Antidepressant-associated mood-switching and transition from unipolar major depression to bipolar disorder: a review

J Affect Disord. 2013 May 15;148(1):129-35. doi: 10.1016/j.jad.2012.10.033. Epub 2012 Dec 6.


Objectives: Compare reported rates of mood-shifts from major depression to mania/hypomania/mixed-states during antidepressant (AD)-treatment and rates of diagnostic change from major depressive disorder (MDD) to bipolar disorder (BPD).

Methods: Searching computerized literature databases, followed by summary analyses.

Results: In 51 reports of patients diagnosed with MDD and treated with an AD, the overall risk of mood-switching was 8.18% (7837/95,786) within 2.39 ± 2.99 years of treatment, or 3.42 (95% CI: 3.34-3.50) %/year. Risk was 2.6 (CI: 2.5-2.8) times greater with/without AD-treatment by meta-analysis of 10 controlled trials. Risk increased with time up to 24 months of treatment, with no secular change (1968-2012). Incidence rates were 4.5 (CI: 4.1-4.8)-times greater among juveniles than adults (5.62/1.26 %/year; p<0.0001). In 12 studies the overall rate of new BPD-diagnoses was 3.29% (1928/56,754) within 5.38 years (0.61 [0.58-0.64] %/year), or 5.6-times lower (3.42/0.61) than annualized rates of mood-switching.

Conclusions: AD-treatment was associated with new mania-like responses in 8.18% of patients diagnosed with unipolar MDD. Contributions to mood-switching due to unrecognized BPD versus mood-elevating pharmacological effects, as well as quantitative associations between switching and later diagnosis of BPD not associated with AD-treatment remain uncertain.

Limitations: Rates and definitions of mood-switching with ADs varied greatly, exposure-times rarely were precisely defined, and there was little information on predictive associations between mood-switches and BPD-diagnosis.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antidepressive Agents / adverse effects*
  • Bipolar Disorder / chemically induced*
  • Depressive Disorder, Major / drug therapy*
  • Humans
  • Randomized Controlled Trials as Topic
  • Risk Assessment
  • Treatment Outcome


  • Antidepressive Agents