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.