Safety and Effectiveness of D-serine in Schizophrenia

PK/PD Study of Escalating Dose D-serine as Adjunctive Treatment in Schizophrenia

This study will determine whether increasing D-serine within the body will improve negative symptoms and cognitive impairments in people with schizophrenia.

Study Overview

• Status: Completed
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: D-serine; Drug: D-serine

Detailed Description

Schizophrenia is a life-long brain disorder affecting approximately 1 percent of Americans each year. Schizophrenia can be extremely disabling, causing people to hear voices, experience paranoia or hallucinations, believe that others are controlling their thoughts, and even fail at maintaining a job or caring for themselves. Current medications help to relieve most of these symptoms, but not all. Some people with schizophrenia still suffer from negative symptoms, such as difficulty with talking, expressing emotions, and motivation; they may also suffer from cognitive impairments, such as decreased concentration and memory loss. D-serine, an amino acid found within the body, activates brain cell receptors that appear to play a role in learning and memory. This study will determine whether adding a D-serine solution to a stable antipsychotic medication regimen will decrease negative symptoms in people with schizophrenia.

Participants in this open-label study will remain on their regular medication regimen for at least 2 weeks. During this time and before starting treatment, participants will be interviewed about their emotional problems, marital status, education, family background, employment history, and any drug or alcohol problems. Participants will also undergo a physical exam, an electrocardiogram (EKG), vital sign measurements, psychological tests, cognitive tasks, and an electroencephalogram (EEG). Participants will then begin 4 weeks of treatment with D-serine. In addition to participants' regular medication regimen, they will drink a D-serine powder mixed with water twice daily. Every 2 weeks, participants will undergo a physical exam and an interview about any changes in symptoms or emotional problems that they may be experiencing. Blood and urine samples will be taken throughout the study. After 4 weeks, participants will undergo an EKG, EEG, and the same psychological tests and cognitive tasks completed prior to treatment. A follow-up visit will occur 2 weeks post-treatment to monitor any changes in negative symptoms.

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06512
      • Yale University School Of Medicine
  • New York
    • Glen Oaks, New York, United States, 11004
      • The Zucker Hillside Hospital
    • Orangeburg, New York, United States, 10962
      • The Nathan S. Kline Institute for Psychiatric Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Structured Clinical Interview for DSM-III-R diagnosis of schizophrenia or schizoaffective disorder
• PANSS 3 factor negative symptom inclusion score greater than 20 prior to study entry
• PANSS total score between 60 and 110
• Simpson-Angus Scale total score of 12 or less
• Calgary Depression Inventory total score of 10 and suicide score less than 2
• No change in Clinical Global Impressions (CGI) Scale score prior to study entry
• Chlorpromazine (CPZ) equivalent of 1500 or less
• Willing to use an effective form of birth control throughout the study if sexually active

Exclusion Criteria:

• High extrapyramidal symptom (EPS) levels
• Began, discontinued, or adjusted psychotropic medication within 2 weeks of study entry
• Taking investigational medication within 2 weeks of study entry
• Contraindication to study medication
• Serious or unstable medical illness
• Pregnant or breastfeeding
• Alcohol or drug abuse within 6 months of study entry
• Diagnosed with neurodegenerative disease or a seizure disorder
• History of a kidney impairment
• Currently taking clozapine
• Currently taking more than two antipsychotic medications
• Currently taking stimulants or cholinesterase inhibitors

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: D-serine 30 mg/kg	Drug: D-serine; D-serine at following dose levels: 30 mg/kg, 60 mg/kg, and 120 mg/kg. PK/PD studies done at day 1. Medication will be administered as powder dissolved in liquid given in two divided doses daily for 4 weeks.; Drug: D-serine
Experimental: D-serine 60 mg/kg	Drug: D-serine; D-serine at following dose levels: 30 mg/kg, 60 mg/kg, and 120 mg/kg. PK/PD studies done at day 1. Medication will be administered as powder dissolved in liquid given in two divided doses daily for 4 weeks.; Drug: D-serine
Experimental: D-serine 120 mg/kg	Drug: D-serine; D-serine at following dose levels: 30 mg/kg, 60 mg/kg, and 120 mg/kg. PK/PD studies done at day 1. Medication will be administered as powder dissolved in liquid given in two divided doses daily for 4 weeks.; Drug: D-serine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Renal Safety Measures	number of renal adverse events (serum and urinalysis)	Measured at Week 4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Positive and Negative Symptoms Scale (PANSS)	Absolute Change in PANSS over four weeks (change between baseline and final measurements). The PANSS is a 30-item rating scale widely used in assessment of medication effects in schizophrenia. The PANSS ranges from 30-210, with lower scores showing less symptoms. Larger change is better.	Measured at Week 4
Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Battery	Change over 4 weeks. The MATRICS is a scale measuring cognition, and reported as T-score, with 50 as the population average and every 10 points representing a change of 1 standard deviation from the population average. Higher scores represent an improvement	Measured at Week 4

Collaborators and Investigators

• Sponsor: Nathan Kline Institute for Psychiatric Research
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Daniel C. Javitt, MD, PhD, Nathan Kline Institute

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: March 1, 2006
• Primary Completion (Actual): January 1, 2009
• Study Completion (Actual): January 1, 2009

Study Registration Dates

• First Submitted: May 2, 2006
• First Submitted That Met QC Criteria: May 2, 2006
• First Posted (Estimate): May 4, 2006

Study Record Updates

• Last Update Posted (Actual): October 5, 2020
• Last Update Submitted That Met QC Criteria: September 11, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: Glutamate; Negative symptoms; Glycine; NMDA
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia
• Other Study ID Numbers: U01MH074356 (U.S. NIH Grant/Contract); DATR A5-EPTD