1This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.Received: August 6, 2015; Revised: September 4, 2015; Accepted: September 10, 2015letter to the editorSuicidal Risks in Reports of Long-Term Treatment Trials for Major Depressive DisorderRoss J. Baldessarini, MD; Wai Keat Lau, MD; Jordan Sim, MD; Min Yi Sum, BA; Kang Sim, MDDepartment of Psychiatry, Harvard Medical School, Boston, MA (Dr Baldessarini); International Consortium  for Psychotic and Mood Disorders Research, McLean Hospital, Belmont, MA (Drs Baldessarini and K Sim);  Yong Loo Lin School of Medicine, National University of Singapore (Drs Lau, J Sim, and K Sim); Research Department (Dr K Sim and Ms Sum), and Department of General Psychiatry (Dr K Sim), Institute of Mental Health, Singapore.Correspondence: R.J. Baldessarini, MD, Mailman Research Center, McLean Hospital, 115 Mill Street, Belmont, MA (rbaldessarini@mclean.harvard.edu).In our recent review and meta-analyses of reports of long-term trials of treatments for major depressive disorder patients, we noted that remarkably little potentially relevant and interesting clinical information was included in most reports (Sim et al., 2015). This limitation seemed particularly remarkable in long-term studies carried out at great effort and expense. In general, reports of clinical trials in various disorders appear to focus rather narrowly on outcomes for which the trials were designed, usually rates of relapse or recurrence of a particular illness (Baldessarini, 2013).In an effort to evaluate this impression more closely, we re-reviewed the reports cited in our review (Sim et al., 2015), focusing specifically on any indications of suicidal behaviors, which are of particular interest with major mood disorder patients. We recorded any comment or data pertaining to sui-cidal events, including completed suicides, attempts or self-injuries, or suicidal ideation typically significant enough as to require removal from the trial. Exposure times include not only the long-term phases of the trials but also lead-in weeks with placebo treatment as well as initial open-label phases of antidepressant treatment prior to randomization to continue active treatment or discontinue to placebo, with categorization based on the treatment assigned during the long-term phases of trials.Very few reports included information concerning suicidal risks, even broadly defined. In all, we found 12 such publications among 85 (14.1%) reviewed reports. Reports with any information about suicidal events included 6 placebo-controlled continuation trials for up to 1 year, 6 antidepressant trials lasting more than 12 months, and no trial of a psychosocial treatment (Sim et al., 2015) (Table 1). Most of the 12 reports provided only brief comments as to whether or not suicides or attempts occurred in active treatment or control arms of the trials, most of which had attempted to exclude cur-rently suicidal subjects. The very low yield of 14.1% of trials report-ing any information about suicidal events during the trials was surprising.It is also noteworthy that the average rates of suicide attempts and suicides were very high despite efforts to exclude currently suicidal patients. The risk of suicide averaged 1.08%/year, and of attempts, 2.24%/year, across treatment arms of trials. In addition, there was an ominously low apparent ratio of attempts/suicides of 2.07, compared with >30 in the gen-eral population (Kessler et  al., 2005; Tondo et  al., 2007). The observed rates of attempts and suicides are far higher than in the general population and even higher than those reported in clinical samples of outpatients diagnosed with major depres-sive disorder, which average approximately 0.045%/year for suicide and 0.480%/year for attempts (Bostwick and Pankratz, 2000; Tondo et al., 2007). Such high levels of suicidal risk may reflect the difficulty of excluding potentially suicidal subjects from trials and the fact that trial entry required being acutely depressed in order to study treatment effects (Sim et al., 2015). Nevertheless, if the findings are valid and representative, they underscore the importance of considering suicidal risks in such trials.Even more remarkable were indications that the overall risk of suicidal events was significantly greater in trial arms involv-ing active, antidepressant treatment vs placebo controls when findings were pooled across all 12 trials and in 9/12 of the tri-als (Table 1). However, since none of the trials was specifically designed to address suicidal risk and the trials yielding data on suicidal risks were few, the summarized observations may merely represent chance findings, with risk of selective overre-porting of high rates. Alternatively, they parallel the unresolved 2 | International Journal of Neuropsychopharmacology, 2016relationships of antidepressant exposure to suicidal risks (Baldessarini et al., 2007; Stone et al., 2009; Nischal et al., 2012), and surely they warrant further study.The present findings strongly encourage the recommenda-tion that important outcomes of clinical and research signifi-cance more routinely be included in reports of treatment trials for psychiatric disorders, especially trials involving long-term observations under controlled conditions, if only to limit biased, selective reporting of unrepresentative findings. Suicidal risk among mood disorder patients is only one example. The pro-vocative and unexpected finding of very high reported, pooled rates of suicide and attempts and greater observed suicidal risks with antidepressant treatment than with placebo indicate the need to pursue these unexpected findings. In general, we support the research practice of including information about suicidal risk as well as other clinical measures of interest, rou-tinely, in the design, conduct, and reporting of psychiatric treat-ment trials.AcknowledgmentsSupported in part by a grant from the Bruce J.  Anderson Foundation and the McLean Private Donors Research Fund (to Dr. Baldessarini).Statement of InterestNone.ReferencesBaldessarini RJ (2013). Chemotherapy in psychiatry, 3rd edition. New York: Springer Press.Baldessarini RJ, Tondo L, Strombom IM, Dominguez S, Fawcett J, Licinio J, Oquendo MA, Tollefson GD, Valuck RJ, Tohen M (2007). Ecological studies of antidepressant treatment and suicidal risks. Harv Rev Psychiatry 15:133–145.Bostwick JM, Pankratz VS (2000). Affective disorders and suicide risk: a reexamination. Am J Psychiatry 157:1925–1932.Kessler RC, Berglund P, Borges G, Nock M, Wang PS (2005). Trends in suicide ideation, plans, gestures, and attempts in the United States, 1990–1992 to 2001–2003. JAMA 293:2487–2495.Nischal A, Tripathi A, Nischal A, Trivedi JK (2012). Suicide and antidepressants: what current evidence indicates. Mens Sana Monogr 10:33–44.Sim K, Lau KL, Sim J, Sum MY, Baldessarini RJ (2015). Pre-vention of relapse and recurrence in adults with major depressive disorder: systematic review and meta-analyses of controlled trials. Intl J Neuropsychopharmacol. In press.Stone M, Laughren T, Jones ML, Levenson M, Holland PC, Hughes A, Hammad TA, Temple R, Rochester G (2009). Risk of suici-dality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Adminis-tration. BMJ 339:b2880.Tondo L, Lepri B, Baldessarini RJ (2007). Risks of suicidal ideation, attempts and suicides among 2826 men and women with types I and II bipolar, and recurrent major depressive disor-ders. Acta Psychiatr Scand 116:419–428.Table 1. Suicidal Events in Long-Term, Controlled Treatment Trials for Major Depressive DisorderStudy TreatmentExposure(years)SubjectsSuicidal Events:  Ideation/Attempts/ SuicidesIncidence (events/ 100 person-years)Treatment Placebo Treatment Placebo Treatment PlaceboDoogan and Caillard 1992 Sertraline 1.17 185 110 0/3/0 0/1/0 3/216.5 (1.39) 1/128.7 (0.78)Montgomery and Dunbar 1993 Paroxetine 1.15 68 67 0/0/1 0/0/0 1/78.2 (1.28) 0/77.0 (0.00)Versiani et al., 1999 Reboxetine 1.08 145 141 0/0/2 0/0/0 2/156.6 (1.28) 0/152.3 (0.00)Rouillon et al., 2000 Milnacipran 1.48 104 110 0/8/2 0/5/1 10/153.9 (6.50) 6/162.8 (3.69)Schmidt et al., 2000 Fluoxetine 0.73 379 122 1/0/0 1/0/0 1/276.7 (0.36) 1/89.7 (1.12)Thase et al., 2001 Mirtazapine 0.98 76 80 0/2/0 0/0/0 2/74.5 (2.68) 0/78.4 (0.00)Kornstein et al., 2006 Escitalopram 1.46 73 66 0/0/0 0/1/0 0/106.6 (0.00) 1/96.4 (1.04)Keller et al., 2007 Venlafaxine 2.65 43 86 0/0/0 1/0/0 0/114.0 (0.00) 1/227.9 (0.44)Kocsis et al., 2007 Venlafaxine 1.65 164 172 1/0/0 1/0/0 1/270.6 (0.37) 1/283.8 (0.35)Kelin et al., 2010 Duloxetine 1.62 64 60 0/0/0 0/0/0 0/103.7 (0.00) 0/97.2 (0.00)Liebowitz et al., 2010 Quetiapine 1.48 391 385 9/0/0 1/0/0 9/578.7 (1.56) 1/569.8 (0.18)Rosenthal et al., 2013 Desvenlafaxine 0.92 272 276 5/5/0 0/0/0 10/2720 (0.37) 0/253.9 (0.00)Totals/Means[95%CI](12 trials) 1.36[1.05–1.68]1964 1675 16/18/5(39)4/7/1(12)39/2671 (1.46)[1.03–2.00]12/2278 (0.53)[0.27–0.92]The observed incidence rate ratio (IRR for suicidal events/100 person-years) indicates 2.77-fold [CI: 1.42–5.82] greater with antidepressants vs placebo (exact P = .0005). Observed incidence (%/y) with antidepressant treatment vs placebo (based on N and time from reporting studies only) was: ideation (1.11 vs 0.32), attempts (2.48 vs 1.79), suicides (1.28 vs 0.61), and suicidal acts (attempts + suicides: 2.03 vs 1.44; corresponding IRR [with 95%CI] were: ideation (3.45 [1.11–14.2]; P = .009), attempts (1.39 [0.55–3.94]; P = .24), suicides (2.08 [0.23–98.2], P = .28), and suicidal acts (1.40 [0.61–3.63], P = .21). References to trials cited are provided in Sim et al. (2015).

Suicidal Risks in Reports of Long-Term Treatment Trials for Major Depressive Disorder

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Suicidal Risks in Reports of Long-Term Treatment Trials for Major Depressive Disorder

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