Efficacy of non-invasive brain stimulation in treatment-resistant schizophrenia: A systematic review and network meta-analysis

About one-third of patients with schizophrenia are classified as treatment-resistant schizophrenia (TRS) experiencing persistent symptoms despite adequate antipsychotic trials. Non-invasive brain stimulation (NIBS) emerged as a promising alternative treatment for TRS, yet its comparative efficacy remains unclear. We conducted a systematic review and network meta-analysis (NMA) to investigate the efficacy of NIBS for TRS patients (PROSPERO: CRD42023442563). Randomized trials comparing NIBS with sham or other active interventions in TRS patients were included. NMA with frequentist random-effects models was conducted, with subgroup and sensitivity analyses. Primary outcomes were changes in positive symptoms, auditory hallucinations, negative symptoms, and overall symptoms, calculated using standardized mean differences (SMD). From 1586 studies, 55 studies with 33 NIBS modalities and 1981 TRS patients were included. Low-frequency repetitive transcranial magnetic stimulation over the left temporoparietal junction (LF-rTMS-LTPJ) and neuronavigated continuous theta burst stimulation targeting the left temporoparietal cortex (cTBS-LTPC) significantly improved positive symptoms and auditory hallucinations compared to sham. LF-rTMS-LTPJ showed robust effects on auditory hallucinations (SMD = -0.784, 95 % CI = -1.202 to -0.366). Multiple NIBS modalities significantly improved negative and overall symptoms, with neuronavigated cTBS-LTPC and neuronavigated intermittent theta burst stimulation targeting the left dorsolateral prefrontal cortex showing superior efficacy than others. All modalities were acceptable. No publication bias and inconsistency were detected, whereas studies on positive symptoms and auditory hallucinations were high in heterogeneity with low confidence in evidence. LF-rTMS-LTPJ demonstrates consistent efficacy for auditory hallucinations in TRS and can be recommended for clinical practice. Other NIBS interventions, particularly neuronavigated cTBS-LTPC, show promise but require further validation through large-scale trials with personalized approaches to optimize treatment outcomes.