Previous studies found that some NMDA-enhancing agents were able to improve clinical symptoms of patients with schizophrenia. Whether treatment of an NMDA-enhancing agent can benefit the treatment of prodromal schizophrenia deserves study.

Several lines of evidence suggest that NMDA hypotheses have been implicated in schizophrenia. Previous studies found that some NMDA-enhancing agents were able to benefit the treatment of schizophrenia. Whether an NMDA-enhancer (NMDAE) can benefit the treatment of prodromal schizophrenia deserves study. Therefore, this study aims to compare NMDAE and placebo in the treatment of prodromal schizophrenia.

The subjects with prodromal schizophrenia at first receive 6 weeks of health-promotion intervention (including exercise and education). A total of 48 subjects who do not respond sufficiently to the health-promotion program are then recruited to this 12-week, randomized, double-blind, placebo-controlled trial, which aims to compare treatment response of NMDAE vs. placebo in 1:1 ratio. Clinical performances and side effects are measured at weeks -6 (before the screening phase), 0 (baseline of the drug trial), 2, 4, 6, 9, and 12. Cognitive functions are assessed at baseline and at endpoint of treatment by a battery of tests.

The efficacies of NMDAE and placebo will be compared. Chi-square (or Fisher's exact test) will be used to compare differences of categorical variables and t-test (or Mann-Whitney test if the distribution is not normal) for continuous variables between treatment groups. Mean changes from baseline in repeated-measure assessments will be assessed using the generalized estimating equation (GEE). All p values for clinical measures will be based on two-tailed tests with a significance level of 0.05.

Inclusion Criteria:

• Individuals meeting Criteria of Prodromal Syndrome (at least one of the following: 1. attenuated positive symptoms; 2. brief intermittent psychotic symptoms; 3. genetic risk and deterioration).
• Subjects remain symptomatic (scoring at least 20 on the Scale of Prodromal Symptoms [SOPS] total score) after the 6-week screening phase (which contains the health-promotion program) and before the 12-week drug-trial period.
• Subjects may be receiving ongoing treatment with antipsychotic medications, or may be medication-free for at least 12 weeks.For the subjects who have already been on such medications, the medications need to be continued for at least 4 weeks before the screening phase and the doses need to be kept unchanged during the study period. For those who have not yet been on such medications, these medications are forbidden during the study period.
• Subjects agree to participate in the study and provide written informed consent after complete description of the study. For the subject < 20 years old, a parent also has to provide written informed consent.

Exclusion Criteria:

• DSM-5 diagnosis of intellectual disability, substance (including alcohol) use disorder, schizophrenia, schizophreniform disorder, delusional disorder, schizoaffective disorder, substance/medication-induced psychotic disorder, or psychotic disorder due to another medical condition.
• History of epilepsy, head trauma, stroke, or serious medical or central nervous system diseases (other than schizophrenia) which may interfere with the study.
• Clinically significant laboratory screening tests (including blood routine, biochemical tests)
• Pregnancy or lactation
• Inability to follow protocol