A Long-Term, Open-Label Study to Evaluate the Safety and Tolerability of Brexpiprazole as Maintenance Treatment in Adults with Schizophrenia
Open accessAbstract
Background: Brexpiprazole is a serotonin-dopamine activity modulator with efficacy in acute schizophrenia and relapse prevention. The aim of this Phase 3, multicenter study was to assess the long-term safety, tolerability, and efficacy of treatment with brexpiprazole flexible-dose 1-4 mg/d. Methods: Patients rolled over into this 52-week open-label study (amended to 26 weeks towards the end) from 3 randomized, double-blind, placebo-controlled Phase 3 studies. De novo patients, not part of the previous studies, were also enrolled. The primary outcome variable was the frequency and severity of treatment-emergent adverse events. Efficacy was assessed as a secondary objective using the Positive and Negative Syndrome Scale and the Personal and Social Performance scale. Results: A total of 1072 patients was enrolled (952 for 52 weeks and 120 for 26 weeks), 47.4% of whom completed the study. Among patients who took at least one dose of brexpiprazole, 14.6% discontinued due to treatment-emergent adverse events, most commonly schizophrenia (8.8%) and psychotic disorder (1.5%). Treatment-emergent adverse events with an incidence of ≥5% were schizophrenia (11.6%), insomnia (8.6%), weight increased (7.8%), headache (6.4%), and agitation (5.4%). Most treatment-emergent adverse events were mild or moderate in severity. The mean increase in body weight from baseline to week 26 was 1.3 kg and to week 52 was 2.1 kg. There were no clinically relevant findings related to prolactin, lipids, and glucose, or QT prolongation. On average, patients' symptoms and functioning showed continual improvement. Conclusions: Treatment with brexpiprazole 1-4 mg/d was generally well tolerated for up to 52 weeks in patients with schizophrenia. ClinicalTrials.gov identifier: NCT01397786 (https://clinicaltrials.gov/show/NCT01397786).
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The relapse-prevention trial was terminated early, and the open-label safety study by Forbes et al was amended to decrease trial length, because the investigative teams noted early collection of adequate safety and efficacy data.
“The relapse-prevention trial8 was terminated early, and the open-label safety study conducted by Forbes et al10 was amended to decrease the trial length, as the investigative teams in both studies noted early collection of adequate safety and efficacy data.”
From Brexpiprazole for the maintenance treatment of adults with schizophrenia: an evidence-based review and place in therapy (2019) · cites this paper as [10]
The Methods (Study Design) confirm that the open-label study was amended to shorten treatment from 52 to 26 weeks for patients enrolled after the amendment. They give the reason as an already well-established safety profile based on completed studies and this study’s population, not early collection of adequate safety and efficacy data by the open-label investigative team. The Methods (Patients) separately report that the relapse-prevention study ended early after an interim analysis demonstrated efficacy versus placebo. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn the open-label safety study, all patients who received at least one dose of brexpiprazole after the conversion phase were included in safety results (1,031), and all patients in the safety group with at least one efficacy evaluation in the open-label phase (1,021) were included in efficacy results.
“All patient data from those who had received at least one dose of brexpiprazole after the conversion phase were included in the represented in the safety results (1,031), and all patients who were in the safety group and had had at least one efficacy evaluation in the open-label phase (1,021) were represented in the efficacy results.”
From Brexpiprazole for the maintenance treatment of adults with schizophrenia: an evidence-based review and place in therapy (2019) · cites this paper as [10]
Methods > Statistical Analyses defines the safety population as patients who received at least one open-label dose and the efficacy population as those safety patients with a post-baseline PANSS evaluation. Results > Patients gives the safety population as 1,031. Our copy does not give 1,021 as the efficacy-population count; Results > Efficacy instead lists 1,024 patients with a baseline efficacy score, so the claimed efficacy count is not supported. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAmong those previously exposed to brexpiprazole in the open-label safety study, the number decreased to 611 (58.5%), as the rest had received placebo in previous trials.
“with regard to those who were previously exposed to brexpiprazole, the number decreased to 611 (58.5%), as the rest had received placebo in one of the previous trials.”
From Brexpiprazole for the maintenance treatment of adults with schizophrenia: an evidence-based review and place in therapy (2019) · cites this paper as [10]
The Results > Patients section reports that 611 of the 1,044 patients entering open-label treatment had received brexpiprazole previously, which is 58.5%. But the remaining 433 were not all prior placebo recipients: 204 rollover patients had received placebo, while 229 were de novo patients. The Discussion also notes that some patients classified as having received placebo had earlier brexpiprazole exposure. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThe literature search identified published results of three phase III 52-week clinical trials assessing the safety and efficacy of brexpiprazole for the management of schizophrenia.
“The literature search identified published results pertaining to three phase III 52-week clinical trials assessing the safety and efficacy of brexpiprazole for the management of schizophrenia.8–10”
From Brexpiprazole for the maintenance treatment of adults with schizophrenia: an evidence-based review and place in therapy (2019) · cites this paper as [10]
In the open-label safety study by Forbes et al, the study was amended to shorten the open-label phase from 52 to 26 weeks based on safety data deemed adequate from pooled acute trials, the relapse-prevention trial, and this investigation.
“During the trial, the investigators amended the study to shorten the open-label phase from 52 to 26 weeks, based on safety data that were deemed adequate when considering pooled results from the acute trials and the relapse-prevention trial, in combination with available data from this investigation.”
From Brexpiprazole for the maintenance treatment of adults with schizophrenia: an evidence-based review and place in therapy (2019) · cites this paper as [10]
Of 1,072 patients enrolled in the open-label safety study, 952 were enrolled prior to the amendment that shortened trial duration to 26 weeks, and 120 additional participants were enrolled after.
“Of the 1,072 patients who were enrolled, most (952) were enrolled prior to the amendment that shortened the trial duration to 26 weeks (120 additional participants).”
From Brexpiprazole for the maintenance treatment of adults with schizophrenia: an evidence-based review and place in therapy (2019) · cites this paper as [10]
Of 1,072 patients in the open-label safety study, only 28 discontinued during the conversion phase, and of the remaining 1,044, most (815) had participated in one of the previous studies.
“Of the 1,072 patients, only 28 discontinued during the conversion phase, and of the remaining 1,044, most (815) had participated in one of the previous studies.”
From Brexpiprazole for the maintenance treatment of adults with schizophrenia: an evidence-based review and place in therapy (2019) · cites this paper as [10]
Among the safety group in the open-label safety study, average PANSS score at entry was 69.5 (SD 17.2), indicative of mild-moderate severity symptoms.
“Among the safety group, the average PANSS score (SD) when entering the trial was 69.5 (17.2), which is indicative of mild–moderate severity symptoms.”
From Brexpiprazole for the maintenance treatment of adults with schizophrenia: an evidence-based review and place in therapy (2019) · cites this paper as [10]
In the open-label safety study, average age was 40.0 years, 38.2% were female, average BMI was 27.9, and 62% were white.
“The average age (SD) of the participants was 40.0 (11.1) years, 38.2% were female, and the average BMI (SD) was 27.9 (6.6). The majority (62%) of the population was white.”
From Brexpiprazole for the maintenance treatment of adults with schizophrenia: an evidence-based review and place in therapy (2019) · cites this paper as [10]
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Self-citation
- Authors
- Forbes, A., Hobart, M., Ouyang, J., Shi, L., Pfister, S., & Hakala, M.
- Affiliations
- Otsuka (United States) (US)
- Lundbeck (Denmark) (DK)
- Corresponding author
- Forbes, Andy
- Venue
- International Journal of Neuropsychopharmacology
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-02-03
- Volume
- 21
- Issue
- 5
- Pages
- 433-441
- ISSN
- 1461-1457 (ISSN-L)
- 1469-5111
- PMC
- PMC5932477
- OpenAlex
- W2793227676
- Cited by
- 52
- References
- 9
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 3 · 2023: 5 · 2022: 5 · 2021: 8 · 2020: 7 · 2019: 10 · 2018: 2
- FWCI
- 5.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- The International Journal of Neuropsychopharmacology (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Otsuka Pharmaceutical
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Keywords
- brexpiprazole, schizophrenia, maintenance therapy, long-term safety, tolerability, treatment-emergent adverse events, weight gain, insomnia, agitation, prolactin, QT prolongation
- MeSH terms
- Adult, Double-Blind Method, Female, Humans, Male, Middle Aged, Schizophrenia, Thiophenes, Antipsychotic Agents, Quinolones, Outcome Assessment, Health Care, Secondary Prevention
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