Biomarkers in Schizophrenia

Effect of an NMDA-based Intervention on Biomarker Measures of Cognitive Dysfunction in Schizophrenia

N-methyl-D-aspartate (NMDA)-type glutamate receptors are thought to play a pivotal role in neurocognitive dysfunction associated with schizophrenia. Further, several novel glutamate-based classes of compound are presently in development as potential novel treatments for persistent negative and cognitive symptoms. The study will assess effectiveness of a NMDA-based intervention on biomarkers related to schizophrenia as a mechanism for developing appropriate outcome batteries for future trials of novel compounds.

Study Overview

• Status: Completed
• Conditions: Schizophrenia; Schizoaffective Disorder
• Intervention / Treatment: Drug: Placebo; Drug: D Serine

Detailed Description

16 in- or outpatients with DSM-IV-TR schizophrenia or schizoaffective disorder and prominent negative symptoms will be recruited for this study. This study will consist of a randomized trial of D-serine (60 mg/kg/d) vs. placebo using a crossover design with a 2-week baseline lead-in, and two 6-week intervention arms separated by a two week, placebo controlled washout period. Biomarkers will be assessed at baseline for each treatment arm, acutely (day 7) following treatment initiation, and following 6 weeks of treatment (6 biomarker sessions total). Primary biomarker outcome measures will include 1) amplitude of the mismatch negativity (MMN) waveform and 2) amplitude of the visual P1 potential. Symptomatic outcome measures will include PANSS and composite score of the MATRICS neuropsychological battery. The study will be supported from ongoing NIMH-funded Cooperative Drug Development Grant (CDDG) to the PI.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • Orangeburg, New York, United States, 10962
      • Nathan Kline Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 64 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• Age 18-64
• SCID diagnosis of Schizophrenia or Schizoaffective Disorder.
• PANSS 3 factor negative symptom (screening and baseline visit 1 and visit 3) score of >20 and PANSS total score between 60-110. Any degree of positive symptoms is acceptable but the total PANSS score must not exceed 110.
• SAS total score less than or equal to 12 and a Calgary Depression Inventory total score less than or equal to 10 and suicide (item 8) less than moderate (<2).
• Two consecutive CGI ratings at screening and baseline (visit 1 and 3) with no change in score.
• Estimated Glomerular Filtration Rate (GFR)(a measure of renal function) greater than or equal to 60.

Exclusion criteria:

• Organic brain disorder, including epilepsy; mental retardation; or a medical condition whose pathology or treatment would likely alter the presentation or treatment of schizophrenia or significantly increase the risk associated with any of the proposed treatments
• Current DSM-IV diagnosis of drug/alcohol abuse in last month and current DSM-IV diagnosis of drug/alcohol dependence in last 6 months
• Pregnant female patients
• Impaired renal function
• Significant extrapyramidal symptoms (as reflected by a total score of 10 or above on the SAS scale), and depressive symptoms (as reflected by a score of 10 or above on the Calgary Depression Scale for Schizophrenia)
• Patients who are unable to or unwilling to participate in the Cognitive assessment (MATRICS) and the electrophysiology tasks .
• Patients on clozapine

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; oral
Experimental: D-serine; 60 mg/kg/day	Drug: D Serine; 60 mg/kg/day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PANSS Total	Positive and Negative Symptom Scale (PANSS) range 30-210	6 weeks
MMN Amplitude	Final MMN amplitude	6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MATRICS	MATRICS assessing 7 domains (Speed of Processing, Attention/Vigilance, Working Memory, Verbal Learning, Visual Learning, Reasoning and Problem Solving, and Social Cognition. Raw scores are converted into a composite T-score (normative mean = 50; standard deviation = 10), where higher values indicated less impairment.	6 weeks
Visual P1		6 weeks

Collaborators and Investigators

• Sponsor: Nathan Kline Institute for Psychiatric Research
• Investigators: Principal Investigator: Daniel C Javitt, MD, PhD, New York University

Publications and helpful links

General Publications

• Kantrowitz JT, Epstein ML, Lee M, Lehrfeld N, Nolan KA, Shope C, Petkova E, Silipo G, Javitt DC. Improvement in mismatch negativity generation during d-serine treatment in schizophrenia: Correlation with symptoms. Schizophr Res. 2018 Jan;191:70-79. doi: 10.1016/j.schres.2017.02.027. Epub 2017 Mar 18.

Study record dates

Study Major Dates

• Study Start: June 1, 2009
• Primary Completion (Actual): July 1, 2011
• Study Completion (Actual): July 1, 2011

Study Registration Dates

• First Submitted: January 5, 2009
• First Submitted That Met QC Criteria: January 5, 2009
• First Posted (Estimate): January 6, 2009

Study Record Updates

• Last Update Posted (Actual): August 2, 2017
• Last Update Submitted That Met QC Criteria: July 7, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Keywords: biomarker; schizophrenia; EEG; NMDA; D-serine
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Psychotic Disorders
• Other Study ID Numbers: 08I/C19-0