The Effects of Atomoxetine on Cognition and Brain Function Based on COMT Genotype - Full Text View

Sponsored by:	National Institute of Mental Health (NIMH)
Information provided by:	National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:	NCT00548327

Purpose

This study will evaluate whether Atomoxetine improves cognition in healthy volunteers as well as patients with schizophrenia. Atomoxetine is a drug that has been FDA approved for Attention Deficit Disorder and allegedly increase the amount of the neurotransmitter dopamine in the frontal cortex of the brain....

Condition	Intervention	Phase
Schizophrenia Working Memory Cognition Healthy Volunteers	Drug: Amoxetine Procedure: Functional MRI Procedure: Neuropsychiatric Testing	Phase II

MedlinePlus related topics: Schizophrenia

Drug Information available for: Dopamine Dopamine hydrochloride Atomoxetine Atomoxetine hydrochloride

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Crossover Assignment, Efficacy Study
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

Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:

Changes in cognitive function [ Designated as safety issue: No ]

Secondary Outcome Measures:

Changes in Psychopathology Rating Scale Scores [ Designated as safety issue: Yes ]

Estimated Enrollment:	180
Study Start Date:	October 2007

Intervention Details:

N/A

Detailed Description:

Psychopharmacological modulation of the catecholaminergic system can enhance some aspects of cognitive function. For example, COMT inhibitors such as tolcapone can improve working memory/executive function. Similarly, modafinil, a catecholaminergic agonist with 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 catechol-O-methyl-transferase (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 NIMH 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 IND waiver will be requested for the present study.

Eligibility

Ages Eligible for Study:	18 Years to 45 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

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 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 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 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 NSAID or with recent history of illicit drug or alcohol abuse will be excluded.
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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00548327

Contacts

Contact: Patient Recruitment and Public Liaison Office	(800) 411-1222	prpl@mail.cc.nih.gov
Contact: TTY	1-866-411-1010

Locations

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

Sponsors and Collaborators

National Institute of Mental Health (NIMH)

More Information

NIH Clinical Center Detailed Web Page This link exits the ClinicalTrials.gov site

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.

Responsible Party:	National Institutes of Health ( Jose A. Apud, M.D./National Institute of Mental Health )
Study ID Numbers:	080002, 08-M-0002
Study First Received:	October 19, 2007
Last Updated:	September 15, 2008
ClinicalTrials.gov Identifier:	NCT00548327
Health Authority:	United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):

Genes
Dorsolateral Prefrontal Cortex
Dopamine
Functional MRI
Neuropsychological Testing
Schizophrenia
Atomoxetine

Cognitive Study
Pharmacogenetics
Normal Volunteers
Catechol-O-methyltransferase
Schizophrenia
Healthy Volunteer
HV

Study placed in the following topic categories:

Schizophrenia
Dopamine
Mental Disorders
Atomoxetine

Psychotic Disorders
Healthy
Schizophrenia and Disorders with Psychotic Features

Additional relevant MeSH terms:

Neurotransmitter Uptake Inhibitors
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Adrenergic Agents

Adrenergic Uptake Inhibitors
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on January 30, 2009