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This study is a sequential multiple-assignment randomized trial (RCT) of antipsychotic medication treatment in first-episode schizophrenia patients in the real-world settings.Through analysis of treatment efficacy rate and adverse reactions and pharmacoeconomic evaluation, this project intends to provide evidence for the selection of antipsychotics in FES patients as well as the efficacy and safety of using clozapine in the early phase of schizophrenia treatment by comparing with other SGAs.
A total of 720 first-episode schizophrenia (FES) patients will be enrolled and followed up for 12 months in this study. The trial includes three treatment phases (each phase lasting for 8 weeks) and a naturalistic follow-up phase. Phase 1 is a 8-week randomized controlled trial; patients will be randomly assigned to one of the treatments with oral olanzapine, risperidone, amisulpride, aripiprazole or perphenazine. Patients who had an acceptable response to the randomly assigned drug therapy will remain on that treatment for a 12-month treatment period. Subjects who fail to respond in phase 1 will switch to phase 2, an equipoise-stratified randomization trial, in which patients will be randomly assigned to oral olanzapine, amisulpride or clozapine for another 8 weeks. No-responders in phase 2 will further enter an open label trial (phase 3). Patients who receive clozapine in phase 2 will be assigned to an extended clozapine treatment or modified electroconvulsive therapy add-on therapy (Phase 3A). Patients who were not assigned to clozapine in phase 2 will be assigned to treatment with clozapine or another SGAs not previously used in phase 1 and 2 (Phase 3B).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 【Phase 1】 Olanzapine RCT | Experimental | Phase 1 of the trial is a 8-week randomized controlled trial (RCT); patients will be randomly assigned to one of five treatment arms with different oral antipsychotics, one of which is 'Olanzapine RCT'. Non-responders or patients with intolerable side effects in phase 1 will switch to phase 2. |
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| 【Phase 1】 Risperidone RCT | Experimental | Phase 1 of the trial is a 8-week randomized controlled trial (RCT); patients will be randomly assigned to one of five treatment arms with different oral antipsychotics, one of which is 'Risperidone RCT'. Non-responders or patients with intolerable side effects in phase 1 will switch to phase 2. |
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| 【Phase 1】 Amisulpride RCT | Experimental | Phase 1 of the trial is a 8-week randomized controlled trial (RCT); patients will be randomly assigned to one of five treatment arms with different oral antipsychotics, one of which is 'Amisulpride RCT'. Non-responders or patients with intolerable side effects in phase 1 will switch to phase 2. |
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| 【Phase 1】 Aripiprazole RCT | Experimental | Phase 1 of the trial is a 8-week randomized controlled trial (RCT); patients will be randomly assigned to one of five 8-week treatment arms with different oral antipsychotics, one of which is 'Aripiprazole RCT'. Non-responders or patients with intolerable side effects in phase 1 will switch to phase 2. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Phase 1: Olanzapine | Drug | Initial dosage: 5-10 mg; recommended dosage: 5-20 mg/d; dosage form: po. duration: 8 weeks |
|
| Measure | Description | Time Frame |
|---|---|---|
| Treatment efficacy rate | A 40% reduction or more of the total score in the Positive and Negative Syndrome Scale (PANSS). 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). | baseline,0.5 months,1 months, 2 months,4 months , 6 months , 8 months and 12 months |
| All-cause dropout rate | Marked by the treatment discontinuation for any reasons, including poor efficacy, intolerance of adverse reactions, poor compliance and other reasons. | baseline,0.5 months,1 months, 2 months,4 months , 6 months , 8 months and 12 months |
| Measure | Description | Time Frame |
|---|---|---|
| Change from baseline in Clinician-Rated Dimensions of Psychosis Symptom severity (CRDPS) | Clinician-Rated Dimensions of Psychosis Symptom severity (CRDPS). The CRDPS scale evaluates eight symptom dimensions of psychosis. Each symptom domain is rated for the past 7 days on a 5-point scale ranging from 0 (absent) to 4 (present and severe). | baseline,0.5 months,1 months, 2 months,4 months , 6 months , 8 months and 12 months |
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Inclusion criteria:
Exclusion criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Beijing Anding Hospital of Capital Medical University | Beijing | Beijing Municipality | 100000 | China | ||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 41811299 | Derived | Li X, Lu C, Zhai Z, Smith RC, Zhang S, Wang H, Wang C, Yao Z, Chen Z, Xu X, Xie S, Feng T, Gao T, Dong Y, Zhuo K, Xiang Q, Jin H, Davis JM, Jiang K, Xu Y, Leucht S, Liu D. Clozapine After 1 Failed Antipsychotic Drug Trial in First-Episode Psychosis: A Randomized Clinical Trial. JAMA Psychiatry. 2026 Jun 1;83(6):570-580. doi: 10.1001/jamapsychiatry.2026.0086. | |
| 33279374 |
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The sequential multiple assignment randomized trial design (SMART) design is based on the combination of sequential therapy and dynamic therapy, which is more suitable to assess the effectiveness of treatment options in the real world setting. Participants who had an acceptable response to the randomly assigned drug therapy will remain on that treatment for a 12-month treatment period, while non-responders will move to the next phase of the study to receive a new treatment.
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| 【Phase 1】 Perphenazine RCT | Experimental | Phase 1 of the trial is a 8-week randomized controlled trial (RCT); patients will be randomly assigned to one of five treatment arms with different oral antipsychotics, one of which is 'Perphenazine RCT'. Non-responders or patients with intolerable side effects in phase 1 will switch to phase 2. |
|
| 【Phase 2】 Olanzapine ESR | Experimental | Non-responders or patients with intolerable side effects in phase 1 will switch to phase 2, a 8-week equipoise-stratified randomization (ESR) trial; patients treated with risperidone, amisulpride, aripiprazole or perphenazine in phase 1 will be randomly assigned to one of three treatment arms, one of which is 'Olanzapine ESR'. Non-responders or patients with intolerable side effects in phase 2 will switch to phase 3. |
|
| 【Phase 2】 Amisulpride ESR | Experimental | Non-responders or patients with intolerable side effects in phase 1 will switch to phase 2, a 8-week equipoise-stratified randomization (ESR) trial; patients treated with olanzapine, risperidone, aripiprazole or perphenazine in phase 1 will be randomly assigned to one of three treatment arms, one of which is 'Amisulpride ESR'. Non-responders or patients with intolerable side effects in phase 2 will switch to phase 3. |
|
| 【Phase 2】 Clozapine ESR | Experimental | Non-responders or patients with intolerable side effects in phase 1 will switch to phase 2, a 8-week equipoise-stratified randomization (ESR) trial; patients in phase 1 will be randomly assigned to one of three treatment arms, one of which is 'Clozapine ESR'. Non-responders or patients with intolerable side effects in phase 2 will switch to phase 3. |
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| 【Phase 3】 Clozapine extended treatment or MECT add-on therapy | Experimental | If a patient received clozapine in phase 2 failed to response, the individual will be assigned to the clozapine extended treatment or modified electroconvulsive therapy (MECT) add-on therapy. |
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| 【Phase 3】 Clozapine or another SGAs (olanzapine, amisulpride, risperidone, or aripiprazole) | Experimental | Non-clozapine users in phase 2 will be assigned to clozapine or another Second generation antipsychotics (SGAs) not previously used in phase 1 and 2. |
|
| Phase 1: Risperidone | Drug | Initial dosage: 1-2 mg; recommended dosage: 2-6 mg/d; dosage form: po. duration: 8 weeks |
|
| Phase 1: Amisulpride | Drug | Initial dosage: 200-400 mg; recommended dosage: 400-1200 mg/d; dosage form: po. duration: 8 weeks |
|
| Phase 1: Aripiprazole | Drug | Initial dosage: 5-10 mg; recommended dosage: 10-30 mg/d; dosage form: po. duration: 8 weeks |
|
| Phase 1: Perphenazine | Drug | Initial dosage: 2-4 mg; recommended dosage: 6-36 mg/d; dosage form: po. duration: 8 weeks |
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| Phase 2: Olanzapine | Drug | Initial dosage: 5-10 mg; recommended dosage: 5-20 mg/d; dosage form: po. duration: 8 weeks |
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| Phase 2: Amisulpride | Drug | Initial dosage: 200-400 mg; recommended dosage: 400-1200 mg/d; dosage form: po. duration: 8 weeks |
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| Phase 2: Clozapine | Drug | Initial dosage: 25-50 mg; recommended dosage: 200-400 mg/d; dosage form: po. duration: 8 weeks |
|
| Phase 3A: Clozapine extended treatment or Combined clozapine-MECT therapy | Other | Clozapine extended treatment: dosage: 200-600 mg/d; dosage form: po. Combined clozapine-MECT therapy: Dosage of clozapine: 200-600 mg/d; The modified electroconvulsive therapy (MECT) will be administered three times per week for the first 2 weeks, then twice a week for the next 2 weeks. The total treatment duration is about one month. |
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| Phase 3B: Clozapine or another SGAs | Drug | Clozapine: Initial dosage: 25-50 mg; recommended dosage: 200-600 mg/d; duration: 8 weeks Another Second generation antipsychotics (SGAs) (not previously used in phase 1 and 2): Olanzapine, risperidone, amisulpride, or aripiprazole The dosage of each drug is the same as that of phase 1 and phase 2. |
|
| Cost inventory | Direct medical costs (for example, antipsychotics costs, medical examinations costs, health care and service costs and adverse events costs) and indirect costs (such as traffic, nursing, and losing of labor) of the treatments. | baseline,2 months,4 months, 6 months and 12 months |
| Change from baseline in Clinical Global Impression Scale-Severity (CGI-S) | Clinical Global Impression Scale-Severity (CGI-S), including assessment of 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). | baseline,0.5 months,1 months, 2 months,4 months , 6 months , 8 months and 12 months |
| Change from baseline in Calgary Depression Scale for Schizophrenia (CDSS) | The Calgary Depression Scale for Schizophrenia (CDSS) consists of nine items, each scored from 0 to 3. A total score greater than 6 is considered depression. | baseline,0.5 months,1 months, 2 months,4 months , 6 months , 8 months and 12 months |
| Social function | Chinese version of UPSA-B, the UCSD (University of California,San Diego) Performance-based Skills Assessment-Brief, consists of two parts: financial skill (A and B) and communication skill. The score of financial skill A range from 0 to 5. The score of financial skill B range from 0 to 6. The score of communication skill range from 0 to 9. The higher scores mean a better outcome. | baseline,2 months,4 months and 6 months and 12 months |
| Life quality: The Heinirich Quality of life Scale (HRQOL) | The Heinirich Quality of life Scale (HRQOL) consists of 21 items, each scored from 0 to 6. The higher scores mean a better outcome. | baseline,2 months,4 months and 6 months and 12 months |
| Life quality: Medication Satisfaction Questionnaire (MSN) | Medication Satisfaction Questionnaire (MSN) has one item, scored from 1 to 7. The higher scores indicate higher satisfaction with the medication. | baseline,2 months,4 months and 6 months and 12 months |
| Life quality: Subjective Well-being under Neuroleptics (SWN) | Subjective Well-being under Neuroleptics (SWN) consists of 20 items, each scored from 1-6. | baseline,2 months,4 months and 6 months and 12 months |
| 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,0.5 months,1 months, 2 months,4 months , 6 months , 8 months and 12 months |
| 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,0.5 months,1 months, 2 months,4 months , 6 months , 8 months and 12 months |
| 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,0.5 months,1 months, 2 months,4 months , 6 months , 8 months and 12 months |
| Sexual dysfunction | Arizona Sexual Experiences Scale (ASEX) includes 5 items, each scored from 1-6. A total score greater than or equal to 19 and any item greater than or equal to 5, or any 3 items greater than or equal to 4, can help clinical diagnosis of sexual dysfunction. | baseline,0.5 months,1 months, 2 months,4 months , 6 months , 8 months and 12 months |
| 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. | baseline,2 months,4 months and 6 months and 12 months |
| Change from baseline in cognitive function: NBSC | New cognitive battery for patients with schizophrenia in China(NBSC). NBSC includes 4 tests from MCCB and 5 new tests (Trial making A, BACS, HVLT-R learning and recall, CPTIP, dominant hand Grooved Pegboard, Color Trails I and II, PASAT) | baseline,2 months,4 months and 6 months and 12 months |
| Safety index: Blood pressure | Blood pressure in mmHg | baseline,2 months,4 months and 6 months and 12 months |
| Safety index: Heart rate | Heart rate | baseline,2 months,4 months and 6 months and 12 months |
| Safety index: Respiratory rate | respiratory rate | baseline,2 months,4 months and 6 months and 12 months |
| Safety index: Vital signs | body temperature in celsius | baseline,2 months,4 months and 6 months and 12 months |
| Safety index: Blood count | Blood count | baseline,2 months,4 months and 6 months and 12 months |
| Safety index: Liver function | *Concentration of ALT, AST, GGT, ALP, TB, and DB. | baseline,2 months,4 months and 6 months and 12 months |
| Safety index: renal function | *Concentration of serum creatinine, blood urea nitrogen, uric acid, serum cystatin C, homocysteine. | baseline,2 months,4 months and 6 months and 12 months |
| Safety index: thyroid function | Thyroid function related hormone levels will be tested, including FT3, FT4, T3, TSH, and T4. | baseline,2 months,4 months and 6 months and 12 months |
| Safety index: prolactin | Serum prolactin level | baseline,2 months,4 months and 6 months and 12 months |
| Safety index: QTc interval | QTc interval | baseline,2 months,4 months and 6 months and 12 months |
| Metabolic side effects: body weight | Weight in kilograms | baseline,2 months,4 months and 6 months and 12 months |
| Metabolic side effects: BMI | BMI in kg/m^2 | baseline,2 months,4 months and 6 months and 12 months |
| Metabolic side effects: waist circumstance | Waist circumstance in centimeter | baseline,2 months,4 months and 6 months and 12 months |
| Metabolic side effects: fasting blood-glucose | Fasting blood-glucose | baseline,2 months,4 months and 6 months and 12 months |
| Metabolic side effects: insulin index | Insulin resistance was assessed using homeostasis model assessment (HOMA-IR). | baseline,2 months,4 months and 6 months and 12 months |
| Metabolic side effects: serum lipid level | Concentration of serum triglyceride, LDL-C(low density lipoprotein cholesterol), HDL-C(high density lipoprotein cholesterol) and apolipoprotein. | baseline,2 months,4 months and 6 months and 12 months |
| Metabolic side effects: assessment of feeding behavior | Three-Factor Eating Questionnaire (TFEQ-21) consists of 21 items, including 3 dimensions (non-controlled eating, cognitively restricted eating, and emotional eating). Each item is scored from 1 to 4, and the first 16 item requires reverse scoring before calculating dimension scores. The higher scores mean a higher tendency for non-controlled eating, cognitively restricted eating, and emotional eating. | baseline,2 months,4 months and 6 months and 12 months |
| Metabolic side effects: Visual Analogue Scale (VAS) | Visual Analogue Scale (VAS) was used to evaluate the desire to eat, hunger sensation and willingness to eat. The scale consists of 3 items, each scored from 0 to 10. The higher scores mean a stronger desire to eat, hunger sensation and willingness to eat. | baseline,2 months,4 months and 6 months and 12 months |
| Metabolic side effects: Physical Activity Evaluation | Physical Activity Evaluation | baseline,2 months,4 months and 6 months and 12 months |
| MRI examinaitons | Change of grey matter volume and functional connectivity in certain brain region was focused in the MRI examinations, to evaluate the ability of MRI examinaitons (structural MRI, functional MRI and Magnetic Resonance Spectroscopy) to predict response to antipsychotic treatment in first-episode schizophrenia. | baseline,2 months and 4 months |
| Pharmacogenomics | *Blood sample was collected and genes related to drug efficacy and adverse reaction were tested to evaluate the ability of pharmacogenomics to predict response to antipsychotic treatment in first-episode schizophrenia. | baseline,2 months,4 months |
| Lipidomics | *Serum sample was collected for lipidomic analysis to investigate correlation between serum lipids and rapid weight gain in first-episode schizophrenia. | baseline,2 months,4 months |
| Renmin Hospital of Wuhan University |
| Wuhan |
| Hubei |
| 430000 |
| China |
| Nanjing Brain Hospital Affiliated to Nanjing Medical University | Nanjing | Jiangsu | 210000 | China |
| Dalian Seventh People's Hospital | Dalian | Liaoning | 116000 | China |
| Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine | Shanghai | Shanghai Municipality | 200030 | China |
| First Affiliated Hospital of Kunming Medical University | Kunming | Yunnan | 650000 | China |
| Hangzhou Seventh People's Hospital | Hangzhou | Zhejiang | 310000 | China |
| Li X, Guo X, Fan X, Feng T, Wang C, Yao Z, Xu X, Chen Z, Wang H, Xie S, He J, Zhuo K, Xiang Q, Cen H, Wang J, Smith RC, Jin H, Keshavan MS, Marder SR, Davis JM, Jiang K, Xu Y, Liu D. Sequential Multiple-Assignment Randomized Trials to Compare Antipsychotic Treatments (SMART-CAT) in first-episode schizophrenia patients: Rationale and trial design. Schizophr Res. 2021 Apr;230:87-94. doi: 10.1016/j.schres.2020.11.010. Epub 2020 Dec 2. |
| ID | Term |
|---|---|
| D012559 | Schizophrenia |
| ID | Term |
|---|---|
| D019967 | Schizophrenia Spectrum and Other Psychotic Disorders |
| D001523 | Mental Disorders |
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