Effectiveness of Herbal Medicine Compared to Antidepressants in Patients with Schizophrenia Spectrum Disorders Accompanied by Depression: a systematic review and meta-analysis.

Objectives: Depression affects approximately 28.6% of patients with schizophrenia spectrum disorders (SSD). Although herbal medicine (HM) has been proposed as a therapeutic option, its comparative effectiveness relative to antidepressants remains uncertain. This systematic review compared HM with antidepressants as adjuncts to antipsychotics in patients with SSD and comorbid depression. Methods: Eight electronic databases were searched from inception to January 15, 2025, without language restrictions. Randomized controlled trials (RCTs) that compared HM plus antipsychotics with antidepressants plus antipsychotics in patients with SSD and depression were included. Primary outcomes were depressive symptom scores (Calgary Depression Scale for Schizophrenia or Hamilton Depression Rating Scale) and response rates. Secondary outcomes included overall psychiatric symptoms and adverse events. Risk of bias was assessed using the Cochrane RoB 2 tool; certainty of evidence was evaluated using the GRADE approach. Results: Seven RCTs comprising 505 participants were included. Meta-analysis demonstrated no significant difference between HM and antidepressants in depressive symptoms (SMD -0.19, 95% CI [-0.54, 0.15]; very low-certainty evidence), response rates (RR 1.00, 95% CI [0.96, 1.04]; low-certainty evidence), or overall psychiatric symptoms (SMD -0.06, 95% CI [-0.84, 0.73]; low-certainty evidence). Adverse event rates showed a nonsignificant trend favoring HM (RR 0.56, 95% CI [0.06, 5.26]; low-certainty evidence). Conclusion: Very low- to low-certainty evidence suggests no significant difference in effectiveness between HM and antidepressants as adjuncts to antipsychotics for depression in SSD. Although HM may serve as an alternative, high-quality, large-scale trials are required to establish definitive conclusions.