Nicotinic Modulation of the Cognitive Control System in Late-Life Depression (R33 Phase)
Overview
- Phase
- Phase 2
- Intervention
- Transdermal Nicotine Patch
- Conditions
- Depressive Disorder
- Sponsor
- Vanderbilt University Medical Center
- Enrollment
- 60
- Locations
- 2
- Primary Endpoint
- MADRS (Montgomery Asberg Depression Rating Scale) Score
- Status
- Recruiting
- Last Updated
- 2 months ago
Overview
Brief Summary
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.
Detailed Description
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). Hyp 1B: Change in the Stroop BOLD response of other brain regions with TDN administration, specifically the DMN, will not be significantly associated with change in depression severity. Hyp 1C: Compared with placebo, TDN will improve depression severity measured by MADRS (primary clinical outcome), reduce apathy and rumination measured by self-report, and reduce negative self-referential thinking measured by the Trait Adjectives Task (secondary outcomes). AIM 2: Examine how TDN's circuit changes affect CCN-mediated cognitive performance. Hyp 2A: Reduction in the Stroop BOLD response will be associated with improvement in attention, working memory, and episodic memory performance. Change in the Stroop BOLD response of other regions, specifically the DMN, will not be associated with change in task performance. Hyp 2B: Compared with placebo, nicotine will improve performance on tasks of attention, working memory, and episodic memory (secondary outcomes).
Investigators
Warren Taylor
Director, Division of General Psychiatry and Division of Geriatric Psychiatry
Vanderbilt University Medical Center
Eligibility Criteria
Inclusion Criteria
- •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
Exclusion Criteria
- •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;
Arms & Interventions
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.
Intervention: Transdermal Nicotine Patch
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.
Intervention: Transdermal Placebo Patch
Outcomes
Primary Outcomes
MADRS (Montgomery Asberg Depression Rating Scale) Score
Time Frame: 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)
Time Frame: 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.
Secondary Outcomes
- 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)