Conditions: Depressive Disorder
Keywords: geriatrics aging elderly cognition memory nicotine transdermal patch depression
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 29
Healthy volunteers: no

Brief summary:
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:
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.

Arms:
arm 1: 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.

Interventions: intervention 1: Transdermal Nicotine patch
Intervention descriptions: intervention 1: 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.

Protocol document:
Prot_SAP_001.pdf: 
DEPRESSED MOOD IMPROVEMENT THROUGH NICOTINE DOSING 2 
(THE DEPRESSED MIND STUDY 2) 
 
PHASE 1: R61 PHASE 
 
NIH Grant R61 MH122464 
Grant Title: Nicotinic modulation of the cognitive control system in late-life depression 
 
Clinicaltrials.gov Identifier: NCT04433767 
 
 
Principal Investigator:  
Warren D. Taylor, MD, MHSc 
James G Blakemore Professor of Psychiatry 
Department of Psychiatry and Behavioral Sciences 
Vanderbilt University Medical Center 
 
Co-Investigators: 
Vanderbilt University Medical Center: 
Patricia Andrews, MD, Department of Psychiatry and Behavioral Sciences 
Hakmook Kang, PhD, Department of Biostatistics 
Paul Newhouse, MD, Department of Psychiatry and Behavioral Sciences 
Baxter Rogers, PhD, Vanderbilt University Institute of Imaging Science, Department of 
Radiology and Radiological Sciences 
 
Weill-Cornell Medical College: 
 
Faith Gunning, PhD, Department of Psychiatry 
 
Consultant: 
Rachel F. Tyndale, PhD, Professor of Pharmacology and Toxicology, Centre for Addiction and 
Mental Health, University of Toronto 
 
 


 
Protocol Version #:1.4 
 
 
Protocol Date:  05/06/2021 
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Table of Contents: 
 
Study Schema 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Animal Studies and Previous Human Studies 
4.0 
Inclusion/Exclusion Criteria 
5.0 
Enrollment and Consent 
6.0 
Study Visits and Assessments 
7.0 
Cognitive Assessments 
8.0 
Study Drug Administration 
9.0 
MRI Procedures 
10.0 
Measurement of Levels of Nicotine and Nicotine Metabolites 
11.0 
Risks – Study Drug 
12.0 
Risks – Other than Study Drug 
13.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to Participants or Others 
14.0 
Study Withdrawal/Discontinuation 
15.0 
Subject Reimbursement 
16.0 
Statistical Considerations 
17.0 
Privacy/Confidentiality Issues 
18.0 
Data Sharing 
19.0 
Follow-up and Record Retention 
20.0 
Literature Cited 
 
Appendices: 
Appendix A List of Abbreviations  
Appendix B List of Prohibited Medications 
 
Separate Attachments: 
Schedule of Events 


 
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1.0 BACKGROUND 
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.  
 
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.  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. Clinically, transdermal nicotine improves mood in smokers while a 
placebo-controlled pilot trial in nonsmoking depressed adults found that transdermal nicotine significantly 
improved mood.  
In our initial pilot trial in LLD (1), we demonstrated that open-label administration of transdermal nicotine 
patches safely improved depression severity.  We also observed trends suggesting that transdermal nicotine 
(TDN) may provide benefit for cognitive performance, specifically in domains of episodic memory, working 
memory, and attention.  In unpublished functional MRI pilot data acquired during this trial, we observed that 
TDN also enhanced activity in the cognitive control network and that such changes were associated with 
greater reductions in depression severity. 
These data supported a successful application to NIMH for a R61/R33 proposal.  This grant mechanism 
initially supports the R61 phase, a 2-year study to establish target engagement of an investigational 
intervention.  If a priori thresholds demonstrating target engagement are met, this would be followed by a 3-
year R33 phase.  The current protocol only covers the initial R61 study phase. 
 
2.0 RATIONALE AND SPECIFIC AIMS 
Cognitive control is a set of interrelated executive processes (2) involving the anterior cingulate-insular 
salience network and the frontoparietal network.  Jointly, these networks are conceptualized as a 
superordinate “multiple-demand” cognitive control network (CCN) (3,4), involved in emotional regulation, 
attention, working memory, and inhibiting irrelevant information. CCN dysfunction is a core feature of late-life 
depression (LLD), contributing to mood disturbances, executive function deficits in inhibitory control and 
working memory, poor antidepressant responses and disability. Improvement of CCN dysfunction could benefit 
cognitive performance and mood, but no current pharmacotherapy targets CCN function in LLD. 
 
We propose that enhancement of CCN function by nicotinic acetylcholine receptor agonists (5) will 
improve mood and cognitive symptoms in LLD (6).  This is supported by our pilot trial in LLD (N=15) 
where 12-weeks of open-label transdermal nicotine (TDN) patches significantly improved depression severity 
(1).  In unpublished pilot data using an emotional Stroop task, TDN reduces the difference in fMRI activation 
between Stroop conditions in a key CCN hub region, the left middle and superior frontal gyri (M/SFG).  As TDN 
also improves emotional Stroop task accuracy and reaction time to incongruent stimuli, in context of past work 
(5) we propose TDN enhances cognitive control function (7,8).  The M/SFG is a compelling imaging target 
as the dorsolateral PFC (including the M/SFG) exhibits reduced activation and functional connectivity in LLD 
(9-13), while antidepressant treatment enhances activity in this region (14,15).  Critically, in our pilot data, 
when TDN administration reduces the difference in M/SFG activation between Stroop conditions, we observe a 
corresponding reduction in depression severity.  Based on these data, we hypothesize that nicotinic 
receptor agonists enhance CCN function in LLD.  This effect in the M/SFG, a region exhibiting 
dysfunction in LLD, benefits depressive symptoms and cognitive performance (5,6).  
 
 


 
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The R61 phase (N=36) will test for target engagement, defined as a TDN exposure-dependent effect on 
cognitive control network (CCN) activation.  Based on pilot data, we will test for enhancement of CCN function 
by examining the M/SFG Stroop BOLD fMRI response, or the reduction in the M/SFG activation difference 
between incongruent and congruent conditions of the emotional Stroop task during fMRI. We will assess the 
effects of variability in nicotine exposure on target engagement by measuring nicotine blood levels in 
conjunction with repeat MRI. 
 
AIM 1: R61 Phase: Test CCN engagement over 12 weeks of open-label transdermal nicotine (TDN) 
Hyp 1A (Target Engagement): TDN will enhance CCN function, measured as a reduction in the M/SFG 
Stroop BOLD 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. 
 
Hyp 1B (Exposure): Higher nicotine exposure measured by patch dose or nicotine metabolite levels will be 
associated with a greater reduction in the M/SFG Stroop BOLD response. 
 
3.0 ANIMAL STUDIES AND PREVIOUS HUMAN STUDIES 
3.a. Overview: Late Life Depression (LLD) has a prevalence of 5% in community-dwelling older adults, high 
healthcare costs, and a high risk of suicide.(16,17)  Individuals with LLD often exhibit a poor response to 
current antidepressant medications(18)  with no differences in response rates between current drug 
classes.(19,20) Cognitive deficits are common in LLD and associated with disability (17,21-25) and poor 
treatment outcomes.(26-34) There are no pharmacological treatments targeting cognition in older adults with 
depression.  Drugs developed for AD either have no benefit (35) or may worsen depression.(36) 
 
3.b. Brief Introduction to the Cognitive Control Network (CCN): Cognitive control refers to the ability to 
dynamically respond to changing contingencies to meet environmental demands.(2,4)  Cognitive control 
mediates executive functions of set shifting and flexibility, inhibition, sustained attention, and working 
memory.(2,4)  These functions are achieved through the cognitive control network (CCN), a regulatory 
superordinate network consisting of regions more active during executive tasks.(4) The CCN includes regions 
of frontoparietal cortices with network hubs in the dorsolateral prefrontal cortex (dlPFC), posterior parietal 
cortex and the dorsal anterior cingulate cortex (dACC).(4)  Recent CCN models include salience network 
regions (37,38) conceptualizing the CCN as a “multiple demand” network addressing diverse cognitive 
challenges.(39) 
 
3.c. Cognitive control deficits in LLD: CCN deficits in LLD clinically manifest as executive dysfunction in 
selective attention, working memory, response inhibition, and performance monitoring.  CCN-mediated 
executive dysfunction is common in LLD,(40-43) clinically presenting as difficulty with planning, sequencing, 
organizing, and abstracting.  Although also influenced by processing speed,(44) CCN dysfunction negatively 
affects other cognitive domains including verbal learning and recall.(45,46)  CCN dysfunction predicts negative 
clinical outcomes, including poor acute responses to antidepressant medications.(28,32,34,47) CCN-mediated 
cognitive performance deficits may persist into remission (48-51) and are associated with persistent 
disability.(52) Antidepressant treatment enhances activity in this region while therapeutic benefit may arise by 
targeting this region. (14,15,53-55)  Much of this work focuses on the dlPFC, a CCN region including the 
middle and superior frontal gyri (M/SFG).(56,57)   
CCN dysfunction also contributes to emotion dysregulation.(58)  The CCN is involved in explicit emotion 
regulation,(59) automatic and effortful processes that modulate emotional responses.(59) For example, 
difficulty inhibiting ruminative or negatively valenced thoughts may lead to persistent depressive 
symptoms.(46)  
 
3.d. Nicotine effects on depressive symptoms: The concept that there is an association between cholinergic 
function and depression dates back decades.  The original cholinergic hypothesis of depression by Janowsky 
and colleagues proposed that depression is associated with hyperactivation of the cholinergic system, resulting 
in decreased noradrenergic activity (60).  Pharmacologically, cholinergic effects on mood must be mediated 
either by the nicotinic receptor (nAChR) family or the muscarinic receptor (mAChR) family.  The cholinergic 


 
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hypothesis is supported by observations that smoking rates are high in MDD (61,62) while depressed smokers 
have difficulty with smoking cessation and are at risk for depression relapse during smoking cessation (63-68). 
However, these data do not inform about specific effects of nAChR stimulation. 
Animal models support that modulation of nAChR activity may be beneficial in depression (69,70).  Several 
studies in rat models of depression demonstrate that nicotine and nAChR agonists reduce depressive behavior 
(71-77). Clinical studies in humans support that nAChR stimulation may have antidepressant properties.  The 
few studies examining nonsmokers with MDD demonstrate that transdermal nicotine administration 
results in significant improvement in mood (78-80) and may have long-term efficacy comparable to that of 
fluoxetine (81).  Although these studies examined small samples, nicotine exhibited antidepressant effects 
even at low doses in a placebo-controlled trial (79).  To our knowledge, only our pilot 12-week trial has 
examined individuals with LLD.  Our study supports that transdermal nicotine may have clinical benefit for 
depressive symptoms (Fig 1).(1) 
 
3.e. Nicotine as a cognitive enhancer: The cholinergic system 
is the primary neurotransmitter system responsible for cognitive 
symptoms in dementia (82), with nicotinic receptors being 
particularly important (83).  Neuronal nicotinic receptors 
(nAChRs) are found throughout the central nervous system and 
nicotinic innervation of the hippocampus, amygdala and frontal 
cortex are vital to memory function (Levin 2000)(84). In addition 
to direct stimulation of nAChRs, nicotine stimulates the release 
of a variety of transmitters involved in cognitive function, 
including dopamine, norepinephrine, serotonin, and glutamate 
(85,86).  
Cognitive improvement is a well-established effect of 
nicotine. A recent meta-analysis of over 41 double-blind placebo-controlled studies concluded that nicotine has 
positive effects on attention, memory, and motor abilities which likely represent true performance enhancement 
(87). In smokers, nicotine improves performance on attentionally and cognitively demanding vigilance tasks 
(88-90) even in the absence of withdrawal effects (87,91). The nicotinic system appears to modulate controlled 
attentional processing when task conditions are difficult (92-94).  Past work in impaired populations further 
supports that nicotine improves CCN-mediated cognitive domains including working memory, learning and 
attention.(6,87)  Specifically, nicotine may show particular benefit for cognitively demanding tasks requiring 
focused attention despite distracting stimuli.(95,96)  Nicotine also benefits episodic memory (87) although this 
may be mediated through improvements in attentional functioning.(95)  
 
3.e.1. Clinical Studies of Nicotinic Stimulation for Cognition in Older 
Populations: Newhouse and colleagues first showed evidence of improved 
memory with intravenous nicotine injection in Alzheimer Disease (AD) 
subjects (97). Subcutaneous nicotine injection (98,99) and nicotine skin 
patch treatment also significantly improves cognitive function in AD patients 
(100,101). In AD, nicotine improves attention and lessen errors (102). 
Newhouse extended this work to show that the novel nicotinic agonist ABT-
418 also has positive effects on learning and memory in AD (103). More 
recently, Newhouse and colleagues (104) showed that chronic 
transdermal nicotine treatment improved attention and episodic 
memory in patients with Mild Cognitive Impairment (MCI) (see Fig 1 
and 2). These findings are being examined in a NIA-funded multi-site MIND 
Study (Memory Improvement through Nicotine Dosing; Newhouse, PI).  
 
3.f.  Pharmacoimaging studies of nicotine: Work in smokers and 
nonsmokers led to hypotheses (5,95,105) that nAChR agonists benefit cognition by increasing task-related 
information processing while decreasing activity in regions involved in task-irrelevant information processing. A 
meta-analysis examining task-independent effects of nAChR agonists supports this, reporting two patterns of 
Figure 1. Continuous 
Performance Task (CPT), change 
from baseline.  Nicotine improved 
performance over placebo (F1,57 = 
14.96, p = 0.003).  
Figure 1 Transdermal nicotine effects 
on depression severity over time 
Figure 2. Episodic Memory.  
A) Paragraph recall, nicotine > placebo 
(F1,60=4.42, p=0.04).  B) Word recall, 
nicotine > placebo (F1,70=5.92, p=0.018).  


 
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activity changes.(5) First, nAChR agonists enhanced activation in CCN regions, including the dorsal ACC, 
lateral prefrontal and dorsomedial prefrontal cortices. Second, nAChR agonists decreased activation in other 
regions, reflecting enhanced deactivation in the ventromedial prefrontal cortex, posterior cingulate cortex, and 
parietal cortex.  Thus nAChR agonists have general neuropharmacological effects of enhancing activation in 
CCN regions while decreasing activation in default mode network (DMN) regions.(5)   
 
3.g. Safety of transdermal nicotine (TDN) patches: TDN patches are well tolerated, with a meta-analysis in 
over 5500 individuals(106) identifying only minor adverse effects such as sleep disturbances, nausea, and 
minor skin irritation. Few adverse cardiovascular events were reported, with no excess of events occurring 
among patch users compared to placebo.  This is concordant with our prior 6-month trial in Mild Cognitive 
Impairment(104) and our pilot LLD trial.(1)  We have not observed withdrawal or craving in past studies.   
In our LLD Pilot trial, participants exhibited > 95% compliance with study patches. There were no SAEs 
and the most common adverse effects included nausea (N=7), dizziness (N=4) and headache (N=4).  These 
were dose-limiting in 7 subjects (including 1 early withdrawal). We observed no significant changes in blood 
pressure or heart rate but observed a decrease in weight (6.7lb, t= 4.30, p<0.01).  Individuals who received 
TDN with an antidepressant tolerated a higher mean dose than those receiving TDN monotherapy (p<0.01).  
We observed no ill effects or craving after tapering and discontinuing TDN over an additional 3 weeks.   
 
4.0 INCLUSION/EXCLUSION CRITERIA 
Men and women of all backgrounds are eligible.  Criteria are similar for both phases. 
 
Inclusion Criteria:  
1) Age > 60 years;  
2) diagnosis of major depressive disorder, single or recurrent episode (DSM5);  
3) On a stable therapeutic dose of an allowed SSRI or SNRI for at least 6 weeks;  
4) severity: MADRS(107) ≥ 15;  
5) cognition: MMSE(108) >24;  
6) fluent in English 
 
Exclusion Criteria:  
1) Other Axis I psychiatric disorders, except for generalized anxiety disorder (GAD) or social phobia symptoms 
occurring in a depressive episode;  
2) Use of other medications for depression, e.g., bupropion or augmenting agents, although short-acting 
sedatives are allowed (see below);  
3) Any use of tobacco or nicotine in the last year;  
4) Living with a smoker or regular exposure to secondhand smoke;  
5) History of  alcohol or drug dependence or abuse in the last 3 year 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;  
6) Acute suicidality;  
7) Acute grief (<1 month);  
8) Current or past psychosis;  
9) Primary neurological disorder, including dementia, stroke, epilepsy, etc.;  
10) MRI contraindication;  
11) Electroconvulsive therapy or transcranial magnetic stimulation in last 2 months;  
12) Current or planned psychotherapy;  
13) Allergy or hypersensitivity to nicotine patches;  
14) In the last 4 weeks, regular use of drugs with central cholinergic or anticholinergic properties or moderate / 
severe CYP2A6 inhibitors /inducers (see Appendix B) 
 
Allowed Antidepressants: Eligibility criteria require current use of a commercially available antidepressant 
medication at a therapeutic dose. To decrease variability in the underlying antidepressant regimen, we define a 
therapeutic dose of allowable antidepressants as: fluoxetine(20mg), sertraline (50mg), citalopram (20mg), 
escitalopram (10mg), venlafaxine (75mg), desvenlafaxine (50mg), levomilnacipran (40mg) or vilazodone 


 
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(20mg), duloxetine (30mg) or their equivalents.  Higher doses are allowable. 
Due to anticholinergic effects, effects on nicotinic acetylcholine receptors, or other safety concerns, we 
exclude for and do not allow for the use of some antidepressants. These exclusions include: a) paroxetine; b) 
bupropion; c) tricyclic antidepressants; and d) monoamine oxidase inhibitors.  We also exclude for current use 
of ketamine or esketamine for depression. 
 
Concomitant Medications: Most non-psychotropic medications are permitted.  The exceptions are for  
medications with substantial procholinergic or anticholinergic properties or medications influencing CYP2A6 
activity (see Appendix B), the main pathway for nicotine metabolism.(109)  Prohibited cholinergic agents  
include but are not limited to acetylcholinesterase inhibitors and some agents used for tremor, incontinence, or 
vertigo. We allow short-acting hypnotics (zolpidem, zalpelon, or eszopiclone) and lorazepam up to 2mg daily 
for sleep or anxiety.   
 
5.0 ENROLLMENT AND CONSENT 
5.a. Recruitment :We will enroll patients from clinical referrals and response to advertisements.  For clinical 
referrals, referring providers may either provide information about the study to the participant, including our 
contact information.  Alternatively, they may obtain permission from the participant for the study team to 
contact them.  With the clinician’s agreement, study staff can review their clinic schedules to help identify 
potentially eligible patients, however data will not be recorded for research purposes.  Advertisements may 
include radio, newspapers, internet, and flyers / brochures.  When responding to advertisements, potential 
participants will contact us by telephone or through email.  During the initial contact, we will describe the study 
purpose and procedures to them, including a description of study entry criteria.  Those who continue to be 
interested will then be scheduled for an evaluation.  After scheduling, a study doctor will review their electronic 
medical record to assure that potential subjects meet entry criteria, however no data will be recorded.  If that 
review determines the individual is not eligible, they will be informed, the screening visit cancelled, and the 
referring clinician notified. 
 
In order to enhance the recruitment efforts, this project is using the services  of Trialfacts. 
Trialfacts is a third-party service which provides specialized recruitment methods in digital advertising. 
Trialfacts provides marketing strategies and campaigns to speed up participant recruitment by leveraging 
social media and digital platforms. Trialfacts creates GCP-compliant advertising and recruitment materials 
used in the recruitment process, including study information pages, landing pages, pre-screening 
questionnaires, and online advertisements. They will only share IRB approved materials with referrals. 
Interested candidates will sign a study interest form and  be  directed to research staff, who will further screen 
potential participants.  
 
 
5.b.  Enrollment and Consent: Potential participants will be initially evaluated using our current telephone or 
REDCap screening approach.  If they appear eligible, they will be scheduled for an in-person or Zoom 
screening evaluation.  Upon presenting for evaluation, we will obtain formal written consent from all 
participants.  Following policies of the Vanderbilt University Health System Institutional Review Board, written 
informed consent will be obtained and documented by the study’s Research Coordinator before any study-
related procedures are performed.  The study coordinator will review study procedures and the consent form 
with each potential participant.  A study doctor will be available should any consent-related questions arise.  
Each individual may take as much time as they like to decide if they do or do not wish to participate.  
 
We also allow that participants can be consented without coming physically to VUMC. This will be conducted 
via HIPAA compliant Zoom teleconferencing, as is recommended for telemedicine. We will use Facetime or 
other videoconferencing software it there are any technical difficulties on Zoom or at the participant’s request. 
An e-consent process will be conducted using a REDCap-based electronic consent form. The consent form 
has been developed in REDCap, a secure, web-based, HIPAA-compliant, data collection platform with a user 
management system allowing project owners to grant and control varying levels of access to data collection 
instruments and data (e.g. read only, de-identified-only data views for other users.  A study coordinator or 


 
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approved study staff will review the consent form while teleconferencing with the participant and answer any 
questions before the participant signs. 
 
Patient signatures will be obtained using REDCap’s ‘Signature’ field type on the survey.  Upon completion of 
the consent, participants will be able to download a signed copy of the consent form.  We will also provide 
them with a copy of their version of the consent document signed by them and by the consenting study staff 
member by mailing of a hard copy of the consent. 
 
A deidentified document confirming that each participant has provided signed informed consent will be signed 
by the research coordinator and the Principal Investigator and kept in the research file. 
 
 
5.c. Anticipated Enrollment: Accounting for screen failures, we anticipate consenting up to 60 subjects total 
to have 36 individuals complete baseline procedures and start study patches.   
 
6.0 STUDY VISITS AND ASSESSMENTS 
Overview: After a screening visit to confirm eligibility and diagnosis, participants will then be scheduled to 
complete a baseline assessment consisting of a broad symptom assessment, memory testing, and cranial 
MRI.  They will then complete 12 weeks of open-label transdermal nicotine patches.  At the end of the 12 
weeks, they will then repeat baseline assessments, have blood drawn for measurement of nicotine 
metabolites, and have study drug tapered over three weeks. 
 
6.a. Assessment Burden:  The clinical and cognitive batteries are similar to those used in our past LLD 
studies.  They are not burdensome and we allow breaks.  Refer to the separate “Schedule of Events” file for a 
timing of all procedures. 
 
6.b. Initial Evaluation: In the initial screening evaluation, current and past psychiatric diagnoses are assessed 
with the MINI (Mini-International Neuropsychiatric Interview), followed by a clinical interview with a study 
clinician that will assess age of initial onset.  The study clinician will assess antidepressant exposure in the 
current episode using a modified Antidepressant Treatment History Form (ATHF)(110,111) updated to include 
current medications approved for MDD.  Medical history and comorbidity will be quantified with the Cumulative 
Illness Rating Scale-Geriatrics (CIRS-G).(112)  Screening for cognitive impairment occurs with the MMSE, 
requiring a score of > 24.   
Concomitant medication use will be documented and anticholinergic burden quantified using the 
Anticholinergic Cognitive Burden (ACB) Scale.(113) We selected this approach as the ACB scale is sensitive 
to drug effects on cognition and disability, while serum anticholinergic activity is not consistently associated 
with cognition.(114-116) 
Smoking history will be assessed by self-report items from the PhenX toolkit.(117)  Questions include 
duration and amount of past smoking, symptoms of smoking dependence, and secondhand smoke exposure. 
Participants will also complete secondary self-report measures of depressive symptoms, including 
rumination (the Ruminative Response Scale) (118), apathy (Apathy Evaluation Scale, AES) (119), sleep 
(Insomnia Severity Index, ISI), worry (Penn State Worry Questionnaire, PSWQ), fatigue (Fatigue Severity 
Scale, FSS), anhedonia (the Dimensional Anhedonia Rating Scale, DARS), anxiety (the Generalized Anxiety 
Disorder 7 item scale, GAD7;  the Anxiety Severity Index 3; ASI3) and participant’s social support , including 
frequency of contacts, subjective and instrument support (Duke Social Support Index, DSSI). They will also 
complete self-reports of perceived cognitive performance, including both the PROMIS Applied Cognition 
Abilities Short Form and the Attentional Control Scale.  Finally, disability will be measured with the World 
Health Organization Disability Assessment Schedule (WHODAS) 2.0. 
 
6.c. Study Visit Schedule: After the baseline visit, where MRI, cognitive, and self-report data are acquired, 
participants will be seen every 3 weeks (+/- 4 working days), allowing us to assess tolerability prior to dose 
increases. At each study visit (Weeks 0, 3, 6, 9, 12), depression severity will be measured using the MADRS, 
administered by a study physician.  Vital signs (weight, heart rate, blood pressure) will be measured.  Blood 


 
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9 
(10ml) will be drawn at each visit after baseline (Weeks 3, 6, 9, 12) to measure levels of nicotine and nicotine 
metabolites. 
Side effects are assessed at each visit using the Frequency and Intensity of Side Effects Rating / Global Rating 
of Side Effect Burden (FISER/GRSEB) scales.(120)  Adherence will be assessed using a count of empty 
wrappers, returned unused patches, and monitoring of blood levels. The Quick Inventory of Depressive 
Symptoms—Self Report questionnaire (QIDS-SR) will provide a self-report measure for depressive symptoms 
at baseline, weeks 3,6,9 and 12. 
 
Safety and thoughts of suicide will be assessed at every contact.  Individuals endorsing thoughts of 
death will be questioned by a psychiatrist about thoughts of suicide, intention, and potential plans.  When there 
are concerns for safety, subjects will be withdrawn from the study and treated per clinical care. 
 
MRI, cognitive data, and self-report measures (both depressive symptoms and perceived cognitive 
performance) will be repeated at weeks 6 and 12. 
 
7. COGNITIVE ASSESSMENTS:  
7.a. Negativity Bias (Secondary Outcome): To evaluate negativity bias, we use an out-of-scanner, adapted 
version of the Trait Adjectives Task.(121) 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.  This 
is followed 15 minutes later with a test of emotional memory ,where in participants must recall the adjectives 
they have viewed.  Positive and negative adjectives are balanced and selected from a normed list, matched for 
word length and arousal.(122)  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.(123)  This task will be administered at baseline, week 3 ,week 6, week9 and week 12.  The follow-
up test of emotional memory will only be conducted at baseline and week 12. 
 
7.b. Cognitive Domain Performance (Secondary Outcomes):  These tasks are administered out -of-scanner 
at baseline and week 12. 
• 
Executive Function: Executive function will be measured using the NIH EXAMINER computerized test 
battery (124).  The EXAMINER battery assesses multiple domains: 
o Inhibition: Inhibition will be measured using the Flanker task (using arrows and response to stimuli 
to probe spatial reorientation); the Continuous Performance Test (CPT)(125) (responding to some 
stimuli and not others); and an antisaccades eye movement task, (where they move their eyes in 
the same or opposite direction of a stimulus). 
o Working Memory: Assessed using the dot counting task and the N-back task.  We will use the 1- 
and 2- back conditions with alternative versions for repeated testing. 
o Set Shifting:  Participants will match a stimulus on the top of the screen to one of two stimuli on 
lower corners of the screen. 
o Fluency:  Tests of phonemic (letter fluency) and category fluency 
o Planning: Using the “Unstructured Task”, subjects complete multiple cognitively simple puzzles 
o Insight: Participants then rate themselves on their performance compared to 100 individuals of their 
same age and education. 
The EXAMINER battery’s primary outcome is its Executive Composite score.  Secondary outcomes include 
its factor scores: Cognitive Control, Fluency, and Working Memory.  The Executive Composite and Factor 
scores are calculated from the tasks above. 
• 
Psychomotor Speed: The Choice Reaction Time task will be used as a test of psychomotor speed.  
Participants must hold a button down until a light appears above one of several other buttons, then move to 
push that button as quickly as possible.  This task measures both response and psychomotor speed. 
• 
Episodic Memory: We will utilize the complex Selective Reminding Task as a test of immediate and 
delayed verbal memory.(126)  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.  
 


 
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8. STUDY DRUG ADMINISTRATION:  
 
8.a. R61 Transdermal Nicotine Dosing: Participants will wear the study patch during the day and remove it at 
night (16 hours).  Titration will be slower than in our pilot project(1) in order to improve tolerability. Per our 
revised schedule (Table 1), participants will receive patches starting at 3.5mg daily, increasing to a maximum 
of 21mg. Doses can be reduced to the previous level if needed for tolerability.  In these cases, if the 
precipitating adverse event resolves, the participant can 
be rechallenged once at the higher dose.  If the adverse 
event reemerges, the participant can again be reduced 
to the prior dose, but cannot be rechallenged again. This 
protocol has been added to Dr. Newhouse’s (co-
investigator) IND 131918 for nicotine transdermal 
patches. 
 
8.b. Assessment Blinding: Study clinicians conducting 
the MADRS will be blinded to levels of nicotine or 
nicotine metabolites and results of the functional MRI 
studies until participants have completed the 12-week 
trial. 
 
8.c. Design Rationale: We obtain MRI biomarker data at 6- and 12-weeks.  This provides an opportunity to 
examine the relationship between exposure and target engagement at lower and higher doses.  Moreover, for 
individuals who cannot tolerate higher doses, it provides a naturalistic opportunity to examine target 
engagement across time in individuals on a stable dose.  Other designs, such as a single administration dose-
finding study, are not feasible given poor tolerability of higher doses without gradual titration.   
We obtain nicotine and metabolite levels every 3 weeks. This will support analyses of target engagement 
and allows us to conduct exploratory analyses of: a) the relationship between dose and exposure in an elderly, 
nonsmoking population; and b) the relationship between dose, metabolism, and adverse events. 
 
8.d. End of study medication procedures:  Following completion of the 12-week trial, doses will be slowly 
lowered and study drug discontinued over 3 additional weeks (Table 1).  This time can be shortened for 
participants who do not reach the target dose of 21mg daily.  If individuals feel the study drug has provided 
benefit and elect to continue its use by purchasing over-the-counter patches, we will not require this 
discontinuation.  Subjects will return for a final safety assessment.  For individuals who have tolerated study 
patch well, this final safety visit can optionally be conducted by telephone. 
 
9. MRI PROCEDURES 
 
9.a. MRI Screening: To assure safety for MRI, we carefully screen participants for metal.  Working with the 
Vanderbilt University Institute for Imaging Science, we identify past medical procedures and surgeries that may 
include metal implants.  In these cases, we request medical records to determine if metal was used, and if so, 
if it is safe for 3Tesla MRI.  However, in some cases these records cannot be obtained.  In such cases we may 
obtain an x-ray if there was a question whether there was or was not implanted metal. 
We will only obtain an x-ray in cases where a) there is a safety concern about a potential implant or 
metal; b) medical records for the surgery are not available; and c) participants do not think that metal was 
involved in the surgery.  Thus this procedure will not be needed for the majority of participants.  If the x-ray 
shows there is implanted metal that could be a MRI contraindication, that participant will be withdrawn from the 
study.  Radiation exposure will vary dependent on the area needing to be evaluated. 
 
9.b.  Image Acquisition: We will image subjects at the Vanderbilt University Institute for Imaging Science 
(VUIIS) on a 3T research-dedicated MRI using a protocol that acquires multi-contrast data to allow automated 
tissue identification and BOLD data at rest and during the cognitive task.  Cranial MRI will be performed over 1 
hour.  Similar MRI durations have been well tolerated in our past studies of LLD.  This protocol includes T1-
Table 1. TDN Dosing 
 
 
Week 
Days 
Patch 
Strength 
Patch 
Application 
Dose 
1 
MRI 
 
 
1 
1-7 
7mg 
0.5 
3.5mg 
2-3 
8-21 
7mg 
1 
7mg 
4-6 
22-42 
21mg 
0.5 
10.5mg 
6 
MRI 
 
 
7-9 
43-63 
14mg 
1 
14mg 
10-12 
44-84 
21mg 
1 
21mg 
12 
MRI 
 
 
13-14 
85-98 
14mg 
1 
14mg 
15 
99-105 
14mg 
0.5 
7mg 


 
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weighted and fluid-attenuated inversion recovery (FLAIR) images.  Functional MRI BOLD acquisitions will be 
obtained at rest where subjects have their eyes open and focus on a fixation cross and during the emotional 
Stroop task. Subjects will complete the emotional Stroop task twice (13.5min each; 3mm isotropic voxels, 
TR=2sec). The emotional Stroop task is presented in E-Prime and described below.  Prior to MRI, participants 
practice the task outside the scanner. 
 
9.c. fMRI Tasks:  
 
Participants will complete two fMRI tasks during each scan. 
 
Similar to our pilot study, for this proposal we will use an emotional Stroop task.(127)  The classic Stroop 
paradigm was modified and adapted to an emotional conflict task in which faces with fearful and happy 
expressions are presented with the words “happy” or “fear” written across them. We ask subjects to identify the 
emotional expression of the faces while ignoring the words, which are either congruent or incongruent with the 
facial expression. Incongruent stimuli are thus associated with a response conflict that arises from an 
emotional incompatibility between task-relevant and task-irrelevant stimulus dimensions (e.g., a fearful 
expression with the word “happy”).  This task dissociates neural systems involved in resolving conflict between 
congruent versus incongruent emotional distractors.(127,128) 
Participants will complete two runs of 148 trials for a total of 27 minutes of testing.  Behavioral response 
times and neural activation will be analyzed as a function of target congruency.  The main variable of interest 
will be activation (percent signal change) of the CCN in response to incongruent-congruent stimuli.   
Our co-I Dr. Gunning obtained emotional Stroop fMRI data on 10 elders before & after 12 weeks.  The 
intraclass correlation coefficient (ICC) for the MFG was 0.61.  This is consistent with the literature on reliability 
of task-elicited activation in older adults (129) and qualifies as good reliability for repeated assessments. 
 
Participants will also complete a scene processing task. While in the scanner, participants will view images of 
scenes, faces, and scrambled images for a brief (4 minute) run. Images are projected to a mirror above the 
participant’s head from a projector located outside the scanner room. Stimuli will be presented in the center of 
the screen at a rate of 750 ms, with a 250 ms interstimulus interval. During the instruction phase, the 
participant views a series of instruction screens while the rater reads the task instructions aloud. Following 
instructions, participants are asked to practice the task and are allowed to ask questions freely. Participants will 
complete 1-2 runs of this task. Scenes depict indoor or outdoor locations (e.g., building exteriors or interior 
rooms). Face images depict male and female faces with neutral or pleasant expressions. To maximize 
participants’ attention to the images, on some trials an image will be repeated. Participants will be instructed to 
push a button to detect these targets. Runs with performance less than 50% correct will be excluded from final 
analyses. 
 
9.d. Image Processing: Functional MRI Analysis: fMRI data will be preprocessed and analyzed using 
SPM12 (https://www.fil.ion.ucl.ac.uk/spm/ ). Given the longitudinal nature of our analyses, we will use the 
SPM12 pairwise longitudinal module to create an average MPRAGE image that can be applied to the 
functional scans.  Standard fMRI preprocessing steps will be utilized, including realignment/ motion estimation, 
slice-timing correction, ART outlier detection, coregistration of functional and averaged anatomical images and 
normalization to the MNI template, and spatial smoothing.  First-level analyses include motion regressors.   
Examining CCN Engagement: To assess target engagement, we will use ROI-level data in native space.  
To generate these data, middle and superior FG will be identified on individual MPRAGE images using the 
Neuromorphetrics atlas (academic subscription; http://neuromorphometrics.com) implemented in SPM. For 
each subject, session, and ROI we will calculate the average percent signal change for the primary contrast of 
incongruent-congruent trials.  We will examine the difference in M/SFG activation between Stroop conditions 
prior to and after TDN administration using a change z-score. This will provide ROI data for the Go Decision. 
Testing for DMN Involvement: To assess potential DMN involvement, we will use an identical approach 
as for the CCN.  We will focus on key DMN hub regions,(130-132) the medial PFC and precuneus.   
 
9.e. Resting State Functional Connectivity Analysis: Preprocessing uses the Conn toolbox in SPM 12 with 


 
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standard steps of: realignment of the functional runs and correction for head motion, coregistration of functional 
and anatomical images, segmentation of the anatomical image, normalization of the anatomical and functional 
images to the standard MNI template, and spatial smoothing with a Gaussian filter. The resulting BOLD time 
series will be band-pass filtered to further reduce noise and increase sensitivity.  
First-level individual whole brain seed-to-voxel functional connectivity maps will be created for each CCN 
seed (6mm sphere) in the bilateral MFG and SFG as well as DMN seeds in the medial PFC and bilateral 
precuneus.  Second-level ANCOVAs will test for differences between baseline and subsequent acquisitions, 
controlling for age and sex while adjusting for multiple comparisons using at FDR = 0.05. Beta values 
(difference between baseline and subsequent acquisitions) for significant clusters will be further examined to 
determine the strength and direction of change. 
 
 
10. MEASUREMENT OF LEVELS OF NICOTINE AND NICOTINE METABOLITES 
Every 3 weeks participants will have 10ml of blood drawn to measure metabolites including nicotine, cotinine, 
and 3 hydroxycotinine. This will occur after at least 2 weeks on a stable dose, and approximately 4 hours after 
patch application.  This schedule allows for participants to be at steady-state levels.(133)  These data will 
provide information on drug level exposure and the nicotine metabolite ratio (3hydroxycotinine / cotinine), a 
measure highly correlated with the rate of nicotine clearance.(134,135) Samples will be stored at -70 degrees 
until sent for analyses to Dr. Tyndale at the University of Toronto.  These compounds will be quantified by LC-
tandem mass spectrometry.(136) 
 
These samples will be de-identified including only the study coded identifier and first and last subject 
initials.  They will also include the date of the blood draw.  Permission for sharing of samples with Dr. Tyndale 
is included in the informed consent document. 
 
11.  RISKS – STUDY DRUG 
Side Effects of Nicotine: At the nicotine doses proposed in this study, the major peripheral action of nicotine 
is facilitation of impulses through all autonomic ganglia, stimulation of the adrenal medulla and stimulation of 
sensory receptors including chemoreceptors in the carotid body.  Ganglionic depression occurs at higher 
nicotine levels.  In cardiovascular systems, mild increases in heart rate and blood pressure from sympathetic 
ganglion stimulation, catecholamine release from adrenal medulla, and aortic and carotid body chemoreceptor 
stimulation may occur.  A mild parasympathetic response may be seen in the gastrointestinal tract and bladder 
(increased tone and motor activity), with increased secretion of exocrine glands.  Nausea and vomiting can 
occur from peripheral (bowel activity and vagal efferent nerve stimulation) and central (medullary emetic 
chemoreceptor trigger zone stimulation) causes.  Low dose stimulation of the CNS could in theory produce 
tremors and respiratory stimulation, although this is rarely seen except in patients with tremor disorders.  Toxic 
nicotinic doses result in CNS depression. With 
use, tolerance develops to virtually all acute 
adverse effects. 
 
General Safety Experience with the Nicotine 
Transdermal Patch: A large meta-analysis was 
conducted examining data from 35 clinical trials 
utilizing the transdermal nicotine patch in over 
5500 individuals (106). Few adverse 
cardiovascular outcomes were reported and no 
excess of these outcomes was detected among 
patients assigned to nicotine patch use 
compared to placebo patch users.  Minor 
adverse effects such as sleep disturbances, 
nausea, localized skin irritation, and respiratory 
symptoms were elevated in patch users 
compared to placebo users.   
 


 
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In our published MCI trial (104), total adverse events (AEs) for the double-blind treatment period were 82 for 
nicotine versus 52 for placebo (p < 0.05). However, the majority of AEs were mild (nicotine 57.3 %; placebo 
54.9%) and there was no statistically significant difference in the proportion of adverse events within the 
different severity classifications between treatments (Mann-Whitney test p = 0.97). No severe AEs were 
classified as related to drug treatment in either treatment group.  Adverse event rates by body systems 
reported in more than 10% of subjects (Figure) were generally comparable with the exception of 
gastrointestinal and neurological for which there were more AEs reported in the nicotine-treated group.  
Approximately 75% of AEs in both placebo and nicotine groups were judged not related or doubtfully related to 
treatment. More nicotine-treated subjects (N=4) discontinued treatment for adverse events than placebo-
treated subjects (N=0) (X2 (1) = 3.79; p = 0.05).  No withdrawal symptoms were reported by subjects or 
informants nor were any subjects reported to be continuing to use nicotine after the six-month study was 
completed. 
 
Dermatologic Safety: The most common adverse side effect of the nicotine transdermal patch is skin irritation 
and accounted for approximately 25 percent of adverse event reports regarding the nicotine transdermal patch 
to the FDA (137).  These effects consist of erythema, pruritus, edema, and rash.  Mild skin irritation is common 
and generally occurs after three weeks of continuous use.  Mild to moderate reddening of the skin is seen in 
25% of subjects and transient itching in 29%. More severe reactions requiring modification of treatment have 
been reported in up to 12% of users (DrugDex Drug Evaluation Monograph). Management of the symptoms is 
usually straightforward and is accomplished by patch rotation, local treatments, and instructing the patient to 
remove the patch prior to going to bed. Dr. Newhouse has experience in administering transdermal nicotine for 
over five years to a non-smoking patient with Huntington's disease for movement disorder control.  This long-
term exposure has been extremely well tolerated with only minor skin irritation seen.  
 
Cardiovascular Safety: There are a number of mechanisms whereby nicotine could potentially cause or 
aggravate cardiovascular disease (138).  Nicotine stimulates CNS sympathetic systems and increases release 
of catecholamines from the adrenal and vascular nerve endings.  While tolerance appears to develop to these 
cardiac stimulatory effects, the tolerance developed is only partial.  While there may be a small chronic cardio-
stimulatory effect (approximately seven beats per minute), the dose response curve appears to be flat (138).  
 
However, studies have not demonstrated that nicotine replacement therapies are associated with increased 
cardiovascular risk or increased incidence of cardiovascular adverse events (DrugDex Drug Evaluation 
Monograph).  The largest and longest such study was the Lung Health Study that enrolled almost 6000 
individuals in a study over 5 years involving nicotine replacement therapies for smoking cessation.  In this 
group with chronic lung disease, nicotine use was found to be marginally protective of cardiovascular health 
compared to non-use of nicotine (139).  This protective effect persisted even when adjusted for smoking 
status.  Even within the ex-smoking sub-group in the same study, nicotine users had substantially lower rates 
of hospitalization then non-users.  Nicotine also showed a marginally protective effect against peptic ulcer 
disease in the same subjects.  In a long-term maintenance study of non-smoking patients with ulcerative colitis, 
there were no increased cardiovascular events and markers of cardiovascular risk either did not change or 
actually decreased (e.g. fibrinogen) (140). An investigation of the effects of 26 weeks of chronic oral nicotine 
showed improved cardiovascular risk parameters (e.g. capillary flow, fibrinogen) after smoking cessation with 
no negative effects of nicotine (141). Nicotine does not appear to promote thrombosis or platelet aggregation 
nor does nicotine replacement therapy increase the risk of acute myocardial infarction (DrugDex Drug 
Evaluation Monograph).  
 
Studies of patients with known cardiovascular disease have similarly not shown an increase in cardiovascular 
events or toxicity secondary to nicotine therapy.  Two large studies of men with documented coronary artery 
disease with up to 10 weeks of nicotine therapy showed lower rates of cardiovascular endpoints and events in 
the nicotine-treated group (142).  A study of myocardial perfusion in men with coronary artery disease showed 
that cigarette smoking was associated with significantly greater myocardial perfusion deficits than nicotine 
therapy alone, suggesting that such a perfusion defect is due to factors from tobacco other than nicotine.  In 
reviewing the available clinical trial literature and data reported to the FDA as of 1998, Rennard and colleagues 


 
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Protocol Date:  05/06/2021 
14 
concluded: "the available clinical trial and the clinical experience reported to date are consistent with the 
relative safety of transdermal nicotine in stable patients with cardiac disease." 
 
In our MCI study, an examination of change in systolic blood 
pressure revealed a significant reduction in systolic blood 
pressure compared to placebo treatment (Figure below). By 
day 182, the placebo group showed an average increase of 
9.6 mmHg in SBP compared to a reduction of 4 mmHg in the 
nicotine-treated group. There was a small reduction in 
diastolic blood pressure by day 182 in the nicotine-treated 
group.  An examination of the change in pulse showed no 
overall treatment effect (p = 0.51). 
 
Safety Experience in Individuals with Cardiovascular Disease: The results of two controlled trials of NRT in 
patients with cardiovascular disease have been published (143,144).  The first study was a 5-week, placebo-
controlled trial of 14 to 21 mg/day of transdermal nicotine in 156 patients with stable coronary artery 
disease (143).  Cardiac symptoms were recorded, and in a subgroup, 24-h ambulatory electrocardiographic 
(ECG) monitoring was performed before and during the first and last weeks of treatment. Of note, the quit rates 
were low, so there was much concomitant smoking and patch use in each group. Frequency 
of angina declined both in nicotine and placebo groups, with no difference between treatments. Ambulatory 
ECG monitoring revealed no differences in arrhythmias or ST segment depression changes in nicotine- versus 
placebo-treated patients. Plasma nicotine concentrations averaged 14.1 ng/ml with transdermal nicotine in 
those who did and 21.1 ng/ml in those who did not quit smoking. Joseph et al. (144) reported the results of a 
large Veterans Affairs cooperative study of 584 smokers with cardiovascular disease. Patients received a 10-
week course of transdermal nicotine (beginning at 21 mg/day and tapering to 7 mg/day) or placebo. Many 
participants continued to smoke cigarettes. The incidence of primary end points (death, myocardial infarction, 
cardiac arrest and admission to the hospital for increased severity of angina, arrhythmias or congestive heart 
failure) was similar in both groups (nicotine group: 5.4%; placebo group: 7.9%). These two studies (143,144) 
found no evidence of aggravation of coronary artery disease by NRT. 
 
An experimental study (145) further supports the safety of transdermal nicotine, even in the setting of 
concomitant cigarette smoking, in patients with severe coronary artery disease. Thirty-six male smokers with 
a baseline ≥5% reversible perfusion defect by quantitative thallium-201 single-photon emission computed 
tomography were treated with 14- and 21-mg nicotine patches sequentially. Despite instructions to stop, most 
continued smoking, although they smoked fewer cigarettes per day. In the setting of increasing plasma 
nicotine levels (average: 15.8 ng/ml at baseline, 24.2 ng/ml for 14-mg nicotine patches, 30.4 ng/ml for 21-mg 
nicotine patches), there was a highly significant reduction in total exercise-induced perfusion defect size 
(average: 17.5% at baseline, 12.6% for 14-mg nicotine patches, 11.8% for 21-mg nicotine patches). No 
patient had a significant increase in myocardial ischemia while using nicotine patches. The 
progressive 
reduction 
in 
defect 
size 
was 
most 
closely 
related 
to 
the 
reduction 
in 
the 
blood carboxyhemoglobin concentration, which had decreased as a consequence of smoking fewer 
cigarettes. This study (145) suggests that carbon monoxide or some other component of tobacco smoke 
rather than nicotine is most important in limiting myocardial nutrient supply in patients with coronary heart 
disease. In that the perfusion defect size is known to have predictive implications for future myocardial 
infarction or death, or both (146), this study (145) suggests that treatment with transdermal nicotine is not 
hazardous in patients with coronary heart disease and may even reduce cardiovascular risk in 
continuing smokers if the smoking rate is reduced. 
 
In another study (147), nicotine replacement therapy was found to improve myocardial function. Thirty-six of 
the 40 enrolled patients had exercise SPECT at baseline and during treatment with at least 14-mg nicotine 
patches. These patients had an initial perfusion defect size of 17.5 +/- 10.6% while smoking an average of 31 
+/- 11 cigarettes per day for 40 +/- 12 years. A significant reduction in the total perfusion defect size (p < 
0.001) was observed from baseline (17.5 +/- 10.6%) to treatment with 14-mg (12.6 +/- 10.1%) and 21-mg 
Systolic Blood Pressure
-15
-10
-5
0
5
10
15
0
50
100
150
200
Day
Change from baseline 
(mm Hg)
Nicotine
Placebo


 
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(11.8 +/- 9.9%) nicotine patches. This reduction occurred despite an increase in treadmill exercise duration (p 
< 0.05) and higher serum nicotine levels (p < 0.001). There was a significant correlation between the 
reduction in defect size and exhaled carbon monoxide levels (p < 0.001) because patients reduced their 
smoking by approximately 74% during the trial. Nicotine patches, when used to promote smoking 
cessation, significantly reduce the extent of exercise-induced myocardial ischemia as assessed by 
exercise thallium-201 SPECT. 
 
Cerebrovascular Safety: Smoking is a preventable risk factor for ischemic stroke and some preclinical studies 
have suggested potential mechanisms by which smoking and/or nicotine might increase the risk of ischemic 
stroke (148-151). However, a large meta-analysis of 35 smoking cessation trials did not find any increased 
incidence of stroke in nicotine replacement therapy users (106).  
 
Conclusion regarding cardio- and cerebrovascular safety: As the subjects to be enrolled in this study will be 
nonsmokers selected for the absence of unstable cardiovascular or cerebrovascular disease, we believe that 
the cardiovascular and cerebrovascular risk profile of transdermal nicotine in such patients is excellent. 
 
Insulin Sensitivity: There have been some epidemiologic studies suggesting a positive relationship between 
smoking and insulin resistance (152) although some studies are contradictory (153). Some investigations have 
suggested that changes in insulin sensitivity may be restricted to smokers who are also diabetic (154). 
Contradictory results were also seen in studies of smokeless tobacco use on cardiovascular risk factors and 
insulin levels with one study of heavy users finding impaired measures of glucose tolerance (155) while 
another study did not (156). At this point, it is not clear that nicotine use alone in nonsmokers is associated with 
changes in insulin sensitivity.  
 
Carcinogenesis:  Nicotine alone has not been shown to be carcinogenic.  Long-term epidemiologic studies of 
oral tobacco use suggest that the nitrosamine content of tobacco is critical to determining the cancer risk from 
non- smoke related tobacco use, rather than nicotine (157).  Whether nicotine can act as a permissive agent to 
encourage the development of cancer is unclear, but it does not seem to have any effect unless co-
administered with tobacco (157). 
 
Fetal Development: The FDA does not recommend the use of transdermal nicotine patches during 
pregnancy. Given how our age entry criterion (age 60 years or older) is concordant with a post-menopausal 
state, we will not require pregnancy testing. 
 
Safety Experience in Older individuals: We have extensive experience in administering nicotine and novel 
nicotinic agonists to older patients with Alzheimer's and Parkinson's disease (158-160) .  We have performed 
over 200 intravenous infusions of nicotine bitartrate salt to such patients with cardiac telemetry.  No instances 
of cardiac ectopy or irritability have been seen and no other significant side effects other than nausea and/or 
vomiting have occurred.  We have also administered nicotine by transdermal patch for four weeks to elderly 
patients with Parkinson's disease (161). Tolerability was excellent, even up to 22 mg nicotine patch per day.  
Only minor gastrointestinal upset was seen that was easily managed by dose reduction.  No incidences of 
cardiovascular symptoms or difficulties occurred. 
 
Chronic nicotine has been administered transdermally by other investigators to nonsmoking AD and PD 
patients in several studies for up to several weeks 
(161-165) without significant problems.  No significant 
cardiovascular problems have been documented. 
Patients reported a vague feeling of lightheadedness, 
and some had mild behavioral changes.  
 
Weight:  In our recently published MCI study, 
examination of the change in body weight across 
visits showed that the nicotine-treated group showing 
Weight
-4
-3
-2
-1
0
1
2
0
50
100
150
200
Day
Change from baseline: 
kg
Nicotine
Placebo


 
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Protocol Date:  05/06/2021 
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a significant decline in body weight by day 91 compared to placebo (-2.6 kg versus -0.1 kg for the placebo-
treated subjects). However the nicotine-treated group stabilized and no further decline in weight occurred 
through day 182.  We observed a similar pattern in our 12-week pilot trial in LLD.  We will monitor weight over 
the course of the study. 
 
Abuse Potential: We believe that the probability that the subjects in this study might be prompted by their 
participation to begin to use nicotine containing products or tobacco is extremely low.  There have been no 
cases reported in the medical literature of primary abuse by never smokers of nicotine replacement therapies.  
Furthermore, there are no cases reported of ex-smokers taking up nicotine replacement therapy and becoming 
addicted or dependent.  Additional reasons for our assertion that the risk of abuse of transdermal nicotine in 
this population is low include: 
 
1) Nicotine replacement therapies have an extremely low abuse liability (166) . Nicotine patches have some 
unpleasant side effects and therefore are unlikely to be reinforcing.  
 
2) Studies (167,168) show that experimental administration of tobacco does not induce ex-smokers to relapse 
into smoking.  In another study (166), when non-smokers and ex-smokers were followed after participating 
in a study of nicotine gum administration, no subjects were found to be smoking or using other nicotine 
products three months following completion of the study.  
 
3) An important characteristic of all drugs that produce dependency is the pharmacokinetic parameters 
associated with the route and form of administration (169). With respect to nicotine, researchers of the 
NIDA Addiction Research Center (170,171), as well as others in the field (172-175), have reported that the 
slower absorption of nicotine offered by the transdermal patch relative to tobacco products substantially 
reduces the likelihood of nicotine dependence in users of the patch.  This was supported by a study 
describing a double-blind placebo-controlled study investigating the therapeutic potential of the transdermal 
nicotine patch for patients suffering from ulcerative colitis (140). Although all of the subjects were adults 
and many former tobacco users, despite 26 weeks of daily applications of 15 mg nicotine patches, no 
withdrawal symptoms were reported from these patients following discontinuation of the patch.  In addition, 
a crossover trial evaluating the "liking" rating for the patch (22mg or 44 mg/24hr) in adults found no 
difference in scores between the active and placebo systems (176).  
 
4) We have administered intravenous and/or transdermal nicotine and structurally related nicotinic agonists 
over the past 20 years to several hundred non-smoking subjects including young and elderly normal 
volunteers, patients with Alzheimer's disease, MCI, and patients with Parkinson's disease.  We have not 
had a single subject take up tobacco use as a consequence of study participation.  Perhaps most 
importantly, in our recently completed MCI trial, no withdrawal symptoms were reported by subjects or 
informants nor were any subjects reported to be continuing to use nicotine after the study was completed. 
 
There are potential unknown risks related to transdermal nicotine patches. 
 
Experience in Late-Life Depression: The majority of adverse events in our published pilot trial of 15 subjects 
with LLD were expected and concordant with what is described above.  There were no SAEs and the most 
common adverse effects included nausea (N=7), dizziness (N=4) and headache (N=4).  These were dose-
limiting in 7 of the 15 subjects (including 1 early withdrawal). One participant reported a sharp increase in 
anxiety when increased from the 7mg patch to the 14mg patch.  This anxiety resolved on lowering the dose. 
We observed no significant changes in blood pressure or heart rate but observed a decrease in weight (6.7lb, 
t= 4.30, p<0.01).  We observed no ill effects or craving after tapering and discontinuing TDN over an additional 
3 weeks.   
 
RISK/BENEFIT RATIO: When the safety record outlined above is considered, the risks of participation in this 
study are low.  The risks mainly consist of temporary side effects from the nicotine and/or the transdermal 
patch that do not constitute a serious danger when administered within a medical environment.  Long-term 


 
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cardiovascular, cerebrovascular, and neurological safety of transdermal nicotine appears to be very favorable. 
Subjects may benefit from cognitive improvement and mood. The benefits to society of greater knowledge 
about the treatment of the cognitive changes in late-life depression and their possible amelioration, considering 
the human and economic costs of this disorder, would appear great.  Overall the risk/benefit ratio appears to 
be in favor of conducting these studies. 
 
12. RISKS – OTHER THAN STUDY DRUG 
1. Diagnostic, Cognitive, and Clinical Interviews:  Subjects may experience boredom or discomfort during the 
clinical interview and evaluations when discussing symptoms and recent life events.  They may also 
experience frustration with some cognitive tasks.  The study coordinators are experienced and skilled in 
interviewing depressed older adults.  Should the subject wish to stop or take a break, the coordinator will 
allow it.  Dr. Taylor or another study doctor will be available as a backup. Should the subject express 
suicidal ideation at any time during the interview, Dr. Taylor or another study doctor will be contacted 
immediately to assess the subject and to determine the appropriate course of action.  Thoughts of suicide 
will be taken very seriously.  Options for addressing this may include contacting the individual’s 
outpatient mental health caregiver, referring for urgent psychiatric evaluation and treatment, or emergent 
evaluation and hospitalization.  Similar practices will be used for other emergencies, including but not 
limited to psychosis, homicidal or violent thoughts, or an acute change in a subject’s physical status. 
 
Safety Procedures for Telemedicine Evaluations: In context of the COVID-19 pandemic, we will allow some 
study procedures, including the initial screening visit, to be conducted at a distance using telemedicine 
approaches.  If there are safety concerns, the study clinician can always require in-person visits instead of 
telemedicine visits.  This is concordant with clinical practice in the Vanderbilt Department of Psychiatry and 
Behavioral Science that is using telemedicine for both new and established patient visits.  We will follow 
their clinical guidance for this study.   
 
Prior to the screening visit, a study clinician will review the potential subject’s Vanderbilt medical record.  If 
there is a history of suicidality in the medical record, the visit will be conducted in person.  For telemedicine 
visits (both screening and follow-up visits), at initiation of the visit we will obtain: 1) the address of the 
subject’s location; 2) a phone number where the subject can be reached; and 3) the identity of any family 
members or friends at their location.  This allows us to contact the subject if disconnected, but also to know 
where they are and who may be available to assist in case of an emergency.  If thoughts of suicide arise 
during the interview, the patient will be directed to the Vanderbilt Psychiatric Hospital emergency 
Psychiatric Admissions Service for further evaluation.  If a family member or friend is available, we will ask 
the subject for permission to share our concerns with them and enlist their assistance.  We will then notify 
the Psychiatric Admissions Service about the expected arrival.  If the subject is unable or unwilling to come 
to Vanderbilt or a local emergency room for evaluation, and a family member or friend is not available, we 
will contact the local police to detail our concerns and request a check on the subject’s welfare.  In either 
case, we will follow-up with the subject to assure their safety and disposition. 
 
2. Magnetic Resonance Imaging:  Although this procedure is generally low-risk, there are particular concerns.  
Individuals will be screened for the presence of implanted metal (including but not limited to medical 
devices, shrapnel, tattoos or permanent makeup); those who screen positive will be excluded from the 
study.  Claustrophobia is also an issue for many potential subjects.  During the MRI, subjects will have 
voice contact with a radiology technician, and may request the scan be stopped at any time. 
Another MRI-related risk is the occurrence of incidental findings on MRI.  All scans are reviewed at time 
of acquisition and concerning findings are reviewed with an attending neuroradiologist.  Should any 
concerning findings be seen, Dr. Taylor or another study doctor will convey these findings to the subject 
along with recommendations for further evaluation and facilitate referrals for such evaluation and treatment. 
 
3. X-Rays:  Occasionally there may be a concern on screening for MRI safety in individuals who may have 
past surgical histories or have been exposed to metal fragments.  We will attempt to acquire medical 
records when possible, but may also obtain an x-ray when it is unclear whether or not there is implanted or 


 
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embedded metal.  In these cases, if metal is found on x-ray and safety cannot be assured, the subject will 
be withdrawn.  This will be an uncommon study procedure, but does involve exposure to a small amount of 
radiation.  As this will be a single x-ray image obtained at one time point, this radiation exposure is of low 
risk. 
 
4. Blood draw for levels of nicotine and nicotine metabolites:  We will draw 10mL of blood to measure levels 
of nicotine and nicotine metabolites four times over the 12-week trial.  This is a minimal risk procedure and 
amount.  Risks involve mild discomfort, bruising, or bleeding.  Blood will be drawn by a phlebotomist using 
sterile technique.  Blood samples will be identified only by a subject ID number, initials (first and last) and 
date.  They will be stored in a secured, locked, research-dedicated -70 degree freezer.   
 
5. Worsening Depressive Symptoms:  If individuals do not experience benefit with the patch, it is possible 
depressive symptoms would worsen and suicidal ideation develop.  We are mitigating this risk by 
examining transdermal nicotine in an augmentation trial, so all participants will be on a stable therapeutic 
dose of a SSRI or SNRI antidepressant. We will safeguard against this risk by frequent monitoring and 
availability for phone calls or urgent in-person visits for worsening depression.  If participants exhibit 
worsening depressive symptoms, they can withdraw or be withdrawn from the study and referred for 
appropriate clinical care.  Similarly, the development of suicidal thoughts will result in study withdrawal and 
referral to the appropriate level of clinical care (outpatient, partial hospital, or inpatient). 
 
6. End of Study Procedures: During the course of the study we will work with study subjects to identify 
providers who will continue their care at the end of the study.  After completion of the 12-week final 
assessments, all subjects will undergo a three-week patch taper.  They will then return for a final safety 
visit.  We will then communicate to their physician about study procedures, their study participation, and if 
they benefited from their participation.  
 
7. Breach of confidentiality:  There is the potential risk of breach of confidentiality of clinical, genetic, and 
laboratory information.  Dr. Taylor has extensive experience as a clinical investigator dealing with such 
sensitive information and have experience assuring that data is adequately protected.  Safeguards to 
protect confidentiality include locked records and firewalls around password-protected electronic data, and 
all study data being coded, with the key linking the code with a subject’s identity being kept in a separate, 
locked file accessible only to key study staff. 
 
12. Reporting of Adverse Events or Unanticipated Problems involving Risk to Participants or Others 
 
Subjects will be assessed for safety, medication tolerability, and unanticipated problems at each contact.  
Emergency contact information will be provided to each subject for urgent, unanticipated problems.   
 
12.a. Definition of Adverse Events (AEs) and serious adverse events (SAEs).  We define reportable non-
serious adverse events as any adverse change in health or development of a side effect occurring in a study 
participant after enrollment.  These may be expected events (known drug effects, as detailed in the consent 
form, safety monitoring plan, or package insert) or unexpected events.  We define a SAE as any event that 
results in hospitalization, disability or permanent damage, is life threatening, results in death, or any other 
serious event that does not fit these outcomes but requires urgent medical intervention.   
 
12.b. AE Monitoring and Reporting.  All adverse events will be reviewed by Dr. Taylor and/or Dr. Newhouse 
approximately weekly as they occur. All AEs, regardless of being judged as related or non-related, will be 
summarized and included in the annual IRB continuing review.  Unanticipated, non-serious AEs will be 
reviewed by Dr. Taylor and Dr. Newhouse.  If felt to be likely related to study participation, we will consider 
whether they need to be added to the consent form.  If so, we will submit them as an AE report and submit an 
amendment adding that risk to the consent form and other study documents.  
 
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procedures, will be reported to the Vanderbilt IRB within 7 calendar days of when study staff learn about the 
event.  SAEs will also be reviewed jointly by Drs. Taylor and Newhouse to consider whether they need to be 
added to the consent form. 
 
12.d. Data Safety Monitoring Board.  As we will be using transdermal nicotine patches off-label in a different 
population than the approved indication, we will establish a DSMB for this study.  The DSMB will consist of 
scientists including a geriatric psychiatrist, a geriatric internist, and a statistician.  These individuals will be 
independent of and not include members of the study team.  The DSMB will be named and the charter 
provided both to NIH and to the Vanderbilt IRB prior to initiation of study enrollment.  It is anticipated the DSMB 
will meet every 6 months after initiation. 
 
The DSMB, based on its review of the protocol, will work to identify the study-specific data parameters and 
format of the information to be regularly reported. All adverse events related to study medication and all severe 
adverse events and SAEs will be reported to the DSMB. The DSMB will convene to review these cumulative    
study medication related AEs, severe AEs and SAEs every 6 months while subjects are participating in the 
study. 
 
DSMB reports will be provided to NIH and the Vanderbilt IRB at each continuing renewal.  
  
Based on the review of safety data, the DSMB will make recommendations regarding the conduct of the study. 
These may include amending safety monitoring procedures, modifying the protocol or consent, terminating the 
study or continuing the study as designed.   
 
 
13. STUDY WITHDRAWAL/DISCONTINUATION 
Participants may withdraw from the study at any time.  If participants leave the study early, we will recommend 
a medication taper and clinical referrals for further care.   
 
A participant will be withdrawn from the study if: 
1) The participant withdraws his or her consent 
2) The PI considers it is in the best interest of the patient for him or her to stop study participation 
3) In the PI’s judgment, the participant’s depressive symptoms have worsened significantly since study drug 
initiation 
4) The patient develops suicidal ideation where he or she should be referred for regular clinical care for safety 
5) The patient is lost to follow-up 
 
14.  SUBJECT REIMBURSEMENT 
 
Participants may receive up to $600.  Reimbursement is pro-rated for each visit: 
• 
Screening Visit: $25 
• 
Assessment visits with MRI (Weeks 0, 6 and 12):  $150 / each.   
• 
Clinic visits with blood draws but without MRI (Weeks 3 and 9): $50 / each 
• 
Final safety visit (Week 15): $25 
 
15. STATISTICAL CONSIDERATIONS 
15.a. Data Management: All study data will be stored in a REDCap study database.  The exception is for the 
raw and processed MRI scans that will be stored in the Vanderbilt XNAT Image Database system.  
 
15.b Statistical Plan: After assessing normality, tests will be conducted as two-sided using alpha=0.05.  If 
data are not normally distributed, we will either transform data or use nonparametric approaches.  For this 
proof of concept study, no multiple comparison corrections will be used and results presented in that context.   
 
Aim 1: Test CCN engagement over 12 weeks of open-label transdermal nicotine (TDN) 


 
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Hyp 1A (Target Engagement): TDN will enhance CCN function, measured as a reduction in the M/SFG 
Stroop BOLD 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. 
 
We will test for change in the difference in M/SFG ROI activation between the incongruent and congruent 
conditions of the emotional Stroop task. We will determine the signal difference between conditions and 
calculate the z-score change as detailed for our Go criteria (Sect C.10). Analyses will include all subjects 
regardless of final dose.   
The primary outcome will be change in activation difference from baseline to week 12.  This will be 
examined as both a continuous variable and a categorical variable, defined by our Go criterion of whether a 
subject exhibits a z-score reduction of at least 0.5 in M/SFG activity at 12-weeks.  Change from baseline to 
week 6 and week 6 to week 12 are secondary outcomes.  Analyses will include key covariates of age and sex.  
Exploratory analyses will examine the relationship between change in the M/SFG Stroop response and change 
in MADRS, using an approach similar to that described for the R33 phase, Hypothesis 2A, described in the 
R33 Phase Section 4.4, Statistical Design and Power. 
 
Hyp 1B (Exposure): Higher nicotine exposure measured by dose or metabolite levels will be associated with a 
greater reduction in the M/SFG Stroop BOLD response. 
 
Subsequent models will be structured as for Hyp 1A but include nicotine blood level exposure or final dose as 
explanatory variables.  Primary analyses will examine 12-week change, with post-hoc analyses examining 
change from baseline to week 6 and week 6 to week 12.  
To test for the association between the change in the Stroop BOLD response and the change in nicotine 
exposure across visits (baseline, week 6, week 12), we will employ a linear model in which change in activation 
will be the outcome variable and explanatory variables include change in blood nicotine level, visit time, and 
the interaction between change in blood levels and visit while adjusting for the effects of age and sex. The 
statistical significance of the regression coefficient associated with the interaction term is of primary interest to 
address the difference in the association between visits.  Similar approaches will be used to examine dose. 
 For each visit, we will also examine contemporaneous correlation between change in the Stroop BOLD 
response and change in the steady-state plasma nicotine concentration or dose. Moreover, the prolonged 
effect of nicotine on the M/SFG Stroop BOLD response will be examined via lagged correlation, i.e., correlation 
between BOLD response at week 6 (or week 12) and blood level of nicotine at week 3 (or week 9). Finally, we 
will examine z-score change in the BOLD response as both a continuous and categorical measure based on 
meeting target engagement Go Criteria.  Jointly, these analyses will inform R33 phase dosing. 
 
Exploratory Analyses: Analyses of blood samples will provide levels of nicotine, cotinine, and the log 3-
HC/cotinine ratio (a measure of nicotine clearance).  We will examine whether nicotine or metabolite levels at 
week 3 predict subsequent dose-limiting effects.  We will also examine how a past smoking history (defined 
as > 100 cigarettes over lifetime) or differences in antidepressant use (SSRI vs SNRI) is associated with target 
engagement, change in depression severity, or vulnerability to adverse effects. 
 
15.c. Statistical Power: Per RFA MH-18-702, the R61 phase focuses on the preliminary evaluation of whether 
an intervention (TDN) modulates the target (M/SFG activity). In pilot data, 64% (7 of 11) of subjects met our 
neural circuit criterion for CCN engagement.  Assuming that this is a reasonable estimate of the true proportion 
of individuals showing target engagement with TDN, N=30 produces a one-sided 95% lower-limit confidence 
interval with a lower bound of at least 0.5, i.e., a chance of 50% of participants meeting this criterion. The 
bootstrap distribution of the delta Z based on our pilot study further supports that we will have 80% power to 
detect at least 50% true positives, i.e., more than 15 out of 30 satisfy the delta Z < -0.5 criterion. 
 
16.0 PRIVACY/CONFIDENTIALITY ISSUES 
16.a. Confidentiality Procedures: As the PI, Dr. Taylor will assure all procedures protecting study data 
designed to guard subject confidentiality conform to the Vanderbilt Human Research Protection Program 
requirements. All non-electronic data (clinical evaluations, paper assessments) will be stored securely in 


 
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locked offices or laboratories accessible only by study staff.  All electronic data will be stored in secured 
servers with limited access.  RedCAP will be used for data management. 
 
Further, all information that could potentially directly identify a subject is removed from all study data.  This 
includes MRI data, electronic and paper assessments.  Direct identifiers will be replaced with a unique four-
digit code.  The key to linking the code to subject identity will be kept separately from study data, in a locked 
file in password-protected computer in Dr. Taylor’s office. Only study staff involved in clinical recruitment and 
assessment will have access to individually identifiable private information.  All other study staff, including 
image analysts, will be blinded to subject identity and will only have access to the coded identifier. 
 
16.b. Privacy Procedures: Informed consent and all study procedures will occur in private research offices 
and private research examination rooms.   
 
16.c. Creation of Global Unique Identifier (GUID): To facilitate NIMH-required data sharing described below, 
participants will be assigned a GUID using the GUID tool (https://nda.nih.gov/s/guid/nda-guid.html).  The GUID 
Tool is software that accepts the personal information of subjects and uses it to create a series of hash codes. 
These codes are sent to the NIH system and checked against the GUID database. If these codes have been 
seen before, that means the information matches an existing GUID, and this GUID is sent back. If no match is 
found, a new GUID is created and sent back. If someone else enters the same information later, the tool will 
detect this match and send back the same GUID. The GUID itself is a series of alpha-numeric characters. With 
this system: 1) No personally identifying information ever leaves the institution’s computers; 2) There is nothing 
about a GUID that would allow someone to infer the identity of the individual to whom it belongs; and 3) The 
same individual's information will result in the same GUID across time, location, and research study. This 
allows researchers to match shared data from that participant regardless of source, without ever sharing or 
viewing personally identifying information. 
To create a GUID, at enrollment we will gather all of the following required information: sex, first name, last 
name, middle name, date of birth, and city/municipality of birth. In all cases, all of this information should be 
obtained and entered as it appears on the birth certificate.  The GUID will serve as a secondary more complex 
coded identifier, in addition to the simpler primary 5-digit identifier.  The GUID will be the only identifier used 
when sharing data outside of UIC, UPMC, and VUMC. 
 
16.d. Transfer of Blood Samples for Analyses: Blood samples will be leaving Vanderbilt University Medical 
Center for analyses of levels of nicotine and nicotine metabolites by Dr. Rachel Tyndale at the Center for 
Addiction and Mental Health at the University of Toronto.  These samples will be deidentified and include only 
the subject’s study ID number, initials (first, last), and date of sample acquisition.   
 
17. DATA SHARING 
 
The proposed research will include clinical, cognitive, and neuroimaging data from older depressed subjects. 
The final dataset will also include sensitive clinical information about subject psychiatric diagnoses, psychiatric 
and medical history.  Data will be deidentified and stored in REDCap and the Vanderbilt XNAT image storage 
database.  Given our data safeguards we feel that subject identity will be protected.  
 
We will also follow NIH guidance by planning to share data.  These data will be shared with investigators 
working under an institution with a Federal Wide Assurance (FWA) and can be used for secondary study 
purposes.  The names and Institutions of persons either given or denied access to the data, and the bases for 
such decisions, will be summarized in the annual NIH progress reports. 
 
All data, the data dictionary, and technical details of assessments will be available for sharing and will be 
facilitated through our study data manager.  All imaging data will have direct identifiers excised from the files 
prior to sharing.  Data will be available for sharing as soon as possible but no later than within one year of the 
completion of the funded project period for the parent award or upon acceptance of the primary data for 
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Given NIMH data sharing requirements and pursuant to NOT-MH-15-012, we will also share data via the 
National Institute of Mental Health Database (NDA) at the National Institutes of Health (NIH). The NDA 
provides a secure platform for data-sharing allowing for communication of research data, tools, and supporting 
documents.  Data to be shared includes clinical data, cognitive data, and neuroimaging data gathered over the 
course of this study.  No direct identifiers will be shared with the NDA and data coded using a GUID.  
Participants can refuse to have their data included in the NDA and still participate in the study. 
 
18. FOLLOW-UP AND RECORDS RETENTION 
 
Study records will be maintained for at least seven years after all study procedures are complete, all subject 
contact has ended, and the study is closed with the IRB.  After that time, study data may be destroyed or 
anonymized, meaning all links to direct identifiers will be destroyed.  Any study data in the medical record will 
be kept indefinitely. 
 
 
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resistance in patients with noninsulin-dependent diabetes mellitus. Journal of Clinical Endocrinology & 
Metabolism. 1997;82(11):3619-24. 
155.  Persson PG, Carlsson S, Svanstrom L, Ostenson CG, Efendic S, Grill V. Cigarette smoking, oral moist 
snuff use and glucose intolerance. Journal of Internal Medicine. 2000;248(2):103-10. 
156.  Eliasson M, Asplund K, Evrin PE, Lundblad D. Relationship of cigarette smoking and snuff dipping to 
plasma fibrinogen, fibrinolytic variables and serum insulin. The Northern Sweden MONICA Study. 
Atherosclerosis. 1995;113(1):41-53. 
157.  Benowitz NL. Risks and benefits of nicotine. In: Benowitz NL, editor. Nicotine Safety and Toxicity. New 
York: Oxford University Press; 1998. p. 185-94. 
158.  Newhouse PA, Sunderland T, Tariot PN, Blumhardt CL, Weingartner H, Mellow A, Murphy DL. 
Intravenous nicotine in Alzheimer's disease: A pilot study. Psychopharmacology. 1988;95:171-5. 


 
Protocol Version #:1.4 
 
 
Protocol Date:  05/06/2021 
30 
159.  Newhouse P, Potter A, Corwin J. Effects of nicotinic cholinergic agents on cognitive functioning in 
Alzheimer's and Parkinson's disease. Drug Development Research. 1996;38(3-4):278-89. 
160.  Potter A, Corwin J, Lang J, Piasecki M, Lenox R, Newhouse P. Acute effects of the selective cholinergic 
channel activator (nicotinic agonist) ABT-418 in Alzheimer's disease. Psychopharmacology. 1999;142:334-42. 
161.  Kelton MC, Kahn HJ, Conrath CL, Newhouse PA. The effects of nicotine on Parkinson's disease. Brain and 
Cognition. 2000;43:274-82. 
162.  Wilson AL, Langley LK, Monley J, Bauer T, Rottunda S, McFalls E, Kovera C, McCarten JR. Nicotine 
patches in Alzheimer's disease: pilot study on learning, memory, and safety. Pharmacology, Biochemistry and 
Behavior. 1995;51(2-3):509-14. 
163.  Katayama S, Hirata K, Tanaka H, Yamazaki K, Fujikane M, Ichimaru Y. Efficacy of transdermal nicotine in 
dementia: a study using event-related potentials and a middle latency response. In: Domino EF, editor. Brain 
Imaging of Nicotine and Tobacco Smoking. Ann Arbor, MI: Npp Books; 1995. p. 289-302. 
164.  Parks RW, Young CS, Rippey RF, Danz V, Vohs C, Matthews JR, Collins GT, Zigler SS, Urycki PG, Keim P, 
Kabatay E, Becker RE. Nicotinic stimulation of anterior regional cerebral glucose metabolism in Alzheimer's 
disease:  preliminary study transdermal patches. In: Giacobini E, Becker R, editors. Alzheimer disease: 
Therapeutic strategies. Boston: Birkhauser; 1994. p. 424-7. 
165.  Fagerstrom KO, Pomerleau O, Giordani B, Stelson F. Nicotine may relieve symptoms of Parkinson's 
disease. Psychopharmacology. 1994;116:117-9. 
166.  Hughes JR, Strickler G, King D, Higgins ST, Fenwick JW, Gulliver SB, Mireault G. Smoking history, 
instructions and the effects of nicotine:  two pilot studies. Pharmacology Biochemistry and Behavior. 
1989;34:149-55. 
167.  Seyler Jr. LE, Pomerleau OF, Fertig JB, Hunt D, Parker K. Pituitary hormone response to cigarette 
smoking. Pharmacology Biochemistry and Behavior. 1986;24:159-63. 
168.  Fertig J, Sayler LE, Pomerleau O, Hunt D, Parker K. Release of five human pituitary hormones during 
smoking correlates with nausea and not with plasma nicotine. Clinical Research. 1982;30(2):270A. 
169.  Farre M, Cami J. Pharmacokinetic considerations in abuse liability evaluation. British Journal of Addiction. 
1991;86(12):1601-6. 
170.  Henningfield JE, Keenan RM. Nicotine delivery kinetics and abuse liability. Journal of Consulting & Clinical 
Psychology. 1993;61(5):743-50. 
171.  Henningfield JE, Keenan RM. Nicotine delivery kinetics and abuse liability. Journal of consulting and 
clinical psychology. 1993;61(5):743-50. 
172.  Pomerleau OF. Nicotine and the central nervous system: biobehavioral effects of cigarette smoking. 
American Journal of Medicine. 1992;93(1A):2S-7S. 
173.  Marks MJ, Stitzel JA, Collins AC. Influence of kinetics of nicotine administration on tolerance development 
and receptor levels. Pharmacology, Biochemistry & Behavior. 1987;27(3):505-12. 
174.  Rose JE, Westman EC, Behm FM. Nicotine/mecamylamine combination treatment for smoking cessation. 
Drug Development Research. 1996;38(3/4):243-56. 
175.  Shytle RD, Silver AA, Philipp MK, McConville BJ, Sanberg PR. Transdermal nicotine for tourette's 
syndrome. Drug Development Research. 1996;38(3/4):290-8. 
176.  Bunker E, Pickworth W, Henningfield J. Nicotine patch: spontaneous smoking. In: Problems of Drug 
Dependence 1991 - proceedings of the 53rd annual scientific meeting of the committee on problems of drug 
dependence, Inc,. 1992:470. 
 
 


 
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31 
APPENDIX A: LIST OF ABBREVIATIONS 
 
ACB 
Anticholinergic Cognitive Burden 
AD 
Alzheimer’s Disease 
AE 
Adverse Event 
AES 
Apathy Evaluation Scale 
ASI3 
Anxiety Severity Index 3 
ATHF 
Antidepressant Treatment History Form 
BOLD 
Blood Oxygen Level Dependent 
CIRS-G 
Cumulative Illness Rating Scale - Geriatrics 
CCN 
Cognitive Control Network 
CPT 
Continuous Performance Test 
dACC 
Dorsal Anterior Cingulate Cortex 
DARS 
Dimensional Anhedonia Rating Scale 
dlPFC 
Dorsolateral Prefrontal Cortex 
DMN 
Default Mode Network 
DSMB 
Data Safety Monitoring Board 
FIBSER 
Frequency, Intensity, Burden of Side Effects Rating 
FLAIR 
Fluid-Attenuated Inversion Recovery 
fMRI 
Functional Magnetic Resonance Imaging 
FSS 
Fatigue Severity Scale 
GAD 
Generalized Anxiety Disorer 
GAD7 
Generalized Anxiety Disorder 7 item scale 
GRSEB 
Global Rating of Side Effect Burden 
ISI 
Insomnia Severity Index 
LLD 
Late-Life Depression 
mAChR 
Muscarinic Receptor 
MADRS 
Montgomery Asberg Depression Rating Scale 
MCI 
Mild Cognitive Impairment 
MINI 
Mini-International Neuropsychiatric Interview 
MMSE 
Mini-Mental State Exam 
MRI 
Magnetic Resonance Imaging 
M/SFG 
Middle / Superior Frontal Gyri 
nAChR 
 Nicotinic Acetylocholiner Receptor  
nAChRs 
Nicotinic Acetylocholine  Receptors 
NDA 
National Institute of Mental Health Database 
PSWQ 
Penn State Worry Questionnaire 
SAE 
Serious Adverse Event 
TDN 
Transdermal Nicotine 
UPRTSO 
Unanticipated Problem Involving Risk to Subjects or Others 
VUMC 
Vanderbilt University Medical Center 
WHODAS 2.0 
World Health Organization Disability Assessment Schedule 2.0 
 


 
Protocol Version #:1.4 
 
 
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32 
APPENDIX B: PROHIBITED MEDICATIONS 
 
Antidepressants: 
 
• 
Monoamine oxidase inhibitors (parnate, selegiline, etc) 
• 
Tricyclic antidepressants (amitriptyline, nortriptyline, imipramine, desipramine, etc) 
• 
Bupropion 
• 
Paroxetine 
 
Other Medications: 
• 
Acetylcholinesterase Inhibitors 
• 
Donepezil 
• 
Galantamine 
• 
Rivastigmine 
 
• 
Other anticholinergic drugs 
• 
Benztropine 
• 
Cyproheptadine 
• 
Diphenhydramine 
• 
Hydroxyzine 
• 
Meclizine 
• 
Promethazine 
• 
Oxybutynin 
 
• 
CYP2A6 Inhibitors / Inducers (1) 
• 
Amiodarone 
• 
Bupenorphine 
• 
Clotrimazole 
• 
Disulfram 
• 
Fenofibrate 
• 
Ketoconozole 
• 
Letrozole 
• 
Miconazole 
• 
Modafinil 
• 
Tioconazole 
 
1.  Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. In: Lucy CF, Armstrong LL, Goldman MP, 
Lance LL, eds. Drug Information Handbook. 15th edition ed. Hudson, OH: LexiComp Inc.; 2007:1899-1912. 
 

ICF_002.pdf: 
VUMC Institutional Review Board
Informed Consent Document for Research
Study Title:
DepressedMoodImprovementThroughNicotine Dosing 2 (Depressed Mind2)
Version:
Date:
PI:
1.6
12/20/2021
Warren D. Taylor, MD
1
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IRB USE ONLY
Do not edit or delete
Name of participant: __________________________________________ Age: ___________ 
The following is given to you to tell you about this research study.  Please read this form with care and 
ask any questions you may have about this study.  Your questions will be answered.  Also, you will be 
given a copy of this consent form.   
Key information about this study: 
What is the purpose of this study? 
The purpose of this study is to better understand whether transdermal nicotine (a skin patch) can 
improve depression and memory performance in older individuals with depression. We also want to 
determine how nicotine affects brain function in order to cause these changes.   
Depression in older adults can be difficult to treat, with some people not responding to currently 
approved antidepressant medicines.  Additionally, depression in older adults is often characterized 
by problems with memory.  There is no current medicine that is approved by the U.S. Food and Drug 
Administration (FDA) to treat memory and attention in depressed adults. 
We are examining nicotine in this study because past research suggests that the stimulation of 
nicotine receptors in the brain may improve mood and depression.  A previous pilot study in older 
adults with depression conducted at Vanderbilt found encouraging results.  Also, in other 
populations, including older adults with memory disorders, nicotine and drugs that affect the brain’s 
nicotine receptor have repeatedly shown to benefit memory.   
In this study, we will use transdermal nicotine patches that are commercially approved by the U.S. 
Food and Drug Administration. Transdermal nicotine patches are approved for the cessation of 
smoking, but are not approved as a treatment for depression. We plan to enroll 32 individuals who 
will complete baseline procedures and start study patches.    
Key Information: 
The first section of this document contains some key points that the research team thought you 
would find important. The study is described in more detail after this section. If you do not 
understand something, please ask someone. 
Date of IRB Approval: 03/29/2022
D
Date of Expiration: 03/28/2023


VUMC Institutional Review Board
Informed Consent Document for Research
Study Title:
DepressedMoodImprovementThroughNicotine Dosing 2 (Depressed Mind2)
Version:
Date:
PI:
1.6
12/20/2021
Warren D. Taylor, MD
  
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What will happen and how long will you be in the study? 
If you agree to be in this study, you will first be asked to sign and date this consent form. The study 
takes place over the course of at least 15 weeks. After we determine you are eligible to participate in 
the study, the first 12 weeks will involve the use of transdermal nicotine patches.   
To be eligible for this study, you will need to be taking a therapeutic dose of an allowable  
antidepressant medication. You will be asked to continue that medication throughout the study. If 
you are not taking an antidepressant medication, or are taking a medication that is not allowed, you 
may be eligible for a separate study that includes treatment with antidepressant medications. 
You will have 7 in-person visits (about every 3 weeks) and 3 brain scans (at baseline, week 6 and 
week 12) over the course of the study. The brain scans are done using Magnetic Resonance Imaging 
(MRI) and do not involve radiation exposure. While not necessary for many people, to confirm it is 
safe for you to have an MRI we may ask you to have an x-ray, which does use radiation, to see if 
there is metal in your body. 
Before starting the nicotine patches, you will have a clinical assessment, neuropsychological 
(memory) testing, and a brain MRI scan. This visit will take about 4.5 hours. You will repeat the brain 
scan after 6 and 12 weeks of receiving the patches. You will repeat the memory testing at the end of 
the 12-week study period. The week 6 visit will take about 4 hours and the week 12 visits will take 
about 5.5 hours.  We will also have you return for a shorter visit at weeks 3 and 9, lasting 2 hours.  
You will have 4 blood draws every three weeks over the course of the study to monitor nicotine 
blood levels. We will collect 10 mL (about 2 tsp) of blood at each blood draw. You will not need to 
fast prior to each blood draw. The total amount of time you may spend at in-person study visits is 
about 21 hours. Study visits will be discussed in more detail in the next section of this document. 
The last three weeks of the study will be used to safely reduce the patch dose and stop it. If you feel 
the nicotine patches have provided a benefit and would like to continue using them, you may 
purchase over-the-counter patches and we will not require that you stop them. 
There is no cost to you for taking part in this research study. You will not have to pay for the study 
patches or the tests and treatments that are being done only for research. You are still responsible 
for paying for the usual care you would normally receive for the treatment of your illness, including 
Date of IRB Approval: 03/29/2022
D
Date of Expiration: 03/28/2023


VUMC Institutional Review Board
Informed Consent Document for Research
Study Title:
DepressedMoodImprovementThroughNicotine Dosing 2 (Depressed Mind2)
Version:
Date:
PI:
1.6
12/20/2021
Warren D. Taylor, MD
  
3
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the cost of your usual antidepressant medication. This will be discussed in more detail later in this 
document. 
You are being asked to take part in this research study because you have depression and are age 60 
years or older. 
You do not have to be in this research study. You may choose not to be in this study and get other 
treatments without changing your healthcare, services, or other rights.  You can stop being in this study 
at any time.  If we learn something new that may affect the risks or benefits of this study, you will be 
told so that you can decide whether or not you still want to be in this study.   Your medical record will 
contain a note saying you are in a research study and may contain some research information about 
you.  Anyone you authorize to receive your medical record will also get this information. 
Side effects and risks that you can expect if you take part in this study:  
Nicotine and Patch Side Effects: Nicotine patches are currently FDA approved for over-the-counter 
sale for smoking cessation. Nicotine has effects that have been well studied for many years. Possible 
common side effects may include nausea, vomiting, dizziness or headaches Dizziness or 
lightheadedness may occur, especially with higher doses or after a dose increases. For many people, 
this effect is mild and short-lived, but can persist for others. For safety, you should avoid risky 
activities that could lead to falls, such as climbing on ladders. Nicotine patches can sometimes cause 
reddening or irritation of the skin where they are applied. Uncommon side effects include increased 
heart rate and blood pressure, irregular heartbeats, possible increase in anxiety, increased sweating, 
and occasionally shakes. In a recent study of older adults with memory problems, we found that 
nicotine patches may result in lower appetite that can cause slight weight loss (about 5-6 pounds on 
average over several months). 
There is no evidence that using nicotine patches would prompt a non-smoker to become a cigarette 
smoker or to abuse nicotine products. The likelihood that participation in this study may cause 
participants to begin to use nicotine products (like tobacco, cigarettes, cigars) is extremely low. There 
have been no cases reported in the medical literature of abuse by non-smokers of nicotine 
Detailed Information:
The rest of this document includes detailed information about this study (in addition to the 
information listed above).
Date of IRB Approval: 03/29/2022
D
Date of Expiration: 03/28/2023


VUMC Institutional Review Board
Informed Consent Document for Research
Study Title:
DepressedMoodImprovementThroughNicotine Dosing 2 (Depressed Mind2)
Version:
Date:
PI:
1.6
12/20/2021
Warren D. Taylor, MD
  
4
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replacement products. We have given nicotine and nicotinic drugs over the years to several hundred 
non-smoking participants including older adults, and have not had any participants take up tobacco 
or nicotine use as a consequence of study participation. 
Studies have shown that nicotine by itself does not appear by itself to be cancer causing. 
Diagnostic, Cognitive, and Clinical Interviews:  You may experience boredom or discomfort during 
the clinical interview and evaluations when discussing symptoms and recent life events.  You may 
also experience frustration with some cognitive tasks. Should you wish to stop or take a break, the 
study coordinator will allow it.  
Should you express suicidal ideation at any time during the interview, Dr. Taylor or another study 
doctor will be contacted to assess you and to determine the appropriate course of treatment.  
Thoughts of suicide will be taken very seriously. 
Blood sampling: We will draw 10mL (about 2 teaspoons) of blood to measure levels of nicotine and 
nicotine metabolites four times over the 12-week trial. Pain, redness, soreness, bruising, or infection 
may occur at the needle stick site. However, this risk is low. Blood will be drawn by a phlebotomist 
using sterile technique. Rarely some people faint.  The study staff may put some cream (called EMLA) 
on your skin to numb the area so you will not feel the needle stick as much.  The numbing cream may 
make your skin or the area have a change in skin color, but this is rare. 
Worsening Depressive Symptoms: If you do not experience benefit with the patch, it is possible your 
depressive symptoms would worsen and suicidal ideation develop.  We are reducing this risk by 
requiring that all participants be on a stable therapeutic dose of a FDA-approved antidepressant 
medication. We will safeguard against this risk by frequent monitoring and availability for phone calls 
or urgent in-person visits for worsening depression.  If you exhibit worsening depressive symptoms, 
you may be withdrawn from the study and referred for appropriate clinical care.   
Radiation Risks: This research study may involve exposure to radiation from up to 1 x-ray in a part of 
the body before an MRI scan to see where a metal object is located. This radiation exposure is not 
necessary for your medical care and is for research purposes only. The total amount of radiation that 
you may receive by participating in this study is equal to your body receiving 8 months of radiation 
from your natural surroundings, or about 4.2% of the amount allowed in a year for people who are 
exposed to radiation as part of their work.
Date of IRB Approval: 03/29/2022
D
Date of Expiration: 03/28/2023


VUMC Institutional Review Board
Informed Consent Document for Research
Study Title:
DepressedMoodImprovementThroughNicotine Dosing 2 (Depressed Mind2)
Version:
Date:
PI:
1.6
12/20/2021
Warren D. Taylor, MD
  
5
This box is for
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Do not edit or delete
Risks of Magnetic Resonance Imaging (MRI): There are no known major risks with an MRI scan. But, 
it is possible that harmful effects could be found out in the future.  Even though the tunnel is open, it 
may bother you to be placed in a tight space (claustrophobia), and to hear the noise made by the 
magnet during the scan.  You will be given earplugs to reduce the noise.  You may also feel the table 
vibrate and/or move slightly during the scan.  It may be hard to lie on the table during the scan.  If 
you have any metal pieces in your body, they could move during the scan and damage nearby tissues 
or organs.  
You will need to take off your transdermal nicotine patch, and any other medication patches you may 
be taking, during the MRI scan.  Transdermal patches slowly deliver medicines through the 
skin.  Some patches have metal in the layer of the patch that is not in contact with the skin (the 
backing).  You may not be able to see the metal in the backing of these patches.  Patches that contain 
metal can overheat during an MRI scan and cause skin burns in the immediate area of the patch.  Tell 
the study doctor that you are using a patch and why you are using it (such as, for pain, smoking 
cessation, hormones).  Ask your doctor for guidance about removing and disposing of the patch 
before having an fMRI scan and replacing it after the procedure.  Tell the fMRI facility that you are 
using a patch during the health history questions you are asked when you arrive for your 
appointment.  
End of Study Procedures: During the course of the study we will work with you to identify providers 
who will continue their care at the end of the study. After completion of the 12-week final 
assessments, you will undergo a three-week patch taper. You will then return for a final safety visit. 
We will then communicate to your physician about study procedures, your study participation, and if 
you benefited from your participation. 
Loss of Confidentiality: There is also the potential risk of loss of confidentiality. Every effort will be 
made to keep your information confidential, however this cannot be guaranteed.
Risks that are not known: 
As with any research, there may be risks of participation or from the study medication that we 
cannot predict. Because this treatment is investigational, meaning non-FDA approved, there may be 
risks that we do not know about at this time. If you experience any unpleasant effects during this 
study not mentioned in this consent form, please contact a study coordinator or study doctor as soon 
as possible. 
Date of IRB Approval: 03/29/2022
D
Date of Expiration: 03/28/2023


VUMC Institutional Review Board
Informed Consent Document for Research
Study Title:
DepressedMoodImprovementThroughNicotine Dosing 2 (Depressed Mind2)
Version:
Date:
PI:
1.6
12/20/2021
Warren D. Taylor, MD
  
6
This box is for
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Do not edit or delete
Good effects that might result from this study:
The benefits to science and humankind that might result from this study: You will be adding to the 
understanding of whether nicotine therapy may help treat depression in older adults, as well as the 
effects of nicotine on memory and cognition. This information will help us determine if nicotine may 
be a useful approach to treating depression or memory problems. 
The benefits you might get from being in this study: By receiving transdermal nicotine patches, you 
may experience an improvement in depression. In addition, you may experience an improvement in 
your memory or cognitive functioning as well. However, as people respond differently to treatments, 
personal benefit cannot be guaranteed. 
 
Procedures to be followed: 
Screening Visit (Total Time: 2 to 2 ½ hours): 
During the initial visit, you will meet with both the study coordinator and a study doctor. Your 
medical and psychiatric history will be carefully reviewed to make sure that you are eligible for the 
study. Additionally, we will assess your current depressive symptoms and your current and past 
medication use. You do not have to answer any questions you do not feel comfortable answering. 
The interview with the study coordinator will take 60 to 90 minutes. Your visit with the study doctor 
will take about an hour. 
For your safety, you must tell a study doctor about all the medications you are taking, including over-
the-counter drugs and herbals, before you start the study and before taking any new medications 
while you are in the study. If there is a problem where you cannot be in the study because of one of 
the medications you are taking, a study doctor will discuss that with you. 
As part of this visit, we will carefully evaluate you to determine if you have any metal in your body 
that could stop you from having the MRI. If you have had any surgeries that used implanted metal 
objects, we will need to request medical records to assure your safety before you could proceed to 
MRI. If you have had surgeries where records are not available, and you do not think those surgeries 
included metal, we may ask you to have an x-ray of that part of your body to make sure there is no 
Date of IRB Approval: 03/29/2022
D
Date of Expiration: 03/28/2023


VUMC Institutional Review Board
Informed Consent Document for Research
Study Title:
DepressedMoodImprovementThroughNicotine Dosing 2 (Depressed Mind2)
Version:
Date:
PI:
1.6
12/20/2021
Warren D. Taylor, MD
  
7
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metal in that site. If it is deemed necessary for you to have an x-ray, this will take place before your 
next visit. 
During this visit, you will also have an option to complete a “mock” MRI scan. Although no actual 
scan is taken, you will be able to experience the process (getting on and off the table, being inside 
the tube, and hearing the sounds the machine produces during a scan) to make sure you are 
comfortable having an MRI scan.  
At the end of the screening visit, you will be emailed a link to complete a series of questionnaires. 
These questionnaires will be completed in REDCap. REDCap is a secure web platform created for 
researchers were data for this study will be collected and stored. If you do not have an email address, 
or if you prefer to complete the questionnaires on paper, you will be given a take-home packet of 
questionnaires to complete. We will ask you to complete them as soon as possible and, if you are 
given paper questionnaires to complete, you will return them to us via the addressed, stamped 
envelope we will provide. If you have any questions, you can contact us at any time. 
Baseline Visit (Total Time: 4.5 hours)
After we are sure that you are safe to complete the MRI, this will be an in-person visit. You will meet 
with a study doctor who will again assess your depressive symptoms. During this visit, you will 
complete the neuropsychological (memory) testing and the MRI scan. This visit can last about 4 
hours. If needed, we can spread the procedures out over two days as long as both visits occur within 
7 days of each other. 
Neuropsychological (Memory) Testing: We will ask you to complete some tasks that measure your 
attention, memory, and cognitive abilities. Most of these tasks will be done on the computer, but 
some of these tasks will be done using pencil and paper. These tasks will take about two hours, and 
will be completed at the beginning and end of the 12-week study period.  
The memory tests are completed for research purposes only. They are not administered by a licensed 
clinical psychologist and thus, we are not able to provide a clinical interpretation of the results. 
MRI: You will complete three brain scans using Magnetic Resonance Imaging (MRI) – one before 
starting the patch, one after 6 weeks of being on the patch, and one after 12 weeks of being on the 
patch.  
Date of IRB Approval: 03/29/2022
D
Date of Expiration: 03/28/2023


VUMC Institutional Review Board
Informed Consent Document for Research
Study Title:
DepressedMoodImprovementThroughNicotine Dosing 2 (Depressed Mind2)
Version:
Date:
PI:
1.6
12/20/2021
Warren D. Taylor, MD
  
8
This box is for
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Each MRI scan will take about 60 minutes. An MRI scan is taken in a large machine that is shaped like 
a tunnel. This scan does not use x-rays. Instead, they use a strong magnet and radio waves, like those 
used in an AM/FM radio to make pictures of your body.  
During the scan, you will be asked to complete two tasks. One measures attention during the MRI. 
This task shows pictures of faces and words, and you will be asked to identify the face’s emotion.  
During the other task, you will see pictures of indoor and outdoor scenes as well as faces. Some of 
these images will be scrambled. You will be asked to detect certain target images during this task. 
You will be able to practice both tasks and ask questions about them before entering the MRI. 
You may not be able to have this scan if you have a device in your body, such as aneurysm clips in 
your brain, heart pacemakers or defibrillators, or cochlear (inner ear) implants. Also, you may not be 
able to have this scan if you have iron-based tattoos or pieces of metal (bullet, BB, shrapnel) close to 
or in an important organ (such as the eye). If we determine that you cannot safely complete the MRI, 
we will withdraw you from the study. 
Certain metal objects like watches, credit cards, hairpins, writing pens, etc. may be damaged by the 
machine or may be pulled away from the body when you are getting the scan. Also, metal can 
sometimes cause poor pictures if it is close to the part of the body being scanned. For these reasons, 
you will be asked to remove these objects before going into the room for the scan. 
You will hear “hammering,” clicking, or squealing noises during the scan. You will be given earplugs 
to reduce the noise. You will also be told how to alert the staff if you need them. 
During the scan, the MRI staff is able to hear and talk to you in between scans.  You will also be able 
to hear the staff in between scans.  They will be talking to you during your scan and may ask you to 
not move or other simple tasks.  You may be asked to lie very still throughout the scan. 
In this study, the MRI scan is for research only. However, if we see something that is not normal, you 
will be told and asked to consult your doctor. The scans will not be routinely examined by health 
professionals for potential abnormalities.  However, in the event an abnormality is detected by the 
investigators or the MRI technologist, the scans will be further examined by a radiologist and the 
investigator may encourage you to consult your physician or provider referrals for further 
evaluations.
Date of IRB Approval: 03/29/2022
D
Date of Expiration: 03/28/2023


VUMC Institutional Review Board
Informed Consent Document for Research
Study Title:
DepressedMoodImprovementThroughNicotine Dosing 2 (Depressed Mind2)
Version:
Date:
PI:
1.6
12/20/2021
Warren D. Taylor, MD
  
9
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This MRI scanner has been used with research animals.  For your safety, we clean the scanner with 
bleach before and after your scan as we do with scanners used only for patients. 
Study Nicotine Patches:  After the MRI is complete, you will receive transdermal nicotine patches. 
You will initially start with half of a 7m patch (3.5mg), and gradually move to a higher dosage. You 
will be instructed to start wearing a new study patch each day when you wake up, then take it off at 
night before bed. 
Follow-Up Visits: We will schedule in-person follow-up visits at weeks 3, 6, and 9. Visits at weeks 3 
and 9 will take about 2 hours. The week 6 visit will take about 4 hours as you will be having a second 
60 minute MRI. At each follow-up visit, will assess depressive symptoms and see if you are having any 
side effects. Vital signs such as blood pressure, weight, and pulse will be taken and recorded during 
each of these visits. You will also complete a variety of questionnaires to assess depression 
symptoms and any side effects. These assessments will be completed during each in-person follow-
up visit. At each follow-up visit you will have a blood draw to measure levels of nicotine in your blood 
(10 mL, which is about 2 tsp). At the week 6 visit, you will complete the questionnaires you 
completed after your screening visit again. These will either be completed on the computer or on 
paper depending on your preference. 
Visit
Approximate 
Time
Study Doctor 
Visit
Questionnaires
Blood 
Draw
MRI
Memory 
Testing
Screening
2-2.5 hours
X
X
Baseline
4.5 hours
X
X
X
x
Week 3
2 hours
X
X
X
Week 6
4 hours
X
X
X
X
Week 9
2 hours
X
X
X
Week 12
5.5 hours
X
X
x
x
X
Week 15
30 minutes
x
x
Nicotine Patches and Dosage: The nicotine patch dose will be increased 4 times during the study. 
During week 1, the dosage will be 3.5 mg. During weeks 2-3, the dose will be increased to 7mg. 
During weeks 4-6, the dose will be increased to 10.5mg. During weeks 7-9, the dose will be increased 
to 14mg. During weeks 10-12, the dose will be increased to 21 mg. At week 12, the dosage will be 
decreased from 21mg to 14mg to 7mg by week 15 before stopping.   You will wear each nicotine 
patch for approximately 16 hours during the day and remove it at night. 
Date of IRB Approval: 03/29/2022
D
Date of Expiration: 03/28/2023




VUMC Institutional Review Board
Informed Consent Document for Research
Study Title:
DepressedMoodImprovementThroughNicotine Dosing 2 (Depressed Mind2)
Version:
Date:
PI:
1.6
12/20/2021
Warren D. Taylor, MD
  
11
This box is for
IRB USE ONLY
Do not edit or delete
Week 3 – Clinic visit with blood draw
$50
Week 6 – Assessment visit with blood 
draw and MRI
$150
Week 9 – Clinic visit with blood draw
$50
Week 12 – Assessment visit with blood 
draw and MRI
$150
Week 15 – Final safety visit
$25
Total
Up to $600
We will ask for your Social Security number and address before you are compensated for taking part 
in this study.  
Costs to you if you take part in this study: 
There is no cost to you for taking part in this study. 
Payment in case you are injured because of this research study: 
If it is determined by Vanderbilt and the Investigator that an injury occurred as a direct result of the 
tests or treatments that are done for research, then you and/or your insurance will not have to pay 
for the cost of immediate medical care provided at Vanderbilt to treat the injury.  
There are no plans for Vanderbilt to pay for any injury caused by the usual care you would normally 
receive for treating your illness or the costs of any additional care. There are no plans for Vanderbilt 
to give you money for the injury.  
Who to call for any questions or in case you are injured: 
If you should have any questions about this research study or if you feel you have been hurt by being 
a part of this study, please feel free to contact the study coordinator, Sarah Siddiqi at
or the study doctor, Dr. Warren Taylor, at 
 If you cannot reach the research staff, 
please page the study doctor at 
Date of IRB Approval: 03/29/2022
D
Date of Expiration: 03/28/2023


VUMC Institutional Review Board
Informed Consent Document for Research
Study Title:
DepressedMoodImprovementThroughNicotine Dosing 2 (Depressed Mind2)
Version:
Date:
PI:
1.6
12/20/2021
Warren D. Taylor, MD
  
12
This box is for
IRB USE ONLY
Do not edit or delete
For additional information about giving consent or your rights as a person in this study, to discuss 
problems, concerns, and questions, or to offer input, please feel free to call the VUMC Institutional 
Review Board Office at (615) 322-2918 or toll free at (866) 224-8273.
Reasons why the study doctor may take you out of this study:  
Your study doctor may withdraw you from study participation if he or she determines that, based on 
the initial study interview, you are not eligible to continue the study. He or she may also withdraw 
you if you are having difficulty completing study procedures, if you need an immediate referral for 
clinical care, or if he/she decides that it is not in your best interest to continue in the study. If you are 
taken out of the study, you will be told the reason. 
What will happen if you decide to stop being in this study? 
If you decide to stop being part of the study, you should tell your study doctor. We may ask you to 
come in for a final study visit. Because you are receiving study medication, it is important to discuss a 
safe and effective plan for continuing, altering, or stopping the medication. If you withdraw or are 
withdrawn from the study early, you will be compensated for the parts of the study you have 
completed.  
All participation in the study is voluntary, and there is no penalty for refusing to participate or for 
early withdrawal. Deciding to not be part of the study will not change your regular medical care in 
any way. 
Clinical Trials Registry:  
A description of this clinical trial will be available on www.clinicaltrials.gov, as required by U.S. Law.  
This website will not include information that can identify you.  At most, the website will include a 
summary of the results.  You can search this Web site at any time. 
Confidentiality:  
All reasonable efforts will be made to keep the personal information in your research record private 
and confidential, but absolute confidentiality cannot be guaranteed. Your records will be kept in 
locked filing cabinets within locked rooms, and only the research team will have access. Your 
Date of IRB Approval: 03/29/2022
D
Date of Expiration: 03/28/2023


VUMC Institutional Review Board
Informed Consent Document for Research
Study Title:
DepressedMoodImprovementThroughNicotine Dosing 2 (Depressed Mind2)
Version:
Date:
PI:
1.6
12/20/2021
Warren D. Taylor, MD
  
13
This box is for
IRB USE ONLY
Do not edit or delete
information may be shared with institutional and/or governmental authorities, such as the 
Vanderbilt University Institutional Review Board, if you or someone else is in danger or if we are 
required to do so by law. 
All data are labeled and coded for protection and confidentiality. Data are kept on secure, password 
protected networked computers and in locked offices. Identification numbers are used instead of 
names for additional protection. Only research staff will have access to participant data. Source 
materials will be labeled and coded with an identification number that is not linked in any way to 
participant personal identifying information for purposes of additional protections and 
confidentiality. This number will be used to identify participants’ self-reported questionnaires, 
memory test results, and MRI/fMRI computerized data. 
A list linking names to identification numbers will be available only to authorized personnel and will 
be kept separately from research charts. Only research personnel authorized by the Principal 
Investigator will have access to these records.  The link between your identity and your identification 
number will not be shared with researchers in other institutions and will not leave VUMC. 
During the study, if we learn you are having thoughts about suicide or hurting yourself or others, the 
research staff will ask you more questions about your thoughts. Based on your response, the staff 
may provide you with help to get treatment. This may include: 

working with you to contact your doctor,  

contact a trusted family member, or a therapist to discuss your thoughts, 

or work with you on a plan that may include getting you to a hospital for safety. 
In these cases, the research team may share information about your condition with other health care 
providers. 
Vanderbilt may share your information, without identifiers, to others or use it for other research 
projects not listed in this form. Vanderbilt, Dr. Taylor and his staff will comply with any and all laws 
regarding the privacy of such information.  There are no plans to pay you for the use or transfer of 
this de-identified information. 
This study is supported by the National Institutes of Health (NIH) and is protected by a Certificate of 
Confidentiality.  This Certificate allows us, in some cases, to refuse to give out your information even 
if requested using legal means. 
Date of IRB Approval: 03/29/2022
D
Date of Expiration: 03/28/2023


VUMC Institutional Review Board
Informed Consent Document for Research
Study Title:
DepressedMoodImprovementThroughNicotine Dosing 2 (Depressed Mind2)
Version:
Date:
PI:
1.6
12/20/2021
Warren D. Taylor, MD
  
14
This box is for
IRB USE ONLY
Do not edit or delete
It does not protect information that we have to report by law, such as child abuse or some infectious 
diseases.  The Certificate does not prevent us from disclosing your information if we learn of possible 
harm to yourself or others, or if you need medical help.
Disclosures that you consent to in this document are not protected. This includes putting research 
data in the medical record orsharing research data for this study or future research. Disclosures that 
you make yourself are also not protected.
Blood samples will be leaving Vanderbilt University Medical Center for analyses of levels of nicotine 
and nicotine metabolites. They will be sent to Dr. Rachel Tyndale at the Center for Addiction and 
Mental Health at the University of Toronto.  These samples will be deidentified.  This means they will 
only include yourstudy-createdidentification number, initials (first, last), and date of sample 
collection.  
Privacy: 
Any samples and information about you may be made available to others to use for research.  To 
protect your privacy, we will not release your name.  You will not receive any benefit as a result of the 
tests done on your samples.  These tests may help us or other researchers learn more about the causes, 
risks, treatments, or how to prevent this and other health problems.  
Data from this study will be submitted to the National Institute of Mental Health Database (NDA) at 
the National Institutes of Health (NIH). NDA is a large database where deidentified study data from 
many National Institute of Mental Health (NIMH) studies is stored and managed. Deidentified study 
data means that all personal information about you (such as name, address, birthdate and phone 
number) is removed and replaced with a code number. Sharing your deidentified study data helps 
researchers learn new and important things about mental health and substance use more quickly than 
before. 
                                                                       
During and after the study, the study researchers will send deidentified study data about your health 
and behavior to the NDA. Other researchers across the world can then request your deidentified study 
data for other research. Every researcher (and institutions to which they belong) who requests your 
deidentified study data must promise to keep your data safe and promise not to try to learn your 
identity. Experts at the NIH who know how to keep your data safe will review each request carefully 
to reduce risks to your privacy. Sharing your study data does have some risks, although these risks are 
Date of IRB Approval: 03/29/2022
D
Date of Expiration: 03/28/2023


VUMC Institutional Review Board
Informed Consent Document for Research
Study Title:
DepressedMoodImprovementThroughNicotine Dosing 2 (Depressed Mind2)
Version:
Date:
PI:
1.6
12/20/2021
Warren D. Taylor, MD
  
15
This box is for
IRB USE ONLY
Do not edit or delete
rare. Your study data could be accidentally shared with an unauthorized person who may attempt to 
learn your identity. The study researchers will make every attempt to protect your identity. 
  
You may not benefit directly from allowing your study data to be shared with NDA. The study data 
provided to NDA may help researchers around the world learn more about mental health and 
substance use and how to help others who have problems with mental health and substance use. 
NIMH will also report to Congress and on its website about the different studies using NDA data. You 
will not be contacted directly about the study data you contributed to NDA.  
You may decide now or later that you do not want your study data to be added to the NDA. You can 
still participate in this research study even if you decide that you do not want your data to be added 
to the NDA. If you know now that you do not want your data in the NDA, please tell the study 
researcher before leaving the clinic today. If you decide any time after today that you do not want your 
data to be added to the NDA, call or email the study staff who conducted this study, and they will tell 
NDA to stop sharing your study data. Once your data is part of the NDA, the study researchers cannot 
take back the study data that was shared before they were notified that you changed your mind. If you 
would like more information about NDA, this is available on-line at http://nda.nih.gov. 
Your samples may be used to make new products or tests.  These may have value and may be 
developed and owned by the study staff, Vanderbilt University, Vanderbilt University Medical Center, 
and/or others.  If this happens, there are no plans to provide money to you. 
Study Results: 
You will not receive results from the study.  However, you will know how the nicotine patches affect 
you.  If it would help your medical care, we can provide copies of your MRI scan to your physician.  This 
would be a copy of the images, not a radiologist report. 
Authorization to Use/Disclose Protected Health Information 
What information is being collected, used, or shared?
To do this research, we will need to collect, use, and share your private health information.  By 
signing this document, you agree that your health care providers (including both Vanderbilt 
University Medical Center and others) may release your private health information to us, and that we 
may use any and all of your information that the study team believes it needs to conduct the 
study.  Your private information may include things learned from the procedures described in this 
Date of IRB Approval: 03/29/2022
D
Date of Expiration: 03/28/2023


VUMC Institutional Review Board
Informed Consent Document for Research
Study Title:
DepressedMoodImprovementThroughNicotine Dosing 2 (Depressed Mind2)
Version:
Date:
PI:
1.6
12/20/2021
Warren D. Taylor, MD
  
16
This box is for
IRB USE ONLY
Do not edit or delete
consent form, as well as information from your medical record (which may include information such 
as HIV status, drug, alcohol or STD treatment, genetic test results, or mental health treatment).    
  
Who will see, use or share the information?
The people who may request, receive or use your private health information include the researchers 
and their staff.  Additionally, we may share your information with other people at Vanderbilt, for 
example if needed for your clinical care or study oversight.  By signing this form, you give permission 
to the research team to share your information with others outside of Vanderbilt University Medical 
Center.  This may include the sponsor of the study and its agents or contractors, outside providers, 
study safety monitors, government agencies, other sites in the study, data managers and other 
agents and contractors used by the study team.   We try to make sure that everyone who sees your 
information keeps it confidential, but we cannot guarantee that your information will not be shared 
with others.  If your information is disclosed by your health care providers or the research team to 
others, federal and state confidentiality laws may no longer protect it.  
  
Do you have to sign this Authorization?
You do not have to sign this Authorization, but if you do not, you may not join the study. 
  
How long will your information be used or shared?
Your Authorization for the collection, use, and sharing of your information does not 
expire.  Additionally, you agree that your information may be used for similar or related future 
research studies. 
The study results will be kept in your research record for at least six years after the study is finished.  
At that time, the research data that has not been put in your medical record will be kept for an 
unknown length of time.  Any research data that has been put into your medical record will be kept 
for an unknown length of time. 
What if you change your mind?
Unless told otherwise, your consent to use or share your PHI does not expire. You may change your 
mind and cancel this Authorization at any time.  If you cancel, you must contact the Principal 
Investigator in writing to let them know.  The mailing address is 1601 23rd Avenue South, Nashville, 
TN 37212. At that time, we will stop getting any more data about you. Your cancellation will not affect 
information already collected in the study, or information that has already been shared with others 
before you cancelled your authorization. The health data we stored before you withdrew your consent 
may still be used for reporting and research quality. 
Date of IRB Approval: 03/29/2022
D
Date of Expiration: 03/28/2023


VUMC Institutional Review Board
Informed Consent Document for Research
Study Title:
DepressedMoodImprovementThroughNicotine Dosing 2 (Depressed Mind2)
Version:
Date:
PI:
1.6
12/20/2021
Warren D. Taylor, MD
  
17
This box is for
IRB USE ONLY
Do not edit or delete
If you decide not to take part in this research study, it will not affect your treatment, payment or 
enrollment in any health plans or affect your ability to get benefits. You will get a copy of this form 
after it is signed. 
STATEMENT BY PERSON AGREEING TO BE IN THIS STUDY 
I have read this consent form and the research study has been explained to me verbally.  All my 
questions have been answered, and I freely and voluntarily choose to take part in this study.    
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
Signature of patient/volunteer  
 
 
 
Consent obtained by:  
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name and Title 
Time: ______________  
 
Date of IRB Approval: 03/29/2022
D
Date of Expiration: 03/28/2023