Effects of Brexpiprazole Across Symptom Domains in Patients With Schizophrenia: Post Hoc Analysis of Short- and Long-Term Studies
Stephen R Marder, Stine R Meehan, Catherine Weiss, Dalei Chen, Mary Hobart, Nanco Hefting, Stephen R Marder, Stine R Meehan, Catherine Weiss, Dalei Chen, Mary Hobart, Nanco Hefting
Abstract
The successful treatment of schizophrenia entails improvement across a spectrum of symptoms. The aim of this post hoc analysis was to characterize the short- and long-term effects of brexpiprazole on Positive and Negative Syndrome Scale (PANSS) 'Marder factors.' Data were included from three 6-week, randomized, double-blind, placebo-controlled studies; a 52-week, randomized, double-blind, placebo-controlled maintenance treatment study; and two 52-week open-label extension (OLEx) studies-all in schizophrenia (DSM-IV-TR criteria). Patients receiving oral brexpiprazole were dosed at 2-4 mg/day (short-term studies) or 1-4 mg/day (long-term studies). At Week 6, least squares mean differences (LSMDs, with 95% confidence limits [CLs]) for brexpiprazole (n = 868) vs placebo (n = 517) were: Positive symptoms: -1.55 (-2.30, -0.80), P < .0001, Cohen's d effect size (ES) = 0.27; Negative symptoms: -1.12 (-1.63, -0.61), P < .0001, ES = 0.29; Disorganized thought: -1.26 (-1.78, -0.74), P < .0001, ES = 0.32; Uncontrolled hostility/excitement: -0.76 (-1.15, -0.37), P = .0002, ES = 0.26; Anxiety/ depression: -0.56 (-0.91, -0.22), P = .0014, ES = 0.22. At last visit of the maintenance study, LSMDs (95% CLs) for brexpiprazole (n = 96) vs placebo (n = 104) were: Positive symptoms: -3.44 (-4.99, -1.89), P < .0001, ES = 0.62; Negative symptoms: -1.23 (-2.52, 0.07), P = .063, ES = 0.27; Disorganized thought: -1.69 (-2.81, -0.56), P = .0035, ES = 0.42; Uncontrolled hostility/excitement: -1.26 (-2.12, -0.39), P = .0046, ES = 0.41; Anxiety/depression: -0.72 (-1.47, 0.03), P = .061, ES = 0.27. In the OLEx studies, improvements were maintained over 58 (6 + 52) weeks of brexpiprazole treatment. In conclusion, these data suggest that brexpiprazole treats the continuum of schizophrenia symptoms, in the short- and long-term. Trial Registration: Data used in this post hoc analysis came from ClinicalTrials.gov identifiers: NCT01396421, NCT01393613, NCT01810380, NCT01668797, NCT01397786, NCT01810783.
Keywords: Marder factors; Positive and Negative Syndrome Scale; antipsychotic; clinical trial.
© The Author(s) 2021. Published by Oxford University Press on behalf of the University of Maryland's school of medicine, Maryland Psychiatric Research Center.
Figures
References
- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013.
- Owen MJ, Sawa A, Mortensen PB. Schizophrenia. Lancet. 2016;388(10039):86–97.
- 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(2-3):339–342.
- Harvey PD, Strassnig M. Predicting the severity of everyday functional disability in people with schizophrenia: cognitive deficits, functional capacity, symptoms, and health status. World Psychiatry. 2012;11(2):73–79.
- Conley RR, Ascher-Svanum H, Zhu B, Faries DE, Kinon BJ. The burden of depressive symptoms in the long-term treatment of patients with schizophrenia. Schizophr Res. 2007;90(1-3):186–197.
- Huhn M, Nikolakopoulou A, Schneider-Thoma J, et al. . Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet. 2019;394(10202):939–951.
- Kay SR, Fiszbein A, Opler LA. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261–276.
- Marder SR, Davis JM, Chouinard G. The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials. J Clin Psychiatry. 1997;58(12):538–546.
- Lindenmayer JP, Bernstein-Hyman R, Grochowski S. A new five factor model of schizophrenia. Psychiatr Q. 1994;65(4):299–322.
- Lindenmayer JP, Czobor P, Volavka J, et al. . Effects of atypical antipsychotics on the syndromal profile in treatment-resistant schizophrenia. J Clin Psychiatry. 2004;65(4):551–556.
- Wallwork RS, Fortgang R, Hashimoto R, Weinberger DR, Dickinson D. Searching for a consensus five-factor model of the Positive and Negative Syndrome Scale for schizophrenia. Schizophr Res. 2012;137(1-3):246–250.
- 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.
- 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.
- 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.
- Marder SR, Hakala MJ, Josiassen MK, et al. . Brexpiprazole in patients with schizophrenia: overview of short- and long-term phase 3 controlled studies. Acta Neuropsychiatr. 2017;29(5):278–290.
- Marder SR, Eriksson H, Zhao Y, Hobart M. Post hoc analysis of a randomised, placebo-controlled, active-reference 6-week study of brexpiprazole in acute schizophrenia. Acta Neuropsychiatr. 2020;32(3):153–158.
- Fleischhacker WW, Hobart M, Ouyang J, et al. . Efficacy and safety of brexpiprazole (OPC-34712) as maintenance treatment in adults with schizophrenia: a randomized, double-blind, placebo-controlled study. Int J Neuropsychopharmacol. 2017;20(1):11–21.
- Forbes A, Hobart M, Ouyang J, Shi L, Pfister S, Hakala M. A long-term, open-label study to evaluate the safety and tolerability of brexpiprazole as maintenance treatment in adults with schizophrenia. Int J Neuropsychopharmacol. 2018;21(5):433–441.
- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, Text Revision. Washington, DC: American Psychiatric Association; 2000.
- Lançon C, Auquier P, Nayt G, Reine G. Stability of the five-factor structure of the Positive and Negative Syndrome Scale (PANSS). Schizophr Res. 2000;42(3):231–239.
- Cohen J.Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Hillsdale, NJ: Lawrence Erlbaum Associates; 1988.
- Kasper S, Lerman MN, McQuade RD, et al. . Efficacy and safety of aripiprazole vs. haloperidol for long-term maintenance treatment following acute relapse of schizophrenia. Int J Neuropsychopharmacol. 2003;6(4):325–337.
- Cutler AJ, Durgam S, Wang Y, et al. . Evaluation of the long-term safety and tolerability of cariprazine in patients with schizophrenia: results from a 1-year open-label study. CNS Spectr. 2018;23(1):39–50.
- Janicak PG, Glick ID, Marder SR, et al. . The acute efficacy of aripiprazole across the symptom spectrum of schizophrenia: a pooled post hoc analysis from 5 short-term studies. J Clin Psychiatry. 2009;70(1):25–35.
- Marder S, Fleischhacker WW, Earley W, et al. . Efficacy of cariprazine across symptom domains in patients with acute exacerbation of schizophrenia: Pooled analyses from 3 Phase II/III studies. Eur Neuropsychopharmacol. 2019;29(1):127–136.
- Citrome L, Meng X, Hochfeld M. Efficacy of iloperidone in schizophrenia: a PANSS five-factor analysis. Schizophr Res. 2011;131(1-3):75–81.
- Loebel A, Cucchiaro J, Silva R, et al. . Efficacy of lurasidone across five symptom dimensions of schizophrenia: pooled analysis of short-term, placebo-controlled studies. Eur Psychiatry. 2015;30(1):26–31.
- Davis JM, Chen N. The effects of olanzapine on the 5 dimensions of schizophrenia derived by factor analysis: combined results of the North American and international trials. J Clin Psychiatry. 2001;62(10):757–771.
- Fleischhacker WW, Galderisi S, Laszlovszky I, et al. . The efficacy of cariprazine in negative symptoms of schizophrenia: Post hoc analyses of PANSS individual items and PANSS-derived factors. Eur Psychiatry. 2019;58:1–9.
- Németh G, Laszlovszky I, Czobor P, et al. . Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial. Lancet. 2017;389(10074):1103–1113.
- Kotler M, Dilbaz N, Rosa F, et al. . A flexible-dose study of paliperidone ER in patients with nonacute schizophrenia previously treated unsuccessfully with oral olanzapine. J Psychiatr Pract. 2016;22(1):9–21.
- Liu-Seifert H, Osuntokun OO, Feldman PD. Factors associated with adherence to treatment with olanzapine and other atypical antipsychotic medications in patients with schizophrenia. Compr Psychiatry. 2012;53(1):107–115.
- Potkin SG, Phiri P, Szegedi A, Zhao J, Alphs L, Cazorla P. Long-term effects of asenapine or olanzapine in patients with persistent negative symptoms of schizophrenia: a pooled analysis. Schizophr Res. 2013;150(2-3):442–449.
- DiBonaventura M, Gabriel S, Dupclay L, Gupta S, Kim E. A patient perspective of the impact of medication side effects on adherence: results of a cross-sectional nationwide survey of patients with schizophrenia. BMC Psychiatry. 2012;12:20.
- Tandon R, Lenderking WR, Weiss C, et al. . The impact on functioning of second-generation antipsychotic medication side effects for patients with schizophrenia: a worldwide, cross-sectional, web-based survey. Ann Gen Psychiatry. 2020;19:42.
- Kane JM, Skuban A, Hobart M, et al. . Overview of short- and long-term tolerability and safety of brexpiprazole in patients with schizophrenia. Schizophr Res. 2016;174(1-3):93–98.
Source: PubMed