Not provided
| ID | Type | Description | Link |
|---|---|---|---|
| Atomoxetine Protocol | |||
| Atomoxetine | Other Grant/Funding Number | National Institute of Mental Health | |
| 08-M-0002 |
Not provided
Not provided
The scientific director decided to terminate: low priority study with slow accrual
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
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.
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.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Atomoxetine | Active Comparator | 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 | Placebo Comparator | 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 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Atomoxetine | Drug | Comparison between Atomoxetine and Placebo |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 2 hours after the first or the second dose of Atomoxetine or placebo on 14th day |
| 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. | 2 hours after the first or the second dose of Atomoxetine or placebo on 14th day |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Blood Plasma Concentration of Atomoxetine | Blood for drug plasma levels is obtained before and 3 hours after dosing on the 14th day receiving Atomoxetine. | before and 3 hours after dosing on the 14th day receiving Atomoxetine |
EXCLUSION CRITERIA:
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Jose A Apud, M.D. | National Institute of Mental Health (NIMH) | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda | Maryland | 20892 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 11209953 | Background | 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. | |
| 11381111 | Background | 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. |
| Label | URL |
|---|---|
| NIH Clinical Center Detailed Web Page | View source |
Not provided
Subjects need to satisfy the inclusion/exclusion criteria for the genetic studies protocol before participating. Normal volunteers will be enrolled as outpatients and patients as inpatients. Females do both arms during the same phase of the menstrual cycle. Patients with Schizophrenia are stabilized for at least 6 weeks before the protocol.
Normal volunteers or patients with schizophrenia will be initially recruited from among individuals who have volunteered for previous genetic studies and for whom genetic data is already available. Power calculations set target accrual at 30 participants per genotype for 3 COMT genotypes per cohort (i.e., 90 patients and 90 healthy volunteers).
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | Healthy Participants | This is a double-blind, placebo-control, cross-over study of Atomoxetine in healthy volunteers. It includes 3 genotypes, the VAL/VAL, VAL/MET and MET/MET. Subjects are 2 weeks on placebo, 2 weeks on active compound and one week wash-out period between arms. Amoxetine 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). Placebo 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). |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Functional magnetic resonance imaging | Procedure | Comparison between Atomoxetine and Placebo arms |
|
| Neuropsychological Testing | Procedure | Comparison between Atomoxetine and Placebo arms |
|
|
| Placebo | Drug | 25 mg, 40 mg, 60 mg and 80 mg Atomoxetine Placebo |
|
| At 14th and 35th days |
| 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. | At 14th and 35th days |
| 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) | At 14th and 35th days |
| 11733706 | Background | 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. |
| FG001 | Patients With Schizophrenia | This is a double-blind, placebo-control, cross-over study of Atomoxetine in patients with schizophrenia. It includes 3 genotypes, the VAL/VAL, VAL/MET and MET/MET. Subjects are 2 weeks on placebo, 2 weeks on active compound and one week wash-out period between arms. Amoxetine 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). Placebo 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). |
| COMPLETED |
|
| NOT COMPLETED |
|
|
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Healthy Participants | This is a double-blind, placebo-control, cross-over study of Atomoxetine in healthy volunteers. It includes 3 genotypes, the VAL/VAL, VAL/MET and MET/MET. Subjects are 2 weeks on placebo, 2 weeks on active compound and one week wash-out period between arms. Amoxetine 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). Placebo 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). |
| BG001 | Patients With Schizophrenia | This is a double-blind, placebo-control, cross-over study of Atomoxetine in patients with schizophrenia. It includes 3 genotypes, the VAL/VAL, VAL/MET and MET/MET. Subjects are 2 weeks on placebo, 2 weeks on active compound and one week wash-out period between arms. Amoxetine 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). Placebo 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). |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Number | participants |
| |||||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| |||||||||||||||||||
| Region of Enrollment | Number | participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Data were not collected for analysis because the study was terminated before target accrual | Posted | 2 hours after the first or the second dose of Atomoxetine or placebo on 14th day |
|
| ||||||||||||||||||||||
| Secondary | 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. | Data were not collected for analysis because the study was terminated before target accrual | Posted | At 14th and 35th days |
|
| ||||||||||||||||||||||
| Primary | 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. | Data were not collected for analysis because the study was terminated before target accrual | Posted | 2 hours after the first or the second dose of Atomoxetine or placebo on 14th day |
| |||||||||||||||||||||||
| Secondary | 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. | Data were not collected for analysis because the study was terminated before target accrual | Posted | At 14th and 35th days |
|
| ||||||||||||||||||||||
| Secondary | 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) | Data were not collected for analysis because the study was terminated before target accrual | Posted | At 14th and 35th days |
|
| ||||||||||||||||||||||
| Other Pre-specified | Blood Plasma Concentration of Atomoxetine | Blood for drug plasma levels is obtained before and 3 hours after dosing on the 14th day receiving Atomoxetine. | Data were not collected for analysis because the study was terminated before target accrual | Posted | before and 3 hours after dosing on the 14th day receiving Atomoxetine |
|
Two years, from 2008 to 2011.
Adverse events are collected during the arm or at the end of each arm.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Atomoxetine-Patient | 0 | 5 | 5 | 5 | |||
| EG001 | Placebo-Patient | 1 | 5 | 2 | 5 | |||
| EG002 | Atomoxetine-Healthy Volunteer | 0 | 6 | 4 | 6 | |||
| EG003 | Placebo-Healthy Volunteer | 0 | 6 | 1 | 6 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Psychosis | Psychiatric disorders | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Palpitations | Cardiac disorders | Systematic Assessment | Mild. Present in both arms of the protocol in one patient |
| |
| Nausea | Gastrointestinal disorders | Systematic Assessment | Mild |
| |
| Difficulty sleeping | Psychiatric disorders | Systematic Assessment | Mild. Present in both arms of the protocol in one healthy volunteer and one patient |
| |
| Loss of Appetite | Gastrointestinal disorders | Systematic Assessment | Mild in two patients,one of them on placebo and moderate in one HV |
| |
| Dry Mouth | Gastrointestinal disorders | Systematic Assessment | Two patients had the side effect during both arms of the protocol |
| |
| Constipation | Gastrointestinal disorders | Systematic Assessment | One subject had the side effect in both arms of the protocol. |
| |
| Fatigue | Psychiatric disorders | Systematic Assessment | Fatigue was present in 2 patients and 1 HV in both arms of the protocol. |
| |
| Sexual dysfuntion | Reproductive system and breast disorders | Systematic Assessment | Side effect was present in both arms of the protocol in one patient |
| |
| Urinary difficulties | Renal and urinary disorders | Systematic Assessment | Mild |
| |
| Sweating | Skin and subcutaneous tissue disorders | Systematic Assessment |
| ||
| Dizziness | Nervous system disorders | Non-systematic Assessment | Side effect present in both arms of the protocol in one patient |
| |
| Restlessness | Nervous system disorders | Non-systematic Assessment | Side effect present in both arms of the protocol in one patient |
| |
| Heartburn | Gastrointestinal disorders | Non-systematic Assessment | Side effect present in one patient in both arms of the protocol |
| |
| Chills | General disorders | Non-systematic Assessment |
| ||
| Itching | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
| ||
| unusual thoughts | Psychiatric disorders | Systematic Assessment |
|
Not provided
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Jose A. Apud MD, PhD | Clinical Brain Disoders Branch-National Institute of Mental Health (NIMH)-National Institute of Health (NIH) | 301 5946561 | apudj@mail.nih.gov |
| ID | Term |
|---|---|
| D012559 | Schizophrenia |
| D008569 | Memory Disorders |
| D003072 | Cognition Disorders |
| ID | Term |
|---|---|
| D019967 | Schizophrenia Spectrum and Other Psychotic Disorders |
| D001523 | Mental Disorders |
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D019965 | Neurocognitive Disorders |
Not provided
Not provided
| ID | Term |
|---|---|
| D000069445 | Atomoxetine Hydrochloride |
| D009483 | Neuropsychological Tests |
| ID | Term |
|---|---|
| D011437 | Propylamines |
| D000588 | Amines |
| D009930 | Organic Chemicals |
| D011581 | Psychological Tests |
| D004191 | Behavioral Disciplines and Activities |
Not provided
Not provided
| Title | Measurements |
|---|---|
|
| >=45 years |
|
| Male |
|
|
|