Brexpiprazole in the Management of Schizophrenia and Comorbid Substance Use Disorders: A Narrative Review of Efficacy, Safety, and Real-World Evidence (2020–2026)

Background: Brexpiprazole, a third-generation antipsychotic with partial dopamine D2/D3 and serotonin 5-HT1A agonist properties, has emerged as a promising therapeutic option for patients with schizophrenia, including those with comorbid substance use disorders (SUDs). Managing psychosis in the presence of substance use represents a major clinical challenge, often associated with poorer outcomes, reduced adherence, and increased relapse risk. Methods: This narrative review(non-systematic) synthesizes evidence from randomized controlled trials, observational real-world studies, and expert consensus reports published between 2020 and 2026. The literature was examined to evaluate the pharmacological mechanisms, clinical efficacy, safety, and practical use of brexpiprazole in psychotic disorders, with particular attention to populations with comorbid substance use disorders. As a narrative review, this work does not employ systematic search protocols or quality appraisal tools; findings should be interpreted with this methodological limitation in mind. Results: Available evidence suggests that brexpiprazole can meaningfully reduce both positive and negative symptoms of psychosis, while also demonstrating beneficial effects on substance craving and functional outcomes in patients with dual diagnoses. Across randomized and real-world studies, brexpiprazole shows a favorable tolerability profile, characterized by minimal activation, low sedation, reduced risk of extrapyramidal symptoms, and limited cardiometabolic burden. These properties support its use in complex clinical populations requiring long-term treatment and polypharmacological management. Clinical Implications and Decision-Making: Based on the available evidence, brexpiprazole may be particularly suitable for: (1) patients with prominent negative symptoms requiring improvement in motivation and social functioning; (2) individuals with comorbid substance use disorders, particularly stimulant use, where dopaminergic modulation may address both psychotic symptoms and craving; (3) patients who have experienced significant metabolic or motor side effects with other antipsychotics; (4) individuals requiring cognitive preservation or enhancement. However, clinicians should consider that most evidence derives from relatively short-term studies with selected populations, and long-term real-world effectiveness data remain limited. Treatment decisions should be individualized based on symptom profile, comorbidity burden, prior medication responses, and patient preferences. Conclusions: Brexpiprazole represents a clinically valuable option for the management of psychosis, particularly in patients with comorbid substance use disorders. Its balanced pharmacological profile, combined with consistent efficacy and good tolerability, supports its role in integrated, long-term treatment strategies for complex and dual-diagnosis populations.