Spotlight On Brexpiprazole and Its Potential in The Treatment of Schizophrenia and As Adjunctive Therapy For The Treatment of Major Depression
Spotlight On Brexpiprazole and Its Potential in The Treatment of Schizophrenia and As Adjunctive Therapy For The Treatment of Major Depression
Spotlight On Brexpiprazole and Its Potential in The Treatment of Schizophrenia and As Adjunctive Therapy For The Treatment of Major Depression
Dawn Bruijnzeel Abstract: Antipsychotic agents, utilized for the treatment of a range of psychiatric disorders,
Rajiv Tandon differ substantially in terms of their pharmacology and adverse effect profiles. Incomplete and
variable efficacy, differences in safetytolerability, and highly heterogeneous response across
Department of Psychiatry, University
of Florida College of Medicine, individuals prompt development of new agents. Brexpiprazole is one of the two most recently
Gainesville, FL, USA introduced antipsychotic agents approved for the treatment of schizophrenia and as an adjunct
for treatment of major depressive disorder. Its pharmacology, clinical trial data, and efficacy
and side effects in comparison with other antipsychotic agents are discussed. Brexpiprazole
is a dopamine D-2 partial agonist with potent activity at the serotonin 5HT1A and 5HT2A and
noradrenergic alpha-1B and alpha-2C receptors. Placebo-controlled clinical trials in persons
with schizophrenia support its efficacy in treating psychosis and preventing relapse. Short-
term clinical trials also support its efficacy as an adjunct to antidepressants in treating major
depressive disorder in individuals inadequately responsive to antidepressant treatment alone.
Adverse effects include akathisia, gastrointestinal side effects, and moderate weight gain. The
recommended oral dose of brexpiprazole is 24 mg/day in schizophrenia and 23 mg/day as
adjunctive treatment in major depression. It must be titrated up to its target dose over 12
weeks and is effective in once-daily dosing. How brexpiprazoles unique pharmacological
profile will translate into clinically meaningful differences from other antipsychotic agents is
unclear. Its place in our antipsychotic armamentarium and potential role in the treatment of
schizophrenia and major depressive disorder will be determined by additional clinical data
and experience.
Keywords: brexpiprazole, partial agonist, schizophrenia, major depression, treatment, phar-
macology, dopamine
Introduction
Twenty antipsychotic medications are currently approved for clinical use in the US
(Figure 1) with brexpiprazole (Rexulti) being one of the most recent agents to become
available. Despite the availability of a number of antipsychotic medications, many
patients either do not benefit from or develop significant side effects to currently avail-
Correspondence: Dawn Bruijnzeel able agents.1 In this article, we review the pharmacological profile of brexpiprazole,
Department of Psychiatry, University of
Florida College of Medicine, 1601 SW
summarize clinical trial data that pertain to its efficacy and safetytolerability, discuss
Archer Rd, 116A, Gainesville, its optimal clinical utilization, compare its clinical profile to that of other commonly
FL 32608, USA
Tel +1 352 376 1611 ext 4381
used antipsychotic agents, and critically evaluate its potential role in the treatment of
Email dheron@ufl.edu schizophrenia and major depressive disorder.
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Dovepress Brexpiprazole in the treatment of schizophrenia and major depression
6-week, Phase II or Phase III double-blind, randomized, it is recommended that 2 mg/day be the initial target dose
placebo-controlled multinational, multicenter clinical trials of brexpiprazole with gradual titration up to this dose and
in 1,769 patients (Table 2).1315 The average age of patients in 4 mg/day the maximum recommended dose.12 In these stud-
these studies was 40 years, with two-thirds being male, and ies, brexpiprazole was found to be effective across multiple
patients had a moderately severe illness burden at baseline dimensions of schizophrenia.16
on average. One of these three studies also included an active Brexpiprazole (up to 4 mg/day) has also been compared to
antipsychotic comparator (ie, aripiprazole).13 This particu- quetiapine extended release (up to 800 mg/day) and placebo
lar study was a failed study in that neither brexpiprazole in 465 patients with an acute exacerbation of schizophrenia
(0.25, 1, 2.5, and 5 mg/day) nor aripiprazole (15 mg/day) in a 6-week randomized clinical trial (NCT01810380), but
was found to be more effective than placebo.13 In the other results of this study are currently unavailable.
two studies, 24 mg of brexpiprazole was found to be more The long-term efficacy of brexpiprazole has been evalu-
effective than placebo. While preliminary data suggest ated in a 1-year double-blind, placebo-controlled mainte-
that the 4 mg/day dose may be more efficacious than the nance study of 202 schizophrenia patients.17 The stabilization
2 mg daily dose, this is not definitive.14,15 Consequently, and medication-withdrawal study design is currently the
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Bruijnzeel and Tandon Dovepress
standard for the evaluation of the effectiveness of treatments explained by the lower intrinsic activity of brexpiprazole
in preventing relapse in schizophrenia.18 Brexpiprazole was versus aripiprazole at the dopamine D2 receptor, rendering
found to be significantly more effective than placebo in brexpiprazole intermediate between aripiprazole and other
preventing relapse, with a significantly lower proportion of antipsychotic agents in this regard. Although a modestly
schizophrenia patients relapsing in the brexpiprazole versus greater weight gain was also observed, no significant differ-
placebo group (13.5% vs 38.5%, P,0.01) over the 1-year ences from placebo were observed with regard to changes in
period. serum glucose or lipids. Lastly, this agent appears to have little
Brexpiprazole at doses between 2 and 4 mg/day has thus effect on the corrected QT interval on electrocardiogram.
far been efficacious in the treatment of schizophrenia in sev- There are several class level warnings included in the
eral short-term studies. How its efficacy compares to that of product label for brexpiprazole. These include increased
other antipsychotic agents is unclear. Only limited data are mortality in elderly patients with dementia-related psychosis
currently available from head-to-head clinical trials, and final (black box), cerebrovascular adverse reactions, including
results of the completed study comparing brexpiprazole to stroke, neuroleptic malignant syndrome, tardive dyskinesia,
quetiapine are not yet available. The hope that brexpiprazole hyperglycemia, dyslipidemia, hyperprolactinemia, leukope-
might offer advantages in treating the cognitive symptoms nia, seizures, orthostatic hypotension, potential for cognitive
of schizophrenia, based on its potent serotonin 5HT1A partial impairment, disrupted body temperature regulation, and
agonism and 5HT2A and 5HT7 antagonism, awaits confirma- dysphagia.
tion in clinical trials current data are inadequate to support In the absence of direct head-to-head trials versus other
the claim.19,20 Similarly, the promise that brexpiprazole might antipsychotic agents, it is difficult to precisely place brexpip-
more effectively treat the mood symptoms of schizophrenia razole in the context of other available antipsychotic agents
(again based on its distinctive pharmacological profile) awaits in terms of its adverse effect profile. It appears intermediate
confirmation in clinical trials. between aripiprazole and other SGAs, with a relatively low
occurrence of metabolic side effects and modest rates of
Adverse events and safetytolerability akathisia. Results of the comparator trials should provide
Data on the safetytolerability of brexpiprazole in the greater clarity.
treatment of schizophrenia were also compiled from the
studies discussed earlier. Dose-dependent side effects of brex- Clinical trials in major depressive
piprazole include nausea, akathisia, headache, and modest disorder
weight gain. In contrast to aripiprazole that reduces prolactin Focus on efficacy
levels, modest dose-dependent increases in prolactin levels The short-term efficacy and safety of brexpiprazole in the
are observed with brexpiprazole. This difference is likely treatment of major depressive disorder have been assessed in
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Dovepress Brexpiprazole in the treatment of schizophrenia and major depression
Table 3 Acute placebo-controlled clinical trials of adjunctive brexpiprazole in the treatment of major depressive disorder inadequately
responsive to antidepressant alone
Study Study duration Daily dose of brexpiprazole Comparator Findings
number of patients antidepressant antidepressant
Thase et al21 6 weeks 0.15 mg Placebo 1.5 mg, but not other doses of
429 patients 0.5 mg brexpiprazole found to be more effective
1.5 mg than placebo in antidepressant response
Thase et al22 6 weeks 2 mg Placebo 2 mg of brexpiprazole found significantly
379 patients more effective than placebo as adjunctive
treatment to antidepressant
Thase et al23 6 weeks 1 mg Placebo 3 mg, but not 1 mg, brexpiprazole,
677 patients 3 mg significantly more effective than placebo in
improving depression
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Bruijnzeel and Tandon Dovepress
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benefits of brexpiprazole relative to other SGA agents need 164:127135.
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Disclosure randomized, withdrawal study of lurasidone for the maintenance of
efficacy in patients with schizophrenia. J Psychopharmacology. 2016;
The authors report no conflicts of interest in this work. 30(1):6977.
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