D-cycloserine Augmentation of Cognitive Remediation in Schizophrenia

A Placebo-controlled Trial of D-cycloserine Augmentation of Cognitive Remediation in Schizophrenia

This study seeks to examine the effects of D-cycloserine augmentation on cognitive remediation for patients diagnosed with schizophrenia. We will test the hypotheses that D-cycloserine will significantly improve cognitive performance, negative symptoms, and measures of functioning compared to placebo when combined with eight weeks of cognitive remediation. We expect that these effects will persist when assessed at six-month follow up.

Study Overview

• Status: Completed
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: D-cycloserine; Behavioral: Cognitive Remediation; Drug: Placebo

Detailed Description

D-cycloserine has been shown to enhance learning in animal models and, in a previous trial, once-weekly D-cycloserine improved negative symptoms in schizophrenia subjects. We set out to test whether DCS combined with cognitive remediation would improve learning of a practiced auditory discrimination task and whether gains would generalize to unpracticed cognitive tasks.

The proposed study consists of an 8-week, placebo-controlled, double-blind, parallel-group trial of D-cycloserine augmentation of cognitive remediation in schizophrenia outpatients. The primary outcome measure is change in performance on the MATRICS cognitive battery composite score after 8 weeks. Secondary outcome measures include a measure of processing speed assessed after weeks 1, 2, 4 & 8, and changes in negative symptoms and measures of functioning after 4 and 8 weeks. In addition, all outcome measures will be repeated at 6 months to assess persistence of benefit.

Hypotheses:

1. D-cycloserine will significantly improve cognitive performance as measured by the composite score on the MATRICS battery compared to placebo after 8 weeks of cognitive remediation.
2. D-cycloserine will significantly improve negative symptoms as measured by the SANS compared to placebo after 8 weeks when combined with cognitive remediation.
3. D-cycloserine will significantly improve measures of functioning (GAS, QoL and CGI) at 8 weeks compared to placebo when combined with cognitive remediation.
4. D-cycloserine effects on cognition, negative symptoms and functioning will persist compared to placebo when assessed at 6-month follow-up.

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female
• Age 18-65 years
• Diagnosis of schizophrenia or schizoaffective disorder, depressed type
• Stable dose of antipsychotic for at least 4 weeks
• Able to provide informed consent
• Able to complete a cognitive battery
• Able to perform the cognitive remediation exercises

Exclusion Criteria:

• Current treatment with clozapine
• Dementia
• Seizure disorder
• Unstable medical illness
• Renal insufficiency measured as eGFR >60mg/dL/min
• Active substance abuse: positive urine toxic screen
• Pregnancy, nursing, or unwilling to use appropriate birth control measures during participation if female and fertile.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: D-cycloserine; Participants will receive D-cycloserine weekly, one hour before the first cognitive remediation session of the week, for eight weeks.	Drug: D-cycloserine; 50 mg by mouth one hour before first cognitive remediation session each week for eight weeks.; Other Names: Cycloserine; Behavioral: Cognitive Remediation; 40 one-hour daily sessions of cognitive remediation (Brain Fitness Program) over eight weeks.; Other Names: Brain Fitness Program
Placebo Comparator: Placebo; Participants will receive placebo weekly, one hour before the first cognitive remediation session of the week, for eight weeks.	Behavioral: Cognitive Remediation; 40 one-hour daily sessions of cognitive remediation (Brain Fitness Program) over eight weeks.; Other Names: Brain Fitness Program; Drug: Placebo; Placebo by mouth one hour before first cognitive remediation session each week for eight weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS)	Change of a composite score from baseline to week 8 on the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS). The MATRICS consists of 10 cognitive tasks that are used to calculate scores in 7 cognitive domains: speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition. The raw scores on each cognitive task are transformed on a normative scale into t-scores, and then these scores are combined to calculate the domain scores. The composite score is calculated by averaging all domain t-scores to come up with one overall cognitive composite t-score. For all scores on the assessment, the higher the score the better the performance on the task.	Baseline vs. Week 8
Scale for Assessment of Negative Symptoms (SANS)	The total scores from baseline and week 8 on the scale for the assessment of negative symptoms (SANS) total score. Total SANS scores range from 0-100. The SANS is comprised of 5 subscores: Affective Flattening or Blunting (score range 0-35), Alogia (score range 0-20), Avolition-Apathy (score range 0-15), Anhedonia-Asociality (score range 0-20), and Attention (0-10). For each scale, the higher the score the more prominent the negative symptoms were. The total score was computed by adding all the sub-scale total scores. Scores are reported for baseline and week 8.	Baseline vs. Week 8
Auditory Discrimination Task: Interstimulus Interval (ISI)	The auditory discrimination task involved trials in which the subject differentiated between rapidly-presented frequency-modulated sweeps separated by a short interstimulus interval (ISI). In this task, sustained successful performance is more difficult with shorter stimulus presentations and ISIs (which were equal within a trial). Thus, our dependent measure was the shortest stimulus duration/ISI, in ms, for trials in which subjects were able to perform the task at 85% accuracy, referred to as ISI for simplicity. The shorter the score the better the performance on the task. Scores are reported for baseline and week 8.	Baseline vs. Week 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Positive and Negative Syndrome Scale (PANSS)	The baseline score on the positive symptom sub-scale of the Positive and Negative Syndrome Scale (PANSS). Total PANSS positive symptom sub-scale scores range from 7-49. The PANSS positive symptom sub-scale is comprised of 7 items rated on a scale of 1-7: delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility. A score of one on each item 1 absent, 2 is minimal, 3 is mild, 4 is moderate, 5 is moderately severe, 6 is severe, and 7 is extreme. The total score was computed by adding all the items on the sub-scale together. The higher a score the more prominent a positive symptom is.	Baseline
Global Assessment of Functioning Scale (GAS)	The Global Assessment of Functioning Scale (GAS) measured at baseline. This scale measures social, occupational, and psychological functioning, on a scale of 0-100. The higher the score, the greater a participant's functioning level.	Baseline
Heinrich Quality of Life Scale (QoL)	Baseline scores of the Heinrich Quality of Life Scale, a 21 item scale designed and validated to measure intrapsychic foundations, interpersonal relations, instrumental role, and common objects and activities in patients diagnosed with Schizophrenia. Patients are rated on each of the 21 items on a scale of 0-6. Total scores are computed by adding up the scores of each individual item, with a total score ranging from 0-126. Higher scores reflect higher functioning.	Baseline
Calgary Depression Scale for Schizophrenia (CDSS)	Baseline scores on the Calgary Depression Scale for Schizophrenia (CDSS). Total CDSS scores range from 0-27. The assessment is comprised of 9 questions covering the topics of Depression, Hopelessness, Self Depreciation, Guilty Ideas of Reference, Pathological Guilt, Morning Depression, Early Wakening, Suicide, Observed Depression. Each item is scored on a scale from 0-3 (0 = absent, 1 = mild, 2 = moderate, 3 = severe). The total score is computed by adding up the individual scores of each item. The higher the score, the more prominent the symptoms of depression are for the participant.	Baseline
Clinical Global Impression (CGI)	Considering you total clinical experience with this patient population, how mentally ill is the patient at this time? 1=Normal, not at all, 2=Borderline mentally ill, 3=Mildy ill, 4=Moderately ill, 5=Markedly ill, 6=Severely ill, 7=Among the most extremely ill patients; a higher score indicates worse outcome	Weeks 0 and 8, and Month 6 after cognitive remediation completion
Side Effects Checklist (SEC)	Each side effect is entered as either yes or no for having had any severity of the side effect at each visit.	Weeks 0 - 8, and Month 6 after cognitive remediation completion

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Donald C. Goff, M.D., Massachusetts General Hospital

Publications and helpful links

General Publications

• Cain CK, McCue M, Bello I, Creedon T, Tang DI, Laska E, Goff DC. d-Cycloserine augmentation of cognitive remediation in schizophrenia. Schizophr Res. 2014 Mar;153(1-3):177-83. doi: 10.1016/j.schres.2014.01.016. Epub 2014 Jan 30.

Study record dates

Study Major Dates

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

Study Registration Dates

• First Submitted: August 20, 2009
• First Submitted That Met QC Criteria: August 20, 2009
• First Posted (Estimate): August 24, 2009

Study Record Updates

• Last Update Posted (Actual): February 6, 2018
• Last Update Submitted That Met QC Criteria: January 9, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Keywords: Neuroplasticity; Cognitive Impairment; Schizoaffective Disorder; Mental Disorders; D-cycloserine; Psychotic Disorders; Antitubercular Agents; NMDA; Anti-Bacterial Agents; Schizophrenia and Disorders with Psychotic Features
• 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: 2008P002237; DATR A3-NSC (National Institute of Mental Health); 5P50MH060450 (U.S. NIH Grant/Contract)