Objectives To investigate the association between antidepressant therapy and the later onset of mania/bipolar disorder.

Design Retrospective cohort study using an anonymised electronic health record case register.

Setting South London and Maudsley National Health Service (NHS) Trust (SLaM), a large provider of inpatient and community mental healthcare in the UK.

Participants 21 012 adults presenting to SLaM between 1 April 2006 and 31 March 2013 with unipolar depression.

Exposure Prior antidepressant therapy recorded in electronic health records.

Main outcome measure Time to subsequent diagnosis of mania or bipolar disorder from date of diagnosis of unipolar depression, censored at 31 March 2014.

Methods Multivariable Cox regression analysis with age and gender as covariates.

Results The overall incidence rate of mania/bipolar disorder was 10.9 per 1000 person-years. The peak incidence of mania/bipolar disorder incidence was seen in patients aged between 26 and 35 years (12.3 per 1000 person-years). Prior antidepressant treatment was associated with an increased incidence of mania/bipolar disorder ranging from 13.1 to 19.1 per 1000 person-years. Multivariable analysis indicated a significant association with selective serotonin reuptake inhibitors (HR 1.34, 95% CI 1.18 to 1.52) and venlafaxine (1.35, 1.07 to 1.70).

Conclusions In people with unipolar depression, antidepressant treatment is associated with an increased risk of subsequent mania/bipolar disorder. These findings highlight the importance of considering risk factors for mania when treating people with depression.