This study will evaluate whether Atomoxetine improves cognition in healthy volunteers as well as patients with schizophrenia. Atomoxetine is a drug that has been Food and Drug Administration (FDA) approved for Attention Deficit Disorder and allegedly increase the amount of the neurotransmitter dopamine in the frontal cortex of the brain.
Psychopharmacological modulation of the catecholaminergic system can enhance some aspects of cognitive function. For example, catechol-O-methyltransferase (COMT) inhibitors such as tolcapone can improve working memory/executive function. Similarly, modafinil, a catecholaminergic agonist with norepinephrine (NA) reuptake blocking properties, was also shown to improve delay-dependent working memory in mice. 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 COMT gene, which produces a 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 dopaminergic 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 atomoxetine, a selective noradrenaline reuptake inhibitor that increases extracellular levels of dopamine in the frontal cortex, on cognitive function. We predict that both normal controls and patients with schizophrenia with the val/val genotype, which present higher COMT activity and, thus, lower extracellular dopamine concentrations in the frontal cortex, will have a significant improvement in working memory. Furthermore, in conjunction with other National Institute of Mental Health imaging protocols, we would like to examine the neurophysiological correlates related to working memory. We predict improved measures in prefrontal efficiency in subjects and patients specifically with the val/val genotype. 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 atomoxetine offers a new treatment, based on genotype, for cognitive impairment in schizophrenia. An Investigational New Drug (IND) waiver will be requested for the present study.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Comparison between Atomoxetine and Placebo
Comparison between Atomoxetine and Placebo arms
Comparison between Atomoxetine and Placebo arms
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States
Changes in Functional Magnetic Resonance Imaging (fMRI) Blood-oxygen-level-dependent (Bold) Activity
Main outcome measures were BOLD fMRI response (activation) while performing a prefrontal cortex-dependent task such as N-Back Working Memory with increasing levels of task difficulty. It was expected to have a greater level of activation in BOLD fMRI in schizophrenic patients with respect to normal volunteers, and a greater activation in individuals (either normal volunteers or patients) who share the val/val genotype with respect to the met/met genotype. Based on prior fMRI studies and on power analysis of neuropsychological variables, at least 28 and 26 subjects are respectively needed to achieve significant power in functional neuroimaging and neuropsychological studies.These sizes provide an 80% power to observe significant differences between drug conditions at the 0.05 level.
Time frame: 2 hours after the first or the second dose of Atomoxetine or placebo on 14th day
Changes in Cognitive Function Measured by Neuropsychological Testing
Neuropsychological testing consists of a battery of 10-12 individual tests to measure cognitive function. We expect both a drug effect and a genotype effect on neuropsychological tasks that measure dorsolateral prefrontal cortex (DLPFC) executive function, mostly in individuals who share the val/val genotype with respect to the met/met genotype.
Time frame: 2 hours after the first or the second dose of Atomoxetine or placebo on 14th day
Change in The Positive and Negative Syndrome Scale (PANSS)
The Positive and Negative Syndrome Scale (PANSS) is a 7-point rating scale with (1) indicating the absence of a symptom or behavior and (7) indicating the most severe symptom. The PANSS includes three scales(Positive and Negative Syndromes and General Psychopathology)and five clusters (Anergia, Thought Disturbance, Activation, Paranoid/Belligerence and Depression.
Time frame: At 14th and 35th days
Change in The Profile of Mood States
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Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
11
25 mg, 40 mg, 60 mg and 80 mg Atomoxetine Placebo
The Profile of Mood States is an instrument that provides a rapid method of assessing transient, fluctuating mood states. The POMS consists of 65 adjectives rated by subjects on a 5-point scale and six factors that derive from this scale are: 1)tension-anxiety, 2)depression-dejection, 3)anger-hostility, 4)fatigue-inertia, 5)vigor-activity and 6)Confusion-bewilderment.
Time frame: At 14th and 35th days
Change in The Hamilton Anxiety Rating Scale
The Hamilton Anxiety Rating Scale is a psychological questionnaire to rate the severity of anxiety.It contains 14 symptom-oriented questions.Each of these symptoms is given a severity rating, from not present(scored as 0)to very severe(scored as 4)
Time frame: At 14th and 35th days