D-serine Monotherapy for Schizophrenia

Study Overview
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Brief Summary
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A first generation of clinical studies, performed during the last decade, demonstrates that adjuvant treatment with compounds that enhance NMDAR-mediated neurotransmission due to their agonistic activity at the NMDAR-associated glycine (GLY) site (e.g. GLY, D-serine (DSR)) leads to significant symptom reductions in chronic schizophrenia patients.Furthermore, preliminary findings suggest that treatment with NMDAR-GLY site modulators may also be beneficial as antipsychotic monotherapy In the proposed project, during a three year period, 60 schizophrenia patients that fulfill treatment resistance criteria will be randomly entered in a 10 week, two phase (fixed/flexible dose), parallel group, double blind controlled study assessing the efficacy of olanzapine (OLA) (up to 40 mg/day) vs. DSR (up to 4000 mg/day) as antipsychotic monotherapy.Clinical, neurocognitive, electrophysiological, and amino acids (i.e. GLY, DSR) levels assessments will be performed during the study. The specific aims of the proposed project are: 1) to assess the efficacy and safety of DSR as a new medication for treatment refractory schizophrenia, and 2) to assess DSR effects in terms of relevant amino acids serum levels, neurocognitive performance, and relevant brain electrophysiological parameters. The overall importance of the proposed project consists of its potential to lay the foundations for an innovative type of intervention for treatment resistant schizophrenia patients.

Official Title
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D-serine Antipsychotic Monotherapy for Treatment Refractory Schizophrenia

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: D-serine
* Drug: Olanzapine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-70; Diagnosis of schizophrenia/schizoaffective disorder according to DSM-IV criteria. Stable dose antipsychotic treatment for at least 4 weeks; Treatment refractoriness according to Kane et al.(1988) criteria. Exclusion Criteria: Meeting criteria for other DSM-IV Axis I diagnoses ; Substance abuse or alcoholism during entire lifetime; Are judged clinically to be at suicidal or homicidal risk; Female patients who are pregnant or lactating; female patients who are not pregnant or lactating, if sexually active, must be using medically accepted means of contraception; Patients with known intolerance to OLA treatment or who have failed an adequate trial of OLA (at least 6 weeks) at high doses (20 mg/day or higher); Patients treated with depot antipsychotics or ECT within the eight weeks prior to study entry.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: D-serine arm<br>6 week fixed dose phase with D-serine 1500 mg/day to be increased starting from week two to 3000 mg/day followed by a 4 week flexible dose phase allowing for two 500 mg/day dose changes. | Drug: D-serine<br>* 6 week fixed dose phase with D-serine 1500 mg/day to be increased starting from week two to 3000 mg/day followed by a 4 week flexible dose phase allowing for two 500 mg/day dose changes<br>* Other names: DSR;|
| Active Comparator: Olanzapine arm<br>6 week fixed dose phase with Olanzapine 15 mg/day to be increased starting from week two to 30 mg/day followed by a 4 week flexible dose phase allowing for two 5 mg/day dose changes. | Drug: Olanzapine<br>* 6 week fixed dose phase with Olanzapine 15 mg/day to be increased starting from week two to 30 mg/day followed by a 4 week flexible dose phase allowing for two 5 mg/day dose changes.<br>* Other names: Zyprexa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PANSS change scores. |  |   biweekly throughout the study | 
| side effects |  |   biweekly throughout the study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| % treatment responders |  | End of the study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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schizophrenia, treatment resistance, D-serine, Olanzapine, treatment refractory schizophrenia