Clinical Trial of Tolcapone for Cognition in Schizophrenia

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.

- 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.