This is a prospective, randomized, interventional study designed to evaluate the efficacy and safety of SEEG-guided deep brain stimulation (DBS) for symptom improvement in patients with treatment-resistant schizophrenia. Using stereo-electroencephalography (SEEG) to record brain activity, we will identify specific abnormal electrophysiological targets and signal features associated with clinical symptoms, followed by a 12-month open-label stimulation period. The study is conducted in three stages: Stage 1 consists of SEEG brain mapping, screening of intervention targets, and optimization of stimulation parameters; Stage 2 consists of DBS implantation surgery and further optimization of stimulation parameters; Stage 3 is a randomized crossover treatment phase, followed by an open-label treatment period.

This clinical trial aims to systematically evaluate the efficacy and safety of SEEG-guided target screening combined with individualized deep brain stimulation (DBS) for treatment-refractory schizophrenia.

The study first employs Stereoelectroencephalography (SEEG) electrodes as the core tool to establish a personalized, minimally invasive neuromodulation surgical framework. After SEEG electrode implantation, researchers will collect and analyze high-spatiotemporal-resolution electrophysiological data during both resting-state and task-state conditions, as well as identify characteristic electrophysiological biomarkers that correlate with clinical symptoms.

Secondly, electrical stimulation is delivered through the SEEG contacts to functionally verify candidate targets in different brain regions. By stimulating specific targets and observing immediate symptomatic or physiological responses, we validate the effects on neural circuits and confirm their functional relevance prior to any permanent intervention. For targets that show preliminary efficacy, we further apply externalized chronic stimulation to continuously monitor symptom improvement and potential adverse effects.

After determine the optimal targets and the intervention is confirmed to be both effective and safe, we implant a permanent brain pacemaker (DBS device). During the efficacy follow-up phase, we employ a randomized crossover design, which is then followed by an open-label period. These two stages enable thorough assessment of clinical efficacy. Meanwhile, we also collect multidimensional data (clinical symptoms, cognition, and neuroimaging) to explore the circuit mechanisms of stimulation.

Inclusion Criteria:

• Meets the International Classification of Diseases, 10th Revision (ICD-10) diagnostic criteria for schizophrenia.
• Male or female, aged 18 to 55 years, with stable vital signs.
• Currently presents with prominent psychotic symptoms, assessed as moderate or severe by the Positive and Negative Syndrome Scale (PANSS) or other equivalent scales.
• Exhibits impaired social functioning, assessed as moderate or severe impairment by the Social and Occupational Functioning Assessment Scale (SOFAS) or other equivalent scales.
• Has a history of sequential treatment with at least two antipsychotic medications of different chemical structures known for strong efficacy against positive symptoms. Treatment must have been at an adequate dose and for an adequate duration (continuous treatment at a therapeutic dose for more than 6 weeks per medication), with good treatment adherence.
• Has been on a stable antipsychotic medication regimen for at least one month prior to enrollment.
• Capable and willing to provide written informed consent.
• Demonstrates good compliance and is able to cooperate with all follow-up procedures.

Exclusion Criteria:

• Diagnosed with any psychiatric disorder other than schizophrenia.
• Presence of a severe personality disorder.
• History of severe neurological diseases, such as seizures or hemorrhagic stroke.
• Presence of structural brain abnormalities.
• Previous history of stereotactic neurosurgery.
• Contraindications to general anesthesia or stereotactic neurosurgery.
• Any current or anticipated condition-including medical, psychological, social, familial support, or geographical factors-that might compromise patient safety or interfere with successful participation in the study.