Sequential Treatment Approaches for Treatment-Resistant Schizophrenia (STATRS)

Sequential Treatment Approaches for Treatment-Resistant Schizophrenia (STATRS): A Randomized Controlled Trial of Pharmacological Optimization and Neuromodulation in Chinese Patients

The goal of this study is to optimize treatment strategies for Chinese patients with treatment-resistant schizophrenia (TRS). It will compare two types of treatment:

1. Drug therapy with clozapine alone or in combination with other medications.
2. Neuromodulation therapy, modified electroconvulsive therapy (MECT) or magnetic seizure therapy (MST).

The study aims to determine which approach provides better symptom improvement, fewer cognitive side effects, and greater overall safety. The results may provide important clinical evidence to guide future treatment decisions for patients with TRS.

Study Overview

• Status: Recruiting
• Conditions: Treatment-resistant Schizophrenia
• Intervention / Treatment: Drug: [Phase 1] Clozapine; Drug: [Phase 1] Aripiprazole; Drug: [Phase 1] Amisulpride; Device: [Phase 2] Modified Electroconvulsive Therapy (MECT); Device: [Phase 2] Magnetic Seizure Therapy (MST)

Detailed Description

This is a sequential, assessor-blinded randomized controlled trial in Chinese patients with treatment-resistant schizophrenia (TRS). The study consists of two treatment components.

First, clozapine-naive TRS participants will enter an 8-week pharmacological optimization phase and be assigned to one of three treatment groups: clozapine monotherapy, clozapine plus amisulpride, or clozapine plus aripiprazole.

Second, eligible participants will enter a 4-week assessor-blinded neuromodulation phase comparing modified electroconvulsive therapy (MECT) and magnetic seizure therapy (MST). Participants for this phase are either (1) patients who have previously received clozapine and are hospitalized due to symptom exacerbation, or (2) participants who completed the pharmacological optimization phase and showed inadequate response, defined as less than 25% reduction in PANSS total score at Week 8.

The study is expected to provide evidence on the effectiveness, cognitive safety, and overall tolerability of these treatments for TRS. The project has important clinical significance.

• Study Type: Interventional
• Enrollment (Estimated): 300
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: DengTang Liu, MD, PhD; Phone Number: +86-18017311138; Email: erliu110@126.com

Study Locations

• China
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China, 200030
      • Recruiting
      • Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine
      • Contact: DengTang Liu, MD, PhD; Phone Number: +862164387250-73775; Email: erliu110@126.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

General inclusion criteria applicable to all participants:

• Aged 18 to 55 years at the time of informed consent.
• Participants must meet DSM-5 diagnostic criteria for schizophrenia.
• Meet TRRIP-based criteria for treatment-resistant schizophrenia, defined as inadequate response to at least two different antipsychotic treatment trials, each administered at an adequate dose equivalent to ≥600 mg/day chlorpromazine for a minimum duration of 6 weeks. Have moderate or greater functional impairment, operationalized as a Personal and Social Performance Scale (PSP) score ≤70. Treatment adherence will be evaluated based on available medical records, prescription history and caregiver report.

Eligibility for the pharmacological optimization phase:

• Participants eligible for the pharmacological optimization phase must meet the general TRS criteria above and must be clozapine-naive.

Eligibility for the neuromodulation phase:

• Participants eligible for the neuromodulation phase must meet the TRS criteria described above.

• Participants may enter the neuromodulation phase through either of the following pathways:

  1. Participants who have previously received clozapine treatment and are hospitalized due to symptom exacerbation or clinical worsening.
  2. Clozapine-naive TRS participants who complete the pharmacological optimization phase and show inadequate response, defined as less than 25% reduction in PANSS total score at Week 8.

Exclusion Criteria:

• Organic brain disease or neurological disorder that may account for psychotic symptoms, including epilepsy where clinically relevant.
• Current psychoactive substance dependence or substance-related disorder.
• Intellectual disability or Mental retardation.
• Pregnancy, breastfeeding, or planning pregnancy during the study period.
• Severe physical illness or medical contraindication to study medication, MECT, MST.
• Extreme agitation, stupor, active suicidal risk, severe non-cooperation, or high-risk conditions.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Single

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: [Phase 1] Clozapine Monotherapy; 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.	Drug: [Phase 1] Clozapine; 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.; Other Names: Clo
Experimental: [Phase 1] Clozapine + Aripiprazole; 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.	Drug: [Phase 1] Clozapine; 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.; Other Names: Clo; Drug: [Phase 1] Aripiprazole; Initial dose: 5-10 mg/day. Aripiprazole recommended dosage:10-15 mg/day. dosage form:po.duration:8 weeks; Other Names: Ari
Experimental: [Phase 1] Clozapine + Amisulpride; 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.	Drug: [Phase 1] Clozapine; 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.; Other Names: Clo; Drug: [Phase 1] Amisulpride; Initial dose: 200-400 mg/day. Amisulpride recommended dosage: 400-800 mg/day. dosage form:po.duration:8 weeks; Other Names: Ami
Active Comparator: [Phase 2] Modified Electroconvulsive Therapy (MECT); 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.	Device: [Phase 2] Modified Electroconvulsive Therapy (MECT); 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.; Other Names: MECT
Experimental: [Phase 2] Magnetic Seizure Therapy (MST); 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.	Device: [Phase 2] Magnetic Seizure Therapy (MST); 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.; Other Names: MST

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PANSS reduction rate at Week 8 during the pharmacological optimization phase	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%.	Baseline of pharmacological optimization phase and Week 8
PANSS reduction rate at Week 4 during the neuromodulation phase	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%.	Baseline of neuromodulation phase and Week 4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in CGI-S score	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).	Pharmacological optimization: baseline and Week 8; Neuromodulation: baseline and Week 4.
Trajectory of PANSS total score improvement during the neuromodulation phase	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.	Baseline of the neuromodulation phase and weekly during the 4-week neuromodulation treatment course
Change in AMT specificity score during the neuromodulation phase	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.	Baseline of the neuromodulation phase and Week 4
Change from baseline in cognitive function: MCCB	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.	Baseline, Month 1, and Month 2 during the pharmacological optimization phase; and Week 4 of the neuromodulation phase.
Change in visuospatial working memory during the neuromodulation phase	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.	Baseline of the neuromodulation phase and weekly during the 4-week neuromodulation phase
Change in visual learning during the neuromodulation phase	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.	Baseline of the neuromodulation phase and weekly during the 4-week neuromodulation phase
Change in personal and social functioning	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.	Baseline, Week 8 of the pharmacological optimization phase and Week 4 of the neuromodulation phase
Extrapyramidal adverse effects: The Barnes Akathisia Scale (BAS)	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.	Baseline, Week 4, Week 8 during the pharmacological optimization phase and Week 1, Week 2, Week 3, Week 4 during the neuromodulation phase
Extrapyramidal adverse effects: Simpson-Angus Extrapyramidal Side Effects Scale (SAS)	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.	Baseline, Week 4, Week 8 during the pharmacological optimization phase and Week 1, Week 2, Week 3, Week 4 during the neuromodulation phase
Extrapyramidal adverse effects: Abnormal Involuntary Movement Scale (AIMS)	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.	Baseline, Week 4, Week 8 during the pharmacological optimization phase and Week 1, Week 2, Week 3, Week 4 during the neuromodulation phase

Collaborators and Investigators

• Sponsor: Shanghai Mental Health Center
• Investigators: Principal Investigator: DengTang Liu, Shanghai Mental Health Center

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2026
• Primary Completion (Estimated): December 1, 2030
• Study Completion (Estimated): December 1, 2030

Study Registration Dates

• First Submitted: July 14, 2026
• First Submitted That Met QC Criteria: November 2, 2026
• First Posted (Actual): November 5, 2026

Study Record Updates

• Last Update Posted (Actual): November 5, 2026
• Last Update Submitted That Met QC Criteria: November 2, 2026
• Last Verified: October 1, 2026

More Information

Terms related to this study

• Keywords: Neuromodulation; Tratment-resistant schizophrenia; Clozapine combination therapy
• Additional Relevant MeSH Terms: Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Schizophrenia; Schizophrenia, Treatment-Resistant; Health Care Quality, Access, and Evaluation; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Investigative Techniques; Epidemiologic Methods; Hydrocarbons; Hydrocarbons, Cyclic; Health Care Evaluation Mechanisms; Quality of Health Care; Public Health; Environment and Public Health; Carboxylic Acids; Hydrocarbons, Aromatic; Amides; Inorganic Chemicals; Chlorine Compounds; Benzene Derivatives; Oxides; Oxygen Compounds; Acids, Noncarboxylic; Acids; Acids, Carbocyclic; Quinolones; Quinolines; Benzoates; Reactive Oxygen Species; Free Radicals; Dibenzazepines; Heterocyclic Compounds, 3-Ring; Benzamides; Piperazines; Epidemiologic Study Characteristics; Clinical Trials as Topic; Clinical Studies as Topic; Aripiprazole; Amisulpride; Clozapine; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Hypochlorous Acid
• Other Study ID Numbers: 2025-SFDL01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

IPD Plan Description

Individual participant data will not be shared because the study involves sensitive clinical, cognitive, imaging, and biological data from patients with schizophrenia, and data sharing is limited by participant consent and institutional ethics requirements. Only aggregate study results will be reported.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No