Efficacy and safety of rTMS for global symptom severity, negative symptoms, and auditory hallucinations in treatment-resistant schizophrenia: a systematic review and meta-analysis.

BACKGROUND: Treatment-resistant schizophrenia (TRS) affects up to one-third of individuals with schizophrenia and remains a major clinical challenge despite optimized pharmacotherapy. Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a neuro-modulatory intervention for refractory symptoms, yet evidence specific to TRS remains limited and inconsistent. OBJECTIVES: To evaluate the efficacy and safety of rTMS for reducing global symptom severity, negative symptoms, and auditory hallucinations in adults with treatment-resistant schizophrenia, and to examine the influence of stimulation parameters on treatment outcomes. METHODS: A systematic review and meta-analysis was conducted following PRISMA guidelines and registered with PROSPERO (CRD420251143558). Eight electronic databases were searched up to 10th September 2025. Randomized controlled trials including adults with TRS and comparing rTMS with sham stimulation were eligible. Standardized mean differences (Hedges' g) were pooled using REML-based random-effects models. Heterogeneity and subgroup effects were examined, and publication bias was explored through visual inspection of funnel plots. RESULTS: Across included trials, rTMS was not associated with statistically significant improvements in overall symptom severity measured by PANSS (SMD 0.14, 95% CI -0.26 to 0.54), negative symptoms (SMD 0.37, 95% CI -0.12 to 0.86), or auditory hallucinations measured by AHRS (SMD -0.03, 95% CI -0.26 to 0.20), based on post-treatment outcome scores. Substantial heterogeneity was observed for PANSS and negative symptoms, while heterogeneity for AHRS was low. Subgroup findings were exploratory and should be interpreted cautiously. CONCLUSIONS: Current evidence does not support a consistent therapeutic benefit of rTMS over sham stimulation for symptom reduction in treatment-resistant schizophrenia. While some subgroup analyses suggested variability in effect estimates across stimulation protocols, these findings were exploratory and should be interpreted with caution. Further large-scale, well-designed trials are needed to clarify the role of rTMS in this population. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251143558, identifier CRD420251143558.