Modafinil for Treatment of Cognitive Dysfunction in Schizophrenia

Schizophrenia is a disorder of cognition. The cognitive deficits of schizophrenia are present at the onset of the disorder, prior to medication exposure, are persistent during periods of remission, and are strongly related to functional outcome. These deficits prominently include prefrontal-dependent functions. While existing medications effectively treat psychotic symptoms, they exhibit modest benefit at best for cognitive dysfunction. Studies of cognition in animal models indicate that the neurotransmitter systems that mediate prefrontal-dependent cognitive processes are not generally augmented by existing antipsychotic medications. Therefore, advances in the treatment of schizophrenia will require the study of agents with novel pharmacological profiles to establish their potential to remediate cognitive dysfunction. Advances in understanding the mechanism of action of these agents will also require the integration of pharmacology with a sophisticated methodology for testing cognition. This goal has been strongly pursued in recent years with the use of functional magnetic resonance imaging (fMRI) to study pharmacological effects on cognition. fMRI studies have identified the cortical network subserving cognitive control and working memory, which are consistently impaired among schizophrenia patients. The study of medication effects on these processes with fMRI (pharmaco-fMRI) will permit the more precise delineation of the cognitive mechanisms amenable to pharmacological intervention. This study will use fMRI to study the effects of modafinil on the functional neuroanatomy underlying prefrontal cognitive processes. Modafinil is an FDA-approved medication with a unique pharmacological profile and an increasing range of off-label indications. Its neurochemical effects in animal models include elevation of extracellular dopamine (DA), noradrenaline (NA) and glutamate in the neocortex. This profile is favorable for the enhancement of prefrontal cognitive processes. These neurochemical effects also appear to be selective for cortical versus subcortical brain regions, suggesting that modafinil may have minimal effects on psychotic symptoms, or extrapyramidal, autonomic and hormonal side effects. In addition, it differs from amphetamine in structure, neurochemical profile and behavioral effects, with a lower risk of addictive or cerebrovascular effects. Recent studies in animal models, healthy adults and adults with psychiatric and neurological disorders indicate that modafinil improves prefrontal cognitive functions. This suggests that modafinil is a leading candidate for the treatment of cognitive dysfunction in schizophrenia. We aim to test modafinil effects on these processes in healthy adults, in order to evaluate modafinil effects on normal-range cognition, and then evaluate the remediation of deficits in these functions in individuals with schizophrenia, both in a single-dose trial and followed by a trial of sustained treatment. Comparison 1. The effect in healthy adults and adults with schizophrenia/schizoaffective disorder, of Modafinil 200 milligrams single oral dose versus placebo (double-blind, balanced crossover design), on cognitive control task performance, and on activity of dorsolateral prefrontal cortical (DLPFC) during context processing, and anterior cingulate cortex (ACC) during conflict monitoring phases of the task, both measured by fMRI. Comparison 2. The effect in adults with schizophrenia/schizoaffective disorder, of 4-week randomized, double-blind treatment with Modafinil 200 milligrams daily versus placebo, on cognitive control task performance, and on activity of dorsolateral prefrontal cortical (DLPFC) during context processing, and anterior cingulate cortex (ACC) during conflict monitoring phases of the task, both measured by fMRI.