The Effects of Atomoxetine on Cognition and Brain Function Based on COMT Genotype
Information source: National Institutes of Health Clinical Center (CC)
Information obtained from ClinicalTrials.gov on February 12, 2009
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Schizophrenia; Working Memory; Cognition; Healthy Volunteers
Intervention: Amoxetine (Drug); Functional MRI (Procedure); Neuropsychiatric Testing (Procedure)
Phase: Phase 2
Status: Recruiting
Sponsored by: National Institute of Mental Health (NIMH) Overall contact:
Patient Recruitment and Public Liaison Office, Phone: (800) 411-1222, Email: prpl@mail.cc.nih.gov
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 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: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Crossover Assignment, Efficacy Study
Primary outcome: Changes in cognitive function
Secondary outcome: Changes in Psychopathology Rating Scale Scores
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
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 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. 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
Patient Recruitment and Public Liaison Office, Phone: (800) 411-1222, Email: prpl@mail.cc.nih.gov
National Institutes of Health Clinical Center, 9000 Rockville Pike, Bethesda, Maryland 20892, United States; Recruiting
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: February 12, 2009
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