Brexpiprazole for the Treatment of Co-occurring Schizophrenia and Substance Use Disorder: A Multisite, Randomized, Controlled Trial

Xiaoduo Fan, MD, MPH; Oliver Freudenreich, MD; L. Fredrik Jarskog, MD; Joseph McEvoy, MD; Amy Harrington, MD

J Clin Psychiatry 2025;86(4):25m15786.

Abstract

Objective: This proof-of-concept study examined the effects of brexpiprazole treatment on substance use, psychiatric symptoms, and quality of life in patients with co-occurring schizophrenia and substance use disorder.

Methods: In this 12-week study, patients diagnosed with schizophrenia and substance use disorder using DSM-5 criteria were randomly assigned to switch from their current antipsychotic medication to brexpiprazole (up to 4 mg/day) or remain on their current antipsychotic treatment (treatment as usual [TAU]). Substance use was assessed by the number of days of substance use and the dollars spent on substance in the past week, and substance craving was assessed using the Visual Analog Scale (VAS). Quality of life was assessed using the Heinrichs-Carpenter Quality of Life Scale (QOL). In addition, psychiatric symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression Scale-Severity of Illness.

Results: Thirty-nine patients were randomized (21 in the brexpiprazole group, 18 in the TAU group). Mixed models for repeated measures showed that, despite the lack of statistical significance, a consistent pattern of decrease in the brexpiprazole group was observed for the number of days of substance use and the dollars spent, as well as substance craving; the brexpiprazole group had a 15.5 points greater decrease in VAS (P=.157) and a $33.3 greater decrease in the dollars spent (P=.108) from baseline to week 12 compared with the TAU group. The brexpiprazole group did show a statistically significant 8.9 points greater increase in QOL compared with the TAU group (P =.020). Even though it was not statistically significant, the brexpiprazole group had a 2.4-point greater decrease in the PANSS General Psychopathology subscale score (P=.150) and a 1.9-point greater decrease in the PANSS Negative Symptom subscale score (P=.126) compared with the TAU group.

Conclusion: This study suggests that brexpiprazole might be beneficial in reducing substance craving and use in patients with schizophrenia and co-occurring substance use disorder; this potential benefit may help improve quality of life and overall psychiatric symptoms in a difficult-to-treat patient population.

Trial Registration: ClinicalTrials.gov identifier: NCT03526354.

J Clin Psychiatry 2025;86(4):25m15786

Author affiliations are listed at the end of this article.

Members Only Content

This full article is available exclusively to Professional tier members. Subscribe now to unlock the HTML version and gain unlimited access to our entire library plus all PDFs. If you’re already a subscriber, please log in below to continue reading.

Subscribe Now

Already a member? Log in

References (35)

Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. JAMA. 1990;264(19):2511–2518. PubMed
Green AI, Salomon MS, Brenner MJ, et al. Treatment of schizophrenia and comorbid substance use disorder. Curr Drug Targets: CNS Neurol Disord. 2002;1(2):129–139. PubMed CrossRef
Volkow ND. Substance use disorders in schizophrenia-clinical implications of comorbidity. Schizophr Bull. 2009;35(3):469–472. PubMed CrossRef
Degenhardt L, Hall W. The relationship between tobacco use, substance-use disorders and mental health: results from the National Survey of Mental Health and Well-being. Nicotine Tob Res. 2001;3(3):225–234. PubMed CrossRef
DeQuardo JR, Carpenter CF, Tandon R. Patterns of substance abuse in schizophrenia: nature and significance. J Psychiatr Res. 1994;28(3):267–275. PubMed CrossRef
van Dijk D, Koeter MW, Hijman R, et al. Effect of cannabis use on the course of schizophrenia in male patients: a prospective cohort study. Schizophr Res. 2012;137(1-3):50–57. PubMed CrossRef
Green AI, Zimmet SV, Strous RD, et al. Clozapine for comorbid substance use disorder and schizophrenia: do patients with schizophrenia have a reward-especially among those more recentdeficiency syndrome that can be ameliorated by clozapine?. Harv Rev Psychiatry. 1999;6(6):287–296. PubMed CrossRef
Chambers RA, Krystal JH, Self DW. A neurobiological basis for substance abuse comorbidity in schizophrenia. Biol Psychiatry. 2001;50(2):71–83. PubMed CrossRef
Martinotti G, Chiappini S, Mosca A, et al. Atypical antipsychotic drugs in dual disorders: current evidence for clinical practice. Curr Pharm Des. 2022;28(27):2241–2259. PubMed CrossRef
Albanese MJ, Khantzian EJ, Murphy SL, et al. Decreased substance use in chronically psychotic patients treated with clozapine. Am J Psychiatry. 1994;151(5):780–781. PubMed CrossRef
Buckley P, Thompson P, Way L, et al. Substance abuse among patients with treatment-resistant schizophrenia: characteristics and implications for clozapine therapy. Am J Psychiatry. 1994;151(3):385–389. PubMed CrossRef
Brunette MF, Drake RE, Xie H, et al. Clozapine use and relapses of substance use disorder among patients with co-occurring schizophrenia and substance use disorders. Schizophr Bull. 2006;32(4):637–643. PubMed CrossRef
Cavallotto C, Chiappini S, Mosca A, et al. Examining lurasidone efficacy in patients with schizophrenia spectrum illness and concurrent alcohol and substance use disorder:a prospective, multicentric, real-world investigation. J Clin Med. 2024;13(8):2206. PubMed CrossRef
Sørensen G, Sager TN, Petersen JH, et al. Aripiprazole blocks acute self-administration of cocaine and is not self-administered in mice. Psychopharmacology. 2008;199(1):37–46. PubMed CrossRef
Wee S, Wang Z, Woolverton WL, et al. Effect of aripiprazole, a partial dopamine D2 receptor agonist, on increased rate of methamphetamine self-administration in rats with prolonged session duration. Neuropsychopharmacology. 2007;32(10):2238–2247. PubMed CrossRef
Brown ES, Jeffress J, Liggin JD, et al. Switching outpatients with bipolar or schizoaffective disorders and substance abuse from their current antipsychotic to aripiprazole. J Clin Psychiatry. 2005;66(6):756–760. PubMed CrossRef
Moreira FA, Dalley JW. Dopamine receptor partial agonists and addiction. Eur J Pharmacol. 2015;752:112–115. PubMed CrossRef
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. PubMed CrossRef
Fleischhacker WW. Aripiprazole. Expert Opin Pharmacother. 2005;6(12):2091–2101. PubMed CrossRef
Carey KB, Carey MP, Maisto SA, et al. Temporal stability of the timeline followback interview for alcohol and drug use with psychiatric outpatients. J Stud Alcohol. 2004;65(6):774–781. PubMed CrossRef
Nicholson AN. Visual analogue scales and drug effects in man. Br J Clin Pharmacol. 1978;6(1):3–4. PubMed CrossRef
Heinrichs DW, Hanlon TE, Carpenter WT Jr. The Quality of Life Scale: an instrument for rating the schizophrenic deficit syndrome. Schizophr Bull. 1984;10(3):388–398. PubMed CrossRef
Kay SR, Fiszbein A, Opler LA. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261–276. PubMed CrossRef
Guy W. ECDEU Assessment Manual for Psychopharmacology. US Dept of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute of Mental Health, Psychopharmacology Research Branch, Division of Extramural Research Programs; 1976. Rev ed.
Lombardozzi G, Trovini G, Amici E, et al. Brexpiprazole in patients with schizophrenia with or without substance use disorder: an observational study. Front Psychiatry. 2023;14:1321233. PubMed CrossRef
Chiappini S, Cavallotto C, Mosca A, et al. Investigating the effectiveness of brexpiprazole in subjects with schizophrenia spectrum illness and co-occurring substance use disorder: a prospective, multicentric, real-world study. Pharmaceuticals. 2024;17(4):535. PubMed CrossRef
Szerman N, Basurte-Villamor I, Vega P, et al. Once-monthly long-acting injectable aripiprazole for the treatment of patients with schizophrenia and co-occurring substance use disorders: a multicentre, observational study. Drugs Real World Outcomes. 2020;7(1):75–83. PubMed CrossRef
Nickols JER, Dursun SM, Taylor AMW. Preclinical evidence for the use of the atypical antipsychotic, brexpiprazole, for opioid use disorder. Neuropharmacology. 2023;233:109546. PubMed CrossRef
Schmidt LM, Hesse M, Lykke J. The impact of substance use disorders on the course of schizophrenia-a 15-year follow-up study: dual diagnosis over 15 years. Schizophr Res. 2011;130(1-3):228–233. PubMed CrossRef
Murthy P, Mahadevan J, Chand PK. Treatment of substance use disorders with co-occurring severe mental health disorders. Curr Opin Psychiatry. 2019;32(4):293–299. PubMed CrossRef
Ziedonis DM. Integrated treatment of co-occurring mental illness and addiction: clinical intervention, program, and system perspectives. CNS Spectr. 2004;9(12):892–925. PubMed CrossRef
Hser YI, Grella C, Evans E, et al. Utilization and outcomes of mental health services among patients in drug treatment. J Addict Dis. 2006;25(1):73–85. PubMed CrossRef
Manseau M, Bogenschutz M. Substance use disorders and schizophrenia. Focus (Am Psychiatr Publ). 2016;14(3):333–342. PubMed CrossRef
Hunt GE, Siegfried N, Morley K, et al. Psychosocial interventions for people with both severe mental illness and substance misuse. Schizophr Bull. 2014;40(1):18–20. PubMed CrossRef
Hunt GE, Siegfried N, Morley K, et al. Psychosocial interventions for people with both severe mental illness and substance misuse. Cochrane Database Syst Rev. 2013;(10):Cd001088. PubMed CrossRef