Clinical Trial of Tolcapone for Cognition in Schizophrenia

Phase 2

Terminated

Conditions: Schizophrenia

Interventions: Other: Placebo
Drug: Tolcapone

Registration Number: NCT00044083

Lead Sponsor: National Institute of Mental Health (NIMH)

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 210

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo Arm	Placebo	Placebo one week
Tolcapone Arm	Tolcapone	Tolcapone one week

Primary Outcome Measures

Name	Time	Method
N-Back Task Activation Genotype Effect in Healthy Volunteers	At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)	Activation beta values (N-Back vs. 0-Back) extracted within the Effect of Genotype cluster around the peak (p \< 0.05 uncorrected) in right and left DLPFC from the contrast maps in Healthy Volunteers. Lower beta values reflect more efficient processing in the DLPFC when performing working memory tasks.
N-Back Task Activation Diagnosis Effect	At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)	Activation beta values (N-Back vs. 0-Back) were extracted within the Main Effect of Diagnosis cluster around the peak (p \< 0.05 uncorrected) from the contrast maps in the Placebo condition. Lower beta values reflect more efficient processing in the DLPFC when performing working memory tasks.
N-Back Task Activation in DLPFC in Patients With Schizophrenia	At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)	Activation Beta values (N-Back vs. 0-Back) extracted within the Effect of Drug cluster around the peak (p \< 0.05 uncorrected) from the contrast maps in patients with schizophrenia. Lower beta values reflect more efficient processing in the DLPFC when performing working memory tasks.
N-Back Task Performance	At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)	Working Memory was measured in HVs and patients with schizophrenia after a 7-day treatment with Tolcapone or placebo in a double-blind, cross-over fashion. The working memory was quantified by taking the number of trials entered correctly divided by the total number of trials multiplied by 100. Values range from 0 to 100. Zero indicates the poorest performance while 100 indicates perfect performance.
N-Back Task Activation in Healthy Volunteers	At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)	Activation Beta values (N-Back vs. 0-Back) extracted within the Effect of Drug cluster around the peak (p \< 0.05 uncorrected) from the contrast maps in Healthy Volunteers. Lower beta values reflect more efficient processing in the DLPFC when performing working memory tasks.
N-Back Task Activation Drug Effect	At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)	Activation beta values (N-Back vs. 0-Back) extracted within the Main Effect of Drug cluster around the peak (p \< 0.05 uncorrected) from the contrast maps across both groups. Lower beta values reflect more efficient processing in the DLPFC when performing working memory tasks.
N-Back Task Activation by Genotype in Patients With Schizophrenia	At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)	Activation beta values (N-Back vs. 0-Back) extracted from DLPFC from the contrast maps in Patients with schizophrenia. Lower beta values reflect more efficient processing in the DLPFC when performing working memory tasks.

Secondary Outcome Measures

Name	Time	Method
Positive and Negative Syndrome Scale	At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)	Rating Scales PANSS. The Positive Scale ranges for 7 to 49 with a higher score indicating greater severity of symptoms. The Negative Scale ranges for 7 to 49 with a higher score indicating greater severity of symptoms. The General Scale ranges from 16 to 112, the higher score indicating greater severity of symptoms.