Antidepressant use associated with increased risk of subsequent mania

1. In a retrospective cohort study of over 21 000 patients with depression, antidepressant use was significantly associated with an increased incidence of manic episode/bipolar disorder.

2. The strongest association was found in those patients who had previously taken selective serotonin reuptake inhibitors (SSRIs) or venlafaxine.

Evidence Rating Level: 3 (Average)

Study Rundown: Manic and hypomanic episodes are well-documented adverse effects of antidepressant therapy. However, whether antidepressants cause mania or trigger the expression of bipolar disorder is unknown. Furthermore, there have been limited population-based studies on the incidence of mania/bipolar disorder in patients using antidepressant therapy. The purpose of this large retrospective cohort trial was to quantify the magnitude of this association.

The study reviewed over 21 000 electronic health records of patients with a diagnosis of unipolar depression. At the conclusion of the trial, patients who had received antidepressant therapy demonstrated a significantly higher risk of developing subsequent mania/bipolar disorder compared to patients not on antidepressant therapy. Furthermore, multi-variable analysis demonstrated that the increased risk of mania/bipolar disorder was greatest in patients taking SSRIs and venlafaxine. The results of this study highlight the importance of clinically evaluating for risk factors of mania prior to starting patients on antidepressant therapy. The study is strengthened by the large sample size, which increases the generalizability of the results. However, since this was an observational study, a causal link between antidepressant treatments and development of mania or bipolar disorder cannot be drawn from these results.

Click to read the study in BMJ Open

Relevant Reading: The use of antidepressants in bipolar disorder

In-Depth [retrospective cohort]: This study analyzed the electronic health records of all adults receiving healthcare from the South London and Maudsley National Health Service (NHS) Foundation trust (SLaM) from 2006 to 2013. Overall, 21 012 patients with a diagnosis of unipolar depression were included in the study. The primary outcome was any diagnosed manic episode or bipolar depression during the follow-up period. At the conclusion of the study, the incidence rate of mania/bipolar disorder overall in this cohort was 10 per 1000 person-years. In patients with previous history of antidepressant use, the incidence of mania/bipolar disorder was found to be significantly higher (13 to 19 per 1000 person-years). Subgroup analysis demonstrated the highest incidence of mania/bipolar disorder in the 26 to 35 year age group. In multivariate analysis, patients with previous exposure to SSRI (HR 1.34, 95% CI 1.18 to 1.52) and venlafaxine (HR 1.35, CI 1.07 to 1.70) demonstrated the strongest association with a subsequent diagnosis of mania/bipolar disorder.

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