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Brexpiprazole in patients with schizophrenia: overview of short- and long-term phase 3 controlled studies

  • Stephen R. Marder (a1), Mika Juhani Hakala (a2), Mette Krog Josiassen (a2), Peter Zhang (a3), John Ouyang (a3), Emmanuelle Weiller (a2), Catherine Weiss (a3) and Mary Hobart (a3)...



Review efficacy, safety, and tolerability of brexpiprazole in patients with schizophrenia in short- and long-term phase 3 studies.


Patients experiencing a current exacerbation of schizophrenia received brexpiprazole in two fixed-dose (2 and 4 mg), 6-week, placebo-controlled studies, one flexible-dose (2–4 mg), 6-week, placebo-control and active reference study, and one fixed-dose (1–4 mg), 52-week, placebo-controlled maintenance study.


The efficacy of brexpiprazole was demonstrated in the two short-term fixed-dose studies with statistically significant improvements from baseline in Positive and Negative Syndrome Scale (PANSS) total score compared with placebo. In the flexible-dose short-term study, treatment with brexpiprazole resulted in numerically greater improvements in PANSS total score than with placebo that approached statistical significance (p=0.056). A meta-analysis of these short-term studies showed a mean change in PANSS total score of −20.1, reflecting a clinically meaningful reduction in symptoms. In the maintenance study, brexpiprazole had a beneficial effect relative to placebo on time to exacerbation of psychotic symptoms/impending relapse (p<0.0001). For all studies, brexpiprazole demonstrated clinically meaningful treatment effects on the Personal and Social Performance scale. Brexpiprazole had a favourable safety profile, with a relatively low prevalence of activating and sedating side effects. Weight gain in the short-term studies was ~1 kg greater than placebo. No safety concerns were observed with brexpiprazole in laboratory values, electrocardiogram, or vital signs.


Overall, the results indicate brexpiprazole, used either short-term or as part of a long-term maintenance treatment programme, is an efficacious therapy option in adults with schizophrenia and has a favourable safety/tolerability profile.


Corresponding author

Dr. Stephen R Marder, Semel Institute for Neuroscience, University of California Los Angeles, 11301 Wilshire Blvd., MIRECC Building 210, Rm 130, Los Angeles, CA 90073, USA. Tel: 310 268 3647; Fax: 310 268 4056; E-mail:


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1. Singh, S, Loke, YK. Drug safety assessment in clinical trials: methodological challenges and opportunities. Trials 2012;13:138.
2. Friedman, LM, Furberg, CD, DeMets, DL. Fundamentals of clinical trials, 4th edn. New York: Springer, 2010.
3. Annemans, L, Kubin, M. Real-life data: a growing need.International Society for Pharmacoeconomics and Outcomes in Research (ISPOR) 2007;13:8–12.
4. The Association of the British Pharmaceutical Industry (ABPI). The vision for real world data – harnessing the opportunities in the UK, White paper, London: ABPI, 2011, pp. 1–23.
5. McGrath, J, Saha, S, Chant, D, Welham, J. Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epidemiol Rev 2008;30:6776.
6. Messias, EL, Chen, CY, Eaton, WW. Epidemiology of schizophrenia: review of findings and myths. Psychiatr Clin North Am 2007;30:323338.
7. Bobes, J, Garcia-Portilla, MP, Bascaran, MT, Saiz, PA, Bousono, M. Quality of life in schizophrenic patients. Dialogues Clin Neurosci 2007;9:215226.
8. Lieberman, JA, Perkins, D, Belger, A et al. The early stages of schizophrenia: speculations on pathogenesis, pathophysiology, and therapeutic approaches. Biol Psychiatry 2001;50:884897.
9. Volavka, J, Citrome, L. Oral antipsychotics for the treatment of schizophrenia: heterogeneity in efficacy and tolerability should drive decision-making. Expert Opin Pharmacother 2009;10:19171928.
10. Browne, S, Clarke, M, Gervin, M, Waddington, JL, Larkin, C, O’Callaghan, E. Determinants of quality of life at first presentation with schizophrenia. Br J Psychiatry 2000;176:173176.
11. Hayhurst, KP, Massie, JA, Dunn, G, Lewis, SW, Drake, RJ. Validity of subjective versus objective quality of life assessment in people with schizophrenia. BMC Psychiatry 2014;14:365.
12. Correll, CU. From receptor pharmacology to improved outcomes: individualising the selection, dosing, and switching of antipsychotics. Eur Psychiatry 2010;25(Suppl. 2):S12S21.
13. Olivares, JM, Sermon, J, Hemels, M, Schreiner, A. Definitions and drivers of relapse in patients with schizophrenia: a systematic literature review. Ann Gen Psychiatry 2013;12:32.
14. American Psychiatric Association (APA). Practice guidelines for the treatment of patients with schizophrenia, 2nd edn, vol. 2. Arlington, VA: APA, 2010, p. 1–184.
15. Tajima-Pozo, K, de Castro Oller, MJ, Lewczuk, A, Montanes-Rada, F. Understanding the direct and indirect costs of patients with schizophrenia. F1000Res 2015;4:182.
16. Young, SL, Taylor, M, Lawrie, SM. ‘First do no harm.’ A systematic review of the prevalence and management of antipsychotic adverse effects. J Psychopharmacol 2015;29:353362.
17. Barnes, TR, Schizophrenia Consensus Group of British Association for Psychopharmacology. Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2011;25:567620.
18. 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;350:605614.
19. 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;350:589604.
20. Fleischhacker, WW. Aripiprazole. Expert Opin Pharmacother 2005;6:20912101.
21. 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;164:127135.
22. 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;172:870880.
23. Fleischhacker, W, Hobart, M, Ouyang, J et al. Efficacy and safety of brexpiprazole (OPC-34712) as maintenance treatment in adults with schizophrenia: a randomised, double-blind, placebo-controlled study. Int J Neuropharmacol 2016, in press, doi: 10.1093/ijnp/pyw076.
24. Kay, SR, Fiszbein, A, Opler, LA. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull 1987;13:261276.
25. Guy, W. ECDEU assessment manual for psychopharmacology: US Department of Health, Education and Welfare Publication (ADM) 76-338. Rockville, MD: National Institute of Mental Health, 1976.
26. Morosini, PL, Magliano, L, Brambilla, L, Ugolini, S, Pioli, R. 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;101:323329.
27. Auquier, P, Simeoni, MC, Sapin, C et al. Development and validation of a patient-based health-related quality of life questionnaire in schizophrenia: the S-QoL. Schizophr Res 2003;63:137149.
28. American Psychiatric Association (APA). Diagnostic and statistical manual of mental disorders, Text Revision (DSM-IV-TR), 4th edn. Arlington, VA: APA, 2000.
29. Simpson, GM, Angus, JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl 1970;212:1119.
30. Barnes, TR. A rating scale for drug-induced akathisia. Br J Psychiatry 1989;154:672676.
31. Posner, K, Brown, GK, Stanley, B et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry 2011;168:12661277.
32. Leucht, S, Kane, JM, Etschel, E, Kissling, W, Hamann, J, Engel, RR. Linking the PANSS, BPRS, and CGI: clinical implications. Neuropsychopharmacology 2006;31:23182325.
33. Rabinowitz, J, Berardo, CG, Bugarski-Kirola, D, Marder, S. Association of prominent positive and prominent negative symptoms and functional health, well-being, healthcare-related quality of life and family burden: a CATIE analysis. Schizophr Res 2013;150:339342.
34. Nasrallah, H, Morosini, P, Gagnon, DD. Reliability, validity and ability to detect change of the Personal and Social Performance Scale in patients with stable schizophrenia. Psychiatry Res 2008;161:213224.
35. Amri, I, Miller, A, Toumi, M. Minimum clinically important difference in the global assessment functioning in patients with schizophrenia. Value Health 2014;17:A765A766.
36. Thwin, SS, Hermes, E, Lew, R et al. Assessment of the minimum clinically important difference in quality of life in schizophrenia measured by the Quality of Well-Being Scale and disease-specific measures. Psychiatry Res 2013;209:291296.
37. Kane, JM, Fleischhacker, WW, Hansen, L, Perlis, R, Pikalov, A III, Assuncao-Talbott, S. Akathisia: an updated review focusing on second-generation antipsychotics. J Clin Psychiatry 2009;70:627643.
38. Rummel-Kluge, C, Komossa, K, Schwarz, S et al. Second-generation antipsychotic drugs and extrapyramidal side effects: a systematic review and meta-analysis of head-to-head comparisons. Schizophr Bull 2012;38:167177.
39. Kane, JM, Zukin, S, Wang, Y et al. Efficacy and safety of cariprazine in acute exacerbation of schizophrenia: results from an international, phase III clinical trial. J Clin Psychopharmacol 2015;35:367373.
40. Calabrese, JR, Keck, PE Jr., Starace, A et al. Efficacy and safety of low- and high-dose cariprazine in acute and mixed mania associated with bipolar I disorder: a double-blind, placebo-controlled study. J Clin Psychiatry 2015;76:284292.
41. Marder, SR, McQuade, RD, Stock, E et al. Aripiprazole in the treatment of schizophrenia: safety and tolerability in short-term, placebo-controlled trials. Schizophr Res 2003;61:123136.
42. Durgam, S, Starace, A, Li, D et al. The efficacy and tolerability of cariprazine in acute mania associated with bipolar I disorder: a phase II trial. Bipolar Disord 2015;17:6375.
43. Citrome, L, Ota, A, Nagamizu, K, Perry, P, Weiller, E, Baker, RA. The effect of brexpiprazole (OPC-34712) and aripiprazole in adult patients with acute schizophrenia: results from a randomized, exploratory study. Int Clin Psychopharmacol 2016;31:192201.
44. Laoutidis, ZG, Luckhaus, C. 5-HT2A receptor antagonists for the treatment of neuroleptic-induced akathisia: a systematic review and meta-analysis. Int J Neuropsychopharmacol 2014;17:823832.
45. Adham, N, Gyertyan, I, Kiss, B. Cariprazine demonstrates greater potency than aripiprazole in animal models of psychosis, cognitive impairment, and negative symptoms. European Neuropsychopharmacology 2014;24(Suppl. 2):S109S804.
46. Leucht, S, Cipriani, A, Spineli, L et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013;382:951962.
47. De Hert, M, Detraux, J, van Winkel, R, Yu, W, Correll, CU. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol 2011;8:114126.
48. De Hert, M, Yu, W, Detraux, J, Sweers, K, van Winkel, R, Correll, CU. Body weight and metabolic adverse effects of asenapine, iloperidone, lurasidone and paliperidone in the treatment of schizophrenia and bipolar disorder: a systematic review and exploratory meta-analysis. CNS Drugs 2012;26:733759.
49. Meltzer, HY, Cucchiaro, J, Silva, R et al. Lurasidone in the treatment of schizophrenia: a randomized, double-blind, placebo- and olanzapine-controlled study. Am J Psychiatry 2011;168:957967.
50. Stahl, SM, Cucchiaro, J, Simonelli, D, Hsu, J, Pikalov, A, Loebel, A. Effectiveness of lurasidone for patients with schizophrenia following 6 weeks of acute treatment with lurasidone, olanzapine, or placebo: a 6-month, open-label, extension study. J Clin Psychiatry 2013;74:507515.
51. Conley, RR, Mahmoud, R. A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder. Am J Psychiatry 2001;158:765774.
52. Rummel-Kluge, C, Komossa, K, Schwarz, S et al. Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic review and meta-analysis. Schizophr Res 2010;123:225233.


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