by Jonathan R. Scarff, MD
Dr. Scarff is with Veterans Affairs Outpatient Clinic, Spartanburg, South Carolina.
Innov Clin Neurosci. 2016;13(7–8):26–29
Funding: No funding was received for the preparation of this manuscript.
Financial disclosures: The author has no financial disclosures relevant to the content of this article.
Key words: Schizophrenia, brexpiprazole, antipsychotic
Abstract: Schizophrenia occurs in approximately 0.3 to 0.7 percent of the world’s population and is associated with significant morbidity and mortality. Although atypical antipsychotics reduce positive and negative symptoms, they are associated with varying degrees of metabolic adverse effects. This necessitates continued development of efficacious yet metabolically favorable treatments. This article reviews brexpiprazole, a medication recently approved to treat patients with schizophrenia. Brexpiprazole was well-tolerated, and adverse reactions were statistically insignificant. They included nausea; insomnia; headache; agitation; akathisia; and weight gain or changes in lipid, creatine phosphokinase, glucose, or prolactin levels. Brexpiprazole is taken once daily without regard to food, and the dose should be adjusted in patients who receive moderate or strong CYP450 inhibitors or inducers and in patients with hepatic or renal disease.
Schizophrenia occurs in approximately 0.3 to 0.7 percent of individuals worldwide and is characterized by at least two of the following symptoms: delusions, hallucinations, disorganized speech, disorganized or catatonic behavior, or negative symptoms.[1,2] It is associated with decreased functioning in work, interpersonal relationships, and/or self-care. Second-generation or atypical antipsychotics reduce positive and negative symptoms and are recommended first-line treatments. However, they are associated with adverse effects such as weight gain, dyslipidemia, and hyperglycemia, which may worsen comorbid cardiovascular conditions.[3,4] This necessitates continued development of effective, tolerable, and metabolically favorable antipsychotics. In July 2015, brexpiprazole was approved to treat schizophrenia and major depressive disorder (as adjunct with antidepressant therapy). However, a discussion of brexpiprazole for both conditions is beyond the scope of this article. This review will highlight efficacy, tolerability, dosing, and precautions for brexpiprazole in patients with schizophrenia.
Mechanisms of Action
Similar to aripiprazole, brexpiprazole is a partial agonist at 5-HT1A, D2, and D3 receptors and an antagonist at 5-HT2A, 5-HT2B, 5-HT7, a1A, a1B, a1D, and a2C receptors.[5,6] Compared to antipsychotics that exert antagonism of dopamine receptors, partial agonism suggests lower risk of akathisia, tardive dyskinesia, extrapyramidal symptoms, and abnormal prolactin levels. Lack of significant histamine receptor antagonism decreases risk for sedation and weight gain. Although brexpiprazole shares a similar mechanism of action with aripiprazole, it exerts greater partial agonism of 5HT1A receptors, greater antagonism of 5HT2A receptors, and less partial agonism of D2 receptors. Due to greater modulation of 5HT1A and 5-HT2A receptors, rats receiving brexpiprazole exhibited less cognitive impairment compared to those receiving aripiprazole. This modulation led to improvements in social recognition in mice, with no such improvement noted in mice receiving olanzapine or risperidone.
Given their similar mechanism of action, brexpiprazole was compared to aripiprazole in two studies; two additional trials assessed efficacy of varying doses for reducing acute symptoms, and one maintenance study evaluated efficacy for preventing exacerbation or relapse.[13–17] Details for each study are provided in Table 1. The primary endpoint in all studies was the total change in the Positive and Negative Syndrome Scale (PANSS). The main secondary endpoint was change in the Clinical Global Impressions—Severity scale (CGI-S) and/or the Personal and Social Performance Scale.[11,12]
Both aripiprazole comparison studies used flexible doses, and the first study noted that decreases in PANSS scores were significant for placebo, brexpiprazole, and aripiprazole groups. In the second study, both brexpiprazole and aripiprazole resulted in significant reductions in PANSS scores. Results are not available for a trial comparing brexpiprazole to extended-release quetiapine.
In the first varying-dose study, the 4mg dose of brexpiprazole was statistically superior to placebo on both primary and secondary endpoints. The second study found that 2mg and 4mg doses significantly reduced PANSS and CGI-S scores, but only the 2mg group experienced a significant change on the Personal and Social Performance Scale. In the maintenance study, patients stabilized on brexpiprazole were randomized to placebo or continued brexpiprazole treatment. Patients in the treatment group experienced fewer relapses compared to placebo.
Brexpiprazole was well-tolerated in acute and maintenance studies. Less than five percent of patients reported adverse effects, which were mild or moderate and included dyspepsia, insomnia, headache, and agitation.[15,16,18] The discontinuation rate was higher in the placebo group and was attributed to adverse effects, withdrawal of consent, or lack of efficacy with emergent symptoms of schizophrenia. Brexpiprazole was associated with statistically insignificant increases in weight and levels of glucose, triglyceride, creatine phosphokinase, and changes (increases or decreases) in prolactin.[15,16 ]Kane et al reported akathisia more frequently in the placebo group, but Correll et al noted akathisia more commonly in patients receiving 2mg and 4mg doses of brexpiprazole. Occurring within the first three weeks of treatment, akathisia tended to be mild and did not lead to discontinuation. In the second comparison study with aripiprazole, patients receiving brexpiprazole reported fewer extrapyramidal symptoms and akathisia.
Brexpiprazole is available in 0.25mg, 0.5mg, 1mg, 2mg, 3mg, and 4mg tablets, given once daily without regard to food. The recommended daily dose is 2 to 4mg, starting with 1mg for four days, then 2mg for three days, then 4mg if indicated. For patients who are CYP2D6 poor metabolizers or who are receiving a moderate or strong CYP3A4 and/or CYP2D6 inhibitor, the dose should be reduced by 50 to 75 percent of the usual dose. The dose should be slowly doubled over 1 to 2 weeks in patients receiving a strong CYP3A4 inducer. The maximum dosage is 3mg/day in patients with moderate or severe hepatic or renal impairment or with end-stage renal disease.
Following oral administration, brexpiprazole reaches peak concentrations within four hours and steady-state within 10 to 12 days, with a half-life of 91 hours. It has a high volume of distribution and is highly protein bound in plasma.6 It is largely metabolized by CYP3A4 and CYP2D6 isozymes, with the metabolite being primarily excreted in feces.
Brexpiprazole is contraindicated in patients with known hypersensitivity to brexpiprazole or its formulation components. As with other atypical antipsychotics, brexpiprazole carries the risk of seizure, tardive dyskinesia, neuroleptic malignant syndrome, orthostatic hypotension, white blood cell count and metabolic abnormalities, cerebrovascular adverse reactions in elderly patients, and a “black box” warning for increased mortality in elderly patients with dementia-related psychosis. Brexpiprazole is not yet assigned a Pregnancy Category, but neonates exposed to brexpiprazole in the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms. While no data are available regarding safety in breastfeeding mothers, the manufacturer recommends prescribers and their patients consider the benefits of breastfeeding and the mother’s need for brexpiprazole and the potential adverse effects on the infant from brexpiprazole or the underlying mental illness.
Schizophrenia is a debilitating condition with significant morbidity and mortality. Many atypical antipsychotics improve functioning, but they carry risks for adverse effects. Brexpiprazole reduced symptoms of acute schizophrenia and prevented relapse with minimal adverse effects. It is an additional option for clinicians who treat patients with schizophrenia, and ongoing trials are assessing its efficacy as an adjunctive treatment for patients with posttraumatic stress disorder or behavioral disturbances associated with dementia.
The views expressed in this article are those of the author and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government.
The author is grateful to Kathy Thomas for her assistance in locating references.
1. McGrath J, Saha S, Chant D, Welham J. Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epidemiol Rev. 2008;30:67–76.
2. American Psychiatric Association. Schizophrenia spectrum and other psychotic disorders. In: Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Press Inc.; 2013:87–122.
3. Hennekens CH. Increasing global burden of cardiovascular disease in general populations and patients with schizophrenia. J Clin Psychiatry. 2007;68 Suppl 4:4–7.
4. Lally J, MacCabe JH. Antipsychotic medication in schizophrenia: a review. Br Med Bull. 2015;114(1):169–179.
5. 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.
6. Rexulti (brexpiprazole) [package insert]. Tokyo, Japan: Otsuka Pharmaceuticals Inc.; 2015.
7. Oosterhof CA, El Mansari M, Blier P. Acute effects of brexpiprazole on serotonin, dopamine, and norepinephrine systems: an in-vivo electrophysiologic characterization. J Pharmacol Exp Ther. 2014;351(3):585–595.
8. Maeda K, Lerdrup L, Sugino H, et al. Brexpiprazole II: antipsychotic-like and procognitive effects of a novel serotonin-dopamine activity modulator. J Pharmacol Exp Ther. 2014;350(3):605–614.
9. Yoshimi N, Futamura T, Hashimoto K. Improvement of dizocilpine-induced social recognition deficits in mice by brexpiprazole, a novel serotonin-dopamine activity modulator. Eur Neuropsychopharmacol. 2015;25(3):356–364.
10. Kay SR, Opler LA, Fiszbein A. Positive and Negative Syndrome Scale (PANSS) rating criteria. Multi-Health Systems, North Tonawanda, NY. 1999.
11. Guy W. ECDEU Assessment Manual for Psychopharmacology (revised). Rockville, MD: National Institute of Mental Health, US Dept of Health, Education, and Welfare; pp 193–198. Publication (ADM) 76-338.
12. Morosini PL, Magliano L, Brambilla L, et al. Development, reliability and acceptability of a new version of the DSM-IV Social and Occupational Functioning Assessment Scale (SOFAS) to assess routine social functioning. Acta Psychiatr Scand. 2000;101(4):323–329.
13. McQuade R, Hobart M, Forbes RA, et al. A Phase II trial assessing the efficacy and safety of OPC-34712 in the acute treatment of adult schizophrenia (Study 331-07-203). Poster presented at the 24th Annual US Psychiatric and Mental Health Congress; November 7-10, 2011; Las Vegas, NV.
14. 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. Biol Psychiatry. 2015;77(9 Supp 1):203S.
15. 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.
16. 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 1;172(9):870–880.
17. Hobart M, Ouyang J, Forbes A, et al. Efficacy and safety of brexpiprazole (OPC-34712) as maintenance treatments in adults with schizophrenia: a randomized, double-blind, placebo-controlled study. Poster presented at the American Society of Clinical Psychopharmacology Annual Meeting; June 22–25, 2015; Miami, FL.
18. 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.