GlyT-1 Inhibitor Treatment for Refractory Schizophrenia

GlyT-1 Inhibitor Treatment for Refractory Schizophrenia and Its Effects on NMDA Modulation

The etiology of schizophrenia remains unclear In recent one decade, hypofunction of N-methyl-D-aspartate (NMDA) receptor has been implicated in the pathophysiology of schizophrenia. Hence, enhancing NMDA neurotransmission was considered as a new approach for schizophrenia treatment.

To date, refractory schizophrenia (particularly clozapine-resistant) is still a difficult clinical issue. However, the effect of NMDA treatment in refractory schizophrenia is still unknown. Therefore, the primary goal of this study is to investigate the efficacy and safety of NMDA adjuvant therapy in refractory schizophrenia, and to identify the predictors for treatment response to NMDA enhancers.

Study Overview

• Status: Completed
• Conditions: Schizophrenia; Treatment Refractory
• Intervention / Treatment: Drug: Placebo; Drug: GlyT-1 inhibitor-1

Detailed Description

The etiology of schizophrenia remains unclear. In recent one decade, hypofunction of N-methyl-D-aspartate (NMDA) receptor has been implicated in the pathophysiology of schizophrenia. Hence, enhancing NMDA neurotransmission was considered as a new approach for schizophrenia treatment. To date, there have been a few pilot studies exploring the efficacy of NMDA enhancers as adjuvant therapy for schizophrenia, for instance, D-serine (an endogenous agonist of the NMDA-glycine site). They were not only well-tolerated but also synergistic in improving positive, negative and cognitive symptoms in those receiving typical and atypical antipsychotics (except clozapine).

Refractory schizophrenia (particularly clozapine-resistant) is still a difficult clinical issue at present. Previous studies revealed that add-on treatment of D-serine or other agonists of NMDA receptor failed to give significant benefits in such patients. The primary goal of this study is to investigate the efficacy and safety of glycine transporter(GlyT)-1 inhibitor adjuvant therapy in refractory schizophrenia, and to identify the predictors for treatment response to NMDA enhancers.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2

Contacts and Locations

Study Locations

• Taiwan
  • Taichung, Taiwan, 400
    • China Medical University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Fulfill the criteria of schizophrenia according to the Diagnostic and Statistic Manual, fourth edition (DSM-IV).
• Poor response of clozapine treatment: a 12-week treatment of clozapine without satisfactory response: a severity score of Clinical Global Impression Scale(CGI)>=4, a total score of Positive and Negative Syndrome Scale(PANSS)>= 60, and a Scale for the Assessment of Negative Symptoms(SANS)score of >=40. the doses of clozapine remain stable for at least 12 weeks prior to their enrollment in this proposed study,
• Agree to participate in the study and provide informed consent.

Exclusion Criteria:

• current substance abuse or history of substance dependence in the past 6 months
• use of depot antipsychotic in the past 6 months
• serious medical or neurological illness
• pregnancy
• inability to follow protocol.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; starch
Experimental: GlyT-1 inhibitor-1; GlyT-1 inhibitor-1 4000 mg/day	Drug: GlyT-1 inhibitor-1; GlyT-1 inhibitor-1(500) 4# BID

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The severity of psychiatric symptoms	The severity of psychiatric symptoms will be assessed by: Positive and Negative Syndrome Scale(PANSS); Assessment of Negative symptoms(SANS); Global assessment of function(GAF)	baseline
The severity of psychiatric symptoms	The severity of psychiatric symptoms will be assessed by: Positive and Negative Syndrome Scale(PANSS); Assessment of Negative symptoms(SANS); Global assessment of function(GAF)	2 weeks after the trial
The severity of psychiatric symptoms	The severity of psychiatric symptoms will be assessed by: Positive and Negative Syndrome Scale(PANSS); Assessment of Negative symptoms(SANS); Global assessment of function(GAF)	4 weeks after the trial
The severity of psychiatric symptoms	The severity of psychiatric symptoms will be assessed by: Positive and Negative Syndrome Scale(PANSS); Assessment of Negative symptoms(SANS); Global assessment of function(GAF)	6 weeks after the trial (The end of the trial)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neurocognitive Function	The neurocognitive functions will be assessed by: Wisconsin Card Sorting Test (WCST); Wechsler Memory Scale- logical memory	baseline
Neurocognitive function	The neurocognitive functions will be assessed by: Wisconsin Card Sorting Test (WCST); Wechsler Memory Scale- logical memory	6 weeks after the trial (The end of the trial)
The severity of psychiatric symptoms	The severity of psychiatric symptoms will be assessed by: Clinical Global Impression(CGI); Subscales of PANSS	baseline
The severity of psychiatric symptoms	The severity of psychiatric symptoms will be assessed by: Clinical Global Impression(CGI); Subscales of PANSS	2 weeks after the trial
The severity of psychiatric symptoms	The severity of psychiatric symptoms will be assessed by: Clinical Global Impression(CGI); Subscales of PANSS	4 weeks after the trial
The severity of psychiatric symptoms	The severity of psychiatric symptoms will be assessed by: Clinical Global Impression(CGI); Subscales of PANSS	6 weeks after the trial (the end of the trial)

Collaborators and Investigators

• Sponsor: China Medical University Hospital
• Investigators: Principal Investigator: Hsien-Yuan Lane, MD.PhD., Department of Psychiatry, China Medical University Hospital

Study record dates

Study Major Dates

• Study Start: April 1, 2010
• Primary Completion (Actual): October 1, 2013
• Study Completion (Actual): October 1, 2013

Study Registration Dates

• First Submitted: November 3, 2010
• First Submitted That Met QC Criteria: November 30, 2010
• First Posted (Estimate): December 1, 2010

Study Record Updates

• Last Update Posted (Estimate): October 29, 2013
• Last Update Submitted That Met QC Criteria: October 27, 2013
• Last Verified: October 1, 2013

More Information

Terms related to this study

• Keywords: schizophrenia; N-methyl-D-aspartate receptor; glycine transporter
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia
• Other Study ID Numbers: DMR-98-096