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Published Online: 23 September 2021

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

Joseph R. Calabrese, M.D., Suresh Durgam, M.D. [email protected], Andrew Satlin, M.D., Kimberly E. Vanover, Ph.D., Robert E. Davis, Ph.D., Richard Chen, Ph.D., Susan G. Kozauer, M.D., Sharon Mates, Ph.D., and Gary S. Sachs, M.D.Authors Info & Affiliations
Publication: American Journal of Psychiatry
Volume 178, Number 12
https://doi.org/10.1176/appi.ajp.2021.20091339
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Abstract

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-Åsberg 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.

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Supplementary Material

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Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Volume 178 • Number 12 • December 2021
Pages: 1098 - 1106
PubMed: 34551584

History

Received: 10 September 2020
Revision received: 5 May 2021
Accepted: 29 June 2021
Published online: 23 September 2021
Published in print: December 2021

Keywords

  1. Antipsychotics
  2. Bipolar and Related Disorders
  3. Bipolar and Related Disorders
  4. Bipolar and Related Disorders
  5. Bipolar II Disorder
  6. Clinical Drug Studies

Authors

Affiliations

Joseph R. Calabrese, M.D.
Department of Psychiatry, Case Western Reserve School of Medicine, Cleveland, and University Hospitals Cleveland Medical Center, Cleveland (Calabrese); Intra-Cellular Therapies, Inc., New York (Durgam, Satlin [formerly], Vanover [formerly], Davis, Chen, Kozauer, Mates); Massachusetts General Hospital, Boston, and Signant Health, Plymouth Meeting, Pa. (Sachs).
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Suresh Durgam, M.D. [email protected]
Department of Psychiatry, Case Western Reserve School of Medicine, Cleveland, and University Hospitals Cleveland Medical Center, Cleveland (Calabrese); Intra-Cellular Therapies, Inc., New York (Durgam, Satlin [formerly], Vanover [formerly], Davis, Chen, Kozauer, Mates); Massachusetts General Hospital, Boston, and Signant Health, Plymouth Meeting, Pa. (Sachs).
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Andrew Satlin, M.D.
Department of Psychiatry, Case Western Reserve School of Medicine, Cleveland, and University Hospitals Cleveland Medical Center, Cleveland (Calabrese); Intra-Cellular Therapies, Inc., New York (Durgam, Satlin [formerly], Vanover [formerly], Davis, Chen, Kozauer, Mates); Massachusetts General Hospital, Boston, and Signant Health, Plymouth Meeting, Pa. (Sachs).
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Kimberly E. Vanover, Ph.D.
Department of Psychiatry, Case Western Reserve School of Medicine, Cleveland, and University Hospitals Cleveland Medical Center, Cleveland (Calabrese); Intra-Cellular Therapies, Inc., New York (Durgam, Satlin [formerly], Vanover [formerly], Davis, Chen, Kozauer, Mates); Massachusetts General Hospital, Boston, and Signant Health, Plymouth Meeting, Pa. (Sachs).
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Robert E. Davis, Ph.D.
Department of Psychiatry, Case Western Reserve School of Medicine, Cleveland, and University Hospitals Cleveland Medical Center, Cleveland (Calabrese); Intra-Cellular Therapies, Inc., New York (Durgam, Satlin [formerly], Vanover [formerly], Davis, Chen, Kozauer, Mates); Massachusetts General Hospital, Boston, and Signant Health, Plymouth Meeting, Pa. (Sachs).
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Richard Chen, Ph.D.
Department of Psychiatry, Case Western Reserve School of Medicine, Cleveland, and University Hospitals Cleveland Medical Center, Cleveland (Calabrese); Intra-Cellular Therapies, Inc., New York (Durgam, Satlin [formerly], Vanover [formerly], Davis, Chen, Kozauer, Mates); Massachusetts General Hospital, Boston, and Signant Health, Plymouth Meeting, Pa. (Sachs).
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Susan G. Kozauer, M.D.
Department of Psychiatry, Case Western Reserve School of Medicine, Cleveland, and University Hospitals Cleveland Medical Center, Cleveland (Calabrese); Intra-Cellular Therapies, Inc., New York (Durgam, Satlin [formerly], Vanover [formerly], Davis, Chen, Kozauer, Mates); Massachusetts General Hospital, Boston, and Signant Health, Plymouth Meeting, Pa. (Sachs).
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Sharon Mates, Ph.D.
Department of Psychiatry, Case Western Reserve School of Medicine, Cleveland, and University Hospitals Cleveland Medical Center, Cleveland (Calabrese); Intra-Cellular Therapies, Inc., New York (Durgam, Satlin [formerly], Vanover [formerly], Davis, Chen, Kozauer, Mates); Massachusetts General Hospital, Boston, and Signant Health, Plymouth Meeting, Pa. (Sachs).
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Gary S. Sachs, M.D.
Department of Psychiatry, Case Western Reserve School of Medicine, Cleveland, and University Hospitals Cleveland Medical Center, Cleveland (Calabrese); Intra-Cellular Therapies, Inc., New York (Durgam, Satlin [formerly], Vanover [formerly], Davis, Chen, Kozauer, Mates); Massachusetts General Hospital, Boston, and Signant Health, Plymouth Meeting, Pa. (Sachs).
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Notes

Send correspondence to Dr. Durgam ([email protected]).

Competing Interests

Dr. Calabrese has served as an advisory board member and/or consultant for Alkermes, Janssen Research and Development, Otsuka Pharmaceutical Development and Commercialization, and Sunovion Pharmaceuticals; he has served as a consultant and received travel funds from Intra-Cellular Therapies, Inc.; and he has served on the speakers bureau for Sumitomo Dainippon Pharma. Drs. Durgam, Davis, Chen, Kozauer, and Mates are employees of Intra-Cellular Therapies, Inc., and some of them hold company stock and/or stock options. Dr. Satlin was an employee of Intra-Cellular Therapies, Inc., when the study was conducted and holds company stock, and is currently an employee of Transposon Therapeutics. Dr. Vanover was an employee of Intra-Cellular Therapies, Inc., when the study was conducted and holds company stock, and is currently an employee of Engrail Therapeutics and serves as a scientific adviser for Evolution Research Group. Dr. Sachs is an employee of Signant Health.

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