Dual Modulation of Sigma-1 and NMDA Receptors in the Treatment of Schizophrenia

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.

Study Overview

• Status: Recruiting
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: S1RA plus NMDAE; Drug: S1RA plus Placebo Cap

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.

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 2

Contacts and Locations

Study Locations

• Taiwan
  • Taichung, Taiwan
    • Recruiting
    • Department of Psychiatry, China Medical University Hospital
    • Contact: Hsien-Yuan Lane, M.D., Ph.D; Phone Number: 1855 886 4 22052121; Email: hylane@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: S1R agonist (S1RA) plus NMDAE; An S1R agonist plus an NMDA enhancer	Drug: S1RA plus NMDAE; Use of an S1R agonist plus an NMDA enhancer for the treatment of treatment-resistant schizophrenia.
Placebo Comparator: S1R agonist (S1RA) plus placebo; An S1R agonist plus placebo	Drug: S1RA plus Placebo Cap; Use of an S1R agonist plus placebo as a comparator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of Positive and Negative Syndrome Scale (PANSS)	Assessment of overall symptoms. Minimum value: 30, maximum value:210, the higher scores mean a worse outcome.	week 0, 2, 4, 6, 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of scales for the Assessment of Negative Symptoms (SANS) total score	Assessment of negative symptoms. Minimum value: 0, maximum value:100, the higher scores mean a worse outcome.	week 0, 2, 4, 6, 8
Positive subscale, Negative subscales, and General Psychopathology subscale of PANSS	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.	week 0, 2, 4, 6, 8
Clinical Global Impression	Assessment of general impression. Minimum value: 1, maximum value:7, the higher scores mean a worse outcome.	week 0, 2, 4, 6, 8
Global Assessment of Functioning	Assessment of social, occupational, and psychological function. Minimum value: 1, maximum value:100, the higher scores mean better function.	week 0, 2, 4, 6, 8
Quality of Life Scale	Assessment of life quality. Minimum value: 0, maximum value:126, the higher scores mean a better outcome.	week 0, 2, 4, 6, 8
Cognitive function	Ten tests for assessment of 7 cognitive domains: speed of processing (assessed by Category Fluency, Trail Marking A, Wechsler Adult Intelligence Scale(WAIS)-III Digit Symbol-Coding); sustained attention (Continuous Performance Test); working memory: verbal (digit span) and nonverbal (spatial span); verbal learning and memory (WMS-III, word listing); visual learning and memory (WMS-III, visual reproduction); reasoning and problem solving (WISC-III, Maze); 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)	Week 0, 8

Collaborators and Investigators

• Sponsor: China Medical University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): September 23, 2024
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): March 1, 2029

Study Registration Dates

• First Submitted: August 25, 2024
• First Submitted That Met QC Criteria: August 25, 2024
• First Posted (Actual): August 27, 2024

Study Record Updates

• Last Update Posted (Actual): March 24, 2026
• Last Update Submitted That Met QC Criteria: March 21, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Schizophrenia; NMDA; sigma-1 receptor
• Additional Relevant MeSH Terms: Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Schizophrenia
• Other Study ID Numbers: CMUH112-REC3-202

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No