Sequential Treatment Approaches for Treatment-Resistant Schizophrenia (STATRS)

Phase 1 of the trial is an 8-week randomized controlled trial(RCT); patients will be randomly assigned to one of three treatment arms with different oral antipsychotics, one is Clozapine Monotherapy. Non-responders in phase 1 will switch to phase 2.

Initial dose: 25-50 mg/day orally. Clozapine will be individually titrated over 8 weeks, with a usual target dose of 300-450 mg/day and a target steady-state trough plasma concentration of ≥350 ng/mL. Plasma clozapine concentration will be assessed at Week 4.

If the concentration is <350 ng/mL, the dose will be further increased as clinically tolerated. A dose of ≥300 mg/day is not required if the target plasma concentration is achieved at a lower dose. Participants who cannot reach either 300 mg/day or the target plasma concentration because of intolerance may remain on their maximum tolerated dose below 300 mg/day.

• Clo

Phase 1 of the trial is a 8-week randomized controlled trial(RCT); patients will be randomly assigned to one of three treatment arms with different oral antipsychotics, one of which is 'Clozapine + Aripiprazole'. Non-responders in phase 1 will switch to phase 2.

Initial dose: 25-50 mg/day orally. Clozapine will be individually titrated over 8 weeks, with a usual target dose of 300-450 mg/day and a target steady-state trough plasma concentration of ≥350 ng/mL. Plasma clozapine concentration will be assessed at Week 4.

If the concentration is <350 ng/mL, the dose will be further increased as clinically tolerated. A dose of ≥300 mg/day is not required if the target plasma concentration is achieved at a lower dose. Participants who cannot reach either 300 mg/day or the target plasma concentration because of intolerance may remain on their maximum tolerated dose below 300 mg/day.

• Clo

Initial dose: 5-10 mg/day. Aripiprazole recommended dosage:10-15 mg/day. dosage form:po.duration:8 weeks

• Ari

Phase 1 of the trial is a 8-week randomized controlled trial(RCT); patients will be randomly assigned to one of three treatment arms with different oral antipsychotics, one of which is 'Clozapine + Amisulpride'. Non-responders in phase 1 will switch to phase 2.

Initial dose: 25-50 mg/day orally. Clozapine will be individually titrated over 8 weeks, with a usual target dose of 300-450 mg/day and a target steady-state trough plasma concentration of ≥350 ng/mL. Plasma clozapine concentration will be assessed at Week 4.

If the concentration is <350 ng/mL, the dose will be further increased as clinically tolerated. A dose of ≥300 mg/day is not required if the target plasma concentration is achieved at a lower dose. Participants who cannot reach either 300 mg/day or the target plasma concentration because of intolerance may remain on their maximum tolerated dose below 300 mg/day.

• Clo

Initial dose: 200-400 mg/day. Amisulpride recommended dosage: 400-800 mg/day. dosage form:po.duration:8 weeks

• Ami

CRS participants will receive modified electroconvulsive therapy while maintaining stable pharmacological treatment. The treatment course consists of 3 times per week for the first two weeks, followed by 2 times per week for the next two weeks, totaling 10 times per month, which is the same number of treatment sessions as the MST group.

MECT will be administered using a Thymatron System IV device. The electrical charge will be determined according to the participant's age and body weight, with treatment parameters adjusted according to the study protocol and clinical response. Participants will continue the pharmacotherapy regimen received before Phase 2. Medication doses will remain stable whenever clinically feasible; changes will be permitted only when clinically necessary for safety or tolerability and will be documented.

• MECT

CRS participants will receive magnetic seizure therapy while maintaining stable pharmacological treatment. The treatment course consists of 3 times per week for the first two weeks, followed by 2 times per week for the next two weeks, totaling 10 times per month, which is the same number of treatment sessions as the MECT group.

MST will be administered using a MagPro X100 magnetic stimulator equipped with the MagOption MST module. The stimulation frequency will be set at 100 Hz and output intensity at 100% of device output. Stimulation duration will be titrated according to the study protocol and individual participant response. Participants will continue the pharmacotherapy regimen received before Phase 2. Medication doses will remain stable whenever clinically feasible; changes will be permitted only when clinically necessary for safety or tolerability and will be documented.

• MST

Percentage reduction in Positive and Negative Syndrome Scale total score from baseline to Week 8. The PANSS scale consists of 30 items, and each item is rated on a 7-point scale, ranging from 1 (no symptoms) to 7 (extremely severe). The PANSS reduction rate is calculated as: (baseline PANSS total score - Week 8 PANSS total score) / (baseline PANSS total score - 30) × 100%.

Percentage reduction in PANSS total score from baseline of the neuromodulation phase to Week 4. The PANSS scale consists of 30 items, and each item is rated on a 7-point scale, ranging from 1 (no symptoms) to 7 (extremely severe). The PANSS reduction rate is calculated as: (baseline PANSS total score - Week 4 PANSS total score) / (baseline PANSS total score - 30) × 100%.

Change in Clinical Global Impression-Severity (CGI-S) score from baseline to the end of assigned treatment. The scale provides an assessment of both disease severity and overall efficacy.The severity of the disease was scored on an eight-point scale ranging from 0 (not rated) to 7 (extremely severe). The overall efficacy was assessed on an 8-point scale ranging from 0 (not assessed) to 7 (significant deterioration).

Rate of change in Positive and Negative Syndrome Scale total score during the 4-week neuromodulation treatment course. The PANSS scale consists of 30 items, and each item is rated on a 7-point scale, ranging from 1 (no symptoms) to 7 (extremely severe). Repeated PANSS assessments will be used to compare the trajectory and speed of symptom improvement between the MECT and MST groups.

Change in Autobiographical Memory Test(AMT) specificity score from baseline of the neuromodulation phase to Week 4. The AMT specificity score is defined as the number of specific autobiographical memories retrieved in response to 12 cue words, with scores ranging from 0 to 12 and higher scores indicating better autobiographical memory specificity. Change is calculated as Week 4 AMT specificity score minus baseline AMT specificity score; negative values indicate decline in autobiographical memory specificity.

MATRICS consensus cognitive battery (MCCB) consists of 10 tests that assess cognitive performance in 7 domains, including processing speed, attention/vigilance, working memory, verbal memory, visual learning, reasoning and problem solving, and social cognition.The MCCB T-score is calculated based on a Chinese community sample, with a normative mean of 50 and a standard deviation of 10. Higher scores indicate a better neurocognitive outcome.

Change in visuospatial working memory from baseline to Week 4, assessed using the Wechsler Memory Scale-III Spatial Span subtest (WMS III). The WMS III total score ranges from 0 to 32, with higher scores indicating better visuospatial working memory performance.

Change in visual learning from baseline to Week 4, assessed using the Brief Visuospatial Memory Test-Revised (BVMT-R).The BVMT-R total recall score ranges from 0 to 36, where higher scores indicate better visual learning ability.

Change in Personal and Social Performance Scale(PSP) score from baseline to the end of the corresponding treatment phase.The PSP score ranges from 0 to 100, where higher scores indicate better personal and social functioning.

The Barnes Akathisia Scale (BAS) will be used to evaluate objective performance and subjective experience of akathisia, scored from 0 to 3, and the overall clinical evaluation of akathisia is scored from 0 to 5. The higher scores mean a more serious side effect.

Simpson-Angus Extrapyramidal Side Effects Scale (SAS) consists of 10 items, each scored from 0 to 4. The higher scores mean a more serious side effect.

Abnormal Involuntary Movement Scale (AIMS) consists of 12 items. The first 10 of 12 items is scored from 0 to 4, and the last 2 is scored from 0 to 1. The higher scores mean the more obvious abnormal involuntary movement.