Efficacy and Safety of Lumateperone for Major Depressive Episodes Associated With Bipolar I or Bipolar II Disorder: A Phase 3 Randomized Placebo-Controlled Trial

Am J Psychiatry. 2021 Dec;178(12):1098-1106. doi: 10.1176/appi.ajp.2021.20091339. Epub 2021 Sep 23.


Objective: In a phase 3 randomized double-blind placebo-controlled study, the authors investigated the efficacy and safety of 42 mg/day of lumateperone in patients with bipolar I or bipolar II disorder experiencing a major depressive episode.

Methods: Patients 18-75 years old with a clinical diagnosis of bipolar I or bipolar II disorder and experiencing a major depressive episode were eligible for the study. Patients were randomized in a 1:1 ratio to receive 42 mg/day of lumateperone (N=188) or placebo (N=189), administered orally once daily in the evening for 6 weeks. The primary and key secondary efficacy endpoints were change from baseline to day 43 in score on the Montgomery-├ůsberg Depression Rating Scale (MADRS) and total score on the Clinical Global Impressions Scale-Bipolar Version severity scale (CGI-BP-S), respectively. Safety assessments included treatment-emergent adverse events, laboratory parameters, vital signs, extrapyramidal symptoms, and suicidality.

Results: At day 43, lumateperone treatment was associated with significantly greater improvement from baseline in MADRS score compared with placebo (least squares mean difference compared with placebo, -4.6 points; effect size=-0.56) and CGI-BP-S total score (least squares mean difference compared with placebo, -0.9; effect size=-0.46). Significant MADRS superiority for lumateperone over placebo was observed both in patients with bipolar I and bipolar II disorders. Somnolence and nausea were the only treatment-emergent adverse events that occurred with lumateperone at a clinically meaningful greater rate than placebo. The incidence of extrapyramidal symptom-related treatment-emergent adverse events was low and similar to that for placebo. Minimal changes were observed in weight, vital signs, or metabolic or endocrine assessments.

Conclusions: Lumateperone at 42 mg/day significantly improved depression symptoms and was generally well tolerated in patients with major depressive episodes associated with both bipolar I and bipolar II disorders.

Trial registration: ClinicalTrials.gov NCT03249376.

Keywords: Antipsychotics; Bipolar II Disorder; Bipolar and Related Disorders; Clinical Drug Studies.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antipsychotic Agents / therapeutic use
  • Bipolar Disorder / complications*
  • Bipolar Disorder / drug therapy
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / etiology
  • Double-Blind Method
  • Female
  • Heterocyclic Compounds, 4 or More Rings / adverse effects
  • Heterocyclic Compounds, 4 or More Rings / therapeutic use*
  • Humans
  • Male
  • Middle Aged
  • Young Adult


  • Antipsychotic Agents
  • Heterocyclic Compounds, 4 or More Rings
  • lumateperone

Associated data

  • ClinicalTrials.gov/NCT03249376
  • EudraCT/2017-002317-58