Effectiveness of herbal medicine as an add-on to antipsychotics in patients with schizophrenia spectrum disorders accompanied by depression: A systematic review and meta-analysis.

Background: Depression is a common comorbidity of schizophrenia spectrum disorder (SSDs) that affects functional outcomes and quality of life. This systematic review and meta-analysis evaluated the effectiveness of herbal medicine as an adjunct therapy to antipsychotics in patients with SSDs and comorbid depression. Methods: Eight databases were searched from inception to January 2025 for randomized controlled trials (RCTs) evaluating herbal medicine combined with antipsychotics vs antipsychotics alone in patients with SSDs and comorbid depression. The primary outcome measure was a depression-specific assessment instrument. Risk of bias was assessed using the Cochrane RoB 2 tool, and evidence certainty was assessed using GRADE. Results: Overall, of 12 RCTs, 884 participants were included. Compared to antipsychotics, combination therapy significantly improved depressive symptoms (standardized mean difference [SMD] -0.91, 95 % confidence interval (CI) -1.05 to -0.76, p<0.00001, N=10, n=768, moderate certainty), enhanced efficacy for schizophrenia symptoms (SMD -0.60, 95 % CI -0.89 to -0.31, p=0.0014, N=9, n=666, moderate certainty), and showed higher response rates (relative risk [RR] 1.26, 95 % CI 1.04 to 1.52, p=0.0277, N=5, n=372, low certainty). Adverse event rates showed no significant difference between groups (RR 1.18, 95 % CI 0.69 to 2.01, p=0.1609, N=2, n=136, low certainty). Conclusions: This review provides evidence that herbal medicine, as an adjunct to antipsychotics, may improve both depressive and psychotic symptoms in patients with SSDs and comorbid depression. Although promising, methodological limitations and the exclusive Chinese origin of the studies indicate the need for more rigorous and diverse trials to establish definitive clinical recommendations. Protocol registration: PROSPERO, CRD42025643148.