Back to resultsThe Effects of Atomoxetine on Cognition and Brain Function Based on Catechol-O-methyltransferase(COMT) Genotype (Atomoxetine)
Primary Purpose
Schizophrenia, Memory Disorders, Cognition Disorders
Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Atomoxetine
Functional magnetic resonance imaging
Neuropsychological Testing
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Schizophrenia focused on measuring Genes, Dorsolateral Prefrontal Cortex, Dopamine, Functional Magnetic Resonance Imaging, Neuropsychological Testing, Schizophrenia, Atomoxetine, Cognitive Study, Pharmacogenetics, Normal Volunteers, Catechol-O-Methyltransferase, Healthy Volunteer
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.
Sites / Locations
- National Institutes of Health Clinical Center, 9000 Rockville Pike
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Placebo Comparator
Arm Label
Atomoxetine
Placebo
Arm Description
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
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
Outcomes
Primary Outcome Measures
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.
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.
Secondary Outcome Measures
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.
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.
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)
Full Information
NCT ID
NCT00548327
First Posted
October 19, 2007
Last Updated
April 30, 2013
Sponsor
National Institute of Mental Health (NIMH)
1. Study Identification
Unique Protocol Identification Number
NCT00548327
Brief Title
The Effects of Atomoxetine on Cognition and Brain Function Based on Catechol-O-methyltransferase(COMT) Genotype
Acronym
Atomoxetine
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
2. Study Status
Record Verification Date
April 2013
Overall Recruitment Status
Terminated
Why Stopped
The scientific director decided to terminate: low priority study with slow accrual
Study Start Date
October 2007 (undefined)
Primary Completion Date
November 2011 (Actual)
Study Completion Date
November 2011 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Mental Health (NIMH)
4. Oversight
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
11 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Atomoxetine
Arm Type
Active Comparator
Arm Description
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
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Atomoxetine
Other Intervention Name(s)
Strattera
Intervention Description
Comparison between Atomoxetine and Placebo
Intervention Type
Procedure
Intervention Name(s)
Functional magnetic resonance imaging
Intervention Description
Comparison between Atomoxetine and Placebo arms
Intervention Type
Procedure
Intervention Name(s)
Neuropsychological Testing
Other Intervention Name(s)
Neuropsychiatric testing
Intervention Description
Comparison between Atomoxetine and Placebo arms
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
25 mg, 40 mg, 60 mg and 80 mg Atomoxetine Placebo
Primary Outcome Measure Information:
Title
Changes in Functional Magnetic Resonance Imaging (fMRI) Blood-oxygen-level-dependent (Bold) Activity
Description
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.
Time Frame
2 hours after the first or the second dose of Atomoxetine or placebo on 14th day
Title
Changes in Cognitive Function Measured by Neuropsychological Testing
Description
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.
Time Frame
2 hours after the first or the second dose of Atomoxetine or placebo on 14th day
Secondary Outcome Measure Information:
Title
Change in The Positive and Negative Syndrome Scale (PANSS)
Description
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.
Time Frame
At 14th and 35th days
Title
Change in The Profile of Mood States
Description
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.
Time Frame
At 14th and 35th days
Title
Change in The Hamilton Anxiety Rating Scale
Description
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)
Time Frame
At 14th and 35th days
Other Pre-specified Outcome Measures:
Title
Blood Plasma Concentration of Atomoxetine
Description
Blood for drug plasma levels is obtained before and 3 hours after dosing on the 14th day receiving Atomoxetine.
Time Frame
before and 3 hours after dosing on the 14th day receiving Atomoxetine
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jose A Apud, M.D.
Organizational Affiliation
National Institute of Mental Health (NIMH)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center, 9000 Rockville Pike
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
11209953
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.
Results Reference
background
PubMed Identifier
11381111
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.
Results Reference
background
PubMed Identifier
11733706
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.
Results Reference
background
Links:
URL
http://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2008-M-0002.html
Description
NIH Clinical Center Detailed Web Page
Learn more about this trial
The Effects of Atomoxetine on Cognition and Brain Function Based on Catechol-O-methyltransferase(COMT) Genotype
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