Do antidepressants increase the risk of mania and bipolar disorder in people with depression? A retrospective electronic case register cohort study

BMJ Open. 2015 Dec 14;5(12):e008341. doi: 10.1136/bmjopen-2015-008341.


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.

Keywords: CRIS; SSRI; antidepressant induced mania; electronic health records; manic switch; venlafaxine.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antidepressive Agents / administration & dosage
  • Antidepressive Agents / adverse effects*
  • Bipolar Disorder / chemically induced*
  • Bipolar Disorder / epidemiology
  • Bipolar Disorder / psychology
  • Depression / complications
  • Depression / drug therapy*
  • Depression / epidemiology
  • Drug Administration Schedule
  • Electronic Health Records
  • Female
  • Humans
  • Incidence
  • Male
  • Registries
  • Retrospective Studies
  • Risk Factors
  • Selective Serotonin Reuptake Inhibitors / administration & dosage
  • Selective Serotonin Reuptake Inhibitors / adverse effects*
  • Treatment Outcome
  • United Kingdom / epidemiology
  • Venlafaxine Hydrochloride / administration & dosage
  • Venlafaxine Hydrochloride / adverse effects*


  • Antidepressive Agents
  • Serotonin Uptake Inhibitors
  • Venlafaxine Hydrochloride