The Last Psychiatrist, July 5, 2005

Do Antidepressants Induce Mania?

No.

This myth is the result of imprecise use of language. Many2 3 4 5 6 have detected a temporal association between the use of tricyclic antidepressants and episodes of mania in patients with bipolar disorder, though no plausible mechanism has been suggested, much less found. It has been assumed that this association could be extended to all antidepressants despite their substantial chemical and pharmacological heterogeneity. However, such an association between mania and selective serotonin reuptake inhibitors has not been found. In fact, the studies 7 8 9 which have been done strongly indicate that the rate of mania with SSRIs is no different than the normal switch rate of bipolar disorder. A recent study10 11 of venlafaxine, sertraline and bupropion found a 13% 10 week switch rate into mania or hypomania (excludes symptoms lasting less than 7 days), and an 18% one year switch rate, but this study was confounded by the concomitant use of mood stabilizers of dubious efficacy (lamotrigine, gabapentin, topiramate) in 22% of the patients, and the lack of a placebo arm to establish the baseline switch rate. Because of the significant phenomenological heterogeneity of the patients with “bipolar disorder” in clinical trials, a placebo arm is vital in order to compare results in different studies.

It must be reiterated that these are studies of temporal associations between mania and antidepressants, and no causal link can be inferred. Despite this, many continue to discuss the question in terms of the induction of mania by antidepressants. This betrays a bias that is supported neither by data nor logic. For example, studies of novel antidepressants cite rates of “induced” mania, while studies of antiepileptics discuss “breakthrough” manias, automatically presupposing a difference in the mechanism of mania. Similarly, it is popularly assumed that bupropion is less likely to induce mania than SSRIs. This assumption is formalized in the Expert Consensus Guidelines 200012, where bupropion “was clearly rated as the antidepressant least likely to precipitate an episode of mania.” It is not immediately obvious why this was so clear, as there is virtually no evidence indicating this. One single study13 (N=19) found bupropion to be less likely to induce a switch than desipramine. The final results of Post, above, are still pending, but it appears evident that if one has decided to accept the myth that antidepressants induce mania, there is no reason to believe bupropion is any less likely to do this.

The accumulated data in the field strongly suggest that the real risk in the treatment of bipolar depression is ineffectiveness, not mania.

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2 Prien RF. Klett CJ. Caffey EM Jr. Lithium carbonate and imipramine in prevention of affective episodes. A comparison in recurrent affective illness. Arch Gen Psych 29(3):420-5, 1973 Sep.

3 Prien RF. Kupfer DJ. Mansky PA. Small JG. Tuason VB. Voss CB. Johnson WE. Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders. Report of the NIMH Collaborative Study Group comparing lithium carbonate, imipramine, and a lithium carbonate-imipramine combination. Arch Gen Psych 41(11):1096-104, 1984 Nov.

4 Boerlin HL. Gitlin MJ. Zoellner LA. Hammen CL. Bipolar depression and antidepressant-induced mania: a naturalistic study. J Clinical Psychiatry. 59(7):374-9, 1998 Jul.

5 Wehr TA. Goodwin FK. Rapid cycling in manic-depressives induced by tricyclic antidepressants. Arch Gen Psychiatry. 36(5):555-9, 1979 May.

6 Jann MW. Bitar AH. Rao A. Lithium prophylaxis of tricyclic-antidepressant-induced mania in bipolar patients. Am J Psychiatry. 139(5):683-4, 1982 May.

7 Amsterdam JD. Garcia-Espana F. Fawcett J. Quitkin FM. Reimherr FW. Rosenbaum JF. Schweizer E. Beasley C. Efficacy and safety of fluoxetine in treating bipolar II major depressive episode. Journal of Clinical Psychopharmacology. 18(6):435-40, 1998 Dec.

8 Peet M. Induction of mania with selective serotonin re-uptake inhibitors and tricyclic antidepressants. British J Psychiatry. 164(4):549-50, 1994 Apr.

9 Nemeroff CB, Evans DL, Gyulai L, Sachs GS, Bowden CL, Gergel IP et al. Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. Am J Psychiatry 2001; 158:906-12.

10 Post RM. Altshuler LL. Frye MA. Suppes T. Rush AJ. Keck PE Jr. McElroy SL. Denicoff KD. Leverich GS. Kupka R. Nolen WA. Rate of switch in bipolar patients prospectively treated with second-generation antidepressants as augmentation to mood stabilizers. [Clinical Trial. Journal Article. Randomized Controlled Trial] Bipolar Disorders. 3(5):259-65, 2001 Oct.

11 Post RM. Leverich GS. Altshuler LL. Frye MA. Suppes TM. Keck PE Jr. McElroy SL. Kupka R. Nolen WA. Grunze H. Walden J. An overview of recent findings of the Stanley Foundation Bipolar Network (Part I). [Journal Article. Review. Review, Tutorial] Bipolar Disorders. 5(5):310-9, 2003 Oct.

12 Sachs GS. Printz DJ. Kahn DA. Carpenter D. Docherty JP. The Expert Consensus Guideline Series: Medication Treatment of Bipolar Disorder 2000. Postgraduate Medicine. Spec No:1-104, 2000 Apr.

13 Sachs GS. Lafer B. Stoll AL. Banov M. Thibault AB. Tohen M. Rosenbaum JF. A double-blind trial of bupropion versus desipramine for bipolar depression. J Clin Psych 55(9):391-3, 1994 Sep.

See also: Bipolar Controversoies