Cognition Disorders, Memory Disorders, Schizophrenia
Conditions
Keywords
Genes, Dorsolateral Prefrontal Cortex, Dopamine, Functional Magnetic Resonance Imaging, Neuropsychological Testing, Schizophrenia, Atomoxetine, Cognitive Study, Pharmacogenetics, Normal Volunteers, Catechol-O-Methyltransferase, Healthy Volunteer
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.
Interventions
DRUGAtomoxetine
Comparison between Atomoxetine and Placebo
PROCEDUREFunctional magnetic resonance imaging
Comparison between Atomoxetine and Placebo arms
PROCEDURENeuropsychological Testing
Comparison between Atomoxetine and Placebo arms
DRUGPlacebo
25 mg, 40 mg, 60 mg and 80 mg Atomoxetine Placebo
Sponsors
National Institute of Mental Health (NIMH)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Functional Magnetic Resonance Imaging (fMRI) Blood-oxygen-level-dependent (Bold) Activity | 2 hours after the first or the second dose of Atomoxetine or placebo on 14th day | 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 | 2 hours after the first or the second dose of Atomoxetine or placebo on 14th day | 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
| Measure | Time frame | Description |
|---|---|---|
| Change in The Positive and Negative Syndrome Scale (PANSS) | At 14th and 35th days | 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 | At 14th and 35th days | 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 | At 14th and 35th days | 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) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Blood Plasma Concentration of Atomoxetine | before and 3 hours after dosing on the 14th day receiving Atomoxetine | Blood for drug plasma levels is obtained before and 3 hours after dosing on the 14th day receiving Atomoxetine. |
Countries
United States
Participant flow
Recruitment details
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).
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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). | 6 |
| 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). | 5 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
Baseline characteristics
| Characteristic | Healthy Participants | Patients With Schizophrenia | Total |
|---|---|---|---|
| Age, Customized <=18 years | 0 participants | 0 participants | 0 participants |
| Age, Customized >=45 years | 0 participants | 0 participants | 0 participants |
| Age, Customized Between 18 and 45 years | 6 participants | 5 participants | 11 participants |
| Region of Enrollment United States | 6 participants | 5 participants | 11 participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 5 | 2 / 5 | 4 / 6 | 1 / 6 |
| serious Total, serious adverse events | 0 / 5 | 1 / 5 | 0 / 6 | 0 / 6 |
Outcome results
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.
Time frame: 2 hours after the first or the second dose of Atomoxetine or placebo on 14th day
Population: Data were not collected for analysis because the study was terminated before target accrual
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.
Time frame: 2 hours after the first or the second dose of Atomoxetine or placebo on 14th day
Population: Data were not collected for analysis because the study was terminated before target accrual
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)
Time frame: At 14th and 35th days
Population: Data were not collected for analysis because the study was terminated before target accrual
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.
Time frame: At 14th and 35th days
Population: Data were not collected for analysis because the study was terminated before target accrual
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.
Time frame: At 14th and 35th days
Population: Data were not collected for analysis because the study was terminated before target accrual
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.
Time frame: before and 3 hours after dosing on the 14th day receiving Atomoxetine
Population: Data were not collected for analysis because the study was terminated before target accrual