GlyT-1 Inhibitor Treatment for Refractory Schizophrenia

Study Overview
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Brief Summary
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The etiology of schizophrenia remains unclear In recent one decade, hypofunction of N-methyl-D-aspartate (NMDA) receptor has been implicated in the pathophysiology of schizophrenia. Hence, enhancing NMDA neurotransmission was considered as a new approach for schizophrenia treatment. To date, refractory schizophrenia (particularly clozapine-resistant) is still a difficult clinical issue. However, the effect of NMDA treatment in refractory schizophrenia is still unknown. Therefore, the primary goal of this study is to investigate the efficacy and safety of NMDA adjuvant therapy in refractory schizophrenia, and to identify the predictors for treatment response to NMDA enhancers.

Detailed Description
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The etiology of schizophrenia remains unclear. In recent one decade, hypofunction of N-methyl-D-aspartate (NMDA) receptor has been implicated in the pathophysiology of schizophrenia. Hence, enhancing NMDA neurotransmission was considered as a new approach for schizophrenia treatment. To date, there have been a few pilot studies exploring the efficacy of NMDA enhancers as adjuvant therapy for schizophrenia, for instance, D-serine (an endogenous agonist of the NMDA-glycine site). They were not only well-tolerated but also synergistic in improving positive, negative and cognitive symptoms in those receiving typical and atypical antipsychotics (except clozapine). Refractory schizophrenia (particularly clozapine-resistant) is still a difficult clinical issue at present. Previous studies revealed that add-on treatment of D-serine or other agonists of NMDA receptor failed to give significant benefits in such patients. The primary goal of this study is to investigate the efficacy and safety of glycine transporter(GlyT)-1 inhibitor adjuvant therapy in refractory schizophrenia, and to identify the predictors for treatment response to NMDA enhancers.

Official Title
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GlyT-1 Inhibitor Treatment for Refractory Schizophrenia and Its Effects on NMDA Modulation

Conditions
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Schizophrenia, Treatment Refractory

Intervention / Treatment
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* Drug: GlyT-1 inhibitor-1
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Fulfill the criteria of schizophrenia according to the Diagnostic and Statistic Manual, fourth edition (DSM-IV). Poor response of clozapine treatment: a 12-week treatment of clozapine without satisfactory response: a severity score of Clinical Global Impression Scale(CGI)>=4, a total score of Positive and Negative Syndrome Scale(PANSS)>= 60, and a Scale for the Assessment of Negative Symptoms(SANS)score of >=40. the doses of clozapine remain stable for at least 12 weeks prior to their enrollment in this proposed study, Agree to participate in the study and provide informed consent. Exclusion Criteria: current substance abuse or history of substance dependence in the past 6 months use of depot antipsychotic in the past 6 months serious medical or neurological illness pregnancy inability to follow protocol.

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* starch<br>|
| Experimental: GlyT-1 inhibitor-1<br>GlyT-1 inhibitor-1 4000 mg/day | Drug: GlyT-1 inhibitor-1<br>* GlyT-1 inhibitor-1(500) 4# BID<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The severity of psychiatric symptoms | The severity of psychiatric symptoms will be assessed by: Positive and Negative Syndrome Scale(PANSS) Assessment of Negative symptoms(SANS) Global assessment of function(GAF) | baseline | 
| The severity of psychiatric symptoms | The severity of psychiatric symptoms will be assessed by: Positive and Negative Syndrome Scale(PANSS) Assessment of Negative symptoms(SANS) Global assessment of function(GAF) | 2 weeks after the trial | 
| The severity of psychiatric symptoms | The severity of psychiatric symptoms will be assessed by: Positive and Negative Syndrome Scale(PANSS) Assessment of Negative symptoms(SANS) Global assessment of function(GAF) | 4 weeks after the trial | 
| The severity of psychiatric symptoms | The severity of psychiatric symptoms will be assessed by: Positive and Negative Syndrome Scale(PANSS) Assessment of Negative symptoms(SANS) Global assessment of function(GAF) | 6 weeks after the trial (The end of the trial) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neurocognitive Function | The neurocognitive functions will be assessed by: Wisconsin Card Sorting Test (WCST) Wechsler Memory Scale- logical memory | baseline | 
| Neurocognitive function | The neurocognitive functions will be assessed by: Wisconsin Card Sorting Test (WCST) Wechsler Memory Scale- logical memory | 6 weeks after the trial (The end of the trial) | 
| The severity of psychiatric symptoms | The severity of psychiatric symptoms will be assessed by: Clinical Global Impression(CGI) Subscales of PANSS | baseline | 
| The severity of psychiatric symptoms | The severity of psychiatric symptoms will be assessed by: Clinical Global Impression(CGI) Subscales of PANSS | 2 weeks after the trial | 
| The severity of psychiatric symptoms | The severity of psychiatric symptoms will be assessed by: Clinical Global Impression(CGI) Subscales of PANSS | 4 weeks after the trial | 
| The severity of psychiatric symptoms | The severity of psychiatric symptoms will be assessed by: Clinical Global Impression(CGI) Subscales of PANSS | 6 weeks after the trial (the end of the trial) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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N-methyl-D-aspartate receptor, glycine transporter, schizophrenia