The Effects of Atomoxetine on Cognition and Brain Function Based on Catechol-O-methyltransferase(COMT) Genotype

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Randomized, Double-Blinded, Placebo Controlled Study of the Effects of Atomoxetine on Cognitive Function in Patients With Schizophrenia and Normal Controls Based on COMT Genotype

Conditions
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Schizophrenia, Memory Disorders, Cognition Disorders

Intervention / Treatment
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* Drug: Atomoxetine
* Procedure: Functional magnetic resonance imaging
* Procedure: Neuropsychological Testing
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Prior participation under NIH protocol # 95-M-0150, or new normal volunteers or schizophrenic patients that meet criteria for NIH protocol # 95-M-0150. No active Axis I or Axis II diagnosis in normal volunteers. Age range: 18-45 years. Normal EKG and blood pressure readings. EXCLUSION CRITERIA: Normal volunteers with an active Axis I or Axis II disorder or patients with an Axis I diagnosis other than schizophrenia or schizoaffective disorder obtained either from prior Structured Clinical Interview for the Diagnostic and Statistical Manual Disorders (SCID) interview in Protocol 95-M-0150 or through a screening interview will be excluded. Subjects with a history of cardiovascular disease, liver disease and other serious medical illnesses, and untreated or uncontrolled hypertension will be excluded because of the potential for drug-drug interaction or because of the potential deleterious effect of the drug on the medical condition. An electrocardiogram, blood pressure, pulse rate, toxicological screen, cell blood count and metabolic panel including Liver Function Tests (LFTs) will be checked on all subjects prior to participation in the study. Any subject with an electrocardiogram deemed abnormal by a cardiologist or with sustained systolic blood pressure of 150 mmHg or above, diastolic blood pressure of 100 mmHg or above will be excluded from the study. Schizophrenic patients taking a COMT inhibitor, any illicit drugs of abuse, or Monoamine Oxidase (MAO) inhibitors will be excluded. Patients taking paroxetine, fluoxetine, bupropion, tricyclic antidepressants, albuterol, modafinil, stimulants or pressor agents will be excluded from the study. No medication will be stopped in order to participate in the study. Normal control subjects taking any medication other than occasional nonsteroidal anti-inflammatory drugs (NSAID) or with recent history of illicit drug or alcohol abuse will be excluded. Normal controls on contraceptive medication will be excluded from the study. Pregnant women: Women of childbearing potential will undergo a urine pregnancy test the day the study initiates and they will be screened by history for the possibility of pregnancy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Atomoxetine<br>Atomoxetine 80 mg final dose. Arm lasts 14 days. Schedule 25 mg Day 1 (or Day 22), 40 mg Day 2-3 (or Days 23-24), 60 mg Days 4-5 (or Days 25-26), 80 mg Days 6-14 (or Days 27-35). After 14 days, subjects undergo functional magnetic resonance imaging (MRI) and neuropsychological testing in addition to psychopathology ratings | Drug: Atomoxetine<br>* Comparison between Atomoxetine and Placebo<br>* Other names: Strattera;Procedure: Functional magnetic resonance imaging<br>* Comparison between Atomoxetine and Placebo arms<br>Procedure: Neuropsychological Testing<br>* Comparison between Atomoxetine and Placebo arms<br>* Other names: Neuropsychiatric testing;|
| Placebo Comparator: Placebo<br>Placebo administered for 14 days. Schedule Atomoxetine 25 mg Placebo Day 1 (or Day 22), Atomoxetine 40 mg Placebo Day 2-3 (or Days 23-24), Atomoxetine 60 mg Placebo Days 4-5 (or Days 25-26), Atomoxetine 80 mg Placebo Days 6-14 (or Days 27-35). After 14 days, subjects undergo functional magnetic resonance imaging and neuropsychological testing in addition to psychopathology ratings | Procedure: Functional magnetic resonance imaging<br>* Comparison between Atomoxetine and Placebo arms<br>Procedure: Neuropsychological Testing<br>* Comparison between Atomoxetine and Placebo arms<br>* Other names: Neuropsychiatric testing;Drug: Placebo<br>* 25 mg, 40 mg, 60 mg and 80 mg Atomoxetine Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 2 hours after the first or the second dose of Atomoxetine or placebo on 14th day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | At 14th and 35th days | 
| Change in The Profile of Mood States | 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. | 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) | At 14th and 35th days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Genes, Dorsolateral Prefrontal Cortex, Dopamine, Functional Magnetic Resonance Imaging, Neuropsychological Testing, Schizophrenia, Atomoxetine, Cognitive Study, Pharmacogenetics, Normal Volunteers, Catechol-O-Methyltransferase, Healthy Volunteer