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

Abstract

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.

Introduction

Many cases of bipolar disorder (BPD) present in episodes of major depressive disorder (MDD), accounting for approximately half of initial episodes (Goodwin and Jamison, 2007, Tondo et al., 2010b, Etain et al., 2012). Many such patients risk switching of mood from depression to disruptive and potentially dangerous manic/hypomanic, mixed, or psychotic states, sometimes in association with treatment with a mood-elevating agent, and some require re-diagnosis to BPD (Lim et al., 2005, Visser and Van der Mast, 2005, Tondo et al., 2010a, Li et al., 2012). Such risk may be particularly high among juvenile depressed patients, who are more likely to be treated with antidepressants (ADs) and stimulants before a diagnosis of BPD is made (Martin et al., 2004, Baldessarini et al., 2005, Lim et al., 2005, Biederman et al., 2009, Offidani et al.,). Moreover, patients who begin BPD with depressive or mixed episodes appear to be at increased risk for long-term morbidity, disability, and suicide (Baldessarini et al., 2010a, Baldessarini et al., 2010b, Baldessarini et al., 2012b). These considerations indicate the importance of quantifying the risk of excessive elevation of mood and behavioral activation during treatment with mood-elevating drugs, and its relationship to later diagnoses of BPD supported by spontaneous mood-elevations (Strober and Carlson, 1982, Akiskal et al., 1983). Finally, it remains unclear to what extent AD-associated mood-switches represent uncovering of potential or unrecognized BPD, or a more direct pharmacologic effect independent of diagnosis (Tondo et al., 2010a, Offidani et al.,).

Accordingly, we carried out a systematic review of reports on AD-associated mood-switching among patients diagnosed with MDD, as well as of reports on diagnostic conversion from MDD to BPD. We aimed to clarify the rates of each phenomenon and to seek relationships between them, as well as considering the possible significance of AD-associated mood-switching.