Modafinil for Treatment of Cognitive Dysfunction in Schizophrenia
| Status: | Completed |
|---|---|
| Conditions: | Cognitive Studies, Schizophrenia, Psychiatric |
| Therapuetic Areas: | Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 18 - 54 |
| Updated: | 10/1/2017 |
| Start Date: | September 2005 |
| End Date: | December 2012 |
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.
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.
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.
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.
Inclusion Criteria:
- adults age 18-54
- diagnosis of schizophrenia or schizoaffective disorder, or healthy with no personal or
family history of mental illness
- able to provide informed consent
Exclusion Criteria:
- history of significant head injury or other neurological illness
- active psychiatric illness requiring significant acute care
- significant intellectual impairment (e.g. standardized full-scale IQ < 70)
- history of medical illness or treatment that either interferes with experimental
measures (e.g. cerebrovascular disease, anemias, etc.) or is associated with
significant increase in risk from modafinil treatment (e.g. cardiac disease)
- significant active substance abuse
- presence of ferromagnetic foreign body or prosthesis
- active pregnancy
- active treatment with medications that have drug interactions with modafinil
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