Efficacy and Safety of Temporal Interference Stimulation in Treatment-Resistant Schizophrenia: An Exploratory Study.

Efficacy and Safety of Temporal Interference Stimulation in Treatment-Resistant Schizophrenia: An Exploratory Study.

This exploratory study aims to evaluate the preliminary efficacy and safety of temporal interference (TI) stimulation in patients with treatment-resistant schizophrenia (TRS). TI is a noninvasive brain stimulation technique that uses two high-frequency electrical currents with slightly different frequencies to generate a lower-frequency modulation at a targeted deep brain region.

A total of 20 patients with TRS will receive 130-Hz TI stimulation targeting the anterior limb of the internal capsule (ALIC). Stimulation will be delivered at a total current intensity of 4 mA for 5 consecutive days, with four 40-minute sessions per day. Participants will continue their stable antipsychotic medication regimen during the study.

Clinical symptoms, cognitive function, social functioning, and safety will be assessed before treatment, after completion of the 5-day treatment course, and at a 2-week follow-up. The primary clinical outcome is the change in the Positive and Negative Syndrome Scale (PANSS) total score. Secondary assessments include PANSS subscale scores, the MATRICS Consensus Cognitive Battery (MCCB), Calgary Depression Scale for Schizophrenia (CDSS), Personal and Social Performance Scale (PSP), and Clinical Global Impression (CGI). Safety will be evaluated through daily monitoring of treatment-related discomfort and adverse events.

Magnetic resonance imaging (MRI) will also be performed before and after treatment to explore treatment-related changes in brain structure, functional activity, functional connectivity, activation, and cerebral blood flow. The study hypothesizes that TI stimulation targeting the ALIC may improve clinical symptoms in patients with TRS and may be associated with measurable changes in neuroimaging markers.

Inclusion Criteria:

1. Right-handed male or female participants aged 18 to 65 years, inclusive.
2. Diagnosis of schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), established by a psychiatrist at the attending-physician level or above and confirmed by the Mini International Neuropsychiatric Interview, version 7.0.2 (MINI 7.0.2).
3. Inadequate response to sequential treatment with at least two antipsychotic medications of different chemical classes, each administered at an adequate dose (≥600 mg/day chlorpromazine equivalents) for an adequate duration (≥6 consecutive weeks at a therapeutic dose).
4. Stable dose of antipsychotic medication for at least 4 weeks before enrollment.
5. A score of 4 (moderate) or higher on at least two of the following Positive and Negative Syndrome Scale (PANSS) items: delusions, hallucinatory behavior, suspiciousness/persecution, or unusual thought content.
6. Ability to understand the study procedures, willingness to participate voluntarily and comply with the study procedures, and provision of written informed consent.

Exclusion Criteria:

1. Current diagnosis of another major psychiatric disorder other than schizophrenia that, in the investigator's judgment, may confound the diagnosis of schizophrenia or interfere with the assessment of treatment efficacy or safety.
2. Receipt of other neuromodulation treatments, including modified electroconvulsive therapy (MECT), repetitive transcranial magnetic stimulation (rTMS), or transcranial direct current stimulation (tDCS), within the previous 3 months, or previous participation in an interventional clinical trial involving vagus nerve stimulation (VNS) or deep brain stimulation (DBS).
3. A score ≥3 on Item 3 (suicide) of the 17-item Hamilton Depression Rating Scale (HAMD-17), or a score >3 on any of the following PANSS items: P4 Excitement, G14 Poor Impulse Control, P7 Hostility, or G8 Uncooperativeness.
4. Contraindications to magnetic resonance imaging (MRI), including intracranial metallic implants, implanted cardiac pacemakers, or cochlear implants.
5. Skull defects or fissures, or inability to tolerate stimulation-related adverse effects.
6. Treatment-resistant epilepsy or other serious medical conditions that, in the investigator's judgment, may potentially affect treatment or participation in the study.
7. Pregnancy.
8. Any other condition that, in the investigator's judgment, makes the participant unsuitable for participation in the study.