Repurposed antihypertensive drugs for negative symptoms in schizophrenia: A systematic review and meta-analysis

Schizophrenia is a complex psychiatric disorder characterized by positive, negative, and general psychopathological symptoms. While antipsychotic drugs are effective for positive symptoms, they provide limited benefit for negative symptoms, which are often persistent and strongly associated with functional disability. Additionally, up to 30% of patients exhibit resistance to current treatments, including clozapine. These challenges underscore the need for novel adjunctive strategies. This systematic review and meta-analysis, preregistered in PROSPERO (CRD42022359199), evaluated the efficacy and safety of repurposed antihypertensive drugs (AHTs) as adjunctive treatments for schizophrenia. PubMed, Web of Science, and Scopus were searched for double-blind, randomized controlled trials (RCTs) published since 2000. Twelve studies were included (n = 436; sodium nitroprusside = 6; diuretics = 4; telmisartan = 1; clonidine = 1). Meta-analyses were conducted on Positive and Negative Syndrome Scale (PANSS) outcomes and adverse event (AE) rates. Standardized mean differences (SMDs) were calculated as Hedges' g using a restricted maximum likelihood estimator. Incidence rate ratios modeled AE rates. AHTs significantly improved negative symptoms (SMD = -0.37 [-0.59, -0.15]; I² = 43.8%), positive symptoms (SMD = -0.29 [-0.53, -0.06]; I² = 25.1%), general psychopathology (SMD = -0.28 [-0.48, -0.08]; I² = 0.0%), and total symptoms (SMD = -0.44 [-0.66, -0.21]; I² = 0.0%). No significant increase in AEs was observed. Overall, repurposed AHTs-particularly sodium nitroprusside-may offer adjunctive therapeutic benefits for schizophrenia treatments. Some diuretics also showed preliminary signals of efficacy. However, findings are preliminary and require confirmation in larger, long-term RCTs.