Journal of Psychosocial Nursing and Mental Health Services

Psychopharmacology 

Brexpiprazole: Another Multipurpose Antipsychotic Drug?

Robert H. Howland, MD

Abstract

Brexpiprazole (also known as OPC-34712 or Lu-AF41156) is a novel molecular compound chemically and structurally similar to aripiprazole. This drug is currently under review by the U.S. Food and Drug Administration as a monotherapy for schizophrenia and an adjunct to antidepressant medication for major depressive disorder. Additional clinical trials include studies of brexpiprazole in attention-deficit/hyperactivity disorder and posttraumatic stress disorder, and for agitation associated with dementia of the Alzheimer’s type. Brexpiprazole is an example that illustrates how pharmacological drug diversity may be translated to multipurpose uses. [Journal of Psychosocial Nursing and Mental Health Services, 53(4), 23–25.]

Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.

The author received a research grant from Otsuka Pharmaceutical.

Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: HowlandRH@upmc.edu.

Abstract

Brexpiprazole (also known as OPC-34712 or Lu-AF41156) is a novel molecular compound chemically and structurally similar to aripiprazole. This drug is currently under review by the U.S. Food and Drug Administration as a monotherapy for schizophrenia and an adjunct to antidepressant medication for major depressive disorder. Additional clinical trials include studies of brexpiprazole in attention-deficit/hyperactivity disorder and posttraumatic stress disorder, and for agitation associated with dementia of the Alzheimer’s type. Brexpiprazole is an example that illustrates how pharmacological drug diversity may be translated to multipurpose uses. [Journal of Psychosocial Nursing and Mental Health Services, 53(4), 23–25.]

Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.

The author received a research grant from Otsuka Pharmaceutical.

Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: HowlandRH@upmc.edu.

Exploring psychotherapeutic issues and agents in clinical practice

The group of drugs referred to as second-generation or atypical antipsychotic drugs includes clozapine (Clozaril®), risperidone (Risperdal®), olanzapine (Zyprexa®), quetiapine (Seroquel®), ziprasidone (Geodon®), aripiprazole (Abilify®), paliperidone (Invega®), asenapine (Saphris®), iloperidone (Fanapt®), and lurasidone (Latuda®). Despite being classified within a single group, these drugs are not all alike with respect to their pharmacologies, therapeutic uses, or side effect profiles. All are approved by the U.S. Food and Drug Administration (FDA) for the treatment of schizophrenia, but some have additional FDA-approved treatment indications for agitation (associated with schizophrenia, bipolar mania, or autism), bipolar disorder (mania and/or depression), and major depressive disorder (MDD; used together with antidepressant medications). In this month’s column, I will review the use of brexpiprazole, an atypical antipsychotic drug currently under review by the FDA for approval for the treatment of schizophrenia and MDD, but which has also been studied in several other therapeutic areas.

What Is Brexpiprazole?

Brexpiprazole (also known as OPC-34712 or Lu-AF41156) is a novel molecular compound chemically and structurally similar to aripiprazole (Maeda et al., 2014a,b). It has its most prominent binding effects as a partial agonist at dopamine D2, dopamine D3, and serotonin 5HT1A receptors, and as an antagonist at serotonin 5HT2A receptors. These receptor properties are thought to be related to the drug’s putative antipsychotic and antidepressant effects. Brexpiprazole has some effect as an antagonist at serotonin 5HT2B, serotonin 5HT7, and alpha-1 adrenergic receptors. The functional or clinical relevance of these binding effects is not well established, although higher doses of brexpiprazole may be associated with orthostatic hypotension (possibly related to alpha-1 receptor antagonism). The drug has no significant effects on histamine receptors (associated with sedation and weight gain), cholinergic receptors (associated with impaired cognitive function), or alpha-2 adrenergic receptors (associated with orthostatic hypotension).

Brexpiprazole is metabolized primarily by the cytochrome-P450 3A4 (CYP3A4) and 2D6 (CYP2D6) enzymes. Hence, the potential exists for drug–drug interactions involving brexpiprazole and drugs that inhibit or induce CYP3A4 or CYP2D6 activity. Brexpiprazole doses will likely need to be adjusted accordingly when other drugs affecting the activity of these enzymes are co-prescribed. Brexpiprazole itself does not influence the activity of cytochrome-P450 metabolic enzymes.

Brexpiprazole has a long half-life of more than 72 hours. One implication of this is that sporadically missed doses are not likely to result in discontinuation effects or loss of therapeutic effect. Brexpiprazole also does not have active drug metabolites. Most of the drug and its inactive metabolites are excreted through the gastrointestinal tract. Drug absorption, metabolism, and excretion are not significantly affected by age, gender, renal impairment, or liver impairment; therefore, dose adjustments are not likely to be necessary based on these factors.

Clinical Studies of Brexpiprazole for Schizophrenia

According to a press release from the brexpiprazole drug sponsor Otsuka Pharmaceutical (2014), the FDA has accepted for review the company’s submission of a New Drug Application (NDA) for a proposed indication for the treatment of schizophrenia. The NDA for schizophrenia was supported by efficacy and safety data from one double-blind, placebo-controlled, phase 2 study (NCT00905307 on ClinicalTrials.gov website) and two double-blind, placebo-controlled, phase 3 pivotal studies (NCT01393613; NCT01396421).

The VECTOR trial (NCT01396421), not yet published, was the first pivotal phase 3 study that demonstrated efficacy for brexpiprazole 2 and 4 mg per day (compared to placebo) in approximately 625 individuals with schizophrenia after 6 weeks of treatment. The BEACON trial (NCT01393613), recently published by Kane et al. (2015), was the second pivotal phase 3 study. In the BEACON trial, 674 individuals with schizophrenia were enrolled. Brexpiprazole 4 mg per day was significantly more effective than placebo. Doses of 1 and 2 mg per day were numerically superior to placebo on efficacy measures, but the differences were not statistically significant. Brexpiprazole was generally well-tolerated in the schizophrenia studies. The rates of discontinuation due to adverse events were lower for brexpiprazole (8.7%) than placebo (12.7%).

Clinical Studies of Brexpiprazole for Major Depressive Disorder

In addition to the NDA submission for schizophrenia, the FDA also accepted a concurrent NDA submission to review a proposed indication for adjunctive treatment of MDD (using brexpiprazole together with an antidepressant drug). The NDA for MDD was supported by efficacy and safety data from two phase 2 studies (NCT00797966; NCT01052077) and two pivotal phase 3 studies (NCT01360645; NCT01360632).

The design of the two phase 3 studies was similar, but each study investigated different brexpiprazole doses (Thase et al., 2014). Patients with MDD who had an inadequate response to one, two, or three different antidepressant drugs were enrolled and received prospective single-blind treatment with an antidepressant agent for 8 weeks. Individuals with an inadequate response after 8 weeks were then randomized to double-blind treatment with the antidepressant agent plus brexpiprazole or the antidepressant agent plus placebo for 6 weeks. The Pyxis trial (NCT01360645) was the first pivotal study demonstrating superior efficacy for brexpiprazole 2 mg per day (compared to placebo) in 379 individuals with MDD (Thase et al., 2014). The Polaris trial (NCT01360632) was the second pivotal study, which demonstrated that brexpiprazole 1 and 3 mg per day were significantly more effective than placebo in 677 individuals with MDD (Thase et al., 2014). Brexpiprazole was well-tolerated in these depression studies. Rates of discontinuation because of adverse events were low overall, but higher for brexpiprazole (2.9%) compared to placebo (0.8%).

Studies of Brexpiprazole for Other Clinical Uses

On the ClinicalTrials.gov website, 41 ongoing or completed clinical studies (phase 1, 2, or 3) are listed for brexpiprazole or OPC-34712. In addition to the seven studies described above as part of the NDA submissions, 27 other studies are listed for schizophrenia or MDD. Additional clinical trials include a completed phase 2 study in attention-deficit/hyperactivity disorder (NCT01074294), an ongoing phase 3 study in posttraumatic stress disorder (NCT01987960), and three ongoing phase 3 studies for agitation associated with dementia of the Alzheimer’s type (NCT01862640; NCT01922258; NCT02192554). The results from completed trials have not been published or posted on ClinicalTrials.gov. The breadth of studies investigating the use of brexpiprazole is impressive, a reflection of the novel pharmacological properties of this drug.

Clinical Use of Brexpiprazole

Because brexpiprazole has not yet been approved, the recommended dosing is unknown. Based on the NDA submission studies, the dosing for schizophrenia and MDD will probably differ. In the depression and schizophrenia studies, brexpiprazole was generally well-tolerated (Kane et al., 2015; Thase et al., 2014). Reported side effects include headache, dizziness, insomnia, somnolence, nausea, anxiety, fatigue, and mild weight gain. Weight gain is comparable to that seen with aripiprazole, which is not surprising given their pharmacological similarity, but is less than that observed for other atypical antipsychotic drugs. Brexpiprazole was associated with very low rates of extrapyramidal (Parkinsonian) symptoms or akathisia compared to placebo. Orthostatic hypotension is possible, but this may be dose-dependent (more likely to occur at high doses). Brexpiprazole does not appear to have other adverse cardiac effects.

Brexpiprazole has not been studied in children or adolescents. A placebo-controlled phase 1 study in older adults (ages 70 to 85) with MDD was completed (NCT01670279), but a phase 3 study (NCT01837797) in a similar population was terminated, apparently because of poor recruitment rather than for safety reasons.

Conclusion

Brexpiprazole is a novel antipsychotic drug compound currently under review by the FDA as a monotherapy for schizophrenia and an adjunct to antidepressant medication for MDD. Although brexpiprazole has been investigated for a variety of potential therapeutic uses in psychiatry, one notable exception is the lack of studies proposed or conducted for the treatment of bipolar depression or mania. How brexpiprazole compares to other antipsychotic drugs will be important to evaluate in head-to-head studies. A randomized study comparing brexpiprazole and aripiprazole in schizophrenia has been completed (NCT02054702). In addition, placebo-controlled studies comparing brexpiprazole and quetiapine have been completed (in schizophrenia; NCT01810380) or are ongoing (as adjunctive treatments for MDD; NCT01727726). Nurses should be familiar with the pharmacology and clinical profile of brexpiprazole, not only because this drug may be approved, but also because it illustrates how pharmacological drug diversity may be translated to multipurpose use.

References

  • Kane, J.M., Skuban, A., Ouyang, J., Hobart, M., Pfister, S., McQuade, R.D. & Eriksson, H. (2015). A multicenter randomized double-blind controlled phase 3 trial of fixed-dose brexpiprazole for the treatment of adults with acute schizophrenia. Schizophrenia Research. Advance online publication. doi:10.1016/j.schres.2015.01.038 [CrossRef]
  • Maeda, K., Lerdrup, L., Sugino, H., Akazawa, H., Amada, N., McQuade, R.D. & Kikuchi, T. (2014a). Brexpiprazole II: Antipsychotic-like and precognitive effects of a novel serotonin-dopamine activity modulator. Journal of Pharmacology and Experimental Therapeutics, 350, 605–614. doi:10.1124/jpet.114.213819 [CrossRef]
  • Maeda, K., Sugino, H., Akazawa, H., Amada, N., Shimada, J., Futamura, T. & Kikuchi, T. (2014b). Brexpiprazole I: In vitro and in vivo characterization of a novel serotonin-dopamine activity modulator. Journal of Pharmacology and Experimental Therapeutics, 350, 589–604. doi:10.1124/jpet.114.213793 [CrossRef]
  • Otsuka Pharmaceutical. (2014, September24). U.S. FDA accepts Otsuka and Lundbeck’s filing for review of brexpiprazole for the treatment of schizophrenia and as adjunctive therapy for the treatment of major depression [Press release]. Retrieved from http://ot-suka-us.com/newsroom/Pages/NewsArticle.aspx?ItemId=9
  • Thase, M., Youakim, J., Skuban, A., Hobart, M., Zhang, P., Legacy, S. & Carson, W. (2014). Efficacy and safety of adjunctive brexpiprazole (OPC-34712) in major depressive disorder: Results of two pivotal clinical studies. Neuro-psychopharmacology, 39, S357.

10.3928/02793695-20150323-01

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