Effects of Modafinil on Brain Function in Patients With 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. Similarly, modafinil, a catecholaminergic agonist that increases
extracellular dopamine in the prefrontal cortex was also shown to improve delay-dependent
working memory. 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% of the variance in performance of working memory tasks in humans
suggest that COMT genotype may predict response to COMT inhibitors or to other agonists that
increase catecholaminergic function in the frontal cortex.

In the present investigation our goal is to examine, in normal controls and patients with
schizophrenia, the effect of modafinil, a drug that increases DA output in the frontal
cortex, on cognitive function and brain physiology. We predict that both normal controls and
patients with schizophrenia with the val/val genotype will have a significant improvement in
working memory compared with individuals possessing other genotypes. Furthermore, in
conjunction with other NIMH imaging protocols, we predict that modafinil will produce a
similar genotype-dependent effect on the neurophysiological correlates related to working
memory assayed with fMRI. 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 modafinil offers a new
treatment -based on genotype - for cognitive impairment in schizophrenia. The FDA granted a
waiver for the use of Modafinil in this study.

- INCLUSION CRITERIA:

Prior participation under NIH protocol # 95-M-0150, or new normal volunteers. Patients
with Schizophrenia or Schizoaffective disorder that meet criteria for NIH protocol #
95-M-0150 will be included.

No active Axis I or Axis II diagnosis in normal volunteers.

Age range: 18-50 years.

EXCLUSION CRITERIA:

Subjects with a history of cardiovascular disease, liver disease and other medical
illnesses, current active substance abuse or history of substance abuse for more than 5
years, and untreated or uncontrolled hypertension will be excluded. Individuals with
persistent tardive dyskinesia will be excluded from the study. An electrocardiogram, blood
pressure, pulse rate and metabolic panel including LFTs will be checked on all subjects
prior to participation in the study.

Schizophrenic patients taking, a COMT inhibitor, buproprion, stimulants, other cognitive
enhancers or any illicit drugs of abuse, or MAO inhibitors will be excluded.

Normal control subjects taking any medications affecting brain function will be excluded.

Pregnant or breastfeeding 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.

Patients with significant history of violence against self or others as established in
protocol # 89-M-0160 (Inpatient Evaluation of Neuropsychiatric Patients)