Antithrombotic agents in the treatment of severe mental illness: A systematic review and meta-analysis of randomized controlled trials

Evidence suggests shared pathophysiologic mechanisms between severe mental illness (SMI) and cardiovascular disease (CVD). Drugs used for CVD, such as antithrombotic agents (ATAs), may therefore be repurposed for the treatment of SMI. We conducted the first systematic review and meta-analysis (PROSPERO registration CRD42024524420) of ATAs for SMI and reported results according to PRISMA guidelines. We searched MEDLINE, Embase, and PsycINFO (October 10, 2024) and performed random-effects meta-analysis. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool, and the certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework. Primary outcomes were symptom severity, risk of recurrence, and tolerability. We included 12 randomized trials investigating aspirin, cilostazol, and dipyridamole in a total of 742 patients with schizophrenia, major depression, and bipolar disorder. Results showed that ATA treatment may reduce depressive symptoms in patients with SMI (SMD -0.62; 95 % CI -1.11 to -0.13; 8 studies; very low-certainty evidence). Based on studies with low risk of bias, ATA treatment may reduce PANSS total score compared with placebo (SMD -0.57; 95 % CI -0.86 to -0.28; 3 studies; very low-certainty evidence). Tolerability of ATAs may not differ from placebo (RR 0.89; 95 % CI 0.57-1.40; 9 studies; very low-certainty evidence). Given the low certainty of the evidence, effect estimates should be interpreted with caution. The therapeutic potential of ATAs in SMI remains uncertain. Well-powered RCTs investigating clinically relevant outcomes in clearly defined populations are needed.