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Clinical Trial of Tolcapone for Cognition in Schizophrenia

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ClinicalTrials.gov Identifier: NCT00044083
Recruitment Status : Completed
First Posted : August 19, 2002
Last Update Posted : September 1, 2016
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )

August 16, 2002
August 19, 2002
September 1, 2016
August 2002
December 2015   (Final data collection date for primary outcome measure)
Genetic differences in working memory testing or fMRI activation1
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Complete list of historical versions of study NCT00044083 on ClinicalTrials.gov Archive Site
Panss, Ham-A, POMS, Blood draws for drug levels and liver enzymes
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Clinical Trial of Tolcapone for Cognition in Schizophrenia
Randomized, Double-Blinded, Placebo Controlled Study of the Effects of Tolcapone and Entacapone on Cognitive Function in Patients With Schizophrenia and Normal Controls Based on COMT Genotype

This study will evaluate whether Tolcapone improves cognition in healthy volunteers as well as patients with schizophrenia. Talcapone is a drug that has been FDA approved for Attention Deficit Disorder and allegedly increase the amount of the neurotransmitter dopamine in the frontal cortex of the brain.

Psychopharmacological modulation of the catecholaminergic system can enhance some aspects of cognitive function. For example, COMT inhibitors can slightly improve working memory/executive function. Differences in the response between individuals might be related to a number of factors, including variations in the genes. The recent finding that a polymorphism in the catechol-o-methyl-transferase (COMT) gene, which produces a 4 fold change in enzyme activity, accounts for 4 percent of the variance in performance of working memory tasks in humans suggest that COMT genotype may predict response to COMT inhibitors. In the present investigation our goal is to examine, in normal controls and patients with schizophrenia, the effect of a centrally acting (tolcapone) and of a peripherally acting (entacapone) COMT inhibitor on cognitive function. We predict that both normal controls and patients with schizophrenia with the val/val genotype will have a significant, though transient, improvement in working memory in subjects treated with tolcapone but not in those treated with entacapone. Furthermore, in conjunction with other NIMH imaging protocols, we would like to examine the neurophysiological correlates related to working memory. We predict, in tolcapone treated subjects, improved measures in prefrontal 'efficiency' in subjects and patients specifically with the val/val genotype. The present protocol will provide new insights on the importance of this genetic polymorphism in the regulation of aminergic-controlled cognitive function in normal individuals. Furthermore, this protocol will test whether COMT inhibitors offer a new treatment-based on genotype - for cognitive impairment in schizophrenia. No IND is required for the present study.
Phase 2
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double
Drug: Tolcapone
Tolcapone 200 mg tid: Placebo 1 week-Wash Out 1 week-Drug 1 week (or vice versa)
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*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
December 2015
December 2015   (Final data collection date for primary outcome measure)

    1. Prior participation under NIH protocol number 95-M-0150, or new normal volunteers or schizophrenic patients that meet criteria for NIH protocol number 95-M-0150.
    2. No Axis I or Axis II diagnosis in normal volunteers.
    3. Age range: 18-50 years.


  1. Normal volunteers with an Axis I or Axis II disorder obtained either from prior SCID interview in Protocol 95-M-0150 or through a screening interview will be excluded.
  2. Subjects with a history of cardiovascular disease, liver disease and other medical illnesses, and untreated or uncontrolled hypertension will be excluded. An electrocardiogram, blood pressure, pulse rate and metabolic panel including LFTs will be checked on all subjects prior to participation in the study. Individuals with persistent tardive dyskinesia or abnormal LFTs, or individuals with significant history of alcoholism or liver enzyme elevation will be excluded from the study.
  3. Schizophrenic patients taking clozapine, a COMT inhibitor, any illicit drugs of abuse, or MAO inhibitors will be excluded.
  4. Normal control subjects taking any medications other than occasional NSAI will be excluded.
  5. Pregnant women. Women of childbearing potential will undergo a urine pregnancy test the day the study initiates and screened by history for the possibility of pregnancy.
Sexes Eligible for Study: All
18 Years to 50 Years   (Adult)
Contact information is only displayed when the study is recruiting subjects
United States
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National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )
National Institute of Mental Health (NIMH)
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Principal Investigator: Jose A Apud, M.D. National Institute of Mental Health (NIMH)
National Institutes of Health Clinical Center (CC)
June 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP