Antidepressants and Bipolar Depression

The role of antidepressants in treating bipolar depression has been hotly debated in psychiatry for over twenty years. During that time many studies involving bipolar patients have been conducted, thousands of articles written, and hundreds if not thousands of experts in bipolar disorder have expressed their opinion on the matter. The most common view is that antidepressants should be used as little as possible in patients with bipolar disorder, and in those not known to have it but who might have it (based on family history, personal history, response to medications in the past).

The concerns go beyond the possibility of causing a switch from depression into mania. It is commonly stated that antidepressants can cause mixed episodes (a combination of manic and depressive symptoms), cycle acceleration (more episodes in a given period of time than would have occurred without an antidepressant being introduced), treatment resistant depression (a prolonged episode of depression unresponsive to the usual treatment measures), increased risk of suicide, and rapid cycling (four or more distinct episodes of depression or mania in one year). Clinicians have been warned not to use antidepressants, and consequently almost all of us feel bad/guilty to one degree or another because we still use them; they remain the most commonly used treatment in bipolar depression. Their continuing popularity is likely multifactorial. I think part of it is the lack of evidence based alternatives that make intuitive sense. Up until recently the only FDA-approved medications were Symbyax (a combination of olanzapine and fluoxetine that has never caught on in spite of considerable effectiveness and ease of use) and Seroquel (why use a sedating antipsychotic to treat depression?).

Where are we now with over twenty years of study and debate? Which of the many questions about the use of antidepressants in patients with manic-depressive illness can we answer and which guidelines can we confidently follow?

To address this important issue, The International Society for Bipolar Disorders ISBD) Task Force on Antidepressant Use in Bipolar Disorders was convened. These global experts were chosen based upon a search of citations on the specific topic of antidepressant use in bipolar disorder. They represent the big names in bipolar disorder from around the world.

Ten topic areas were researched and the quality of the evidence rated from A (excellent ) to D (poor). Topics covered included the efficacy of antidepressants as monotherapy for bipolar depression, antidepressants used as adjuncts to mood stabilizers such as Lithium and Valproate in bipolar depression, antidepressants  used as part of maintenance treatment and risks of antidepressant use including switches into mania or mixed episodes, cycle acceleration and precipitation of suicidal thoughts and behavior.

The interested reader can study the entire article. It is easy to summarize the findings: We know almost nothing about the use of antidepressants in bipolar disorder in general, and in bipolar depression in particular. Do antidepressants work in bipolar depression? We don’t know. Do antidepressants hurt or cause harm in bipolar disorder? This is unknown. Of the ten questions researched, the data base was rated as poor for seven of them; this is the lowest rating that could be given. Only one out of the ten questions asked had a good data base available for answering the question; none had an excellent data base. The only question that could be answered with some confidence is that Symbyax (the combination of the antidepressant fluoxetine and the second generation antipsychotic olanzapine) works for bipolar depression, and that paroxetine and bupropion in combination with a mood stabilizer probably do not work. It is ironic that experts have for many years stated that bupropion is likely the best antidepressant to use in bipolar depression, and now one of the few things we can say with confidence is that bupropion does not help.

What is the take away message? If we are going to use antidepressants in bipolar disorder, and most of us are (the data is very clear about that), we need to be frank with our patients that we don’t know if they are helpful, or harmful. And that there are alternative treatments, such as quetiapine (Seroquel), fluoxetine/olanzapine (Symbyax), and lurasidone (Latuda) that do have evidence to back up their effectiveness in decreasing symptoms of depression in patients with bipolar disorder. These other medications have more potential side effects, some of which are quite serious, but we know they can work.

The International Society for Bipolar Disorders (ISBD) Task Force Report on Antidepressant Use in Bipolar Disorders

Isabella Pacchiarotti, M.D., Ph.D.; David J. Bond, M.D., Ph.D.; Ross J. Baldessarini, M.D.; Willem A. Nolen, M.D., Ph.D.; Heinz Grunze, M.D.; Rasmus W. Licht, M.D., Ph.D.; Robert M. Post, M.D.; Michael Berk, M.D., Ph.D.; Guy M. Goodwin, F.Med.Sci.; Gary S. Sachs, M.D.; Leonardo Tondo, M.D.; Robert L. Findling, M.D.; Eric A. Youngstrom, Psy.D., Ph.D.; Mauricio Tohen, M.D., Dr.P.H.; Juan Undurraga, M.D.; Ana González-Pinto, M.D., Ph.D.; Joseph F. Goldberg, M.D.; Ayşegül Yildiz, M.D.; Lori L. Altshuler, M.D.; Joseph R. Calabrese, M.D.; Philip B. Mitchell, M.B.B.S., M.D.; Michael E. Thase, M.D.; Athanasios Koukopoulos, M.D.; Francesc Colom, Psy.D., Ph.D.; Mark A. Frye, M.D.; Gin S. Malhi, M.D.; Konstantinos N. Fountoulakis, M.D., Ph.D.; Gustavo Vázquez, M.D., Ph.D.; Roy H. Perlis, M.D.; Terence A. Ketter, M.D.; Frederick Cassidy, M.D.; Hagop Akiskal, M.D.; Jean-Michel Azorin, M.D.; Marc Valentí, M.D., Ph.D.; Diego Hidalgo Mazzei, M.D.; Beny Lafer, M.D.; Tadafumi Kato, M.D., Ph.D.; Lorenzo Mazzarini, M.D.; Anabel Martínez-Aran, Psy.D., Ph.D.; Gordon Parker, M.D., Ph.D.; Daniel Souery, M.D., Ph.D.; Ayşegül Özerdem, M.D., Ph.D.; Susan L. McElroy, M.D.; Paolo Girardi, M.D.; Michael Bauer, M.D., Ph.D.; Lakshmi N. Yatham, M.D.; Carlos A. Zarate, M.D.; Andrew A. Nierenberg, M.D.; Boris Birmaher, M.D.; Shigenobu Kanba, M.D., Ph.D.; Rif S. El-Mallakh, M.D.; Alessandro Serretti, M.D., Ph.D.; Zoltan Rihmer, M.D., Ph.D.; Allan H. Young, M.D., Ph.D.; Georgios D. Kotzalidis, M.D.; Glenda M. MacQueen, M.D., Ph.D.N.; Charles L. Bowden, M.D.; S. Nassir Ghaemi, M.D., M.P.H.; Carlos Lopez-Jaramillo, M.D., Ph.D.; Janusz Rybakowski, M.D., Ph.D.; Kyooseob Ha, M.D.; Giulio Perugi, M.D.; Siegfried Kasper, M.D.; Jay D. Amsterdam, M.D.; Robert M. Hirschfeld, M.D.; Flávio Kapczinski, M.D., Ph.D.; Eduard Vieta, M.D., Ph.D.

Am J Psychiatry 2013;170:1249-1262. doi:10.1176/appi.ajp.2013.13020185

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