A systematic review and network meta-analysis (NMA) by researchers from the University of Hong, University of Minnesota, and Hong Kong Polytechnic University finds that low-frequency repetitive transcranial magnetic stimulation over the left temporoparietal junction (LF-rTMSLTPJ) is consistently efficient for alleviating auditory hallucinations in treatment-resistant
schizophrenia (TRS).
Despite pharmacological advancements, about one-third of the schizophrenia population are considered treatment-resistant. [Braz J Psychiatry 2023;45:448-458] Noninvasive brain stimulation (NIBS) techniques modulate neural activity and potentially promote neuroplastic changes and have been explored as potential adjunctive interventions for schizophrenia. [Neurosci Biobehav Rev 2023;152:105300] However, evidence remains inconsistent and insufficient for regulatory approval of its clinical use; furthermore, comparative efficacy of various techniques is unclear. [Mol Psychiatry 2022;27:2709-2719]
“The current systematic review and NMA aimed to investigate the comparative efficacy of different NIBS interventions in reducing positive symptoms, auditory hallucinations, negative symptoms, and overall symptoms in TRS,” stated the researchers. [Neurosci Biobehav Rev 2026;doi:10.1016/j.neubiorev.2026.106549]
The present research analyzed data from 1,981 patients with TRS (mean age, 36.8 years; female, 40.7 percent) across 55 studies. Six NIBS techniques were included in the analysis: continuous theta burst stimulation (cTBS) (six studies; n=135), electroconvulsive therapy (ECT) (three studies; n=49), intermittent theta burst stimulation (iTBS) (three studies; n=64), repetitive transcranial magnetic stimulation (rTMS) (32 studies; n=654), transcranial alternating current stimulation (tACS) (two studies; n=22), and transcranial direct current stimulation (tDCS) (11 studies; n=217).
NMA revealed that LF-rTMS-LTPJ (standardized mean difference [SMD], -0.430; p=0.013) and neuronavigated cTBS targeting the left temporoparietal cortex (LTPC) (SMD, -0.768; p=0.045) significantly improved positive symptoms compared with sham conditions, but were not significantly superior to otherinterventions. “For LF-rTMS-LTPJ, the effect remained significant in subgroups with higher baseline symptom severity, more recent publications, fewer intervention sessions, non-Western countries, smaller sample sizes, and younger population,” noted the researchers.
Although positive symptoms include auditory hallucination, to align with previous meta-analyses, auditory hallucination was assessed separately. As with results obtained for the positive symptoms comparison, NMA showed that that LF-rTMS-LTPJ (SMD, -0.784; p<0.001) and neuronavigated cTBS-LTPC (SMD, -1.118; p=0.011) led to significant improvements vs sham conditions, but were not superior to other interventions. In subgroup analyses, LF-rTMS-LTPJ efficacy remained significant across all subgroups except in studies with larger sample sizes and older populations, while neuronavigated cTBS-LTPC only showed efficacy in subgroups with smaller sample size and more recent publications.
“LF-rTMS-LTPJ demonstrates consistent efficacy for auditory hallucinations in TRS and can be recommended for clinical practice,” suggested the researchers.
While NIBS modalities significantly improved negative and overall symptoms, neuronavigated cTBS-LTPC and neuronavigated intermittent theta burst stimulation targeting the left dorsolateral prefrontal cortex showed superior efficacy vs others. At the same time, neuronavigated cTBS-LTPC and iTBS targeting the left dorsolateral prefrontal cortex (DLPFC) showed particularly strong effects on negative and overall symptoms. Additionally, tDCS over bilateral DLPFC exhibited consistent efficacy for overall symptoms.
“Comparable dropout rates between NIBS interventions and sham conditions indicated good tolerability of NIBS techniques. However, evidence for ECT’s efficacy in TRS remained limited and inconclusive based on available randomized controlled trials,” highlighted the researchers.
