Glutamate, Learning, and Working Memory

The Effects of D-cycloserine on Neuroplasticity and Working Memory in Healthy Adults and Patients With Schizophrenia

Impairments in plasticity and working memory in schizophrenia have been hypothesized to reflect dysfunction at the N-methyl-D-aspartate glutamate receptor (NMDAR). However, the specific mechanisms through which the NMDAR is involved in working memory versus plasticity differ. Towards gaining a deeper understanding of how NMDAR signaling relates to individual cognitive functions in healthy adults and patients with schizophrenia, the investigators used a single dose of d-cycloserine (DCS) as an experimental probe to examine the effects of enhancing NMDAR signaling on plasticity versus working memory in healthy adults and individuals with schizophrenia.

Study Overview

• Status: Completed
• Conditions: Schizophrenia
• Intervention / Treatment: Other: Placebo; Drug: D-cycloserine

Detailed Description

Background: Cognitive impairments in schizophrenia, such as deficits in plasticity and working memory, have been hypothesized to reflect dysfunction at the N-methyl-D-aspartate glutamate receptor (NMDAR). However, given that divergent properties of the NMDAR underlie its roles in plasticity versus working memory and that various aspects of NMDAR function are abnormal in schizophrenia, examining the effects of DCS in both healthy and patient populations is crucial.

Methods: The investigators used a single dose of the partial NMDAR agonist, d-cycloserine (DCS) to probe the effects of enhancing NMDAR signaling on working memory and plasticity. Working memory was assessed using a spatial n-back task. Plasticity was assessed using two learning tasks, the weather prediction task and information integration task, and an EEG paradigm that assesses changes in visual evoked potential amplitude following high frequency visual stimulation. Sixty-five healthy adults and forty-five schizophrenia patients were randomized to receive 100 mg acute DCS (healthy adult n = 32; schizophrenia n = 24) or placebo (healthy adult n = 33; schizophrenia n = 21).

• Study Type: Interventional
• Enrollment (Actual): 110
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion criteria for healthy subjects:

1. between the ages of 18 and 30 years
2. comfortable reading in English
3. normal visual acuity or corrected vision
4. normal or corrected hearing.

Exclusion criteria for healthy subjects:

1. history or seizures or neurologic diseases
2. currently prescribed medication for any psychiatric conditions
3. any medical condition affecting fine motor movement of the hands
4. pregnancy or suspected pregnancy
5. use of recreational drugs or drugs taken not as prescribed in the past month
6. having a full scale intelligence quotient (IQ) < 70, as assessed by the Wechsler Abbreviated Scale of Intelligence (WASI)
7. having consumed alcohol in the 24 hours prior to the first lab visit
8. known allergy to any antibiotics.

Inclusion criteria for patients with schizophrenia:

1. between the ages of 18 and 50 years
2. comfortable reading in English
3. normal visual acuity or corrected vision
4. normal or corrected hearing
5. meets criteria for Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV) diagnosis of schizophrenia.

Exclusion criteria for patients with schizophrenia:

1. history or seizures or neurologic diseases
2. currently prescribed Clozapine or medications contraindicated for DCS
3. any medical condition affecting fine motor movement of the hands
4. pregnancy or suspected pregnancy
5. history of traumatic brain injury requiring hospitalization for 2 or more days
6. IQ < 70, as assessed by the WASI
7. having consumed drugs other than as prescribed in the 48 hour prior to the testing visit or having consumed alcohol in the 24 hours prior to the testing visit
8. known allergy to any antibiotics
9. current alcohol or substance dependence

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Healthy Adult - Placebo; Single dose placebo pill in healthy adults	Other: Placebo; Placebo administered orally as encapsulated pill
Experimental: Healthy Adult - D-cycloserine; Single 100 mg dose D-cycloserine pill in healthy adults	Drug: D-cycloserine; 100 mg D-cycloserine administered orally as encapsulated pill
Placebo Comparator: Schizophrenia - Placebo; Single dose placebo pill in schizophrenia patients	Other: Placebo; Placebo administered orally as encapsulated pill
Experimental: Schizophrenia - D-cycloserine; Single 100 mg dose D-cycloserine pill in schizophrenia patients	Drug: D-cycloserine; 100 mg D-cycloserine administered orally as encapsulated pill

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Performance on Information Integration Learning Task	Percent Correct Responses out of 240 trials (for schizophrenia patients) or 320 trials (for healthy adults) on the Information Integration Learning Task, which is a classification learning task in which participants learn to classify visual stimuli as category A or B following practice with stimuli and auditory feedback indicating correct versus incorrect responses.	Testing Day (i.e. approx 3-5 hrs following placebo or D-cycloserine administration)
Performance on Weather Prediction Learning Task	Percent Correct Responses out of 240 trials (for schizophrenia patients) or 320 trials (for healthy adults) on the Weather Prediction Learning Task, which is a probabilistic classification learning task in which participants learn to predict the weather (i.e. "sun" or "rain" outcomes) based on combinations of cues that predict "sun" versus "rain" outcomes.	Testing Day (i.e. approx 3-5 hrs following placebo or D-cycloserine administration)
Performance on N-Back Working Memory Task	Percent Correct Responses out of 240 trials (for schizophrenia patients) or 320 trials (for healthy adults) on the N-Back Task, which is a spatial working memory task in which participants identify whether each new stimulus on the computer screen is in the same location as the stimulus shown in trials ago. Patients with schizophrenia completed 80 trials at each of 3 working memory loads (0-, 1-, 2-back loads) and healthy adults completed 80 trials at each of 4 working memory loads (0-, 1-, 2-, 3-back loads).	Testing Day (i.e. approx 3-5 hrs following placebo or D-cycloserine administration)
Change in Visual Evoked Potential Amplitude using Electroencephalograph (EEG)	EEG data were recorded using a 128 channel cap while participants viewed a black and white checkerboard stimulus on a computer screen in 6 x 2-minute blocks before and after viewing a quickly flashing checkerboard stimulus for 2 minutes. Change in the mean amplitude of the visual evoked potential from before versus after viewing the quickly flashing checkerboard stimulus was used to assess plasticity.	Testing Day (i.e. approx 3-5 hrs following placebo or D-cycloserine administration)

Collaborators and Investigators

• Sponsor: University of California, Los Angeles

Study record dates

Study Major Dates

• Study Start: November 1, 2013
• Primary Completion (Actual): July 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: May 10, 2016
• First Submitted That Met QC Criteria: May 11, 2016
• First Posted (Estimate): May 12, 2016

Study Record Updates

• Last Update Posted (Estimate): May 12, 2016
• Last Update Submitted That Met QC Criteria: May 11, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Keywords: Receptors; N-Methyl-D-Aspartate
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antimetabolites; Anti-Bacterial Agents; Antitubercular Agents; Antibiotics, Antitubercular; Anti-Infective Agents, Urinary; Renal Agents; Cycloserine
• Other Study ID Numbers: 13-000409

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED