Clinical trial NCT00548327: The Effects of Atomoxetine on Cognition and Brain Function Based on Catechol-O-methyltransferase(COMT) Genotype
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 type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Schizophrenia
Memory Disorders
Cognition Disorders
Keywords: Genes
Dorsolateral Prefrontal Cortex
Dopamine
Functional Magnetic Resonance Imaging
Neuropsychological Testing
Schizophrenia
Atomoxetine
Cognitive Study
Pharmacogenetics
Normal Volunteers
Catechol-O-Methyltransferase
Healthy Volunteer
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2007-10-23
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief 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.

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 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.

Primary outcomes:
measure: Changes in Functional Magnetic Resonance Imaging (fMRI) Blood-oxygen-level-dependent (Bold) Activity
timeFrame: 2 hours after the first or the second dose of Atomoxetine or placebo on 14th day
measure: Changes in Cognitive Function Measured by Neuropsychological Testing
timeFrame: 2 hours after the first or the second dose of Atomoxetine or placebo on 14th day
Secondary outcomes:
measure: Change in The Positive and Negative Syndrome Scale (PANSS)
timeFrame: At 14th and 35th days
measure: Change in The Profile of Mood States
timeFrame: At 14th and 35th days
measure: Change in The Hamilton Anxiety Rating Scale
timeFrame: At 14th and 35th days
Other outcomes:
measure: Blood Plasma Concentration of Atomoxetine
timeFrame: before and 3 hours after dosing on the 14th day receiving Atomoxetine
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Institute of Mental Health (NIMH)
name: Jose A Apud, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Beracochea D, Cagnard B, Celerier A, le Merrer J, Peres M, Pierard C. First evidence of a delay-dependent working memory-enhancing effect of modafinil in mice. Neuroreport. 2001 Feb 12;12(2):375-8. doi: 10.1097/00001756-200102120-00038.
citation: 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. doi: 10.1073/pnas.111134598. Epub 2001 May 29.
citation: 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. doi: 10.1097/00001756-200111160-00032.