Schizophrenia
Conditions
Keywords
Schizophrenia, NMDA, sigma-1 receptor
Brief summary
sigma-1 receptor (S1R) agonistic property have been tested in clinical trials for the treatment of schizophrenia. In addition, previous studies found that some NMDA receptor (NMDAR)-enhancing agents were able to improve clinical symptoms of patients with chronic schizophrenia. Whether combined treatment of an S1R agonist and an NMDA-enhancing agent can be better than an S1R agonist alone deserves study.
Detailed description
The current treatment for schizophrenia remains unsatisfactory; thus, development of new treatments is vital. Both sigma-1 receptor (S1R) dysfunction and NMDA receptor (NMDAR) hypofunction contribute to pathogenesis of schizophrenia, especially treatment-resistant schizophrenia. Several S1R agonists have been tested for its potential for schizophrenia treatment; however, its efficacy appears limited. In addition, previous studies also found that some NMDA-enhancing agents were able to augment efficacy of antipsychotics in the treatment of chronic schizophrenia. Whether combined treatment of an S1R agonist and an NMDA-enhancer (NMDAE) can be better than an S1R agonist alone deserves study. Therefore, this study aims to compare an S1R agonist plus an NMDAE and an S1R agonist plus placebo in the treatment of treatment-resistant 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) S1R agonist (S1RA) plus NMDAE, or (2) S1RA plus placebo. Clinical performances and side effects are measured at weeks 0, 2, 4, 6, and 8. Cognitive functions are assessed at baseline and at endpoint of treatment by a battery of tests. The efficacies of S1RA plus NMDAE and S1RA 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.
Interventions
DRUGS1RA plus NMDAE
Use of an S1R agonist plus an NMDA enhancer for the treatment of treatment-resistant schizophrenia.
DRUGS1RA plus Placebo Cap
Use of an S1R agonist plus placebo as a comparator
Sponsors
China Medical University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Have a DSM-5 (American Psychiatric Association) diagnosis of schizophrenia * Are resistant to adequate treatments of at least two antipsychotics (excluding clozapine) * 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 8-week trial * PANSS total score \>70 * Hamilton Depression Rating Scale-17 items (HAMD) \<7 * Are physically healthy and laboratory assessments (including blood routine, biochemical tests) are clinically insignificant. * Have sufficient education to communicate effectively and are capable of completing the assessments of the study. * 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, central nervous system diseases or mental disorders other than schizophrenia (including major depressive disorder, bipolar disorders, persistent depressive disorder, obsessive-compulsive disorder) * Pregnancy or lactation * Inability to follow protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change of Positive and Negative Syndrome Scale (PANSS) | week 0, 2, 4, 6, 8 | Assessment of overall symptoms. Minimum value: 30, maximum value:210, the higher scores mean a worse outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change of scales for the Assessment of Negative Symptoms (SANS) total score | week 0, 2, 4, 6, 8 | 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 | week 0, 2, 4, 6, 8 | 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 | week 0, 2, 4, 6, 8 | Assessment of general impression. Minimum value: 1, maximum value:7, the higher scores mean a worse outcome. |
| Global Assessment of Functioning | week 0, 2, 4, 6, 8 | Assessment of social, occupational, and psychological function. Minimum value: 1, maximum value:100, the higher scores mean better function. |
| Quality of Life Scale | week 0, 2, 4, 6, 8 | Assessment of life quality. Minimum value: 0, maximum value:126, the higher scores mean a better outcome. |
| Cognitive function | Week 0, 8 | Ten tests for assessment of 7 cognitive domains: 1. speed of processing (assessed by Category Fluency, Trail Marking A, Wechsler Adult Intelligence Scale(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 (MSCEIT Version 2) For the domain (a. and c.) with more than one test, a composite T score will be calculated by standardizing the average of each T score. Furthermore, a global composite score (for all seven domains) and a neurocognitive composite score (for the first 6 domains) will be also calculated by standardizing the average of the T score (Lane HY et al, JAMA Psychiatry 2013) |
Countries
Taiwan
Outcome results
None listed