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D-cycloserine Augmentation of Cognitive Remediation in Schizophrenia

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ClinicalTrials.gov Identifier: NCT00963924
Recruitment Status : Completed
First Posted : August 24, 2009
Results First Posted : August 20, 2014
Last Update Posted : February 6, 2018
Sponsor:
Collaborator:
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
Donald C. Goff, MD, Massachusetts General Hospital

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Schizophrenia Drug: D-cycloserine Drug: Placebo Behavioral: Cognitive Remediation Not Applicable

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  (Clinical Trial)
Actual Enrollment : 54 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Placebo-controlled Trial of D-cycloserine Augmentation of Cognitive Remediation in Schizophrenia
Study Start Date : August 2009
Actual Primary Completion Date : May 2011
Actual Study Completion Date : June 2011

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Schizophrenia
Drug Information available for: Cycloserine
U.S. FDA Resources

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 Name: Cycloserine
Behavioral: Cognitive Remediation
40 one-hour daily sessions of cognitive remediation (Brain Fitness Program) over eight weeks.
Other Name: 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.
Drug: Placebo
Placebo by mouth one hour before first cognitive remediation session each week for eight weeks.
Behavioral: Cognitive Remediation
40 one-hour daily sessions of cognitive remediation (Brain Fitness Program) over eight weeks.
Other Name: Brain Fitness Program



Primary Outcome Measures :
  1. Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) [ Time Frame: Baseline vs. Week 8 ]
    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.

  2. Scale for Assessment of Negative Symptoms (SANS) [ Time Frame: Baseline vs. Week 8 ]
    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.

  3. Auditory Discrimination Task: Interstimulus Interval (ISI) [ Time Frame: Baseline vs. Week 8 ]
    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.


Secondary Outcome Measures :
  1. Positive and Negative Syndrome Scale (PANSS) [ Time Frame: Baseline ]
    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.

  2. Global Assessment of Functioning Scale (GAS) [ Time Frame: Baseline ]
    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.

  3. Heinrich Quality of Life Scale (QoL) [ Time Frame: Baseline ]
    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.

  4. Calgary Depression Scale for Schizophrenia (CDSS) [ Time Frame: Baseline ]
    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.

  5. Clinical Global Impression (CGI) [ Time Frame: Weeks 0 and 8, and Month 6 after cognitive remediation completion ]

    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


  6. Side Effects Checklist (SEC) [ Time Frame: Weeks 0 - 8, and Month 6 after cognitive remediation completion ]
    Each side effect is entered as either yes or no for having had any severity of the side effect at each visit.



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Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00963924


Locations
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Sponsors and Collaborators
Massachusetts General Hospital
National Institute of Mental Health (NIMH)
Investigators
Principal Investigator: Donald C. Goff, M.D. Massachusetts General Hospital

Publications of Results:
Responsible Party: Donald C. Goff, MD, Director of the Schizophrenia Clinical and Research Program, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT00963924     History of Changes
Other Study ID Numbers: 2008P002237
5P50MH060450 ( U.S. NIH Grant/Contract )
DATR A3-NSC
First Posted: August 24, 2009    Key Record Dates
Results First Posted: August 20, 2014
Last Update Posted: February 6, 2018
Last Verified: January 2018

Keywords provided by Donald C. Goff, MD, Massachusetts General Hospital:
Cognitive Impairment
Neuroplasticity
D-cycloserine
NMDA
Anti-Bacterial Agents
Mental Disorders
Psychotic Disorders
Antitubercular Agents
Schizophrenia and Disorders with Psychotic Features
Schizoaffective Disorder

Additional relevant MeSH terms:
Schizophrenia
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders
Cycloserine
Anti-Infective Agents, Urinary
Anti-Infective Agents
Renal Agents
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action