7 Pharmacological Agents That Benefit Acute Bipolar Depression

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A large systematic review assessing more than 60 drugs for bipolar depression shows only a handful were statistically signifcantly better than placebo per depressive symptom outcomes.

An approximate half-dozen agents designated to treat a number of psychiatric conditions were each found to be more efficacious than placebo in treating acute bipolar depression among adult patients, according to new research.1

In what investigators believed to be the largest network meta-analysis of pharmacotherapy interventions for bipolar depression, 7 agents were shown to benefit adults with acute bipolar depression based on substantial clinical evidence:

  • Olanzapine plus fluoxetine
  • Quetiapine
  • Olanzapine
  • Lurasidone
  • Lumateperone
  • Cariprazine
  • Lamotrigine

The findings provide greater rationale behind evidence-based prescribing practices in what has been constituted as an increasingly concerning disease in the US. Indeed, previous research has elucidates that Americans in particular are at a heightened risk of bipolar disorder and relevant depressive episodes.2

A multinational team of experts—led by Aysegul Yildiz, MD, of the department of psychiatry at Dokuz Eylul University in Turkey—conducted an investigation of comparative efficacy and tolerability of available pharmacological interventions in patients with acute bipolar depression.

“Bipolar depression constitutes a major public health problem due to its substantial burden of disease,” investigators wrote. “Although pharmacological interventions are available, guidelines required updated evidence synthesis to improve their current recommendations.”

The team conducted a systematic review and network meta-analysis of randomized, controlled trials in which pharmacological agents were compared to either each other or placebo in adults with acute bipolar depression. Eligible cohort patients were diagnosed with type I, II or otherwise specified bipolar disorder; those with a history of substance misuse, unipolar depression or schizophrenia were excluded from the analysis.

Yildiz and colleagues assessed 8 clinical databases from their inception up to April 2023 for relevant trials. Each included study ran for a duration of 2 – 16 weeks; outcome assessments were masked; either combination, add-on design or monotherapy studies were included for analysis.

Investigators sought co-primary outcomes of depressive symptoms per standardized mean differences (SMDs) and manic switch per odds ratios (ORs). They additionally sought safety and tolerability outcomes including trial dropouts and adverse events in treated patients.

The final analysis included 101 randomized controlled trials comprised of 20,081 participants. A majority of participants were women (n = 11,263 [58.3%]); mean participant age was 41.0 years old (mean ranges, 28.7 – 53.6). A total of 68 medications, plus placebo, were analyzed for treating acute bipolar depression.

The team reported that each of olanzapine plus fluoxetine; quetiapine; olanzapine; lurasidone; lumateperone; cariprazine; and lamotrigine were more efficacious than control in reducing depressive symptoms in adult patients at moderate confidence in clinical evidence. SMDs for these agents ranged from 0.41 (95% CI, 0.19 – 0.64) with olanzapine plus fluoxetine, to 0.16 (95% CI, 0.3 – 0.29) for lamotrigine.

Investigators additionally noted that while several other assessed drugs may be efficacious for acute bipolar depression, the outcome was not considering statistically significant based on confidence intervals.

“Antidepressants as a class seem to be efficacious, but had a higher risk for manic switch compared to antipsychotics,” investigators wrote. “Medications differed in their side-effect profiles.”

The team concluded that the 7 observed agents of benefit were more efficacious than placebo in adult patients, with “good confidence in the evidence, and to differ in their side-effect profiles.”

“These findings can inform evidence-based care and the development of treatment guidelines internationally,” investigators concluded.


  1. Yildiz A, Siafis S, Mavridis D, Vieta E, Leucht S. Comparative efficacy and tolerability of pharmacological interventions for acute bipolar depression in adults: a systematic review and network meta-analysis. Lancet Psychiatry. 2023;10(9):693-705. doi:10.1016/S2215-0366(23)00199-2
  2. Gardner A. U.S. has highest bipolar rate in 11-nation study. Published March 7, 2011.