This randomized controlled trial (RCT) is the first to evaluate the efficacy and safety of a multi-target TMS protocol targeting the left dorsolateral prefrontal cortex (L-DLPFC), left inferior parietal lobule (L-IPL), and right orbitofrontal cortex (R-OFC) for negative symptoms of schizophrenia.

Schizophrenia is a chronic and severe mental disorder. Although antipsychotic medications are effective for positive symptoms, they offer limited improvement for negative symptoms and cognitive deficits. Effective treatments for these symptoms are still lacking. To address current clinical bottlenecks, there is an urgent need to develop novel, effective treatment strategies. Repetitive transcranial magnetic stimulation (rTMS) is a recently developed neuromodulation technique. The latest evidence-based guidelines indicate that the level of evidence for rTMS in treating schizophrenia remains low (i.e., Level C evidence, possibly effective). However, the critical parameter of target selection has not received sufficient attention. This randomized controlled trial (RCT) is the first to evaluate the efficacy and safety of a multi-target TMS protocol targeting the Left Dorsolateral Prefrontal Cortex (L-DLPFC), Left Inferior Parietal Lobe (L-IPL), and Right Orbitofrontal Cortex (R-OFC) for negative symptoms of schizophrenia. MRI-guided neuronavigation will be used to localize targets in each subject. Stimulation will be delivered at 100% of the resting motor threshold (RMT), with a total of 50 Theta Burst Stimulation (TBS) sessions, which include intermittent TBS (iTBS) and continuous TBS (cTBS). In the order of L-DLPFC (iTBS)→ L-IPL (iTBS) → R-OFC (cTBS), each target receives 600 pulses, for a total of 1800 pulses across three targets. Five sessions will be administered per day for 10 consecutive working days, with a 60-minute interval between sessions. Clinical assessments, cognitive evaluations, and resting-state functional Magnetic Resonance Imaging (MRI) scans will be performed before and after TBS treatment.

Inclusion Criteria:

1. Outpatients or inpatients at the Department of Psychiatry, Shanghai Mental Health Center;
2. Meet the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for first-episode schizophrenia (diagnosed using the Structured Clinical Interview for DSM-5, SCID-5); disease duration less than 5 years at enrollment;
3. Male or female aged 16-45 years;
4. Education duration ≥ 9 years;
5. Stable medication regimen for at least 6 weeks prior to baseline visit and throughout the study period; psychiatric symptoms generally stable within 1 month prior to baseline visit;
6. Participants and their guardians can understand and sign written informed consent;
7. Total score on the PANSS Negative Symptom subscale (PANSS-N) > 15, and at least one item score ≥ 3.

Exclusion Criteria:

1. Current or lifetime psychiatric disorders as determined by SCID-5 assessment;
2. Severe or unstable physical illnesses, including: neurological disorders (delirium, dementia, stroke, epilepsy, migraine, etc.), congestive heart failure, angina pectoris, myocardial infarction, arrhythmia, hypertension, hyperglycemia, malignant tumors, and immunocompromised conditions;
3. Alcohol abuse within 30 days prior to the study or alcohol/drug dependence within 6 months prior to the study; participation in any clinical trial within 30 days prior to baseline;
4. Pregnant or breastfeeding women;
5. Intellectual disability (IQ < 70).

Other researchers should submit a request to the PI. Data sharing will only occur after the PI's approval.