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
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 11
- 试验地点
- 1
- 主要终点
- Changes in Functional Magnetic Resonance Imaging (fMRI) Blood-oxygen-level-dependent (Bold) Activity
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Atomoxetine
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
干预措施: Atomoxetine (Drug)
Atomoxetine
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
干预措施: Functional magnetic resonance imaging (Procedure)
Atomoxetine
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
干预措施: Neuropsychological Testing (Procedure)
Placebo
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
干预措施: Functional magnetic resonance imaging (Procedure)
Placebo
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
干预措施: Neuropsychological Testing (Procedure)
Placebo
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
干预措施: Placebo (Drug)
结局指标
主要结局
Changes in Functional Magnetic Resonance Imaging (fMRI) Blood-oxygen-level-dependent (Bold) Activity
时间窗: 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
时间窗: 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.
次要结局
- Change in The Positive and Negative Syndrome Scale (PANSS)(At 14th and 35th days)
- Change in The Profile of Mood States(At 14th and 35th days)
- Change in The Hamilton Anxiety Rating Scale(At 14th and 35th days)