rTMS in Schizophrenia: A Comprehensive Evidence Review

Scope and Framing

This review synthesizes the evidence on repetitive transcranial magnetic stimulation (rTMS) as an adjunctive treatment in adults with schizophrenia, organized by symptom target: treatment-resistant auditory verbal hallucinations (AVH), negative symptoms, cognitive impairment, and emerging domains. It covers conventional rTMS and theta burst stimulation (TBS) protocols, stimulation targets and dosing, safety, and current guideline positions. rTMS remains investigational for schizophrenia; it is not FDA-cleared for this indication, which is approved only for major depression, OCD, and smoking cessation.[1][2] Pediatric data are minimal and not covered in depth.

Background and Rationale

Two neurobiological rationales anchor the field. For hallucinations, the bilateral temporal speech-processing regions are hyperactive during ongoing AVH, motivating inhibitory low-frequency stimulation of the left temporoparietal cortex.[3] For negative and cognitive symptoms, the model is prefrontal hypofunction ("hypofrontality") and disrupted mesocortical dopamine signaling, motivating excitatory high-frequency stimulation of the left dorsolateral prefrontal cortex (DLPFC), which increases DLPFC–ventral tegmental connectivity.[4] Newer targets extend to cerebello-thalamo-cortical circuitry ("cognitive dysmetria").[5]

Auditory Verbal Hallucinations

Low-frequency (1 Hz) rTMS over the left temporoparietal cortex/junction is the most replicated paradigm, typically delivering 600–2,000 pulses/session at 90–110% of resting motor threshold over 10–15 sessions, targeted at T3–P3 or via MRI neuronavigation.[3][6][7] The efficacy signal, however, has attenuated as trials have grown larger and more rigorous. Slotema et al. reported a moderate weighted effect size of 0.44 overall (0.63 for the 1 Hz left-TPC subset), but subsequent meta-analyses have been smaller and unstable: He et al. (SMD −0.29) and Li et al. (SMD −0.27) both became non-significant on sensitivity analysis, and Guttesen et al. found no significant effect (SMD −0.19, p=0.21).[8][9][10][11] A within-group sham effect size of ~0.29 contributes substantially to observed responses.[12]

The most recent syntheses diverge sharply. A 2026 network meta-analysis restricted to treatment-resistant schizophrenia found a robust effect for LF-rTMS at the left TPJ (SMD −0.784), whereas a 2026 pairwise meta-analysis in the same population found essentially no benefit on the AHRS (SMD −0.03).[13][14] This disagreement reflects heterogeneity in targeting, dosing, and trial quality, notably a geographic-bias signal, where excluding mainland-China trials reduced pooled effects to a small, imprecise estimate.[15]

Individual RCTs illustrate both extremes. The 2024 imaging-navigated 1 Hz trial by Hua et al. (N=62, JAMA Network Open) reported large effects (Cohen d=1.17 at week 2, rising to 1.49 at week 6) with a 47% vs 13% response rate (NNT ≈3), suggesting neuronavigation may materially improve targeting and outcomes.[16] In contrast, several rigorous trials, Bais et al., Koops et al. (cTBS), and Lv et al. (2025), were negative, with active and sham improving equally.[17][18][19] A dose-response analysis found a bell-shaped curve plateauing near ~5,000 total pulses, with no added benefit beyond that.[20]

A major recent advance is the first multicenter phase 3 trial (Plewnia et al., 2025, Lancet Psychiatry, N=138): sequential bilateral continuous TBS (600 pulses each side, 15 sessions over 3 weeks) was safe and effective on PSYRATS-AH, with efficacy concentrated in patients receiving >10 sessions and >6,000 total pulses.[21] This reinforces that adequate dosing (≥15 sessions, bilateral targeting) may be decisive, and helps reconcile earlier negative cTBS trials that used fewer sessions.[22] Across studies, durability is limited: benefit typically lasts 4–6 weeks without maintenance, underscoring continued antipsychotic treatment.[12]

Negative Symptoms

High-frequency (10–20 Hz) rTMS to the left DLPFC is the standard approach, with ≥15 sessions at 100–110% motor threshold over ≥3 weeks associated with better outcomes.[23][24] Meta-analyses consistently show a statistically significant but small-to-moderate effect, though estimates vary widely by outcome scale and vintage.

Meta-analysisYearStudies (N)Effect size (95% CI)
Lorentzen et al. (all TMS)202257 (n=2,633)SMD 0.41 (0.26–0.56), NNT ≈5
Aleman et al.201822 (n=827)d 0.64 (0.32–0.96)
Osoegawa et al.201831 (n=1,272)g 0.19 (0.07–0.32)
Wang et al. (HF, PANSS)202417 (n=791)SMD −0.31 (−0.49 to −0.14)
Chen et al. (HF)202523 (n=1,024)SMD −0.47 (−0.71 to −0.24)
Tseng et al. NMA (10 Hz L-DLPFC)2022—SMD −0.43 (−0.68 to −0.18)
Tseng et al. NMA (20 Hz L-DLPFC)2022—SMD −0.45 (−0.79 to −0.12)

Subgroup analyses favor 20 Hz modestly over 10 Hz (SMD −0.48 vs −0.26, overlapping CIs), ≥15 sessions, and left DLPFC over other sites (SMD 0.55 vs 0.04).[25][23]

Two important cautions temper these pooled results. First, the largest and most rigorous single RCT, the multicenter RESIS trial (Wobrock et al., N=175), was negative (effect size 0.09, p=0.53, with no benefit through day 105), directly contradicting the meta-analytic signal.[28] Second, the clinical significance is uncertain: a 2026 meta-analysis of 451 RCTs found brain-stimulation effects did not consistently reach the threshold for a clinically meaningful (1-point CGI-S) improvement in high-quality studies.[29] Studies using SANS report larger effects (SMD −0.99) than PANSS-negative studies (SMD −0.31), with very high heterogeneity, and few trials distinguish primary from secondary negative symptoms.[23] Where reported, benefit persists modestly at ≥4 weeks (SMD 0.27).[25]

Theta Burst Stimulation

TBS compresses stimulation into shorter sessions. The most comprehensive synthesis (Kishi et al., 2024, JAMA Network Open network meta-analysis, 30 RCTs, N=1,424) found that iTBS over the left DLPFC was the only protocol significantly superior to sham, across negative, overall, general, depressive, anxiety, and cognitive domains, while no TBS protocol improved positive symptoms.[1] Discontinuation did not differ from sham.

DomainiTBS over L-DLPFC SMD (95% CI)
Negative symptoms−0.89 (−1.24 to −0.55)
Overall symptoms−0.81 (−1.15 to −0.48)
PANSS general subscale−0.57 (−0.89 to −0.25)
Depressive symptoms−0.70 (−1.04 to −0.37)
Overall cognitive symptoms−0.52 (−0.89 to −0.15)
Anxiety symptoms−0.58 (−0.92 to −0.24)
Positive symptoms0.18 (−0.26 to 0.63), not significant

Source: Kishi T, Ikuta T, Sakuma K, et al. Theta Burst Stimulation Protocols for Schizophrenia: A Systematic Review and Network Meta-Analysis. JAMA Network Open. 2024;7(10):e2441159. doi:10.1001/jamanetworkopen.2024.41159.

As with conventional rTMS, negative trials exist: a 2026 double-blind study (N=141) found experimental left-DLPFC iTBS did not significantly outperform sham for negative symptoms, and some network analyses rank iTBS and even tDCS/tRNS above conventional HF-rTMS, keeping optimal modality unsettled.[30][31][4]

Cognitive and Other Symptom Domains

TMS produces a small but significant cognitive effect overall (SMD 0.50; 0.43 for left-PFC targets), with the most consistent gains in working memory, verbal fluency/language, and certain memory domains, but not attention or processing speed.[32][31] Delayed benefits emerging at 6-month follow-up have been reported.[33][34] Social cognition (facial emotion recognition, theory of mind) improved with accelerated iTBS to the left DLPFC.[35] A distinct domain, psychomotor slowing, responded to 1 Hz inhibitory rTMS over the supplementary motor area in a JAMA Psychiatry RCT (68% vs 32% response).[36] Negative cognition trials also exist (e.g., a 156-patient study of 10 Hz left-PFC rTMS).[12]

Emerging Targets and Personalization

Beyond the DLPFC and temporoparietal cortex, several novel targets are under active study, guided increasingly by E-field modeling that maps symptom-specific optimal sites:

  • Cerebellar vermis / crus: Multiple RCTs of cerebellar vermal iTBS or TBS show improvements in negative symptoms (sometimes maximal and sustained at 24 weeks), cognition, and social function, alongside enhanced fronto-cerebellar connectivity and normalization of the Glx/GABA ratio, though at least one adequately-engaged trial was clinically negative, attributed to under-dosing.[37][38][39][40]
  • Orbitofrontal cortex: 1 Hz right-OFC rTMS improved symptoms and visuospatial memory in first-episode schizophrenia.[41][42]
  • Dorsomedial prefrontal cortex, superior frontal gyrus, medial SFG: early positive signals for negative and cognitive symptoms.[43][44][45]
  • Personalized targeting: MRI-guided neuronavigation improved negative-symptom outcomes, with smaller stimulation-to-target deviation correlating with response (r=−0.42); functional-connectivity-based and α-peak-frequency-guided targeting are also promising.[46][47][3]
  • Accelerated and combination protocols: accelerated iTBS (multiple daily sessions) and combinations with working-memory training or CBT show additive benefits in small trials.[35][43][48][49]

Safety

The largest schizophrenia-specific safety analysis (126 studies, N=4,122) concluded rTMS is safe and well tolerated, with no increased risk of adverse events overall versus sham except more headache/scalp pain, dizziness, facial twitching, and nausea, and, importantly, no increased seizure risk.[50] General rTMS seizure rates are very low (≈0.08 per 1,000 sessions overall; <1 per 60,000 when guidelines are followed in patients without risk factors), with figure-8 coil risk estimated near 1 in 30,000 treatments.[51][2] Dropout does not differ from sham.[52]

The clozapine interaction deserves specific attention in treatment-resistant patients: clozapine lowers the seizure threshold dose-dependently (1.0% at <300 mg/day up to 4.4% at ≥600 mg/day) and carries the highest seizure risk among antipsychotics.[53][54] No formal contraindication exists, but pre-treatment screening for seizure history, threshold-lowering drugs, and other risk factors, plus a documented seizure-management plan, is standard.[2]

Current Guidelines

No major guideline currently endorses rTMS as standard care for schizophrenia. The VA/DoD (2023) guideline found insufficient evidence to recommend for or against rTMS (confidence rated "very low").[55] The Lefaucheur et al. evidence-based guidelines did not reach Level A/B for any schizophrenia indication, with prior versions assigning only "possible efficacy" (Level C) to 1 Hz left-TPC rTMS for hallucinations.[56][16] The APA acknowledges safe use and some benefit but finds insufficient evidence for routine clinical application, and a 2025 Nature Reviews Disease Primers review confirms most guidelines do not recommend rTMS as standard treatment while allowing it may help in individual cases.[2][57]

Evidence Gaps and Emerging Data

Key uncertainties include: substantial protocol heterogeneity and absence of a standardized regimen; the discrepancy between positive meta-analyses and negative large multicenter RCTs (RESIS for negative symptoms; equivocal cTBS trials for AVH); a documented geographic-quality bias; substantial sham responses (~30%); short durability (4–6 weeks) with unstudied maintenance strategies; and low-to-very-low GRADE evidence overall.[15][12][14][57] The most promising near-term directions are the positive phase 3 bilateral cTBS trial for hallucinations, neuronavigated/E-field-personalized targeting, iTBS to the left DLPFC for negative and cognitive symptoms, and novel cerebellar and multi-target accelerated protocols.[21][46][31][1][37][58]

Summary

The totality of evidence supports rTMS as a safe, well-tolerated adjunct with modest and inconsistent efficacy in schizophrenia. The best-characterized applications are 1 Hz rTMS to the left temporoparietal cortex for treatment-resistant auditory hallucinations and high-frequency (or iTBS) stimulation of the left DLPFC for negative symptoms, both yielding small-to-moderate effect sizes that are fragile on sensitivity analysis and contradicted by the largest rigorous RCTs. Adequate dosing (≥15 sessions, sufficient pulse totals), precise/neuronavigated targeting, and newer TBS and cerebellar protocols represent the most credible paths to improved outcomes, but no regulatory body or major guideline currently recommends rTMS as standard treatment.

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