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

Information source: National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Schizophrenia; Memory Disorders; Cognition Disorders

Intervention: Atomoxetine (Drug); Functional magnetic resonance imaging (Procedure); Neuropsychological Testing (Procedure); Placebo (Drug)

Phase: Phase 2

Status: Terminated

Sponsored by: National Institute of Mental Health (NIMH)

Official(s) and/or principal investigator(s):
Jose A Apud, M.D., Principal Investigator, Affiliation: National Institute of Mental Health (NIMH)

Summary

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.

Clinical Details

Official title: 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

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome:

Changes in Functional Magnetic Resonance Imaging (fMRI) Blood-oxygen-level-dependent (Bold) Activity

Changes in Cognitive Function Measured by Neuropsychological Testing

Secondary outcome:

Change in The Positive and Negative Syndrome Scale (PANSS)

Change in The Profile of Mood States

Change in The Hamilton Anxiety Rating Scale

Detailed description: 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.

Eligibility

Minimum age: 18 Years. Maximum age: 45 Years. Gender(s): Both.

Criteria:

- 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.

Locations and Contacts

National Institutes of Health Clinical Center, 9000 Rockville Pike, Bethesda, Maryland 20892, United States
Additional Information

NIH Clinical Center Detailed Web Page

Related publications:

Béracochéa D, Cagnard B, Célérier A, le Merrer J, Pérès M, Piérard C. First evidence of a delay-dependent working memory-enhancing effect of modafinil in mice. Neuroreport. 2001 Feb 12;12(2):375-8.

Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, Goldman D, Weinberger DR. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6917-22. Epub 2001 May 29.

de Saint Hilaire Z, Orosco M, Rouch C, Blanc G, Nicolaidis S. Variations in extracellular monoamines in the prefrontal cortex and medial hypothalamus after modafinil administration: a microdialysis study in rats. Neuroreport. 2001 Nov 16;12(16):3533-7.

Starting date: October 2007
Last updated: April 30, 2013

Page last updated: August 23, 2015

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