Depressed Mood Improvement Through Nicotine Dosing 2

Study Overview
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Brief Summary
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Deficits in cognitive control are core features of late-life depression, 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 CCN deficits in LLD. Supported by pilot data, Investigators propose that nicotine acetylcholine receptor agonists enhance CCN function and resultantly improve mood and cognitive performance in late-life depression. The objective of this initial R61-phase trial is to first determine whether transdermal nicotine enhances CCN neural activity in an exposure-dependent fashion during an emotional response inhibition task (the emotional Stroop task). Investigator's approach for the R61 phase is to examine in 36 older adults with Major Depressive Disorder whether transdermal nicotine patches enhance CCN activity over 12 weeks as measured during fMRI with the emotional Stroop task while measuring nicotine and nicotine metabolite levels. Transdermal nicotine has a mechanism of action that is distinct from current antidepressants, potentially making it a potentially important antidepressant augmentation agent. If hypotheses are correct, as patches are commercially available, this approach could be rapidly moved into definitive studies and may have applicability to other psychiatric disorders characterized by CCN dysfunction.

Detailed Description
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Late-life depression (LLD) is characterized both by affective symptoms and broad cognitive deficits. The co-occurrence of cognitive deficits in LLD, particularly executive dysfunction, 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. This is particularly important, as the cognitive deficits appear to directly contribute to disability and poor antidepressant treatment outcomes. The lack of clear pharmacologic targets and therapies aimed at improving cognitive deficits in depression is a substantial deficiency in current therapeutics. Modulation of the cholinergic system by nicotinic receptor stimulation may improve both mood and cognition in depressed elders. Clinically, transdermal nicotine improves mood in smokers and a placebo-controlled pilot trial in nonsmoking adults found that transdermal nicotine significantly improved mood. As observed in smokers, nicotine's effect to increase cognitive control network activity while reducing default mode network activity will reduce depression's characteristic bias to negatively valenced stimuli and decrease rumination. Supporting this theory, nicotinic receptor activity stimulates serotonin release and protects against worsening mood with tryptophan depletion. The Depressed Mind 2 Study examines whether enhancement of CCN function by nicotinic acetylcholine receptor agonists will improve mood and cognitive symptoms in LLD. This is supported by pilot data demonstrating that open-label administration of transdermal nicotine (TDN) patches safely improved depression severity. The investigators also observed trends suggesting that TDN may provide benefit for cognitive performance, specifically in domains of episodic memory, working memory, and attention. In other pilot data using an emotional Stroop task, TDN reduces the differences in functional magnetic resonance imaging (fMRI) activation in the cognitive control network (CCN) between Stroop conditions. Importantly, this activation change was associated with a corresponding reduction in depression severity. Based on these data, investigators hypothesize that nicotinic receptor agonists enhance CCN function in LLD and in turn this may improve depressive symptoms. Thirty-six participants will be enrolled to test for target engagement, defined as TDN exposure dependent effect in CCN activation. Based on pilot data, the study will test for enhancement of CCN function by examining the Stroop fMRI response, or the reduction in CCN activation between incongruent and congruent conditions of the emotional Stroop task during fMRI. Investigators will assess the effects of variability in nicotine exposure on target engagement by measuring nicotine blood levels in conjunction with repeat MRI. Primary aim: To test CCN engagement over 12 weeks of Open labeled Transdermal Nicotine(TDN). Hypothesis1A(Target Engagement): TDN will enhance CCN function, measured as a reduction in the middle or superior frontal gyri (M/SFG) Stroop functional MRI response (the activation difference between incongruent and congruent conditions of the emotional Stroop task). 60% or more of subjects will exhibit a M/SFG z-score reduction of 0.5 or greater. Hypothesis1B (Exposure): Higher nicotine exposure measured by patch dose or nicotine metabolite levels will be associated with a greater reduction in the M/SFG Stroop fMRI response.

Official Title
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Nicotinic Modulation of the Cognitive Control System in Late-life Depression

Conditions
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Depressive Disorder

Intervention / Treatment
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* Drug: Transdermal Nicotine 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 selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) for at least 8 weeks; Severity: Montgomery-Asberg Depression Rating Scale (MADRS) score ≥ 15; Cognition: Mini-Mental State Examination (MMSE) score ≥ 24; Fluent in English Exclusion Criteria: Other Axis I psychiatric disorders, except for generalized anxiety disorder (GAD) symptoms occurring in a depressive episode; Use of other medications for depression, e.g., bupropion or augmenting agents, although short-acting sedatives are allowed (see below); 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 neurological disorder, including dementia, stroke, epilepsy, etc.; MRI contraindication; Electroconvulsive therapy or transcranial magnetic stimulation in last 2 months; Current or planned psychotherapy; 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: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Transdermal Nicotine Patch<br>Participants will wear open label transdermal nicotine patch daily for 12-15 weeks. They will apply study patch each morning and remove at bedtime. Dosage will begin at 3.5mg patch / day, increasing to a possible maximum of 21mg patch / day. | Drug: Transdermal Nicotine patch<br>* Participants will begin a 12- week open label trial of transdermal nicotine patch during the day and remove it at night (16 hours). Dose titration starting at 3.5 mg patch/daily to maximum of 21mg patch/daily. After week 12 , dose will be slowly tapered over 3 weeks.<br>* Other names: Nicotrol;|

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 Change | 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. Change is calculated as the difference between week 12 and baseline. | Baseline to week 12 | 
| Number of Participants Exhibiting Reduction in Frontal Activation During the Emotional Stroop Task During Functional Magnetic Resonance Imaging (MRI) | MRI scans will be performed at baseline, week 6 and week 12. MRI will measure cognitive control network function, operationalized as a reduction in the emotional Stroop task functional MRI response in the middle and superior frontal gyri. The Stroop functional MRI response is calculated as the activation difference between incongruent and congruent conditions of the emotional Stroop task. The primary outcome is change in activation difference across the three time points. This is examined as a categorical variable, operationalized as those subjects who exhibit a middle / superior frontal gyri z-score reduction in activation over time of 0.5 or greater, relative to baseline at either week 6 and/or week 12. The a priori threshold being tested was that 60% or more of participants would exhibit a z-score reduction of 0.5 or greater, examined separately in the left and right middle and superior frontal gyri. | Baseline, week 6, week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NIH EXAMINER Test Battery Executive Composite Score Change | Secondary Cognitive Outcome: This neuropsychological test battery assesses a range of executive functions. Its Executive Composite Score is a single score that represents overall executive function performance across multiple individual neuropsychological tests, including the Dot counting test, the N-back test, the Flanker task, a continuous performance test, anti-saccades test, a set shifting test, and fluency tests. Higher scores indicate better executive function, with a range of -3.0 to 3.0. This composite is generated separately from EXAMINER sub scales. | Baseline to week 12 | 
| NIH EXAMINER Test Battery Cognitive Control Factor Change | Secondary Cognitive Outcome: This neuropsychological test battery assesses a range of executive functions. Its Cognitive Control Factor Score is a single score that represents cognitive control function performance across multiple individual neuropsychological tests, including the Flanker task, a continuous performance test, anti-saccades test, and a set shifting test. Higher scores indicate better executive function, with a range of -3.0 to 3.0. This is calculated independently of the executive composite or other factor scores. 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 | 
| NIH EXAMINER Test Battery Fluency Factor Change | Secondary Cognitive Outcome: This neuropsychological test battery assesses a range of executive functions. Its Fluency Factor Score is a single score that represents verbal fluency performance across phonemic and categorical fluency assessments. Higher scores indicate better executive function, with a range of -3.0 to 3.0. This is calculated independently of the executive composite or other factor scores. | Baseline to week 12 | 
| NIH EXAMINER Test Battery Working Memory Factor Change | Secondary Cognitive Outcome: The EXAMINER test battery Working Memory Factor Score is a single score that represents working memory performance across multiple individual neuropsychological tests, including the Dot counting and n-back tests. Higher scores indicate better executive function, with a range of -3.0 to 3.0. This is calculated independently of the executive composite or other factor scores. 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 Change | Secondary cognitive outcome, a neuropsychological test measure of attention. We will examine change in total reaction time for the CRT. Lower reaction time indicates better performance. | Baseline to week 12 | 
| Selective Reminding Task Performance Change | 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. Scores range from 0-60, with higher scores indicating better performance. Change in the recall over 12 weeks reflect the verbal memory function, with higher scores indicating better verbal memory performance. | Baseline to week12 | 
| Trait Adjectives Task, Change in Positive Items Endorsed | 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. These are assessed separately for positive items endorsed and negative items rejected. Task performance assesses self-referential negativity bias and is associated with antidepressant response. Task completed at baseline, week 6, and week 12. Scores for positive items endorsed range from 0 to 24, with higher scores indicating more positive items being endorsed, so a reduction in negativity bias. | Assessed at baseline, week 6, and week 12, change from baseline to week 12 reported | 
| Trait Adjectives Task, Change in Negative Items Rejected | 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. These are assessed separately for positive items endorsed and negative items rejected. Task performance assesses self-referential negativity bias and is associated with antidepressant response. Task completed at baseline, week 6, and week 12. Scores for negative items rejected range from 0 to 24, with higher scores indicating that more negative items are rejected, thus a reduction in negativity bias. | Assessed at baseline, week 6, and week 12, change from baseline to week 12 reported | 
| Trait Adjectives Task, Change in Reaction Time to Endorse Positive Items | 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. These are assessed separately for positive items endorsed and negative items rejected. Task performance assesses self-referential negativity bias and is associated with antidepressant response. Task completed at baseline, week 6, and week 12. A score reduction represents increased reaction time. | Assessed at baseline, week 6, and week 12, change from baseline to week 12 reported | 
| Trait Adjectives Task, Change in Reaction Time to Reject Negative Items | 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. These are assessed separately for positive items endorsed and negative items rejected. Task performance assesses self-referential negativity bias and is associated with antidepressant response. Task completed at baseline, week 6, and week 12. A reduction in score indicates a faster reaction time. | Assessed at baseline, week 6, and week 12, change from baseline to week 12 reported | 
| Ruminative Response Scale Score Change | 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 | Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported. | 
| Apathy Evaluation Scale (AES) Score Change | Secondary Mood Outcomes: Change in apathy as measured by the self-report AES, a questionnaire with a range of 0-54, where higher scores indicate greater apathy. Measured at baseline, week 6, and week 12. | Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported. | 
| Insomnia Severity Index Score Change | 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. Assessed at baseline, week 6, and week 12. | Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported. | 
| Penn State Worry Questionnaire (PSWQ) Score Change | 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. Assessed at baseline, week 6, and week 12. | Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported. | 
| Fatigue Severity Scale Score Change | Secondary outcome examining fatigue using a self-report questionnaire that ranges from 0- 56, where higher scores indicate more severe fatigue. Questionnaire administered at baseline, week 6, and week 12. | Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported. | 
| Dimensional Anhedonia Rating Scale (DARS) Score Change | Secondary mood outcome: Change in anhedonia measured by DARS, a self-report questionnaire that ranges from 0-68, where lower scores indicate greater anhedonia. Conversely, higher scores indicate greater ability to enjoy activities. Assessed at baseline, week 6, and week 12. | Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported. | 
| General Anxiety Disorder-7 Item Scale (GAD7) Score Change | Secondary Mood outcome: self-reported questionnaire to measure the severity of anxiety. Questionnaire ranges 0-24, higher scores indicates greater anxiety state. Assessed at baseline, week 6, and week 12. | Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported. | 
| Patient Reported Outcome Measurement Information System (PROMIS) Applied Cognition Abilities Short Form Score Change | 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. Assessed at baseline, week 6, and week 12. | Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported. | 
| Attentional Control Scale Score Change | Secondary Attention outcome: The Attentional Control Scale (ACS) is a self-report questionnaire that has been developed to measure individual differences in attentional control. The scale ranges from 0-80, with higher scores indicative of better attentional control, and a positive change indicated improved attentional control. Assessed at baseline, week 6, and week 12. | Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported. | 
| Anxiety Sensitivity Index 3 (ASI-3) Score Change | The ASI-3 is a self-report questionnaire assesses anxiety sensitivity, or the fear of arousal-related sensations. Specifically these derive from the belief that anxiety- or arousal-based sensations have negative consequences. This self-report scale includes 18 items with scores ranging from 0 to 72, where higher scores indicate greater anxiety sensitivity. | Assessed at baseline, Week 6, and Week 12; only baseline to week 12 reported. | 

 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