• Change of scales for the Assessment of Negative Symptoms (SANS) total score [ Time Frame: 0, 2, 4, 6, 9, 12 ]
  Assessment of negative symptoms. Minimum value: 0, maximum value:100, the higher scores mean a worse outcome.
• Positive subscale, Negative subscales, and General Psychopathology subscale of PANSS [ Time Frame: week 0, 2, 4, 6, 9, 12 ]
  PANSS-positive: Assessment of positive symptoms. Minimum value: 7, maximum value:49, the higher scores mean a worse outcome. PANSS-negative: Assessment of negative symptoms. Minimum value: 7, maximum value:49, the higher scores mean a worse outcome. PANSS-general psychopathology: Assessment of general psychopathology. Minimum value: 16, maximum value:112, the higher scores mean a worse outcome
• Clinical Global Impression [ Time Frame: week 0, 2, 4, 6, 9, 12 ]
  Assessment of general impression. Minimum value: 1, maximum value:7, the higher scores mean a worse outcome.
• Global Assessment of Functioning [ Time Frame: week 0, 2, 4, 6, 9, 12 ]
  Assessment of social, occupational, and psychological function. Minimum value: 1, maximum value:100, the higher scores mean better function.
• Hamilton Rating Scale for Depression [ Time Frame: week 0, 2, 4, 6, 9, 12 ]
  Assessment of depressive symptoms. Minimum value: 0, maximum value:52, the higher scores mean a worse outcome.
• Quality of Life Scale [ Time Frame: week 0, 2, 4, 6, 9, 12 ]
  Assessment of life quality. Minimum value: 0, maximum value:126, the higher scores mean a better outcome.
• Cognitive function [ Time Frame: Week 0, 12 ]
  The measure is the composite from multiple measures. Ten cognitive tests for assessment of 7 cognitive domains:

  1. speed of processing (assessed by 3 tests: Category Fluency, Trail Marking A, WAIS-III Digit Symbol-Coding);
  2. sustained attention (Continuous Performance Test);
  3. working memory: verbal (digit span) and nonverbal (spatial span);
  4. verbal learning and memory (WMS-III, word listing);
  5. visual learning and memory (WMS-III, visual reproduction);
  6. reasoning and problem solving (WISC-III, Maze);
  7. social cognition (the Mayer-Salovey-Caruso Emotional Intelligence Test [MSCEIT] Version 2)

Several lines of evidence suggest that both NMDA and inflammatory hypotheses have been implicated in schizophrenia. Previous studies found that some NMDA-enhancing agents were able to augment efficacy of antipsychotics in the treatment of chronic schizophrenia. In addition, several drugs with anti-inflammatory properties have been tested in clinical trials for the treatment of schizophrenia too. Whether a drug with anti-inflammatory property can strengthen the efficacy of an NMDA-enhancer (NMDAE) in the treatment of schizophrenia remains unknow. Therefore, this study aims to compare NMDAE plus a drug with anti-inflammatory property and NMDAE plus placebo in the treatment of schizophrenia. The subjects are the patients with treatment-resistant schizophrenia who have responded poorly to two or more kinds of antipsychotics treatment. They keep their original treatment and are randomly, double-blindly assigned into two treatment groups for 12 weeks: (1) NMDAE plus Anti-inflammatory Agent (AIFA), or (2) NMDAE plus placebo. Clinical performances and side effects are measured at weeks 0, 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 plus AIFA and NMDAE plus 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.

• Drug: NMDAE plus AIFA
  Use of an NMDA enhancer plus a drug with anti-inflammatory property for the treatment of schizophrenia.
• Drug: NMDAE plus Placebo Cap
  Use of an NMDA enhancer plus placebo as a comparator

• Experimental: NMDAE plus Anti-inflammatory Agent (AIFA)
  An NMDA enhancer plus a drug with anti-inflammatory property
  Intervention: Drug: NMDAE plus AIFA
• Placebo Comparator: NMDAE plus Placebo
  An NMDA enhancer plus Placebo
  Intervention: Drug: NMDAE plus Placebo Cap

Inclusion Criteria:

• Have a DSM-5 (American Psychiatric Association) diagnosis of schizophrenia
• Are resistant to adequate treatments of at least two antipsychotics
• Remain symptomatic but without clinically significant fluctuation, while their antipsychotic doses are unchanged for at least 3 months and will be maintained during the period of the 12-week trial
• PANSS total score ≥ 70
• Agree to participate in the study and provide informed consent

Exclusion Criteria:

• DSM-5 diagnosis of intellectual disability or substance (including alcohol) use disorder
• 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