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Randomized Controlled Trial
. 2021 Aug;35(8):971-982.
doi: 10.1177/0269881120985102. Epub 2021 Mar 10.

Two randomized, double-blind, placebo-controlled trials and one open-label, long-term trial of brexpiprazole for the acute treatment of bipolar mania

Eduard Vieta  1 , Gary Sachs  2 , Denise Chang  3 , Johan Hellsten  4 , Claudette Brewer  3 , Timothy Peters-Strickland  3 , Nanco Hefting  4
Affiliations
Randomized Controlled Trial

Two randomized, double-blind, placebo-controlled trials and one open-label, long-term trial of brexpiprazole for the acute treatment of bipolar mania

Eduard Vieta et al. J Psychopharmacol. 2021 Aug.

Abstract

Background: Brexpiprazole is a dopamine/serotonin receptor partial agonist (D2, 5-HT1A) and antagonist (5-HT2A) approved for treatment of schizophrenia and major depressive disorder (adjunct to antidepressants).

Aims: This study aimed to investigate brexpiprazole as monotherapy in acute mania (bipolar I disorder) in two short-term (ST) studies (study 080 and study 081) and one open-label (OL) extension (study 083).

Methods: ST studies were three-week randomized, double-blind, flexible dose (2-4 mg/day), placebo-controlled studies. The primary endpoint was mean change in Young Mania Rating Scale (YMRS) total score from baseline to day 21. The OL study was a 26-week flexible dose (2-4 mg/day) study for patients completing the ST studies.

Results: A total of 164 and 158 (study 080) and 170 and 162 (study 081) inpatients with DSM-5 mania with/without mixed features were randomized to placebo or brexpiprazole, respectively. The primary analyses did not show a statistically significant difference between brexpiprazole and placebo: study 080: least squares mean difference (95% confidence limits): 0.14 (-1.74, 2.03), p = 0.8797; study 081: -1.62 (-3.56, 0.32), p = 0.1011. OL study patients (n = 381) demonstrated a gradual improvement in YMRS total score. Akathisia was the only adverse event, with an incidence of ⩾5% with brexpiprazole and more than placebo in the ST studies, or ⩾5% in the OL study. Brexpiprazole was more efficacious in patients with impaired or no insight (predominantly EU patients) than in patients with excellent insight (predominantly US patients).

Conclusions: Further studies are necessary to address the potential efficacy of brexpiprazole in acute mania, which should ensure that the study sample is severe enough (especially with regard to insight), and that the dose/titration schedule is not too modest.

Keywords: Bipolar I disorder; brexpiprazole; clinical trial; dopamine; insight; serotonin receptor partial agonist and antagonist.

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Conflict of interest statement

Data availability: To submit inquiries related to Otsuka clinical research, or to request access to individual participant data (IPD) associated with any Otsuka clinical trial, please visit https://clinical-trials.otsuka.com/. For all approved IPD access requests, Otsuka will share anonymized IPD on a remotely accessible data sharing platform.

Declaration of conflicting interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: E.V. has received grants and served as consultant, advisor, or CME speaker for the following entities: AB-Biotics, Abbott, Allergan, Angelini, Dainippon Sumitomo Pharma, Galenica, Janssen, Lundbeck, Novartis, Otsuka, Richter, Sage, Sanofi-Aventis, and Takeda, outside the submitted work. G.S. reports consulting fees from AstraZeneca, Blackthorne, Intra-Cellular Therapies, Otsuka, Pfizer, Sunovion, Supernus, Takeda, and Teva outside the submitted work and is a full-time employee of Signant Health. D.C., C.B., and T.P.-S. are full-time employees of Otsuka Pharmaceutical Development and Commercialization, Inc., Princeton, NJ, USA. J.H. and N.H. are full-time employees of H. Lundbeck A/S, Valby, Denmark.

Figures

Figure 1.
Figure 1.
Study design. C-SSRS: Columbia Suicide Severity Rating Scale; YMRS: Young Mania Rating Scale.
Figure 2.
Figure 2.
Study flow chart: (a) study 080; (b) study 081. YMRS: Young Mania Rating Scale.
Figure 3.
Figure 3.
Primary efficacy analysis—mean change from baseline to day 21 in YMRS total score: (a) study 080; (b) study 081. SE: standard error; YMRS: Young Mania Rating Scale.
Figure 4.
Figure 4.
Mean change from baseline to day 21 in YMRS total score by region: (a) study 080; (b) study 081. YMRS: Young Mania Rating Scale.
Figure 5.
Figure 5.
Mean change from baseline to week 26 in YMRS total score. SD: standard deviation; YMRS: Young Mania Rating Scale.
See this image and copyright information in PMC

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