Monotherapy Antidepressant Treatment is Not Associated With Mania in Bipolar I Disorder.

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Back to table of contents Previous article Next article Communications and UpdatesFull AccessMonotherapy Antidepressant Treatment is Not Associated With Mania in Bipolar I DisorderMichael J. Ostacher, M.D., M.P.H., M.M.Sc., Roy H. Perlis, M.D., M.Sc., John Geddes, M.D., F.R.C.Psych.Michael J. OstacherSearch for more papers by this author, M.D., M.P.H., M.M.Sc., Roy H. PerlisSearch for more papers by this author, M.D., M.Sc., John GeddesSearch for more papers by this author, M.D., F.R.C.Psych.Published Online:1 Jun 2015https://doi.org/10.1176/appi.ajp.2015.14111443AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: While impressed with the creativity of the study by Alexander Viktorin, M.Sc., et al. (1), published in the October 2014 issue of the Journal, regarding the risk of transition to mania during antidepressant treatment in bipolar I disorder, we disagree with their conclusions, especially the conclusion that antidepressants are associated with mania.We disagree that there is “an increased risk of manic switch among patients with bipolar disorder on antidepressant monotherapy.” The authors report a hazard ratio of 2.83 for mania in patients taking antidepressants alone compared with those taking antidepressants with a mood stabilizer. With an uncorrected p value of 0.028 for the hazard ratio (and multiple hypothesis tests), the event rate is so low as to leave great uncertainty about whether this is a true effect and what is its actual magnitude. On closer examination, the increase in absolute risk associated with antidepressant monotherapy in this study is small and not likely clinically significant. Of 1,117 patients, only 10 additional cases of mania were found during monotherapy antidepressant treatment compared with the period without antidepressant treatment, a 0.9% increase in absolute risk. Using the number needed to harm, 112 patients would need to be treated with monotherapy antidepressants before a single one would develop mania. This would be considered insignificant even in a well-controlled, randomized trial. For comparison, the number needed to harm for metabolic abnormalities associated with atypical antipsychotics (often used for bipolar depression) has been estimated at 6 for quetiapine and 10 for olanzapine/fluoxetine (2). While evidence of efficacy in bipolar depression for some atypical antipsychotics is much more substantial than that for antidepressants, so are their risks.Furthermore, if one is to conclude from this study that monotherapy antidepressants increase mania risk in bipolar I disorder patients, then one must also conclude that antidepressants are protective against mania. After all, with a hazard ratio of 0.68, the risk of mania for patients taking antidepressants long-term compared with those not taking antidepressants was actually reduced by 32%.It is argued that the within-subjects design controls for confounding, but this assumes that the pattern of illness remains constant over time within any patient. These results may still represent confounding by indication. Registries and electronic health records represent powerful but not infallible tools for pharmacovigilance; confounding must be considered in any nonrandomized design.Perhaps confirmation bias inadvertently led the authors to interpret their data in line with what is already conventional wisdom: that antidepressants increased risk of mania—and to deemphasize the much stronger association that they report in their study: that antidepressant use in bipolar I disorder prevents mania. Examining the same data, we conclude that neither finding is likely related to the properties of antidepressants themselves. The data certainly do not support the notion that monotherapy antidepressant treatment is unsafe in bipolar I disorder. The risks (or benefits) of antidepressant use in bipolar I disorder, particularly relative to potentially more harmful strategies, remain uncertain.From the Department of Psychiatry, VA Palo Alto Health Care System, Palo Alto, Calif. and the Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, Calif.; the Department of Psychiatry, Harvard Medical School, Massachusetts General Hospital, Boston; and the Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, United Kingdom.Dr. Ostacher has served as a consultant to Bristol-Myers Squibb, Eli Lilly, Janssen Pharmaceuticals, and Sunovion, and has provided CME for Takeda. Dr. Perlis has served on advisory boards or served as a consultant to Genomind, Healthrageous, Perfect Health, Pfizer, Proteus Biomedical, PsyBrain, and RID Ventures, and he receives royalties from Concordant Rater Systems. Dr. Geddes reports no financial relationships with commercial interests.References1 Viktorin A, Lichtenstein P, Thase ME, et al.: The risk of switch to mania in patients with bipolar disorder during treatment with an antidepressant alone and in combination with a mood stabilizer. Am J Psychiatry 2014; 171:1067–1073Link, Google Scholar2 Spielmans GI, Berman MI, Linardatos E, et al.: Adjunctive atypical antipsychotic treatment for major depressive disorder: a meta-analysis of depression, quality of life, and safety outcomes. PLoS Med 2013; 10:e1001403Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited ByNone Volume 172Issue 6 June 01, 2015Pages 586-586 Metrics PDF download History Accepted 1 February 2015 Published online 1 June 2015 Published in print 1 June 2015