Depressed Mood Improvement Through Nicotine Dosing 3

Study Overview
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Brief Summary
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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
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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).

Official Title
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Nicotinic Modulation of the Cognitive Control System in Late-Life Depression (R33 Phase)

Conditions
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Depressive Disorder

Intervention / Treatment
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* Drug: Transdermal Nicotine Patch
* Drug: Transdermal Placebo Patch


Participation Criteria
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Eligibility Criteria
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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; Use of other augmentation medication treatments for depression (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

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Transdermal Nicotine Patch<br>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. | Drug: Transdermal Nicotine Patch<br>* Participants will wear nicotine transdermal patches daily for 12-15 weeks. They will apply a study patch each morning and remove at bedtime. Active dose will titrate up from 3.5mg to 7mg, and then can optionally be further titrated to a maximum dose of 14mg. After week12, the dose will be slowly tapered over 2-3 weeks.<br>* Other names: Nicotrol;|
| Placebo Comparator: Transdermal Placebo Patch<br>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. | Drug: Transdermal Placebo Patch<br>* Participants will wear placebo transdermal patches daily for 12-15 weeks. They will apply a study patch each morning and remove at bedtime. Placebo patch dose will titrate up from 3.5mg to 7mg, and then can optionally be further titrated to a maximum dose of 14mg. After week12, the dose will be slowly tapered over 2-3 weeks.<br>* Other names: Placebo Patches;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MADRS (Montgomery Asberg Depression Rating Scale) Score | 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. | Baseline to week 12 | 
| Functional Magnetic Resonance Imaging (MRI) | 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. | Baseline to week 6. | 
| Continuous Performance Task (CPT) Performance | Primary cognitive outcome, the CPT is a neuropsychological test that measures attention conducted as part of the NIH EXAMINER Test Battery. In this test, participants are asked to respond to a target image and not to other images. This test is conducted at baseline and at week12. The specific primary outcome metric is standard error of change in the inter-stimulus hit reaction time or variability between different trials. There is not absolute range, but lower scores indicate decreased variability across trials and overall better performance. | Baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NIH EXAMINER Test Battery | Secondary Cognitive Outcome: This neuropsychological test battery assesses a range of executive functions. We will examine its Executive Composite Score and the three factor scores (Cognitive Control, Fluency, and Working Memory). Higher scores indicate better performance. | Baseline to Week 12 | 
| Choice Reaction Time (CRT) Performance | Secondary cognitive outcome, a neuropsychological test measure of attention. We will examine the total response time for the CRT. Lower scores indicate better performance. | Baseline to Week 12 | 
| Selective Reminding Task | Secondary cognitive outcome, Selective Reminding Task as a test of immediate and delayed verbal memory. This is an 8-trial, 16-word test where the interviewer reads unrelated words to the participant who must recall them. Any missed items are then repeated before the next attempt. Alternative word lists are available for repeated assessments. A delayed trial is administered after 20 minutes. Change in the recall, failure to recall and consistency over 12 weeks reflect the verbal memory function. | Baseline to Week 12 | 
| Trait Adjectives Task | Participants view a series of randomized, rapidly presented positive and negative characteristics and quickly indicate whether each adjective does or does not apply to them. Positive and negative adjectives are balanced. Measures include number of adjectives endorsed or rejected, and RT for those trials. Task performance assesses self-referential negativity bias and is associated with antidepressant response. Anticipate increased endorsement of positive adjective and increased rejection of negative adjectives in the active arm. | Baseline to Week 12 | 
| Ruminative Response Scale | Secondary mood outcome: Change in rumination measured by the Ruminative Response Scale total score measured at Screening visit, week 6 and week 12. This is a self-report scale with a range of 0-66, where higher scores indicate higher levels of rumination. | Baseline to Week 12 | 
| Apathy Evaluation Scale (AES) | Secondary Mood Outcomes: Change in apathy as measured by the self-report AES, a questionnaire with a range of 0-54, where lower scores indicate greater apathy. | Baseline to Week 12 | 
| Insomnia Severity Index | Secondary Mood Outcomes: Change in the severity of insomnia measures as self-report, a questionnaire with the range of 0-21, where higher scores indicate increase in severity. | Baseline to Week 12 | 
| Penn State Worry Questionnaire (PSWQ) | Secondary mood outcome: Change in anxiety and worry measured by PSWQ, a self-report questionnaire with a range of 16-80, where higher scores indicate greater anxiety and worry. | Baseline to Week 12 | 
| Fatigue Severity Scale | Secondary fatigue out come :self-reported questionnaire that ranges from 0- 56;where higher scores indicate severe fatigue. | Baseline to Week 12 | 
| General Anxiety Disorder Scale (7 Item) | Secondary Mood outcome: self-reported questionnaire to measure the severity of anxiety. Questionnaire ranges 0-24, higher scores indicates greater anxiety state. | Baseline to Week 12 | 
| PROMIS Applied Cognition Abilities Short | Secondary Cognitive outcome:PROMIS (Patient reported outcome measurement information system) is a self-reported questionnaire to measure mental acuity, concentration, verbal and nonverbal memory, verbal fluency, and perceived changes in these cognitive functions, ranges from 0-32 , where higher scores indicate improvement. | Baseline to Week 12 | 
| Attentional Control Scale | Secondary Cognitive outcome: The Attentional Control Scale (ACS) is a self-report questionnaire that has been developed to measure individual differences in attentional control. These findings are discussed in relation to previous studies on attentional and executive control in anxiety and depression. Higher scores indicative of better attentional control. | Baseline to Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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geriatrics, aging, elderly, cognition, memory, nicotine transdermal patch, depression