N-methyl-D-aspartate receptor (NMDAR) agonist, added to classical or atypical antipsychotic medication, has reduced negative, depressive, and cognitive symptomatology. We will be investigating the effect of D-serine, (DSR), a selective and potent NMDAR agonist, as monotherapy for treatment resistant schizophrenics.

40 subjects on stable doses of risperidone will be randomized under double-blind conditions into a treatment group, which will receive D-serine 2100 mg, or a control group, which will continue to receive risperidone. Treatment will continue for 14 weeks.

Symptoms and side effects will be rated biweekly with the CGI, PANSS, BPRS, SAS, AIMS, and UKU. Before and after the trial subjects will undergo neuropsychological assessments. Baseline and post-trial levels of amino acids relevant to glutamatergic neurotransmission (glutamate, glutamine, aspartate, glycine, serine, alanine) will be assessed.

The primary outcome measures of the study will be the PANSS total scores and the positive and negative symptom cluster scores.

Inclusion Criteria:

1. DSM-IV criteria for chronic schizophrenia
2. Treatment resistant
3. aged 18-70
4. Two months on stable risperidone dose
5. PANSS positive symptom cluster score >20
6. PANSS negative symptom cluster score >22

Exclusion Criteria:

1. Substance abuse
2. Concurrent DSM IV axis I disorder
3. Serious medical disorder
4. Concurrent drug therapy that can obscure the effect of risperidone or DSR.