Clinical Trial of Tolcapone for Cognition in Schizophrenia

The purpose of this study is to test whether the drug tolcapone improves the memory of patients with schizophrenia.

The purpose of this study is to test whether the drug tolcapone improves the memory of patients with schizophrenia.The catecholaminergic system can enhance some aspects of cognitive function, such as working memory. Studies suggest that drugs that inhibit COMT may improve working memory and executive function. However, individuals differ in their response to COMT inhibitors. These response differences may be related to genotypic variations in COMT. This study will examine the effect of tolcapone, a COMT inhibitor, on the cognitive function of people with schizophrenia, compared to healthy volunteers. Participants with schizophrenia will be admitted to the NIH Clinical Center for 4 to 12 weeks during their participation in the study. Healthy volunteers will participate as outpatients. During Week 1 of the study, participants will receive either tolcapone or a placebo (an inactive pill) three times a day for 7 days. Participants will not receive tolcapone or placebo in Week 2. During Week 3, medications will be crossed over in all participants (those given placebo during week 1 will receive tolcapone, and vice versa). Participants will undergo psychological testing, blood tests, and a magnetic resonance imaging (MRI) scan of the brain. Condition: – Schizophrenia Study Type: InterventionalStudy Design: Treatment, Safety/Efficacy Official Title: Randomized, Double-Blinded, Placebo Controlled Study Of The Effects Of Tolcapone On Cognitive Function In Patients With Schizophrenia And Normal Controls Based On COMT Genotype Further Study Details: 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 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. Furthermore, in conjunction with other NIMH protocols, we would like to examine the neurophysiological correlates related to working memory. We predict 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 Genders Eligible for Study: Both Accepts Healthy VolunteersCriteria 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-0150.2) No Axis I or Axis II diagnosis in normal volunteers.3) Age range: 18-60 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.Expected Total Enrollment: 180 [1] National Institute of Mental Health (NIMH) (US)