Clinical trial NCT00044083: Clinical Trial of Tolcapone for Cognition in Schizophrenia
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Schizophrenia
Keywords: Catecholamines
Dopamine
Clinical Trial
fMRI
PFC
Vitamin B2
Riboflavin
Tolcapone
Placebo
Normal Volunteers
Schizophrenia
Healthy Volunteers
HV
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2002-08-19
Enrollment: 210
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: OTHER

Brief summary: 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.

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Detailed description: 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.

Eligibility criteria: * INCLUSION CRITERIA:

  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 (NCT00001486).
  2. No Axis I or Axis II diagnosis in normal volunteers.
  3. Age range: 18-50 years.

EXCLUSION CRITERIA:

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.

Primary outcomes:
measure: N-Back Task Performance
timeFrame: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)
measure: N-Back Task Activation Diagnosis Effect
timeFrame: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)
measure: N-Back Task Activation Drug Effect
timeFrame: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)
measure: N-Back Task Activation in DLPFC in Patients With Schizophrenia
timeFrame: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)
measure: N-Back Task Activation in Healthy Volunteers
timeFrame: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)
measure: N-Back Task Activation Genotype Effect in Healthy Volunteers
timeFrame: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)
measure: N-Back Task Activation by Genotype in Patients With Schizophrenia
timeFrame: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)
Secondary outcomes:
measure: Positive and Negative Syndrome Scale
timeFrame: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Institute of Mental Health (NIMH)
name: Jose A Apud, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Aksoy S, Klener J, Weinshilboum RM. Catechol O-methyltransferase pharmacogenetics: photoaffinity labelling and western blot analysis of human liver samples. Pharmacogenetics. 1993 Apr;3(2):116-22. doi: 10.1097/00008571-199304000-00008.
citation: Andreasen NC, Arndt S, Cizadlo T, O'Leary DS, Watkins GL, Ponto LL, Hichwa RD. Sample size and statistical power in [15O]H2O studies of human cognition. J Cereb Blood Flow Metab. 1996 Sep;16(5):804-16. doi: 10.1097/00004647-199609000-00005.
citation: Arnsten AF. Catecholamine regulation of the prefrontal cortex. J Psychopharmacol. 1997;11(2):151-62. doi: 10.1177/026988119701100208.
citation: Magalona SC, Rasetti R, Chen J, Chen Q, Gold I, Decot H, Callicott JH, Berman KF, Apud JA, Weinberger DR, Mattay VS. Effect of tolcapone on brain activity during a variable attentional control task: a double-blind, placebo-controlled, counter-balanced trial in healthy volunteers. CNS Drugs. 2013 Aug;27(8):663-73. doi: 10.1007/s40263-013-0082-x.