Brexpiprazole for treatment-resistant major depressive disorder

ABSTRACT

Introduction:Treatment-resistant depression (TRD), seldom interchangeably referred to as ‘depression inadequately responding to the standard antidepressant drug,’ carries a significant burden. The atypical antipsychotics represent a popular augmentation strategy for antidepressant-resistant depression, although their efficacy/safety profiles vary across different agents and presentations of depression.

Areas covered: This review appraises the evidence supporting the use of brexpiprazole augmentation for major depressive disorder (MDD) adults showing an inadequate response to standard antidepressants, covering the related regulatory affairs, and essential pharmacology.

Expert opinion: Brexpiprazole is a ‘third-generation’ antipsychotic featuring dopaminergic D₂ and serotonergic 5-HT_1A partial agonism approved by the U.S. Food and Drug Administration for the treatment of MDD, besides schizophrenia in adults. The clinical trials leading to the extended approval of brexpiprazole rely on the definition of ‘inadequate response’ to antidepressants, which seems to poorly represent the most severe cases of TRD seen in clinical practice. TRD definitions appraised in the literature are likewise inconsistent and questionable from a clinical-standpoint. Compared to aripiprazole, brexpiprazole has lower D₂ intrinsic activity, although the latter features a more potent serotonergic 5-HT_2A antagonism. The actual propensity of brexpiprazole to induce akathisia and tardive dyskinesia warrants assessment by ad-hoc designed long-term, controlled trials.

KEYWORDS:

• Brexpiprazole
• treatment-resistant depression
• atypical antipsychotic
• augmentation

Article highlights

• Unsatisfactory response to standard antidepressants is a relatively common, burdensome, scenario of major depressive disorder.

• The atypical antipsychotics represent a popular augmentation strategy of standard antidepressants in case of inadequate response or treatment-resistance in depression.

• Brexpiprazole is a dopamine D2 and serotonin 5-HT1A partial agonist antipsychotic approved by the U.S. Food and Drug Administration as a standard-antidepressant augmentation for major depression showing an inadequate response to antidepressants, besides its approval for the treatment of schizophrenia, in adults.

• The pivotal trials leading to the approval of brexpiprazole as an augmentation treatment of antidepressants for major depression rely on the definition of “inadequate response,” as a failure to respond to 1-3 trials with antidepressants.

• The operational definition of “inadequate response” is nonetheless elusive, and the most severe cases of “treatment-resistant depression” may have gone missing, thus undermining the overall generalizability to the clinical practice.

• Additional controlled trials and real-world clinical experience is warranted to assess the long-term efficacy and tolerability of the drug, especially for most severe cases of depression.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One referee declares that they have both authored a paper previously on brexpiprazole and in the past/are currently conducting trials on it. They also declare to having: conducted research, consulted on and have spoken on several other atypical antipsychotic medications as well as other drugs used for the treatment of treatment-resistant depression. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

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Funding

This manuscript has not been funded.