Depressed Mood Improvement Through Nicotine Dosing-3 (Depressed MIND3) Extension

Study 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 is an open-label, extension to the blinded Depressed MIND 3 (Depressed Mood Improvement through nicotine dosing) study. It will evaluate longer-term safety and efficacy of Transdermal Nicotine Patches for potential benefit in cognitive and depression outcomes in elderly depressed participants. Subjects complete blinded randomized trial of Depressed MIND-3 will be eligible for continuation in this extension. This extension study will consist of up to 12 weeks of treatment and a 3 -week safety follow-up period.

Detailed Description
-----------------
The purpose of this open-label extension to the Depressed MIND 3 study will be to gather data on longer-term benefits and safety in patients with late-life depression (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. Investigators 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 an open-label extension of a randomized double blind placebo control trial that will enroll 80 participants over a 3-year period. After randomization and completion of the blinded study phase, participants will be eligible for this 12-week extension. At the completion of Week-12 visit of the Depressed MIND -3, all eligible subjects will be offered enrollment in the open label extension study. Study visits during the treatment period for all subjects will occur approximately 3 weeks with flexible dose titration. This will be followed by a 1-3 week taper phase. The total duration of study participation will be approximately 15 weeks.

Official Title
-----------------
Open Label Extension Study of Depressed Mood Improvement Through Nicotine (Depressed MIND3)

Conditions
-----------------
Depressive Disorder

Intervention / Treatment
-----------------
* Drug: Transdermal Nicotine patch


Participation Criteria
=================
Eligibility Criteria
-----------------
Only individuals who complete 12 weeks of the blinded Depressed MIND trial will be eligible for enrollment. Eligibility criteria for the blinded phase includes: 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 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
-----------------
Minimum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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 nicotine transdermal patches daily for 12-15 weeks. Participants 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. | Drug: Transdermal Nicotine patch<br>* Participants will wear nicotine transdermal patches daily for 12-15 weeks. Participants 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;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 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 | 
| Change in Continuous Performance Task (CPT) Performance | Primary cognitive outcome, the CPT is a neuropsychological test that is conducted as part of the NIH EXAMINER Test Battery. 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
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Geriatrics, aging, elderly, cognition, memory, Transdermal Nicotine Patch, depression