Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers

Am J Psychiatry. 2006 Feb;163(2):232-9. doi: 10.1176/appi.ajp.163.2.232.


Objective: The authors examined the comparative risks of switches in mood polarity into hypomania or mania during acute and continuation trials of adjunctive antidepressant treatment of bipolar depression.

Method: One hundred fifty-nine patients with bipolar I disorder or bipolar II disorder participated in a total of 228 acute (10-week) randomized trials of bupropion, sertraline, or venlafaxine as an adjunct to a mood stabilizer. Patients in 87 of these trials entered continuation treatment for up to 1 year. Antidepressant response and the occurrence of subthreshold brief hypomania (emergence of brief hypomania [at least 1 but <7 days] or recurrent brief hypomania) and threshold switches (emergence of full-duration hypomania [> or =7 days] or mania) were blindly assessed by using clinician-rated daily reports of mood-associated dysfunction on the National Institute of Mental Health Life Chart Method.

Results: Threshold switches into full-duration hypomania and mania occurred in 11.4% and 7.9%, respectively, of the acute treatment trials and in 21.8% and 14.9%, respectively, of the continuation trials. The rate of threshold switches was higher in the 169 trials in patients with bipolar I disorder (30.8%) than the 59 trials in patients with bipolar II disorder (18.6%). The ratio of threshold switches to subthreshold brief hypomanias was higher in both the acute (ratio=3.60) and continuation trials (ratio=3.75) of venlafaxine than in the acute and continuation trials of bupropion (ratios=0.85 and 1.17, respectively) and sertraline (ratios=1.67 and 1.66, respectively). In only 37 (16.2%) of the original 228 acute antidepressant trials, or in only 23.3% of the patients, was there a sustained antidepressant response in the continuation phase in the absence of a threshold switch.

Conclusions: Adjunctive treatment with antidepressants in bipolar depression was associated with substantial risks of threshold switches to full-duration hypomania or mania in both acute and long-term continuation treatment. Of the three antidepressants included in the study, venlafaxine was associated with the highest relative risk of such switching and bupropion with the lowest risk.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anticonvulsants / therapeutic use*
  • Antidepressive Agents / therapeutic use*
  • Antipsychotic Agents / therapeutic use*
  • Bipolar Disorder / diagnosis*
  • Bipolar Disorder / drug therapy*
  • Bipolar Disorder / epidemiology
  • Bipolar Disorder / psychology*
  • Bupropion / therapeutic use
  • Cohort Studies
  • Cross-Sectional Studies
  • Cyclohexanols / therapeutic use
  • Drug Therapy, Combination
  • Female
  • Humans
  • Lithium / therapeutic use*
  • Male
  • Psychiatric Status Rating Scales / statistics & numerical data
  • Risk
  • Selective Serotonin Reuptake Inhibitors / therapeutic use
  • Sertraline / therapeutic use
  • Treatment Outcome
  • Venlafaxine Hydrochloride


  • Anticonvulsants
  • Antidepressive Agents
  • Antipsychotic Agents
  • Cyclohexanols
  • Serotonin Uptake Inhibitors
  • Bupropion
  • Venlafaxine Hydrochloride
  • Lithium
  • Sertraline