SMART Design to Compare Antipsychotic Treatments in Treatment-Resistant Schizophrenia

Study Overview
=================
Brief Summary
-----------------
The project intends to take treatment-resistant schizophrenia as the research object and uses sequential multiple assignment randomized trial(SMART) design to define the treatment recommendations of different drug regimen for treatment resistant schizophrenia and to determine the physical enhancement regimen for clozapine-resistant schizophrenia and to explore targeted regulation scheme for ultra-resistant schizophrenia.

Detailed Description
-----------------
This trial is a sequential multiple-assignment RCT design of antipsychotic drugs, planning to recruit 162 people with treatment-resistant schizophrenia followed for 12 months. The study includes three treatment phases and a naturalistic follow-up phase. Participants who meet the response criteria remain on that treatment for the duration of 12-month treatment. If the participants fail the treatment or can't tolerant the side effects, the patient moves to the next phase of the study to receive a new treatment.

Official Title
-----------------
Sequential Multiple-Assignment Randomized Trials to Compare Antipsychotic Treatments in Treatment-Resistant Schizophrenia

Conditions
-----------------
Treatment-resistant Schizophrenia

Intervention / Treatment
-----------------
* Drug: Clozapine
* Device: MECT
* Device: DBS


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: meet the DSM-5 diagnostic criteria for schizophrenia, be 18-55 years of age, treatment-resistant schizophrenia:no response to sufficient doses (400-600 mg/ day CPZ equivalent) of at least two antipsychotics in the past 5 years, Informed consent. Exclusion Criteria: Patients with medical or psychiatric comorbidities and those who require concomitant other medications are excluded. Patients with contraindications to even one of the proposed treatment arms are excluded. Patients with risks such as extreme agitation, stupor or suicide are excluded. Female patients with pregnancy or breast-feeding are also excluded.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Clozapine<br>Clozapine 400   600mg/d or plasma concentration >350ng/ml | Drug: Clozapine<br>* Clozapine 400   600mg/d or plasma concentration >350ng/ml Amisulpride 200-800mg/d Gingke biloba 120-360mg/d<br>* Other names: Clozapine+Gingke biloba;|
| Experimental: Clozapine+Amisulpride<br>Clozapine 400   600mg/d or plasma concentration >350ng/ml Amisulpride 200-800mg/d | Drug: Clozapine<br>* Clozapine 400   600mg/d or plasma concentration >350ng/ml Amisulpride 200-800mg/d Gingke biloba 120-360mg/d<br>* Other names: Clozapine+Gingke biloba;|
| Experimental: Clozapine+Gingke biloba<br>Clozapine 400   600mg/d or plasma concentration >350ng/ml Gingke biloba 120-360mg/d | Drug: Clozapine<br>* Clozapine 400   600mg/d or plasma concentration >350ng/ml Amisulpride 200-800mg/d Gingke biloba 120-360mg/d<br>* Other names: Clozapine+Gingke biloba;|
| Experimental: MECT<br>MECT:The treatment lasted for 4 months,16 times in total | Device: MECT<br>* MECT:The treatment lasted for 4 months,16 times in total MST:The treatment lasted for 4 months,16 times in total<br>* Other names: MST;|
| Experimental: MST<br>MST:The treatment lasted for 4 months,16 times in total | Device: MECT<br>* MECT:The treatment lasted for 4 months,16 times in total MST:The treatment lasted for 4 months,16 times in total<br>* Other names: MST;|
| Experimental: DBS<br>Two electrode emplacement groups (target nucleus accumbens and hippocampus respectively) | Device: DBS<br>* Two electrode emplacement groups (target nucleus accumbens and hippocampus respectively)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate | 25% or greater change in Positive and Negative Syndrome Scale (PANSS) | Change from baseline PANSS score at 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse reactions | The Barnes Akathisia Scale (BAS) (0,14,higher scores mean a worse outcome), | baseline, 4 weeks, 8 weeks, 12 weeks, 14 weeks, 16 weeks,32 weeks | 
| Adverse reactions | Simpson-Angus Extrapyramidal Side Effects Scale (SAS) (0,40,higher scores mean a worse outcome) | baseline, 4 weeks, 8 weeks, 12 weeks, 14 weeks, 16 weeks,32 weeks | 
| Adverse reactions | Abnormal Involuntary Movement Scale (AIMS) (0,42,higher scores mean a worse outcome) | baseline, 4 weeks, 8 weeks, 12 weeks, 14 weeks, 16 weeks,32 weeks | 
| Neurocognitive assessments and social function | The University of California, San Diego (UCSD) Performance- based Skills Assessment-Brief (UPSA-B) (0,100,higher scores mean a better outcome) is used to evaluate the social function, | baseline, 6 weeks, 3 months, 6 months, 9 months, 12 months | 
| Neurocognitive assessments and social function | The MATRICS consensus cognitive battery (MCCB) has been widely used to evaluate cognitive deficits in schizophrenia patients(0%,100%,higher scores mean a better outcome) | baseline, 6 weeks, 3 months, 6 months, 9 months, 12 months | 
| Clinical assessements | PANSS (30,210,higher scores mean a worse outcome), | baseline, 4 weeks, 8 weeks, 12 weeks, 14 weeks, 16 weeks,32 weeks | 
| Clinical assessements | Clinician-Rated Dimensions of Psychosis Symptom Severity (CRDPS) (0,32,higher scores mean a worse outcome), | baseline, 4 weeks, 8 weeks, 12 weeks, 14 weeks, 16 weeks,32 weeks | 
| Clinical assessements | Calgary Depression Scale for Schizophrenia (CDSS) (0,27,higher scores mean a worse outcome) | baseline, 4 weeks, 8 weeks, 12 weeks, 14 weeks, 16 weeks,32 weeks | 
| Clinical assessements | Clinical Global Impression Scale-Severity (CGI-S) (0,7,higher scores mean a worse outcome) | baseline, 4 weeks, 8 weeks, 12 weeks, 14 weeks, 16 weeks,32 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Schizophrenia, Treatment-resistant, Antipsychotics, Combination