D-amino Acid Oxidase Inhibition (DAAOI-1) add-on Treatment for Chronic Schizophrenia

Study Overview
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Brief Summary
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Adjuvant N-methyl-D-aspartic acid (NMDA)-enhancing agents, such as GlyT-1 inhibitors and NMDA-glycine site agonists have been demonstrated to be beneficial for chronic schizophrenia patients. The purpose of this study is to evaluate efficacy and safety of add-on treatment of an inhibitor of D-amino acid oxidase (DAAOI), DAAOI-1, in chronically stable schizophrenia patients who have been stabilized with antipsychotics.

Detailed Description
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The etiology of schizophrenia remains unclear. Schizophrenia patients reveal positive symptoms, negative symptoms, and cognitive impairments. In addition to dopamine system hyperactivity, hypofunction of N-methyl-D-aspartate (NMDA) receptor plays a role in the pathophysiology of schizophrenia. Consequently, enhancing NMDA receptor neurotransmission has been regarded as a novel treatment approach. To date, several reported trials on adjuvant NMDA-enhancing agents, including glycine, D-amino acids (D-serine, D-alanine), and sarcosine (a glycine transporter I inhibitor), revealed beneficial but limited efficacy for positive and negative symptoms. DAAOI-1 is a D-amino acid oxidase (DAAO) inhibitor which can elevate synaptic concentration of D-amino acids. The aim of this project is to examine the efficacy and safety of add-on treatment of DAAOI-1 in chronically stable schizophrenia patients who have been stabilized with antipsychotics. In the study, 60 schizophrenic patients are recruited into the 6-week trial and randomly assigned into the two groups (1 gm/dDAAOI-1, or placebo) with a double-blind manner. Positive and Negative Syndrome Scale (PANSS), Scales for the Assessment of Negative symptoms (SANS), Global Assessment of Function (GAF), quality of life (QOL), Hamilton Depression rating scale 17(HAM-D 17), Clinical Global Impression(CGI)and side effects are evaluated every two weeks during the trial. Cognitive function (7 domains of Measurement and Treatment Research to Improve Cognition in Schizophrenia [MATRICS])are assessed at weeks 0 and 6. The efficacies of two groups are compared.

Official Title
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D-amino Acid Oxidase Inhibition for NMDA Modulation in Schizophrenia

Conditions
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Schizophrenias, Psychoses, Psychotic Disorders, Schizophrenic Disorders

Intervention / Treatment
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* Drug: D-amino acid oxidase inhibition (DAAOI-1)
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Are physically healthy and have all laboratory assessments (including urine/blood routine, biochemical tests, and electrocardiograph) within normal limits Aged 18-65 year Fulfill the criteria of schizophrenia according to the Diagnostic and Statistical Manual, fourth edition (DSM-IV) Remain symptomatic but without clinically significant fluctuation and the antipsychotic doses are unchanged for at least 3 months Have a minimum baseline total score of 60 on the Positive and Negative Syndrome Scale (PANSS) Agree to participate in the study and provide informed consent Exclusion Criteria: DSM-IV diagnosis of substance (including alcohol) abuse or dependence, DSM_IV diagnosis of mental retardation History of epilepsy, head trauma or CNS diseases History of epilepsy, head trauma or CNS diseases Pregnancy or lactation Inability to follow protocol

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DAAOI-1<br> | Drug: D-amino acid oxidase inhibition (DAAOI-1)<br>* 1g/day(500mg BID), oral, for 6 weeks<br>* Other names: DAAOI-1;|
| Placebo Comparator: placebo<br> | Drug: placebo<br>* 1# BID, oral, for 6 weeks<br>* Other names: starch;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total scores of PANSS, SANS, GAF, and QOL |  | week 0, 2, 4, 6. | 
| Cognitive function | MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia), including:1) speed of processing;(2) sustained attention; 3) working memory, verbal and nonverbal; 4) verbal learning and memory; 5) visual learning and memory; 6) reasoning and problem solving, and 7) social cognition | Week 0, 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The subscales of PANSS |  | week 0,2,4,6 | 
| Hamilton Depression rating scale 17(HAM-D 17) |  | Week 0, 2, 4, 6 | 
| Clinical Global Impression(CGI) |  | Week 0, 2, 4, 6 |