Modafinil for Treatment of Cognitive Dysfunction in Schizophrenia
Condition: Schizophrenia; Schizoaffective Disorder
MeSH terms: Schizophrenia; Cognitive Dysfunction; Psychotic Disorders
Study type: Interventional
Phase: Phase 4

Summary: 
      Patients with schizophrenia have problems in thinking, known as cognitive dysfunction. This
      appears to be responsible for their difficulties in social and occupational functioning. One
      particular cognitive function that may be important for schizophrenia is called context
      processing. This refers to the ability to properly use information in the environment to
      guide thinking and behavior so that it is appropriate to the present circumstance. Problems
      with this function may explain why patients with schizophrenia think and act in unusual ways,
      and often have problems managing aspects of their lives that healthy adults take for granted.
      This cognitive function depends on a region of the brain called the prefrontal cortex, which
      shows impaired function in schizophrenia as well. Unfortunately, the biochemical aspects of
      this dysfunction are presently unknown, and it is not clear whether current psychiatric
      medications can improve this function. A recent FDA-approved medication that may improve this
      function is modafinil. Studies in animals and healthy adults show that this medication can
      improve cognitive functions which are related to context processing. We plan to study the
      effects of modafinil on context processing and the brain activity that underlies this
      function. We will use functional MRI and electrophysiology to examine the effects of
      modafinil, both after a single dose and after sustained (4 week) treatment. We predict that
      when patients receive modafinil they will perform better on cognitive tests and have improved
      activity in the regions of the brain that are responsible for these cognitive processes.
    

Detailed description: 
      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.
    

Intervention name(s): modafinil; Placebos
Intervention type(s): Drug; Drug
Intervention description(s): 200 milligrams daily dose; capsule containing placebo
Other intervention name(s): Provigil
Intervention MeSH terms: Modafinil
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: cognition; memory