The purpose of the study is to determine the safety and efficacy of D-serine as an early intervention treatment for the schizophrenia prodrome condition. This study is a placebo-controlled trial of D-serine in the symptomatic treatment of patients with the schizophrenia prodrome. Seventy two subjects meeting criteria for the schizophrenia prodrome will be included in this study, 24 at each site (Yale, Nathan Kline Institute and Zucker Hillside Hospital). The primary outcome measures will include symptom and neuropsychological measures. The duration of this study is two and a half years.

This research with D-serine holds out the prospect of direct benefit for the patient's current symptoms. Subjects may also benefit from the close monitoring of their symptoms, so that, if schizophrenic psychosis does occur, the psychosis will be recognized and treatment may begin with minimal delay. This study also could be of benefit by suggesting a promising lead in early intervention in the schizophrenic prodrome.

Overall Design Summary. We propose for prodromal patients to be randomized to D-serine vs placebo for 16 weeks. To insure that all subjects have the opportunity to receive D-serine, there will be an optional 16 week cross-over trial on the alternate study medication. No subject will be on D-serine for longer than 16 weeks. Admission criteria, Assessment Procedures, and Study Design will be the same across all sites. The procedures and timeline are shown in Table 1. The procedures and timeline are the same for the initial randomized 16 week trial and the optional cross-over trial on the alternate study medication. If patient's opt for the 16 week treatment on the alternate medication, we will use their assessments from end of initial treatment as baseline for 16 week treatment on alternate medication. Subjects will be seen for two preliminary visits, then once in treatment, subjects will be seen weekly for the first 5 visits then biweekly thereafter. A safety blood and urine collection will be done on day 3 (3 days after the start of study medication). Vital signs and weight, blood draw and urine collection for safety measures, urine pregnancy test and urine for toxicology will be repeated throughout treatment. Adverse effects ratings and symptom assessments will be repeated at each visit. Neuropsychological assessment and optional "Biomarker study" visual, auditory and ERPs tasks will be administered during one of the two preliminary visits then again at study endpoint. Any patients who convert to frank psychosis will be referred/offered immediate treatment.

Inclusion criteria:

1. treatment seeking subjects ages 13-35 who meet criteria for the schizophrenia prodrome (see criteria below) and who are able to give written informed assent or consent.
2. Subjects must score at least 20 on the Scale of Prodromal Symptoms (SOPS) total score at visit -1.
3. Patients may be receiving ongoing treatment with antipsychotic, antidepressant or anti-anxiety medications as prescribed by their treating physician, or may be medication free.
4. Patients may enroll in the treatment phase only if they have been on fixed medication dosage for at least 4 weeks. If possible, medication will be held constant during course of study. Subjects will not be excluded or dropped from the study if they have a psychiatric diagnosis or must start a new medication unless the diagnosis is "psychosis". Medication changes and increases or decreases in medication will be permitted at the discretion of the treating physician, and, if they occur, will be treated as secondary outcome measures.

Exclusion criteria:

1. inability to give informed assent or consent,
2. history of psychosis (e.g. frank delusions, hallucinations, or thought disorder),
3. psychotropic medication begun or dose adjusted within 4 weeks of visit 0,
4. contraindication to study medication,
5. inclusion symptoms better accounted for by comorbid diagnosis,
6. treatment need for comorbid diagnosis outweighs that for prodromal symptoms,
7. unstable medical illness,
8. females who are of childbearing potential but are not taking adequate contraceptive precautions or who are pregnant or breast feeding,
9. alcohol or drug abuse or dependence in the past three months,
10. either of the following: Subjects with significant renal disease or estimated GFR below 60 (MDRD, http://www.kidney.org/professionals/kdoqi/gfr\_calculator.cfm) will be excluded (see below for details). Any subject taking or unwilling to avoid other nephrotoxic agents during the course of the study (NSAIDS, ACE inhibitors, ARB's, calcineurin inhibitors, or aminoglycosides) will also be excluded. Therefore, patients will be asked during the study to take acetaminophen (e.g. if they have a headache) and to avoid taking ibuprofen.

For adolescents (ages 13-17), more stringent renal exclusion criteria will be adhered to:

1. estimated GFR is < 89 cc/min/1.73 m2 as calculated by the Schwartz formula (http://www.kidney.org/professionals/kdoqi/gfr\_calculatorPed.cfm),
2. difference of ≥0.3mg/dl between the two baseline serum creatinine values,
3. baseline proteinuria defined by a spot urine protein:creatinine of 0.2 or greater, or
4. baseline glucosuria (the presence of glucosuria).

Schizophrenia Prodrome Criteria:

We will be enrolling both Attenuated Positive Syndrome (APS) [1], Genetic Familial Risk (GFR) [1] and Clinically High Risk Negative (CHR-) symptom prodromes to this study. A separate analysis will be done for the APS and CHR- patients.

1. Attenuated Positive Syndrome: One or more of the 5 SOPS positive items scoring in the prodromal range (rating of 3-5) AND Symptoms beginning within the past year or increasing 1 or more points within the past year AND Symptoms occurring at least once per wk for last month.
2. Genetic Familial Risk: First degree relative with history of any psychotic disorder OR Criteria for schizotypal personality disorder met in patient AND GAF drop of at least 30% over the last month vs 1 year ago. In our experience, very few patients only meet criteria for this syndrome.
3. CHR-: To make criteria, social isolation must be present along with either flat affect or impairment in the occupational role. Therefore to meet criteria for CHR-, Social Anhedonia (N1) has to be present at a score of 3 or above, and, in addition, one of the other two symptoms (N3 or N6) listed must also present at a minimum level of 3. Note: a score of "6" on these items is not considered exclusionary.

Includes 35 subjects who received at least one post-baseline efficacy evaluation