Schizophrenia
Conditions
Keywords
Schizophrenia;, Antipsychotics；, first-episode;, switch
Brief summary
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.
Detailed description
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).
Interventions
DRUGPhase 1: Olanzapine
Initial dosage: 5-10 mg; recommended dosage: 5-20 mg/d; dosage form: po. duration: 8 weeks
DRUGPhase 1: Risperidone
Initial dosage: 1-2 mg; recommended dosage: 2-6 mg/d; dosage form: po. duration: 8 weeks
DRUGPhase 1: Amisulpride
Initial dosage: 200-400 mg; recommended dosage: 400-1200 mg/d; dosage form: po. duration: 8 weeks
DRUGPhase 1: Aripiprazole
Initial dosage: 5-10 mg; recommended dosage: 10-30 mg/d; dosage form: po. duration: 8 weeks
DRUGPhase 1: Perphenazine
Initial dosage: 2-4 mg; recommended dosage: 6-36 mg/d; dosage form: po. duration: 8 weeks
DRUGPhase 2: Olanzapine
Initial dosage: 5-10 mg; recommended dosage: 5-20 mg/d; dosage form: po. duration: 8 weeks
DRUGPhase 2: Amisulpride
Initial dosage: 200-400 mg; recommended dosage: 400-1200 mg/d; dosage form: po. duration: 8 weeks
DRUGPhase 2: Clozapine
Initial dosage: 25-50 mg; recommended dosage: 200-400 mg/d; dosage form: po. duration: 8 weeks
OTHERPhase 3A: Clozapine extended treatment or Combined clozapine-MECT therapy
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.
DRUGPhase 3B: Clozapine or another SGAs
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.
Sponsors
Shanghai Mental Health Center
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
16 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
1. Patients must meet the DSM-5 diagnostic criteria for schizophrenia , schizophreniform disorder or schizoaffective disorder, based upon the structured clinical interview by research psychiatrist using Mini International Neuropsychiatric Interview 7.0 (M.I.N.I. 7.0), review of their clinical records, and input from available informants. 2. Inpatients or outpatients. 3. 16-45 years of age. 4. First episode, and the course no more than 3 years. 5. Drug-naïve, or any antipsychotic medication had been used no more than 2 weeks, and the cumulative antipsychotic drug exposure time no more than 6 weeks in lifetime. 6. The severity of psychotic symptoms is moderate or above, and the specific criteria including: have a score ≥4 on at least one item of Positive and Negative Syndrome Scale (PANSS) (delusions, conceptual disorganization, hallucinatory behavior, grandiosity, or suspiciousness/persecution), and PANSS total score \>70. 7. Patients must demonstrate adequate decisional capacity to make a choice about participating in this research study and must provide informed consent to participate.
Exclusion criteria
1. Patients were excluded if more than 3 years had passed since the onset of psychosis; 2. They met any of the contraindications for any of the study drugs; 3. Mental symptoms were caused by organic disease, severe physical illness, psychoactive substance dependence, mental retardation; 4. They were pregnancy or breast-feeding; they were extreme agitation, stupor or negative suicide.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment efficacy rate | baseline,0.5 months,1 months, 2 months,4 months , 6 months , 8 months and 12 months | 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). |
| All-cause dropout rate | baseline,0.5 months,1 months, 2 months,4 months , 6 months , 8 months and 12 months | Marked by the treatment discontinuation for any reasons, including poor efficacy, intolerance of adverse reactions, poor compliance and other reasons. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline in Clinical Global Impression Scale-Severity (CGI-S) | baseline,0.5 months,1 months, 2 months,4 months , 6 months , 8 months and 12 months | 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). |
| Change from baseline in Calgary Depression Scale for Schizophrenia (CDSS) | baseline,0.5 months,1 months, 2 months,4 months , 6 months , 8 months and 12 months | 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. |
| Social function | baseline,2 months,4 months and 6 months and 12 months | 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. |
| Life quality: The Heinirich Quality of life Scale (HRQOL) | baseline,2 months,4 months and 6 months and 12 months | The Heinirich Quality of life Scale (HRQOL) consists of 21 items, each scored from 0 to 6. The higher scores mean a better outcome. |
| Life quality: Medication Satisfaction Questionnaire (MSN) | baseline,2 months,4 months and 6 months and 12 months | Medication Satisfaction Questionnaire (MSN) has one item, scored from 1 to 7. The higher scores indicate higher satisfaction with the medication. |
| Life quality: Subjective Well-being under Neuroleptics (SWN) | baseline,2 months,4 months and 6 months and 12 months | Subjective Well-being under Neuroleptics (SWN) consists of 20 items, each scored from 1-6. |
| Extrapyramidal adverse effects: The Barnes Akathisia Scale (BAS) | baseline,0.5 months,1 months, 2 months,4 months , 6 months , 8 months and 12 months | 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. |
| Extrapyramidal adverse effects: Simpson-Angus Extrapyramidal Side Effects Scale (SAS) | baseline,0.5 months,1 months, 2 months,4 months , 6 months , 8 months and 12 months | 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. |
| Extrapyramidal adverse effects: Abnormal Involuntary Movement Scale (AIMS) | baseline,0.5 months,1 months, 2 months,4 months , 6 months , 8 months and 12 months | 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. |
| Sexual dysfunction | baseline,0.5 months,1 months, 2 months,4 months , 6 months , 8 months and 12 months | 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. |
| Change from baseline in cognitive function: MCCB | baseline,2 months,4 months and 6 months and 12 months | 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. |
| Change from baseline in cognitive function: NBSC | baseline,2 months,4 months and 6 months and 12 months | 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) |
| Safety index: Blood pressure | baseline,2 months,4 months and 6 months and 12 months | Blood pressure in mmHg |
| Safety index: Heart rate | baseline,2 months,4 months and 6 months and 12 months | Heart rate |
| Safety index: Respiratory rate | baseline,2 months,4 months and 6 months and 12 months | respiratory rate |
| Safety index: Vital signs | baseline,2 months,4 months and 6 months and 12 months | body temperature in celsius |
| Safety index: Blood count | baseline,2 months,4 months and 6 months and 12 months | Blood count |
| Change from baseline in Clinician-Rated Dimensions of Psychosis Symptom severity (CRDPS) | baseline,0.5 months,1 months, 2 months,4 months , 6 months , 8 months and 12 months | 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). |
| Safety index: renal function | baseline,2 months,4 months and 6 months and 12 months | \*Concentration of serum creatinine, blood urea nitrogen, uric acid, serum cystatin C, homocysteine. |
| Safety index: thyroid function | baseline,2 months,4 months and 6 months and 12 months | Thyroid function related hormone levels will be tested, including FT3, FT4, T3, TSH, and T4. |
| Safety index: prolactin | baseline,2 months,4 months and 6 months and 12 months | Serum prolactin level |
| Safety index: QTc interval | baseline,2 months,4 months and 6 months and 12 months | QTc interval |
| Metabolic side effects: body weight | baseline,2 months,4 months and 6 months and 12 months | Weight in kilograms |
| Metabolic side effects: BMI | baseline,2 months,4 months and 6 months and 12 months | BMI in kg/m\^2 |
| Metabolic side effects: waist circumstance | baseline,2 months,4 months and 6 months and 12 months | Waist circumstance in centimeter |
| Metabolic side effects: fasting blood-glucose | baseline,2 months,4 months and 6 months and 12 months | Fasting blood-glucose |
| Metabolic side effects: insulin index | baseline,2 months,4 months and 6 months and 12 months | Insulin resistance was assessed using homeostasis model assessment (HOMA-IR). |
| Metabolic side effects: serum lipid level | baseline,2 months,4 months and 6 months and 12 months | Concentration of serum triglyceride, LDL-C(low density lipoprotein cholesterol), HDL-C(high density lipoprotein cholesterol) and apolipoprotein. |
| Metabolic side effects: assessment of feeding behavior | baseline,2 months,4 months and 6 months and 12 months | 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. |
| Metabolic side effects: Visual Analogue Scale (VAS) | baseline,2 months,4 months and 6 months and 12 months | 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. |
| Metabolic side effects: Physical Activity Evaluation | baseline,2 months,4 months and 6 months and 12 months | Physical Activity Evaluation |
| MRI examinaitons | baseline,2 months and 4 months | 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. |
| Pharmacogenomics | baseline,2 months,4 months | \*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. |
| Lipidomics | baseline,2 months,4 months | \*Serum sample was collected for lipidomic analysis to investigate correlation between serum lipids and rapid weight gain in first-episode schizophrenia. |
| Safety index: Liver function | baseline,2 months,4 months and 6 months and 12 months | \*Concentration of ALT, AST, GGT, ALP, TB, and DB. |
| Cost inventory | baseline,2 months,4 months, 6 months and 12 months | 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. |
Countries
China
Outcome results
None listed