Nicotinic Modulation of the Cognitive Control System in Late-Life Depression (R33 Phase)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 40
- 试验地点
- 2
- 主要终点
- MADRS (Montgomery Asberg Depression Rating Scale) Score
研究概览
简要总结
Deficits in cognitive control are core features of late-life depression (LLD), contributing both to emotion dysregulation and problems with inhibiting irrelevant information, conflict detection, and working memory. Clinically characterized as executive dysfunction, these deficits are associated with poor response to antidepressants and higher levels of disability. Improvement of cognitive control network (CCN) dysfunction may benefit both mood and cognitive performance, however no current pharmacotherapy improves Cognitive Control Network deficits in LLD.
The study examines the hypothesis that nicotine acetylcholine receptor agonists enhance Cognitive Control Network function. This effect may resultantly improve mood and cognitive performance in LLD. Small, open-label studies of transdermal nicotine (TDN) patches have supported potential clinical benefit and provided support that transdermal nicotine administration engages the Cognitive Control Network.
This blinded study will expand past open-label trials supporting potential benefit in LLD. It will examine TDN's effect on depression severity and cognitive control functions measured by neuropsychological testing. The study will evaluate 60 eligible and enrolled participants over a 3-year period.
详细描述
The purpose of the Depressed MIND3 study is to determine whether blinded, placebo-controlled administration of transdermal nicotine results in significant cognitive, clinical and functional improvement in participants with LLD. Neuronal nicotinic receptors have long been known to play a critical role in memory function in preclinical studies, with nicotine improving attention, learning, and memory function. This may be particularly relevant in LLD, which is characterized both by affective symptoms and broad cognitive deficits. The co-occurrence of cognitive deficits in LLD is a clinically relevant phenotype characterized by significant disability and poor antidepressant response. Cognitive deficits can persist even with successful antidepressant treatment and increase the risk of depression relapse. Despite the clinical importance of cognitive deficits in LLD, there are no established treatments that specifically target cognition in this population. The lack of clear pharmacologic targets and therapies aimed at improving cognitive deficits in depression is a substantial deficiency in current therapeutics.
We propose that modulation of the cognitive control network by stimulation of cholinergic system nicotinic acetylcholine receptors will improve both mood and cognition in depressed elders. The study is a randomized double blind placebo control trial that will enroll 80 participants over a 3-year period. Participants will be randomized (2:1) to receive either active transdermal nicotine (TDN) patches or matching placebo patches. Participants will apply patches daily for 12 weeks, followed by a 3-week taper period.
The Aims of this blinded trial are to: 1) validate target engagement and determine whether change in brain activation to an emotional Stroop task is related to improvement in depression severity and cognitive performance; and 2) determine the specificity of TDN's effects by examining whether changes in the default mode network (DMN) or other regions occur with TDN and if so, are they related to change in clinical measures.
AIM 1: Examine how TDN's neural circuit changes affect depressive symptoms in a blinded RCT.
Hyp 1A: Compared with placebo, TDN administration will significantly reduce the Stroop BOLD response on functional Magnetic Resonance Imaging. This change will be associated with reduction in depression severity by the Montgomery-Asberg Depression Rating Scale (MADRS).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
Double Blinded, using matching placebo patches.
入排标准
- 年龄范围
- 60 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 60 years;
- •diagnosis of major depressive disorder, single or recurrent episode (DSM5);
- •On a stable therapeutic dose of an allowed SSRI or SNRI for at least 6 weeks;
- •severity: at least mild active depression symptoms, defined as MADRS ≥ 15;
- •cognition: MMSE ≥ 24;
- •fluent in English
排除标准
- •Other Axis I psychiatric disorders, except for generalized anxiety disorder (GAD) or social phobia symptoms occurring in a depressive episode or diagnosis of an attentional disorder, such as Attention Deficit Hyperactivity Disorder (ADHD);
- •Use of other augmentation medication treatments for depression or ADHD e.g., stimulant medications (e.g., adjunctive bupropion or other augmenting agents) that the participant does not want to stop, although short-acting sedatives are allowed;
- •Any use of tobacco or nicotine in the last year.
- •Living with a smoker or regular exposure to secondhand smoke.
- •History of alcohol use disorder or substance use disorder of moderate or greater severity (endorsing 4 or more of the 12 criteria) in the last 12 months.
- •Acute suicidality.
- •Acute grief (<1 month);
- •Current or past psychosis.
- •Primary central nervous system neurological disorder, including dementia, stroke, epilepsy, etc.;
- •Presence of unstable medical illness requiring urgent treatment or intervention;
- •MRI contraindication.
- •Electroconvulsive therapy or transcranial magnetic stimulation in last 2 months;
- •Current or planned psychotherapy where the potential participant does not want to pause therapy for the duration of the study;
- •Allergy or hypersensitivity to nicotine patches;
- •In the last 4 weeks, regular use of drugs with central cholinergic or anticholinergic properties or moderate / severe CYP2A6 inhibitors /inducers
研究组 & 干预措施
Transdermal Placebo Patch
Participants will be randomized to apply placebo transdermal patches during waking hours. Placebo patch titration will mirror the active arm, increasing the dose will titrate up from 3.5mg to 7mg in the first 3 weeks. Doses can be optionally titrated to a maximum of 14mg over 12 weeks, based on tolerability and perceived benefit. After 12 weeks, the patch dose will be tapered over 2-3 weeks.
干预措施: Transdermal Placebo Patch (Drug)
Transdermal Nicotine Patch
Participants will be randomized to apply nicotine transdermal patches during waking hours. Active dose will titrate up from 3.5mg to 7mg in the first 3 weeks. Doses can be optionally titrated to a maximum of 14mg over 12 weeks, based on tolerability and perceived benefit. After 12 weeks, the patch dose will be tapered over 2-3 weeks.
干预措施: Transdermal Nicotine Patch (Drug)
结局指标
主要结局
MADRS (Montgomery Asberg Depression Rating Scale) Score
时间窗: Baseline to week 12
Primary mood outcome measured by the total score of the clinician rated MADRS. MADRS will be measured every 3 weeks (baseline, week 3, week 6, week 9, and week 12). MADRS total score range is 0-60, where higher scores indicate greater depression severity.
Functional Magnetic Resonance Imaging (MRI)
时间窗: Baseline to week 6.
MRI scans will be performed at baseline and week 6. MRI will measure cognitive control network function, operationalized as a reduction in the Stroop BOLD response in the middle and superior frontal gyri. The Stroop BOLD response is calculated as the activation difference between incongruent and congruent conditions of the emotional Stroop task. The primary outcome will be change in activation difference from baseline to week 6. This will be examined as both a continuous variable and a categorical variable, operationalized as those subjects will exhibit a middle / superior frontal gyri z-score reduction in activation over time of 0.5 or greater.
MADRS (Montgomery Asberg Depression Rating Scale) Score
时间窗: Baseline to week 12
Primary mood outcome measured by the total score of the clinician rated MADRS. MADRS will be measured every 3 weeks (baseline, week 3, week 6, week 9, and week 12). MADRS total score range is 0-60, where higher scores indicate greater depression severity.
Functional Magnetic Resonance Imaging (MRI)
时间窗: Baseline to week 6.
MRI scans will be performed at baseline and week 6. MRI will measure cognitive control network function, operationalized as a reduction in the Stroop BOLD response in the middle and superior frontal gyri. The Stroop BOLD response is calculated as the activation difference between incongruent and congruent conditions of the emotional Stroop task. The primary outcome will be change in activation difference from baseline to week 6. This will be examined as both a continuous variable and a categorical variable, operationalized as those subjects will exhibit a middle / superior frontal gyri z-score reduction in activation over time of 0.5 or greater.
次要结局
- NIH EXAMINER Test Battery(Baseline to Week 12)
- Selective Reminding Task(Baseline to Week 12)
- Trait Adjectives Task(Baseline to Week 12)
- Ruminative Response Scale(Baseline to Week 12)
- Apathy Evaluation Scale (AES)(Baseline to Week 12)
- Insomnia Severity Index(Baseline to Week 12)
- Penn State Worry Questionnaire (PSWQ)(Baseline to Week 12)
- Fatigue Severity Scale(Baseline to Week 12)
- General Anxiety Disorder Scale (7 Item)(Baseline to Week 12)
- PROMIS Applied Cognition Abilities Short(Baseline to Week 12)
- Attentional Control Scale(Baseline to Week 12)
- Monetary Incentive Delay Task(Baseline and to week 12)
- Probabilistic Selection Task(Baseline and to week 12)
- NIH EXAMINER Test Battery(Baseline to Week 12)
- Selective Reminding Task(Baseline to Week 12)
- Trait Adjectives Task(Baseline to Week 12)
- Ruminative Response Scale(Baseline to Week 12)
研究者
Patricia Andrews
Assistant Professor of Psychiatry
Vanderbilt University Medical Center