Out Of The Pipeline

Brexpiprazole for schizophrenia and as adjunct for major depressive disorder

Current Psychiatry. 2015 October;14(10):73-78

References

1. Rexulti [package insert]. Rockville, MD: Otsuka; 2015.
2. Correll CU, Skuban A, Ouyang J, et al. Efficacy and safety of brexpiprazole for the treatment of acute schizophrenia: a 6-week randomized, double-blind, placebo-controlled trial. Am J Psychiatry. 2015;172(9):870-880.
3. Kane JM, Skuban A, Ouyang J, et al. A multicenter, randomized, double-blind, controlled phase 3 trial of fixed-dose brexpiprazole for the treatment of adults with acute schizophrenia. Schizophr Res. 2015;164(1-3):127-135.
4. Thase ME, Youakim JM, Skuban A, et al. Adjunctive brexpiprazole 1 and 3 mg for patients with major depressive disorder following inadequate response to antidepressants: a phase 3, randomized, double-blind study [published online August 4, 2015]. J Clin Psychiatry. doi: 10.4088/ JCP.14m09689.
5. Thase ME, Youakim JM, Skuban A, et al. Efficacy and safety of adjunctive brexpiprazole 2 mg in major depressive disorder: a phase 3, randomized, placebo-controlled study in patients with inadequate response to antidepressants [published online August 4, 2015]. J Clin Psychiatry. doi: 10.4088/JCP.14m09688.
6. Citrome L. Brexpiprazole for schizophrenia and as adjunct for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antipsychotic—what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract. 2015;69(9):978-997.
7. Maeda K, Sugino H, Akazawa H, et al. Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator. J Pharmacol Exp Ther. 2014;350(3):589-604.
8. Volavka J, Citrome L. Oral antipsychotics for the treatment of schizophrenia: heterogeneity in efficacy and tolerability should drive decision-making. Expert Opin Pharmacother. 2009;10(12):1917-1928.
9. Citrome L. Adjunctive aripiprazole, olanzapine, or quetiapine for major depressive disorder: an analysis of number needed to treat, number needed to harm, and likelihood to be helped or harmed. Postgrad Med. 2010;122(4):39-48.
10. Hobart M, Ouyang J, Forbes A, et al. Efficacy and safety of brexpiprazole (OPC-34712) as maintenance treatment in adults with schizophrenia: a randomized, double-blind, placebo-controlled study. Poster presented at: the American Society of Clinical Psychopharmacology Annual Meeting; June 22 to 25, 2015; Miami, FL.
11. Citrome L, Ota A, Nagamizu K, Perry P, et al. The effect of brexpiprazole (OPC‐34712) versus aripiprazole in adult patients with acute schizophrenia: an exploratory study. Poster presented at: the Society of Biological Psychiatry Annual Scientific Meeting and Convention; May 15, 2015; Toronto, Ontario, Canada.

Participants who responded adequately to the antidepressant in the prospective single-blind phase were not randomized, but instead continued on antidepressant treatment plus single-blind placebo for 6 weeks.

The phase-III studies showed positive results for brexpiprazole, 2 mg/d and 3 mg/d, with change in MADRS from baseline to endpoint superior to that observed with placebo.^4,5

When examining treatment response, defined as a reduction of ≥50% in MADRS total score from baseline, NNT vs placebo for response were 12 at all dosages tested, however, NNT vs placebo for remission (defined as MADRS total score ≤10 and ≥50% improvement from baseline) ranged from 17 to 31 and were not statistically significant.⁶ When the results for brexpiprazole, 1 mg/d, 2 mg/d, and 3 mg/d, from the 2 phase-III trials are pooled together, 23.2% of the patients receiving brexpiprazole were responders, vs 14.5% for placebo, yielding a NNT of 12 (95% CI, 8-26); 14.4% of the brexpiprazole-treated patients met remission criteria, vs 9.6% for placebo, resulting in a NNT of 21 (95% CI, 12-138).⁶

Tolerability
Overall tolerability can be evaluated by examining the percentage of patients who discontinued the clinical trials because of an adverse event (AE). In the acute schizophrenia double-blind trials for the recommended dosage range of 2 to 4 mg, the discontinuation rates were lower overall for patients receiving brexpiprazole compared with placebo.^2,3 In the acute MDD trials, 32.6% of brexpiprazole-treated patients and 10.7% of placebo-treated patients discontinued because of AEs,^4,5 yielding a number needed to harm (NNH) of 53 (95% CI, 30-235).⁶

The most commonly encountered AEs for MDD (incidence ≥5% and at least twice the rate for placebo) were akathisia (8.6% vs 1.7% for brexpiprazole vs placebo, and dose-related) and weight gain (6.7% vs 1.9%),¹ with NNH values of 15 (95% CI, 11-23), and 22 (95% CI, 15-42), respectively.⁶ The most commonly encountered AE for schizophrenia (incidence ≥4% and at least twice the rate for placebo) was weight gain (4% vs 2%),¹ with a NNH of 50 (95% CI, 26-1773).⁶

Of note, rates of akathisia in the schizophrenia trials were 5.5% for brexpiprazole and 4.6% for placebo,¹ yielding a non-statistically significant NNH of 112.6 In a 6-week exploratory study,¹¹ the incidence of EPS-related AEs including akathisia was lower for brexpiprazole-treated patients (14.1%) compared with those receiving aripiprazole (30.3%), for a NNT advantage for brexpiprazole of 7 (not statistically significant).

Short-term weight gain appears modest; however, outliers with an increase of ≥7% of body weight were evident in open-label long-term safety studies.^1,6 Effects on glucose and lipids were small. Minimal effects on prolactin were observed, and no clinically relevant effects on the QT interval were evident.

Contraindications
The only absolute contraindication for brexpiprazole is known hypersensitivity to brexpiprazole or any of its components. Reactions have included rash, facial swelling, urticaria, and anaphylaxis.¹

As with all antipsychotics and antipsychotics with an indication for a depressive disorder:
• there is a bolded boxed warning in the product label regarding increased mortality in geriatric patients with dementia-related psychosis. Brexpiprazole is not approved for treating patients with dementia-related psychosis
• there is a bolded boxed warning in the product label about suicidal thoughts and behaviors in patients age ≤24. The safety and efficacy of brexpiprazole have not been established in pediatric patients.

Dosing
Schizophrenia. The recommended starting dosage for brexpiprazole for schizophrenia is 1 mg/d on Days 1 to 4. Brexpiprazole can be titrated to 2 mg/d on Day 5 through Day 7, then to 4 mg/d on Day 8 based on the patient’s response and ability to tolerate the medication. The recommended target dosage is 2 to 4 mg/d with a maximum recommended daily dosage of 4 mg.

Major depressive disorder. The recommended starting dosage for brexpiprazole as adjunctive treatment for MDD is 0.5 mg or 1 mg/d. Brexpiprazole can be titrated to 1 mg/d, then up to the target dosage of 2 mg/d, with dosage increases occurring at weekly intervals based on the patient’s clinical response and ability to tolerate the agent, with a maximum recommended dosage of 3 mg/d.

Other considerations. For patients with moderate to severe hepatic impairment, or moderate, severe, or end-stage renal impairment, the maximum recommended dosage is 3 mg/d for patients with schizophrenia, and 2 mg/d for patients with MDD.

In general, dosage adjustments are recommended in patients who are known CYP2D6 poor metabolizers and in those taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers¹:
• for strong CYP2D6 or CYP3A4 inhibitors, administer one-half the usual dosage
• for strong/moderate CYP2D6 with strong/moderate CYP3A4 inhibitors, administer a one-quarter of the usual dosage
• for known CYP2D6 poor metabolizers taking strong/moderate CYP3A4 inhibitors, also administer a one-quarter of the usual dosage
• for strong CYP3A4 inducers, double the usual dosage and further adjust based on clinical response.

Brexpiprazole for schizophrenia and as adjunct for major depressive disorder

References

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