Cognitive impairment, the core psychopathology of schizophrenia, usually persists in schizophrenia patients even during symptomatic remission. While cognitive impairment associated with schizophrenia (CIAS) is an important therapeutic target, hypofunction of N-methyl-D-aspartate receptor (NMDAR) is a key factor of CIAS. This study aims to examine the efficacy and safety of an NMDA-enhancer (NMDAE) for the treatment of CIAS in schizophrenia patients during symptomatic remission.

Cognitive impairment, the core psychopathology and the outcome determinant of schizophrenia, usually persists in schizophrenia patients even during symptomatic remission. Cognitive impairment associated with schizophrenia (CIAS) is an important therapeutic target; and hypofunction of N-methyl-D-aspartate receptor (NMDAR) is a key factor of CIAS. Whether NMDAR-enhancing treatment can truly improve cognitive function needs to be tested in schizophrenia patients during symptomatic remission. This study aims to examine the efficacy and safety of an NMDA-enhancer (NMDAE) for the treatment of CIAS in schizophrenia patients during symptomatic remission.

The subjects are the patients with schizophrenia during symptomatic remission. They keep their original treatment and are randomly, double-blindly assigned into two treatment groups for 12 weeks: (1) NMDAE, or (2) placebo. At weeks 0 and 12, 7 cognitive domains will be measured. At weeks 0, 4, 8, and 12, Global Assessment of Function, Quality of Life Scale, various clinical-symptom rating scales, and side effects scales will be measured too.

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:

• Have a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5 -TR) diagnosis of schizophrenia
• Fulfill the Remission in Schizophrenia Working Group (RSWG) criteria for remission (Andreasen et al., 2005): each of eight items (delusions, unusual thought content, hallucinatory behavior, conceptual disorganization, mannerisms/posturing, blunted affect, passive/apathetic social withdrawal, and lack of spontaneity and flow of conversation) in the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987) scoring 3 or lower for 6 months or longer; in addition, have a baseline total score of 59 or lower in the PANSS
• Are physically healthy and laboratory assessments (including blood routine, biochemical tests) are clinically insignificant;
• Have been keeping a fixed dose of antipsychotics (excluding clozapine) for at least 6 months, and that is not allowed to change during the 12-week study period
• Have sufficient education to communicate effectively and are capable of completing the assessments of the study
• Agree to participate in the study and provide written informed consent

Exclusion Criteria:

• DSM-5-TR diagnosis of intellectual disability or substance (including alcohol) use disorder
• History of epilepsy, head trauma, or serious medical or central nervous system diseases (other than schizophrenia) which may interfere with the study
• Pregnancy or lactation
• Inability to follow protocol