Conditions: Major Depressive Disorder
Keywords: Geriatrics Depression Elderly Cognition Memory
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 15
Healthy volunteers: no

Brief summary:
Late-life depression is characterized by both affective (mood) symptoms and cognitive deficits. There is currently no intervention that may provide consistent benefits to both mood and cognitive performance. Agonist activity at the nicotinic acetylcholine receptors via transdermal nicotine patches may provide benefit to both mood and cognition, working through nicotine's effects on brain neural networks, specifically the cognitive control network and default mode network.

In this initial pilot project, the investigators will test this hypotheses in 15 nonsmoking depressed elders with subjective cognitive impairment. Following baseline neuroimaging and cognitive testing, participants will receive 12 weeks of open-label transdermal nicotine. Afterwards, participants will repeat neuroimaging and cognitive assessments.

Detailed description:
Late-life depression (LLD) is characterized both by affective symptoms and cognitive deficits. The co-occurrence of cognitive deficits in LLD is a clinically relevant phenotype characterized by significant disability and poor antidepressant response. Cognitive deficits can persist even with successful antidepressant treatment and increase the risk of depression relapse. Despite the clinical importance of cognitive deficits in LLD, there are no established treatments that specifically target cognition in this population. The lack of treatments that improve cognitive deficits in depression is a 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. In a previous trial examining Mild Cognitive Impairment, transdermal nicotine safely improved cognitive function on tests of attention, episodic memory, and processing speed. These same cognitive domains are impaired in LLD. The investigators hypothesize that these effects on mood and cognition are mediated through nicotine's effect to increase cognitive control network activity and reduce default mode network (DMN) activity. This pattern of network activity during tasks demanding external attention is associated with better task performance. Furthermore, as seen in smokers, nicotine's effect on these networks reduces depression's bias to negatively valenced stimuli and decreases rumination.

The central hypothesis is that in LLD, transdermal nicotine will safely improve depression by increasing activity in cognitive control regions and decreasing activity in DMN regions. This will result in a decreased attentional bias to and reactivity to negative stimuli. A secondary hypothesis is that transdermal nicotine will also improve subjective and objective cognitive performance through these same network effects.

Primary Aim 1: To determine whether administration of transdermal nicotine over 12 weeks improves clinical symptoms in patients with LLD with subjective cognitive impairment (SCI).

Hypothesis 1: Transdermal nicotine administration will result in reductions in depression severity measured by the Montgomery-Asberg Depression Rating Scale (MADRS; primary mood outcome). It will also result in improvement in broader assessments of depressive symptomatology, including anhedonia, apathy, fatigue, sleep, and rumination (secondary outcomes).

Hypothesis 2: Transdermal nicotine administration will result in improvements in attentional performance on the Conner's Continuous Performance Task (CPT; primary cognitive outcome). It will also result in improvement in subjective and objective cognitive performance on other tasks measuring attention, episodic memory, working memory, processing speed, and executive function (secondary outcomes).

Secondary Aim 2: To determine whether administration of transdermal nicotine over 12 weeks modulates canonical intrinsic functional network activity in LLD with SCI.

Hypothesis 3: On repeat administration of the Posner task of external attention, transdermal nicotine administration will result in increased activity within the cognitive control network and decreased activity within the default mode network.

Hypothesis 4: Transdermal nicotine administration will result in increased functional connectivity within the cognitive control network and decreased connectivity within the default mode network at rest.

Hypothesis 5: Changes in intrinsic network activity / connectivity with transdermal nicotine administration will be associated with changes in mood symptoms and subjective and objective cognitive performance.

Arms:
arm 1: Transdermal nicotine patch, administered on awakening and removed at bedtime (16h/d). Dosing 3.5mg patch/daily, titrated over study to maximum dose of 21mg patch/daily.

Interventions: intervention 1: Nicotine
Intervention descriptions: intervention 1: Open-label transdermal nicotine patch

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
Depressed Mood Improvement through Nicotine Dosing (Depressed MIND Study) 
Version 1.3, 04/13/2017 
 
VICTR: VR20324 
Clinicaltrials.gov Identifier: NCT02816138 
 
PI:  
Warren D. Taylor, MD, MHSc 
Department of Psychiatry 
Vanderbilt University Medical Center 
1601 23rd Avenue South 
Nashville TN 37212 
 
Co-Investigators 
 
Hakmook Kang, PhD 
Department of Biostatistics 
Vanderbilt University Medical Center 
 
Paul Newhouse, MD 
Department of Psychiatry 
Vanderbilt University Medical Center 
 
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 cholinergic system by nicotinic receptor stimulation will improve 
both mood and cognition in depressed elders.  Through its effects on cognitive control and default mode 
networks, we hypothesize that nicotine will benefit 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. 
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 previous trial examining Mild Cognitive Impairment, we demonstrated that transdermal nicotine 
safely improved cognitive function as measured by tests of attention, episodic memory, and processing speed. 
These data support the current NIH-funded multi-site MIND (Memory Improvement through Nicotine Dosing) 
study (Newhouse, PI).  These same cognitive domains are impaired in LLD and we anticipate individuals with 
LLD will experience similar benefit. Nicotinic acetylcholine receptor stimulation appears to increase or “tune” 
activity in attention and cognitive control networks while improving default mode network deactivation during 
tasks.  We hypothesize that these neural effects of nicotine will mediate nicotine’s cognitive benefit in LLD. 
 
2.0 RATIONALE AND SPECIFIC AIMS 
Our central hypothesis is that in LLD, transdermal nicotine will safely improve depression by increasing activity 
in cognitive control regions and decreasing activity in DMN regions.  This will result in a decreased attentional 
bias to and reactivity to negative stimuli.  Secondarily, we hypothesize that transdermal nicotine will also 
improve subjective and objective cognitive performance through these same network effects.  In this initial pilot 


 
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project, we will test our hypotheses in 15 nonsmoking depressed elders with subjective cognitive impairment.  
Following baseline neuroimaging and cognitive testing, participants will receive 12 weeks of open-label 
transdermal nicotine. Afterwards, participants will repeat neuroimaging and cognitive assessments. 
 
Primary Aim 1: To determine whether administration of transdermal nicotine over 12 weeks improves 
clinical symptoms in patients with LLD with SCI. 
Hypothesis 1: Transdermal nicotine administration will result in reductions in depression severity measured 
by the Montgomery-Asberg Depression Rating Scale (MADRS; primary outcome).  It will also result in 
improvement in broader assessments of depressive symptomatology, including anhedonia, apathy, fatigue, 
sleep, and rumination (secondary outcomes).  
Hypothesis 2: Transdermal nicotine administration will result in improvements in attentional performance on 
the Conner’s Continuous Performance Task (CPT; primary outcome).  It will also result in improvement in 
subjective and objective cognitive performance on other tasks measuring attention, episodic memory, 
working memory, processing speed, and executive function (secondary outcomes). 
 
Secondary Aim 2: To determine whether administration of transdermal nicotine over 12 weeks 
modulates canonical intrinsic functional network activity in LLD with SCI. 
Hypothesis 3: On repeat administration of the Posner task of external attention, transdermal nicotine 
administration will result in increased activity within the cognitive control network and decreased activity 
within the default mode network.   
Hypothesis 4: Transdermal nicotine administration will result in increased functional connectivity within the 
cognitive control network and decreased connectivity within the default mode network at rest. 
Hypothesis 5: Changes in intrinsic network activity / connectivity with transdermal nicotine administration will 
be associated with changes in mood symptoms and subjective and objective cognitive performance. 
 
3.0 ANIMAL STUDIES AND PREVIOUS HUMAN STUDIES 
 
3.1. Nicotine effects on depression: 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 (1).  Pharmacologically, cholinergic effects on mood must be mediated either 
by the nicotinic receptor (nAChR) family or the muscarinic receptor (mAChR) family, with muscarinic 
mechanisms being implicated in the studies of scopolamine by Furey and Drevets (2,3).  The cholinergic 
hypothesis is supported by observations that smoking rates are high in MDD (4,5) while depressed smokers 
have difficulty with smoking cessation and are at risk for depression relapse during smoking cessation (6-11). 
However, these data do not inform about specific effects of nAChR stimulation. 
Animal models support that modulation of nAChR activity is beneficial in depression (12,13).  Several 
studies in rat models of depression demonstrate that nicotine and nAChR agonists reduce depressive behavior 
(14-20). 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 (21-23) and may have long-term efficacy comparable to that of 
fluoxetine (24).  Although these studies examined small samples, nicotine exhibited antidepressant effects 
even at low doses in a placebo-controlled trial (22).  In contrast, results have not been encouraging for nAChR 
antagonists.  Despite early results suggesting the nAChR antagonist mecamylamine could have 
antidepressant augmentation effects in MDD (25), large-scale trials examining mecamylamine’s s-enantiomer 
in MDD did not find antidepressant efficacy (Targacept press release).  To our knowledge, there has not been 
a study examining either nAChR agonists or antagonists in late-life depression (LLD). 
 
3.1.a. Nicotine and affective cognition: Nicotine also modulates affective stimuli processing.  Transdermal 
nicotine in nondepressed smokers reduces the attentional bias to negatively valenced stimuli (26,27) and the 
distraction caused by negative stimuli (28).  Similar effects are seen in nondepressed nonsmokers (29), 
although another study of nondepressed nonsmokers found increased reactivity to negative stimuli (30). 
These findings have great significance in context of depression.  Dating back to Beck’s cognitive model 


 
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(31), depression is characterized by negative schema and dysfunctional attitudes that filter and bias affective 
information. Individuals with MDD exhibit greater and prolonged neural reactivity to negative stimuli (32-36), 
attend to negative stimuli longer (37) and show enhanced memory for negatively valenced information (38,39).  
A drug that reduces attention to negative stimuli may have great benefit for depressed individuals.  Moreover, it 
has the potential to improve cognitive performance, a significant problem for many individuals with LLD. 
 
3.2. Nicotine as a cognitive enhancer: The cholinergic system is the primary neurotransmitter system 
responsible for cognitive symptoms in dementia (40), with nicotinic receptors being particularly important (41).  
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)(42). 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 (43,44).  
 
3.2.a Cognitive Effects of Nicotinic Stimulation: 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 (45). In smokers, nicotine improves 
performance on attentionally and cognitively demanding vigilance tasks (46-
48) even in the absence of withdrawal effects (45,49). The nicotinic system 
appears to modulate controlled attentional processing when task conditions 
are difficult (50-52).  
Experimental pharmacological approaches are illuminating.  Newhouse 
et al (53,54) examined blockade of nAChRs with mecamylamine and found 
that nAChR blockade impaired cognitive performance in a way that 
modeled age- and disease-related learning impairments. The use of 
nicotinic agonists also reveals a role for the cholinergic system in attention 
and memory. Studies of nicotine in younger adults showed that the nicotinic 
system is involved in the partitioning of attentional resources, working 
memory, inhibition of irrelevant information, and improved performance on 
effortful tasks (55-57). Nicotine improves aspects of selective attention (58), 
spatial attention (59), and reaction time in an attention tasks (60).  
3.2.b. Clinical Studies of Nicotinic Stimulation for Cognition: Newhouse 
and colleagues first showed evidence of improved memory with intravenous 
nicotine injection in Alzheimer Disease (AD) subjects (61). Subcutaneous 
nicotine injection (62,63) and nicotine skin patch treatment also significantly 
improves cognitive function in AD patients (64,65). In AD, nicotine improves 
attention and lessen errors (66). Newhouse extended this work to show that 
the novel nicotinic agonist ABT-418 also has positive effects on learning 
and memory in AD (67). Most recently, Newhouse and colleagues (68) 
showed that chronic transdermal nicotine treatment improved 
attention and episodic memory in patients with MCI (see Fig 1 and 2). 
This supported the current NIA-funded multi-site MIND Study (Memory 
Improvement through Nicotine Dosing; Newhouse, PI).  
Crucial for use in the LLD population, nicotine also improves executive 
dysfunction.  Newhouse and colleagues demonstrated the positive effects 
of nicotinic stimulation on executive function measures in adolescents and 
adults with ADHD (69,70). Additional studies in ADHD also report that 
stimulating nAChRs can improve executive function (69-79). 
 
3.3. Effects of Nicotinic Stimulation on Brain Function: Nicotinic effects 
on cognitive processing and brain circuitry have been examined in 
neuroimaging studies (80,81). With normal aging, nicotinic activity 
Figure 1. Continuous 
Performance Task (CPT), change 
from baseline.  Nicotine improved 
performance over placebo (F1,57 = 
14.96, p = 0.003).  
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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increasingly engages frontally-mediated attentional processes to resolve uncertainties regarding sensory input 
and the contents of working memory (82). This may have the effect of increasing frontal activation, as 
observed when older adults exhibit task performance similar to younger adults during fMRI (83). This increase 
in frontal activity is necessary to maintain performance accuracy (84,85). 
Across multiple studies, nAChR agonists appear to enhance activity in cognitive control networks while 
suppressing activity in the default mode network (DMN) (86).  The DMN is a set of midline regions more active 
at rest that exhibit decreased activity during task performance (87).  During tasks in younger nonsmokers, 
nicotine improved accuracy and speeded performance (88) while increasing activation in frontal, cingulate, and 
parietal regions (89). In contrast, during attention and memory tasks, nicotine reduces activation in default 
mode regions (90,91).  
In summary, nicotinic receptors are widely distributed and intimately involved with several neurotransmitter 
systems important for cognitive function. These systems have modulatory effects on attentional and executive 
function and secondarily on learning and memory. Human studies support that nAChR stimulation is practical 
and potentially therapeutic, particularly in age-related disorders. Nicotine treatment may be more effective in 
older adults with less severe cognitive impairment and more nicotinic receptors, such as in MCI or LLD with 
cognitive complaints.  Thus stimulation of nAChRs may be a promising strategy to improve cognitive function in 
LLD. As the cognitive impairment of LLD also involves difficulty in effortful processing, age-related changes in 
nicotinic functioning may be contributing to this impairment (83). Although nicotine has beneficial effects on 
cognition in older adults with MCI and AD, no studies thus far have examined the effects of nicotinic stimulation 
on cognitive functioning in LLD.  Similarly, there are no reports of nicotine’s effect on neural circuits in LLD. 
 
3.4. Safety of transdermal nicotine patches in nonsmokers: Given the historical context of nicotine 
administration through tobacco, there are often concerns for effects on nicotine administration on health.  
However much of these data do not clearly delineate risks of nicotine from risks associated with smoking 
cigarettes or cigars, which contain many more components than just nicotine.  We address potential risks 
below.  Overall, data do not support that transdermal nicotine carries significant risks.  Further, transdermal 
nicotine was well tolerated in our previous MCI study where we had no severe adverse events related to drug 
treatment and found no withdrawal symptoms reported following drug treatment.   
 
4.0 INCLUSION/EXCLUSION CRITERIA 
Inclusion Criteria:  
1) Age > 60 years;  
2) DSM-IV-TR diagnosis of major depressive disorder, single or recurrent episode;  
3) Subjective cognitive decline, defined as endorsing 20% of items on the Cognitive Complaint Index (CCI);  
4) severity: MADRS (92) ≥ 15;  
5) cognition: MOCA t 24;  
6) fluent in English;  
7) intact hearing / vision allowing completion of study procedures;  
8) for individuals on antidepressants at study entry, they must be on a stable dose for at least 8 weeks. 
 
Exclusion Criteria:  
1) Other Axis I psychiatric disorders, except for anxiety symptoms occurring in a depressive episode;  
2) History of alcohol or drug dependence or abuse in the last 3 years;  
3) Tobacco or nicotine use in last year;  
4) History of a developmental disorder or IQ score < 70;  
5) Acute suicidality;  
6) Acute grief (<1 month);  
7) Current or past psychosis;  
8) Primary neurological disorder, including dementia, stroke, brain tumors, etc.  Coexisting mild cognitive 
impairment is allowable;  
9) Any MRI contraindication;  
10) Unstable medical illness;  
11) Allergy or hypersensitivity to nicotine patches;  


 
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12) Regular use of drugs with centrally acting cholinergic or anticholinergic properties in the last 4 weeks, 
including acetylcholinesterase inhibitors;  
13) Current or planned psychotherapy;  
14) Electroconvulsive therapy (ECT) or transcranial magnetic stimulation (TMS) in last two months. 
 
5.0 ENROLLMENT 
We will enroll patients from clinical referrals and response to advertisements.  In these cases, potential 
participants will call our study contact number.  We will describe the study to them, including a description of 
the 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.  Occasionally a clinician may identify a patient who may be 
eligible and request that we initiate contact.  We will do this, but the referring clinician must first broach the idea 
of research and secure the patient’s agreement to be contacted. 
 
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. 
 
Accounting for screen failures, we anticipate consenting up to 35 subjects total.  We will start study 
patches on only 15 participants. 
 
6.0 STUDY PROCEDURES 
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. CLINICAL ASSESSMENTS:  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.a.i. Diagnoses and Past History: Current and past psychiatric diagnoses will be assessed using the 
electronic version of the validated Mini-International Neuropsychiatric Interview Plus (MINI+) (93,94) & 
confirmed through a clinical interview which will assess age of initial onset.  The study physician will assess 
prior antidepressant exposure in the current episode using a modified Antidepressant Treatment History Form 
(ATHF) (95,96) updated to include current antidepressants and antipsychotics approved for MDD.  We will 
request medical records as needed. 
 
6.a.ii. Mood Symptom Assessments: Depression severity will be assessed by a study physician using the 
MADRS (92) as our primary mood outcome measure. This measure will be collected at each visit. Secondary: 
We will examine in-depth a number of depressive symptoms through discrete, validated questionnaires.  These 
will be obtained at study entry and exit and include: 
o Anhedonia: Snaith-Hamilton Pleasure Scale (SHAPS) 
o Anxiety: Penn State Worry Questionnaire (PSWQ) 
o Apathy: Apathy Evaluation Scale 
o Fatigue: Fatigue severity scale 
o Negative Affect: Type D Scale (DS-14) 
o Rumination: Ruminative Response Scale (97).   
o Sleep: Insomnia Severity Index 
o Stress: Perceived Stress Scale (PSS) (98).   
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 


 
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concerns for safety, subjects will be withdrawn from the study and treated per clinical care. 
 
6.a.iii. Medical Assessments: Medical history and comorbidity will be quantified using the Cumulative Illness 
Rating Scale (CIRS) (99), which covers all major systems and provides a composite medical morbidity score. 
Individuals with unstable or previously unrecognized medical disorders will be excluded.  Concomitant 
medications and vital signs (blood pressure, pulse, weight) will be reviewed at each visit.  We also will assess 
past tobacco use, including duration of use and age of cessation.  
 6.a.iv. Side Effects and Treatment Compliance: Side effects are assessed using the Frequency and 
Intensity of Side Effects Rating / Global Rating of Side Effect Burden (FISER/GRSEB) scales (100).  
Compliance is assessed with a patch count and the Medication Adherence Questionnaire (MAQ) (101). 
 
6.b. COGNITIVE ASSESSMENTS:  
6.b.i. Subjective Cognitive Functioning: For eligibility, participants must meet criteria for subjective cognitive 
decline, defined as endorsing at least 20% of all items on the Cognitive Complaints Index (CCI).  The CCI 
score is calculated from a broad battery integrating questions from multiple instruments, including: the Memory 
Functioning Questionnaire, Memory Self-Rating Questionnaire, the Neurobehavioral Function and Activities of 
Daily Living Rating Scale (ADL-self), the Informant Questionnaire on Cognitive Decline in the Elderly (IQCDE), 
30 cognitive items from the Geriatric Depression Scale (GDS), 12 items from a telephone-based screening for 
mild cognitive impairment (MCI), and 20 items from the Memory Assessment Questionnaire adapted in part 
from the Functional Activities Questionnaire. The CCI score is calculated as the percentage of all items 
endorsed.  We will use the Memory Functioning Questionnaire and the PROMIS Applied Cognition Abilities 
Short Form as measures of subjective cognitive function.  These will be obtained every 3 weeks at clinic visits. 
 
6.b.ii. Objective Cognitive Functioning / Neuropsychological 
Test Battery (Table 1):  We developed this battery to obtain a 
wide representation across cognitive domains.  We are 
particularly focused on domains of attention (known to be 
modified by nicotinic receptor stimulation), executive function 
(often impaired in LLD and associated with poor response to 
antidepressant medication), and memory.  We use a number of 
tests obtained with the Cogstate cognitive battery to assure 
consistency with the larger MIND study examining transdermal 
nicotine in MCI.  We augment this with tasks particularly relevant 
for depression.  The Conners Continuous Performance Task 
(CPT) will be the primary cognitive measure given its known 
sensitivity to nicotinic receptor stimulation. 
• 
Attention: The primary measure is the Conners Continuous 
Performance Test (CPT), measuring sustained and selective 
attention control (102). Secondary measures of attention and 
reaction time include the Choice Reaction Time (CRT) task 
that decomposes overall reaction time into recognition and 
motor components and also the Identification Test 
(Cogstate). 
• 
Executive Function: We will examine performance on the 
Trail-Making Test Part B (examining set-shifting) and 
performance on the color-word interference condition of the 
Stroop (examining response inhibition).  Poorer performance 
on these tasks is associated with LLD and poor 
antidepressant response.  We will augment these with the Groton Maze Learning Task (Cogstate) of 
spatial problem solving, a repeatable task sensitive to nicotinic receptor stimulation (103).  
• 
Episodic Memory: The Shopping List Task (Cogstate; Immediate verbal recall and delayed verbal 
recall).  This will be supplemented by the NYU Paragraph Recall test (Immediate and delayed).  Both 
tasks have alternate forms for repeated assessments.  Additionally, the one-card learning task 
TABLE 1. COGNITIVE TASK 
Task 
Time (m) 
Attention 
 
Continuous Performance Task 
12 
Choice Reaction Time 
4 
Identification Test (Cogstate) 
3 
Executive Function 
 
Trail Making Test (A & B) 
7 
Stroop Color-Word 
3 
Groton Maze (Cogstate) 
7 
Episodic Memory 
 
NYU Paragraph Recall 
5 
1-Card Learning (Cogstate) 
6 
Shopping List, imm (Cogstate) 
5 
Shopping List, delay (Cogstate) 
1 
Processing Speed 
 
Detection Test (Cogstate) 
3 
Trails A / Stroop Color naming 
- 
Working Memory 
 
One-back test (Cogstate) 
4 
Emotion Processing 
 
Emotional Dot Probe 
11 
Trait Adjectives Task 
5 
Trait Adjectives Recall 
2 
TOTAL TIME 
78 


 
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(Cogstate) will assess visual learning and memory. 
• 
Working Memory: 1-back test (Cogstate) wherein participants indicate if a card is identical to the one 
seen just before. 
• 
Processing Speed: Processing speed will be assessed using tasks discussed above, including the Stroop 
(color naming), Trail-Making Test Part A, and the Detection Test (Cogstate). 
• 
Emotional Processing: We will examine the effects of emotional stimuli on attentional performance using 
an emotional dot-probe test.  We will examine negativity bias using the Trait Adjectives Task, wherein 
participants must quickly indicate whether positive and negative adjectives apply to them.  This is followed 
15 minutes later with a test of emotional memory, wherein participants must recall adjectives they viewed.  
As early change in performance on the Trait Adjectives Task is related to subsequent antidepressant 
response, we will also repeat this task at week 3 (after 2 weeks at a transdermal nicotine dose of 7mg). 
 
6.c. STUDY DRUG ADMINISTRATION:  
6.c.i. Overview: After completing the cognitive battery and MRI, eligible participants will begin a 12-week 
open-label trial of transdermal nicotine patch. MRI and the cognitive battery will be repeated after this blinded 
phase.  During the study drug phase, participants will be seen in-clinic every 3 weeks (+/- 4 working days). 
6.c.ii. Transdermal Nicotine: Dosing and drug administration will be concordant with the MIND study.  
Participants will be instructed to wear the study patch during the day and remove it at bedtime (target goal of 
16 hours/day).  Following our titration schedule (Table 2), participants will receive active 24-hour patch starting 
at 3.5mg daily (one-half of a 7mg patch) for 1 week, then 7mg daily for 2 weeks, then 14mg daily for 3 weeks, 
then 21mg daily starting at week 7. Doses can be reduced to the previous level or patches divided to reduce 
the dose if needed for tolerability.  
 
6.c.iii. Duration & Dosing Rationale: We selected a 12-week duration as in MCI we detected differences in 
cognitive performance at 90-days (68).  Thus this will be a sufficient period to detect changes in cognitive 
performance.  Such a time period will also be sufficient to detect differences in mood as the majority of  
individuals remitting to current antidepressants do within 12 weeks (104). 
We selected the highest available daily dose of transdermal nicotine as we 
have no a priori knowledge of the optimally tolerated dose.  However, we do 
know the highest dose was well tolerated and effective in MCI.  Given the lack 
of knowledge of possible benefits at lower doses, we will advance to the highest 
dose, providing for dose reductions as needed for tolerability. 
6.c.iv. Compliance:  We will assess compliance using the Medication 
Adherence Questionnaire (MAQ) (101) and a patch count at each study visit. 
6.c.v. 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 2).  This 
time will 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. 
6.c.vi. Concomitant medications: To enhance generalizability, most nonpsychotropic medications will be 
permitted. However, an exclusion criterion specifies regular use in the last 4 weeks of agents that have 
substantial procholinergic or anticholinergic properties.  This includes acetylcholinesterase inhibitors 
(donepezil, rivastigmine, or galantamine) or other agents used for tremor, urinary control, or vertigo 
(amantadine, benzotropine, cyproheptadine, diphenhydramine, hydroxyzine, meclizine, prochlorperazine, or 
promethazine). 
 As we are examining the effects of transdermal nicotine as an augmentation agent, we will allow 
concomitant use of any psychotropic medication approved by the US FDA for treatment of depression, except 
for tricyclic antidepressants that are prohibited due to their anticholinergic properties.  Concomitant 
psychotherapy will not be allowed as it is an effective treatment that contributes to remission through different 
mechanisms.  We allow short-acting hypnotics (eszopicione, zolpidem, or zaleplon) for sleep and lorazepam 
up to 2mg daily for anxiety.  Hypnotics will be discouraged the day of cognitive testing. 
 
Table 2. Dosing 
Week 
Days 
Dose 
1 
0-7 
3.5mg 
2-3 
8-21 
7mg 
4-6 
22-42 
14mg 
7-12 
43-84 
21mg 
13-14 
85-98 
14mg 
15 
99-105 
7mg 


 
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8 
6.d. MRI PROCEDURES 
6.d.i. 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. 
 
6.d.ii.  Image Acquisition: We will image subjects on a 3T Philips Achieva system 
using a protocol that acquires multi-contrast data to allow automated tissue 
identification and BOLD data at rest and during the cognitive tasks (Table 3).  Cranial 
MRI will be performed over 1 hour.  Similar MRI durations have been well tolerated in 
our past studies of LLD.  This protocol will acquire proton density (PD), T1-weighted, T2-weighted, fluid-
attenuated inversion recovery (FLAIR), and a specific T2-weighted hippocampal acquisition for assessment of 
hippocampal subfield structure. 
Functional MRI is performed using echoplanar BOLD imaging. For whole brain fMRI scanning, a reference 
scan is obtained first. For the fMRI sequences, a single-shot, gradient-echo, echoplanar pulse sequence will be 
used (TR 2500 ms/TE 35 ms/flip angle 90 degrees/1 NSA).  Resolution is 3.5 mm x 3.5 mm x 3.5 mm. Thirty 
contiguous slices of 3.5mm thickness and no gap will be obtained in the axial oblique plane parallel to the AC-
PC line. Field map correction for magnetic inhomogeneities is accomplished by acquiring images with offset TE 
at the end of the functional series. During pre-processing, reconstruction options permit adjustment of the 
functional image series for bandpass asymmetry correction and unwarping to remove spatial artifact.  
6.d.iii. fMRI Tasks: We will assess intrinsic resting state functional connectivity (rsFC) during an 8-min period 
in which participants are instructed to rest without moving and focus on a fixation cross presented in the center 
of the screen.  This will be accompanied by a task examining nonemotional attentional performance (Posner 
task) and a task examining the effect of affective stimuli on executive function performance (emotional Stroop). 
A version of the Posner Task of attentional orienting (105) will assess the ability of subjects to disengage 
attention and shift to a new target. Subjects will be asked to press a button corresponding to the side of the 
screen on which a stimulus appears. Before the stimulus, a cue will indicate the side on which the stimulus will 
next appear. This cue will be valid (occur on the same side as the stimulus) 90% of the time and invalid 
(occurring on the opposite side of the stimulus) during the remainder.  This paradigm is sensitive to nicotinic 
stimulation effects (106-108).  
 
We will additionally use a modified emotional Stroop task (109).  The classic Stroop paradigm was 
modified and adapted to an emotional conflict task in which faces with fearful and happy expressions were 
presented with the words “happy” or “fear” written across them. We then asked subjects to identify the 
emotional expression of the faces while ignoring the words, which were 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 has been demonstrated to dissociate neural systems involved in 
resolving conflict between congruent versus incongruent emotional distractors (109,110).   
6.d.iv. Image Processing: Functional MRI Analysis: Preprocessing and analysis of the functional data will 
be performed with SPM8 (111). Volumes will be realigned to minimize head movement. Further data 
preprocessing includes a correction for slice x time errors and spatial (6 mm full-width half-maximum isotropic 
Gaussian kernel) as well as temporal (high pass filter: 1 cycles/run) smoothing to remove aliased signal 
correlated with background respiration and heart rate. Anatomical and functional images are co-registered and 
normalized to the MNI template.  
Statistical analysis will be performed by multiple linear regression of the signal time course at each 
Table 3. MRI Scans 
Scan  
Time 
T1 
4.5 
FLAIR 
7.5 
T2/HPC 
4 
Rest fMRI 
8 
Posner 
7 
Emotional 
Stroop 
13 
TOTAL 
44 m 


 
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voxel. The expected BOLD signal change for each different type will be modeled by a canonical hemodynamic 
response function. One mean image per individual for relevant contrasts will be created.  For both the Posner 
task and emotional Stroop task, we will examine relevant contrasts from each session.  For the Posner task, 
we will examine change in the contrast between responses to valid and invalid cues.  For the emotional Stroop 
task, we will examine a) change in response to congruent negative stimuli (fearful face with “fear” written 
across it) and b) change in the contrast between responses to congruent and incongruent stimuli, also 
examining for differences based on the emotional valence of the presented face.  These contrast images are 
then used for second level analyses examining within-subject changes in brain activity over the course of the 
12-week trial.  The critical significance level for treatment-level analyses will be based on clusters of activated 
voxels with the probability threshold set at pcorr < 0.05 and cluster threshold with false discovery rate less than 
0.05 corrected for multiple comparisons (with alpha simulation in REST toolbox for SPM). 
 
6.d.v. Resting State Functional Connectivity Analysis: Resting-state scans will undergo the following 
preprocessing steps: slice timing correction, motion correction, coregistration to structural images, spatial 
normalization to the MNI152 template, and 6mm spatial smoothing.  We will use the “scrubbing” procedure to 
guard against spurious correlations introduced by head motion.  Volumes within a run with frame-wise 
displacement greater than 0.5mm and BOLD intensity changes between frames greater than 0.5% will be 
tagged and excluded from the connectivity analysis by including the tagged scans as nuisance regressors in 
the connectivity analysis.  We will extract quality assurance metrics from scans, including signal-to-noise ratio, 
to include as covariates in analyses. We will us canonical network seed regions for connectivity analyses, with 
our analyses focused on the Default Mode Network (midline posterior cingulate gyrus seed) and the Cognitive 
Control Network (bilateral dorsolateral prefrontal seed). Connectivity between these seeds and whole-brain 
connectivity maps will be calculated using the CONN Functional Connectivity toolbox.  The mean BOLD signal 
time-series is extracted and the ROI-to-voxel correlation matrix is created. A 2nd level whole-brain seed-to 
voxel analyses of all participants’ baseline functional connectivity will be used to define a mask for the DMN 
and CCN networks.  Repeating the process before and after the 12-week trial, we will be able to assess 
within-participant changes in each functional network map.  We can then examine how this change is 
related to change in mood and cognitive performance. 
 
6.e. MEASUREMENT OF NICOTINE METABOLITES: At the time of the 12-week MRI, participants will have 
10ml of blood drawn for measurement of nicotine metabolites, including nicotine, cotinine, and 3HC/COT (a 
measure of nicotine clearance).  This will be done at least 4 hours after the patch is applied that morning.  
Samples will be frozen and stored in a -70 freezer.  After all sample collections are complete, they will be sent 
for analyses to our collaborator, Dr. Rachel Tyndale at the Center for Addiction and Mental Health at the 
University of Toronto. 
 
6.f. OPTIONAL STUDY PROCEDURE:  Electroencephalogram /Event Related Potential Test (EEG/ERP): 
Participants will be asked to complete an optional EEG session at two points during the testing period. 
Previous research found that patients with LLD display slower sensory processing as shown in longer P300 
latencies to auditory stimuli, as well as diminished inhibitory processing compared to healthy controls 
(112,113). LLD patients have also been observed to exhibit greater slow wave power at rest compared to age-
matched controls (112). This EEG session will examine whether nicotine intervention alters the sensory and 
inhibitory processing of patients with LLD.  This will be examined in parallel with assessments of mood, 
cognition, and repeated MRI. 
 
Methodology: Each participant will be tested individually in a quiet private room at the baseline visit and then 
again at week 12. Visual and auditory EEG signals will be recorded using a 128-channel Geodesic sensor net 
(EGI, Inc., Eugene, OR) (114-116). The net is made of Ag/AgCl-coated carbon electrodes embedded in soft 
electrolytic sponges and arranged into a net using elastomer strings. Each electrode is connected via carbon 
wiring to a high-impedance (1MOhm) low-noise amplifier that provides analogue-to-digital (A/D) conversion of 
the EEG signals. Prior to application, the net is soaked in warm saline (KCl) solution. The electrode 
impedances will be kept at or below 40 kOhms. The use of high-impedance amplifiers minimizes any decrease 
in signal-to-noise ratio and allows collection of high quality data without having to abrade the scalp, thus 


 
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minimizing any discomfort and reducing infection risks. Tests of this system reported no significant signal loss 
over a range of EEG frequencies. Another advantage of this system is fast electrode application and 
impedance adjustments (< 10 minutes).  The EEG signals will be sampled every 4ms with filters set at 0.1 Hz - 
100 Hz. During data collection, all electrodes will be referred to vertex (Cz). EEG will be continuously 
monitored and during periods of motor activity or inattention, stimulus presentation will be suspended until 
behavior quiets and the researchers will use redirect the child to the task. The entire recording session will last 
approximately 30 minutes.  
• 
Resting state EEG session: 
The participants will complete a short resting state EEG session, consisting of an eyes-open block and an eyes 
closed block. During the eyes open block, the participants will be asked to fixate on a cross in the middle of 
monitor. Each block will last for 3 minutes for a total task time of 6 minutes. 
 
• 
Auditory oddball task: 
The “oddball”, or P300 response, will assess attention and memory in auditory modalities. A pair of two pure 
tones (single formant) at 1000 and 1500 Hz will serve as stimuli. Tones will be equated in duration (300 ms) 
and rise/decay times. One tone (standard) will occur 70% of the time while the other (target) will be presented 
in 30% of the trials. Tone frequency (i.e., high vs. low) assignment to conditions will be counterbalanced across 
participants. Tones will be presented at 75 dB SPL (measured at the ear) through a speaker positioned 1 
meter in front of the participant.  
Procedure: 150 trials will be presented with the inter-stimulus interval varying randomly between 1000-1300 
ms to prevent habituation to stimulus onset. Each participant will be asked to press a button using their 
preferred hand every time they detect the target stimulus. On average, the auditory tasks will last ~8 minutes. 
Variables of interest: Analyses will focus on the parietal (P300) and frontal (P3a) responses to standard and 
target stimuli.  
• 
Cued Go/Nogo Task: 
A cued go/nogo task will be used to assess response preparation and inhibition. During this task participants 
will be presented with a cue which will instruct them to prepare a response to with either their left or right 
hands. After an interval of 1500ms either a valid target (66% of trials) or a nogo target (33% of trials) will be 
presented. Participants will have to either respond with the indicated hand, or withhold their response. The task 
will consist of 180 trials with a 1000-2000ms inter-stimulus interval to prevent habituation. The task will last ~15 
minutes. There will be a short practice block to familiarize participants with the task before recording 
commences. 
 
7.0 LONG-TERM FOLLOWUP (SUB-STUDY) 
Individuals who complete the trial will be asked to enter long-term follow-up over the next year.  This will 
include only minimal-risk interviews and questionnaires occurring 6-months and 12-months after study exit.  
This will not affect clinical treatment decisions over this period.  The goal of this sub-study is to gather data on 
long-term rates of depression relapse and subjective memory performance.  For individuals who elect to 
continue commercially available transdermal nicotine patches, it will also obtain data on long-term tolerability. 
 
7.1. Consent: We will discuss this optional sub-study at their final study visit.  Those who are agreeable will be 
asked to sign a separate sub-study consent form. 
7.2.  Procedures:  This will only involve a telephone interview and completion of study questionnaires at 6- 
and 12-months after study completion.  The telephone interview will include assessments of current medication 
use with the ATHF, transdermal nicotine use and tolerability, any recent smoking, and depression severity 
using the MADRS. The telephone interview will be followed by a completion of study questionnaires assessing 
depressive symptoms – these are listed in Section 7.1.d above. 
7.3. Safety:   For any participants who are depressed at either assessment, we will assure that they are 
currently receiving treatment for their depression.  If so, we will encourage them to let their physician know 
about their symptoms.  If they are not, we will provide referral recommendations, including a referral to the 
Vanderbilt Psychiatry Outpatient Clinics.  As we make these referrals at the end of the main study, we do not 
anticipate that many individuals will be without treatment.   
 
We will also assess for thoughts of death or suicide as part of measuring depression severity with the 


 
)GDID8DA/:GH>DC


)GDID8DA6I:
11
MADRS.  A study physician will then assess the safety of anyone endorsing these thoughts and act as is 
clinically indicated.  This may include feedback to the patient’s treating psychiatrist or referrals to intensive 
outpatient or inpatient hospitalization.  
 
 
8.0  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 (117). 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.   
 
In our published MCI trial (68), 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 (118).  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 


 
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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 (119).  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 (119).  
 
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 (120).  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) (121). 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 (122). 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 (123).  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 
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). 
 
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 (124-127). 
However, a large meta-analysis of 35 smoking cessation 
trials did not find any increased incidence of stroke in 
nicotine replacement therapy users (117).  
 
Conclusion regarding cardio- and cerebrovascular safety: As 
the subjects to be enrolled in this study will be nonsmokers 
Systolic Blood Pressure
-15
-10
-5
0
5
10
15
0
50
100
150
200
Day
Change from baseline 
(mm Hg)
Nicotine
Placebo


 
Protocol Version #: 1.3 
 
 
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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 (128) although some studies are contradictory (129). Some investigations have 
suggested that changes in insulin sensitivity may be restricted to smokers who are also diabetic (130). 
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 (131) while 
another study did not (132). 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 (133).  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 (133). 
 
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 (134-136) .  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 (137). 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 
(137-141) 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 
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 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: 
 
Weight
-4
-3
-2
-1
0
1
2
0
50
100
150
200
Day
Change from baseline: 
kg
Nicotine
Placebo


 
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1) Nicotine replacement therapies have an extremely low abuse liability (142) . Nicotine patches have some 
unpleasant side effects and therefore are unlikely to be reinforcing.  
 
2) Studies (143,144) show that experimental administration of tobacco does not induce ex-smokers to relapse 
into smoking.  In another study (142), 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 (145). With respect to nicotine, researchers of the 
NIDA Addiction Research Center (146,147), as well as others in the field (148-151), 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 (121). 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 (152).  
 
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 (3/3/2017 update): To date, the majority of adverse events are expected 
and concordant with what is described above.  However, 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 and 
occurred again on rechallenge.  
 
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 
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. 
 
9.0 RISKS – OTHER THAN STUDY DRUG 
9.1 Interview, emergencies, and possible suicidal ideation.  Subjects may experience discomfort during the 
clinical interview and evaluations when discussing symptoms, life events, and social support.  The Project 
Coordinator is experienced and skilled in interviewing depressed subjects.  Should the subject wish to stop or 
take a break, the coordinator will allow it.  Dr. Taylor or Dr. Newhouse will be available as a backup.  In 
addition, should the subject express suicidal ideation at any time during the interview, Dr. Taylor or Dr. 
Newhouse 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 mental health caregiver, referring for urgent evaluation and treatment, or emergent evaluation 
and hospitalization.  Similar practices will be used for other emergencies, including but not limited to psychosis, 


 
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homicidal or violent thoughts, or an acute change in a subject’s physical status. 
 
9.2 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. 
 
9.3 Incidental Findings: Magnetic Resonance Imaging: Another risk is the occurrence of incidental findings on 
MRI.  All scans are reviewed at time of acquisition and concerning findings are discussed with an attending 
neuroradiologist.  Should any concerning findings be seen, Dr. Taylor or Dr. Newhouse will convey these 
findings to the subject along with recommendations for further evaluation, and facilitate referrals for such 
evaluation and treatment. 
 
9.4 Venipuncture: Risks of blood draw include pain from the needle, bruising or infection at the site of 
venipuncture, or fainting as a response to blood draw. 
 
9.5 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.  Participants will undergo a blinded three-week 
taper of transdermal nicotine.  They will then return for a final safety visit.  If they feel they have benefited from 
study drug, they will be able to continue it as transdermal nicotine patches are available over-the-counter.  In 
these cases, participants will not be required to progress through the three-week taper.  However, we will 
extensively re-discuss potential risks and lack of knowledge of risks of long-term use. 
 
9.6 Breach of confidentiality:  There is the potential risk of breach of confidentiality of clinical, genetic, and 
laboratory information.  Both Dr. Taylor and Dr. Newhouse have extensive experience as clinical investigators 
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. 
 
10.0 Reporting of Adverse Events or Unanticipated Problems involving Risk to Participants or Others 
We define an adverse event 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 serious adverse 
event 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 require urgent medical intervention. 
 
We will carefully monitor adverse events throughout the study.  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.  All adverse events will be reviewed by Dr. Taylor 
at least 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.  All serious adverse events will be reported to 
the VUMC IRB within 7 working days.  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. Dr. Taylor will have responsibility for this reporting requirement.   
 
11.0 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: 


 
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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 
 
 
12.0 STATISTICAL CONSIDERATIONS 
12.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.  
 
12.b. Statistical Analyses: As these data will be used to support future grant applications, these data will 
primarily be used to estimate variance in response and effect sizes for future power calculations.  For primary 
analyses (Primary Aim, Hypothesis 1) we will examine change in MADRS over the course of study participation 
using a last-observation carried forward (LOCF) paired t-test approach.  In secondary analyses we will use a 
similar approach to examine change in scores on other mood symptom questionnaires (Sect. 6.a.ii.).  We will 
also report remission rates, defined as achieving a final MADRS <= 8.  A similar approach will be used for 
analyses of cognitive performance (Primary Aim, Hypothesis 2) examining change in CPT performance, 
specifically change in hit reaction time, as the primary cognitive outcome.  In secondary analyses we will also 
examine the other cognitive measures.  Jointly, these data and analyses will inform our scientific model and 
how to focus our hypotheses in subsequent larger-scale proposals. 
Our Secondary Aim focuses on functional MRI data.  Analytic plans for Hypotheses 3 and 4 are discussed 
above, in Sections 6.d.iii. and 6.d.iv.  For Hypothesis 5, we will conduct exploratory analyses examining 
whether change in fMRI signal (during tasks or during rest) over the study drug period is associated with 
change in mood or cognitive test measures.  After creating the contrast from the pre- and post-study drug 
scans, we will extract the change in BOLD signal (during tasks) and connectivity (at rest) in the identified 
regions of difference.  We will then examine correlations between these MRI measures and clinical measures. 
 
12.c. Power: We calculated power for our Primary Aim / Outcome of change in depression severity with the 
MADRS.  Using a SD of 7 based from a previous 12-week open-label antidepressant study, at N=15 and 
alpha=0.05, we have 79% power to detect a 5-point change in MADRS (compared with a change of 0).  This 
change is a clinically meaningful reduction in depression severity, particularly in individuals who have not 
responded to a current antidepressant. 
 
13.0 PRIVACY/CONFIDENTIALITY ISSUES 
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.  Additionally, the Vanderbilt IRB 
must approve all procedures and safety precautions before the study can begin.  All non-electronic data 
(clinical evaluations, paper assessments) will be stored securely in 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. 
 
Samples and specific data will be leaving Vanderbilt University Medical Center.  First, we will send blood for 
analysis of nicotine metabolites to Dr. Rachel Tyndale at the Center for Addiction and Mental Health at the 


 
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University of Toronto.  These samples will be deidentified and include only the subject’s study ID number.  
Second, raw results from neuropsychological testing done with the Cogstate battery will be sent to Cogstate 
and results will be returned to the study.  This allows calculation of test results and normalization by age and 
sex.  These data will also be deidentified, including only the subject’s study ID, date of administration, date of 
birth, and sex. 
 
14.0 FOLLOW-UP AND RECORD RETENTION 
 
We anticipate participant recruitment and contact with subjects will be completed within 12-18 months.  Study 
records will be maintained for at least six years after 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. 
 
 
REFERENCES 
1.  Janowsky DS, el-Yousef MK, Davis JM, Sekerke HJ. A cholinergic-adrenergic hypothesis of mania and 
depression. Lancet. 1972;2(7778):632-5. 
2.  Drevets WC, Furey ML. Replication of scopolamine's antidepressant efficacy in major depressive disorder: a 
randomized, placebo-controlled clinical trial. Biol Psychiatry. 2010;67(5):432-8. PMCID: PMC3264395. 
3.  Furey ML, Drevets WC. Antidepressant efficacy of the antimuscarinic drug scopolamine: a randomized, 
placebo-controlled clinical trial. Arch Gen Psychiatry. 2006;63(10):1121-9. PMCID: PMC3250308. 
4.  Kalman D, Morissette SB, George TP. Co-morbidity of smoking in patients with psychiatric and substance 
use disorders. The American journal on addictions / American Academy of Psychiatrists in Alcoholism and 
Addictions. 2005;14(2):106-23. PMCID: PMC1199553. 
5.  Lasser K, Boyd JW, Woolhandler S, Himmelstein DU, McCormick D, Bor DH. Smoking and mental illness: A 
population-based prevalence study. JAMA. 2000;284(20):2606-10. 
6.  Dani JA, Harris RA. Nicotine addiction and comorbidity with alcohol abuse and mental illness. Nat Neurosci. 
2005;8(11):1465-70. 
7.  Hughes JR. Depression during tobacco abstinence. Nicotine & tobacco research : official journal of the 
Society for Research on Nicotine and Tobacco. 2007;9(4):443-6. 
8.  Gilbert DG, Crauthers DM, Mooney DK, McClernon FJ, Jensen RA. Effects of monetary contingencies on 
smoking relapse: influences of trait depression, personality, and habitual nicotine intake. Experimental and 
clinical psychopharmacology. 1999;7(2):174-81. 
9.  Gilbert DG, McClernon FJ, Rabinovich NE, Plath LC, Masson CL, Anderson AE, Sly KF. Mood disturbance fails 
to resolve across 31 days of cigarette abstinence in women. J Consult Clin Psychol. 2002;70(1):142-52. 
10.  Glassman AH, Covey LS, Stetner F, Rivelli S. Smoking cessation and the course of major depression: a 
follow-up study. Lancet. 2001;357(9272):1929-32. 
11.  Covey LS, Glassman AH, Stetner F. Major depression following smoking cessation. Am J Psychiatry. 
1997;154(2):263-5. 
12.  Philip NS, Carpenter LL, Tyrka AR, Price LH. Nicotinic acetylcholine receptors and depression: a review of 
the preclinical and clinical literature. Psychopharmacology (Berl). 2010;212(1):1-12. 
13.  Mineur YS, Picciotto MR. Nicotine receptors and depression: revisiting and revising the cholinergic 
hypothesis. Trends Pharmacol Sci. 2010;31(12):580-6. PMCID: PMC2991594. 
14.  Tizabi Y, Getachew B, Rezvani AH, Hauser SR, Overstreet DH. Antidepressant-like effects of nicotine and 
reduced nicotinic receptor binding in the Fawn-Hooded rat, an animal model of co-morbid depression and 
alcoholism. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33(3):398-402. PMCID: PMC2871164. 
15.  Djuric VJ, Dunn E, Overstreet DH, Dragomir A, Steiner M. Antidepressant effect of ingested nicotine in 
female rats of Flinders resistant and sensitive lines. Physiol Behav. 1999;67(4):533-7. 
16.  Andreasen JT, Henningsen K, Bate S, Christiansen S, Wiborg O. Nicotine reverses anhedonic-like response 
and cognitive impairment in the rat chronic mild stress model of depression: comparison with sertraline. J 
Psychopharmacol. 2011;25(8):1134-41. 


 
Protocol Version #: 1.3 
 
 
Protocol Date:04/13/2017 
18
17.  Popik P, Kozela E, Krawczyk M. Nicotine and nicotinic receptor antagonists potentiate the antidepressant-
like effects of imipramine and citalopram. Br J Pharmacol. 2003;139(6):1196-202. PMCID: PMC1573951. 
18.  Andreasen JT, Redrobe JP. Nicotine, but not mecamylamine, enhances antidepressant-like effects of 
citalopram and reboxetine in the mouse forced swim and tail suspension tests. Behav Brain Res. 
2009;197(1):150-6. 
19.  Semba J, Mataki C, Yamada S, Nankai M, Toru M. Antidepressantlike effects of chronic nicotine on learned 
helplessness paradigm in rats. Biol Psychiatry. 1998;43(5):389-91. 
20.  Tizabi Y, Overstreet DH, Rezvani AH, Louis VA, Clark E, Jr., Janowsky DS, Kling MA. Antidepressant effects 
of nicotine in an animal model of depression. Psychopharmacology (Berl). 1999;142(2):193-9. 
21.  Salin-Pascual RJ, Drucker-Colin R. A novel effect of nicotine on mood and sleep in major depression. 
Neuroreport. 1998;9(1):57-60. 
22.  McClernon FJ, Hiott FB, Westman EC, Rose JE, Levin ED. Transdermal nicotine attenuates depression 
symptoms in nonsmokers: a double-blind, placebo-controlled trial. Psychopharmacology (Berl). 
2006;189(1):125-33. 
23.  Salin-Pascual RJ, Rosas M, Jimenez-Genchi A, Rivera-Meza BL, Delgado-Parra V. Antidepressant effect of 
transdermal nicotine patches in nonsmoking patients with major depression. J Clin Psychiatry. 1996;57(9):387-
9. 
24.  Haro R, Drucker-Colin R. Effects of long-term administration of nicotine and fluoxetine on sleep in 
depressed patients. Arch Med Res. 2004;35(6):499-506. 
25.  George TP, Sacco KA, Vessicchio JC, Weinberger AH, Shytle RD. Nicotinic antagonist augmentation of 
selective serotonin reuptake inhibitor-refractory major depressive disorder: a preliminary study. J Clin 
Psychopharmacol. 2008;28(3):340-4. 
26.  Asgaard GL, Gilbert DG, Malpass D, Sugai C, Dillon A. Nicotine primes attention to competing affective 
stimuli in the context of salient alternatives. Experimental and clinical psychopharmacology. 2010;18(1):51-60. 
PMCID: PMC2846408. 
27.  Rzetelny A, Gilbert DG, Hammersley J, Radtke R, Rabinovich NE, Small SL. Nicotine decreases attentional 
bias to negative-affect-related Stroop words among smokers. Nicotine & tobacco research : official journal of 
the Society for Research on Nicotine and Tobacco. 2008;10(6):1029-36. 
28.  Gilbert DG, Sugai C, Zuo Y, Rabinovich NE, McClernon FJ, Froeliger B. Brain indices of nicotine's effects on 
attentional bias to smoking and emotional pictures and to task-relevant targets. Nicotine & tobacco research : 
official journal of the Society for Research on Nicotine and Tobacco. 2007;9(3):351-63. 
29.  Wachter NJ, Gilbert DG. Nicotine differentially modulates antisaccade eye-gaze away from emotional 
stimuli in nonsmokers stratified by pre-task baseline performance. Psychopharmacology (Berl). 
2013;225(3):561-8. PMCID: PMC3547148. 
30.  Kobiella A, Ulshofer DE, Vollmert C, Vollstadt-Klein S, Buhler M, Esslinger C, Smolka MN. Nicotine 
increases neural response to unpleasant stimuli and anxiety in non-smokers. Addict Biol. 2011;16(2):285-95. 
31.  Beck AT. Cognitive models of depression. J Cogn Psychother. 1987;1:5-37. 
32.  Dannlowski U, Ohrmann P, Bauer J, Kugel H, Arolt V, Heindel W, Kersting A, Baune BT, Suslow T. 
Amygdala reactivity to masked negative faces is associated with automatic judgmental bias in major 
depression: a 3 T fMRI study. J Psychiatr Neurosci. 2007;32(6):423-9. PMCID: PMC2077348. 
33.  Suslow T, Konrad C, Kugel H, Rumstadt D, Zwitserlood P, Schoning S, Ohrmann P, Bauer J, Pyka M, 
Kersting A, Arolt V, Heindel W, Dannlowski U. Automatic mood-congruent amygdala responses to masked 
facial expressions in major depression. Biol Psychiatry. 2010;67(2):155-60. 
34.  Siegle GJ, Thompson W, Carter CS, Steinhauer SR, Thase ME. Increased amygdala and decreased 
dorsolateral prefrontal BOLD responses in unipolar depression: related and independent features. Biol 
Psychiatry. 2007;61(2):198-209. 
35.  Siegle GJ, Steinhauer SR, Thase ME, Stenger VA, Carter CS. Can't shake that feeling: event-related  fMRI 
assessment of sustained amygdala activity in response to emotional information in depressed individuals. Biol 
Psychiatry. 2002;51:693-707. 


 
Protocol Version #: 1.3 
 
 
Protocol Date:04/13/2017 
19
36.  Sheline YI, Barch DM, Donnelly JM, Ollinger JM, Snyder AZ, Mintun MA. Increased amygdala response to 
masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study. Biol 
Psychiatry. 2001;50:651-8. 
37.  Eizenman M, Yu LH, Grupp L, Eizenman E, Ellenbogen M, Gemar M, Levitan RD. A naturalistic visual 
scanning approach to assess selective attention in major depressive disorder. Psychiatry Res. 
2003;118(2):117-28. 
38.  Gilboa-Schechtman E, Erhard-Weiss D, Jeczemien P. Interpersonal deficits meet cognitive biases: memory 
for facial expressions in depressed and anxious men and women. Psychiatry Res. 2002;113(3):279-93. 
39.  Ridout N, Noreen A, Johal J. Memory for emotional faces in naturally occurring dysphoria and induced 
sadness. Behav Res Ther. 2009;47(10):851-60. 
40.  Bartus RT, Dean III RL, Beer B, Lippa AS. The cholinergic hypothesis of geriatric memory dysfunction. 
Science. 1982;217:408-17. 
41.  Rusted JM, Newhouse PA, Levin ED. Nicotinic treatment for degenerative neuropsychiatric disorders such 
as Alzheimer's disease and Parkinson's disease. Behav Brain Res. 2000;113(1-2):121-9. 
42.  Levin ED. Nicotinic receptor subtypes and cognitive function. J Neurobiol. 2002;53(4):633-40. 
43.  McGehee DS, Heath MJ, Gelber S, Devay P, Role LW. Nicotine enhancement of fast excitatory synaptic 
transmission in CNS by presynaptic receptors. Science. 1995;269(5231):1692-6. 
44.  Wonnacott S, Soliakov L, Wilkie G, Redfern P, Marshall D. Presynaptic nicotinic acetylcholine receptors in 
the brain. Drug Develop Res. 1996;38(3-4):149-59. 
45.  Heishman SJ, Kleykamp BA, Singleton EG. Meta-analysis of the acute effects of nicotine and smoking on 
human performance. Psychopharmacology (Berl). 2010;210(4):453-69. PMCID: PMC3151730. 
46.  Provost SC, Woodward R. Effects of nicotine gum on repeated administration of the Stroop test. 
Psychopharmacology (Berl). 1991;104(4):536-40. 
47.  Rusted J, Graupner L, O'Connell N, Nicholls C. Does nicotine improve cognitive function? 
Psychopharmacology (Berl). 1994;115(4):547-9. 
48.  Wesnes K, Warburton DM. Effects of scopolamine and nicotine on human rapid information processing 
performance. Psychopharmacology (Berl). 1984;82(3):147-50. 
49.  Warburton DM, Arnall C. Improvements in performance without nicotine withdrawal. Psychopharmacology 
(Berl). 1994;115(4):539-42. 
50.  Warburton DM, Rusted JM. Cholinergic control of cognitive resources. Neuropsychobiology. 1993;28(1-
2):43-6. 
51.  Newhouse PA, Potter A, Kelton M, Corwin J. Nicotinic treatment of Alzheimer's disease. Biol Psychiatry. 
2001;49(3):268-78. 
52.  Sarter M, Hasselmo ME, Bruno JP, Givens B. Unraveling the attentional functions of cortical cholinergic 
inputs: interactions between signal-driven and cognitive modulation of signal detection. Brain Res Brain Res 
Rev. 2005;48(1):98-111. 
53.  Newhouse PA, Potter A, Corwin J, Lenox R. Acute nicotinic blockade produces cognitive impairment in 
normal humans. Psychopharmacology (Berl). 1992;108(4):480-4. 
54.  Newhouse PA, Potter A, Corwin J, Lenox R. Age-related effects of the nicotinic antagonist mecamylamine 
on cognition and behavior. Neuropsychopharmacology. 1994;10(2):93-107. 
55.  Newhouse PA, Potter A, Kelton M, Corwin J. Nicotinic treatment of Alzheimer's disease. Biological 
Psychiatry. 2001;49(3):269-78. 
56.  Warburton DM, Rusted JM. Cholinergic control of cognitive resources. Neuropsychobiology. 1993;28(1-
2):43-6. 
57.  Rycroft N, Hutton SB, Rusted JM. The antisaccade task as an index of sustained goal activation in working 
memory: modulation by nicotine. Psychopharmacology (Berl). 2006;188(4):521-9. 
58.  Heishman SJ, Taylor RC, Henningfield JE. Nicotine and smoking: a review of effects on human 
performance. Experimental and clinical psychopharmacology. 1994;2:345-95. 
59.  Park S, Knopick C, McGurk S, Meltzer HY. Nicotine impairs spatial working memory while leaving spatial 
attention intact. Neuropsychopharmacology. 2000;22(2):200-9. 


 
Protocol Version #: 1.3 
 
 
Protocol Date:04/13/2017 
20
60.  Le Houezec J, Halliday R, Benowitz NL, Callaway E, Naylor H, Herzig K. A low dose of subcutaneous 
nicotine improves information processing in non-smokers. Psychopharmacology (Berl). 1994;114(4):628-34. 
61.  Newhouse PA, Sunderland T, Tariot PN, Blumhardt CL, Weingartner H, Mellow A, Murphy DL. Intravenous 
nicotine in Alzheimer's disease: a pilot study. Psychopharmacology (Berl). 1988;95(2):171-5. 
62.  Jones GM, Sahakian BJ, Levy R, Warburton DM, Gray JA. Effects of acute subcutaneous nicotine on 
attention, information processing and short-term memory in Alzheimer's disease. Psychopharmacology (Berl). 
1992;108(4):485-94. 
63.  Sahakian BJ, Jones GM. The effects of nicotine on attention, information processing, and working memory 
in patients with dementia of the Alzheimer type. In: Adlkofer F, Thurau K, editors. Effects of nicotine on 
biological systems. Berlin: Birkhauser Basel; 1991. p. 623-30. 
64.  White HK, Levin ED. Four-week nicotine skin patch treatment effects on cognitive performance in 
Alzheimer's disease. Psychopharmacology (Berl). 1999;143(2):158-65. 
65.  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. Pharmacol Biochem Behav. 1995;51(2-
3):509-14. 
66.  Newhouse PA, Potter A, Singh A. Effects of nicotinic stimulation on cognitive performance. Current 
Opinion in Pharmacology. 2004;4:36-46. 
67.  Potter A, Corwin J, Lang J, Piasecki M, Lenox R, Newhouse PA. Acute effects of the selective cholinergic 
channel activator (nicotinic agonist) ABT-418 in Alzheimer's disease. Psychopharmacology (Berl). 
1999;142(4):334-42. 
68.  Newhouse P, Kellar K, Aisen P, White H, Wesnes K, Coderre E, Pfaff A, Wilkins H, Howard D, Levin ED. 
Nicotine treatment of mild cognitive impairment: a 6-month double-blind pilot clinical trial. Neurology. 
2012;78(2):91-101. PMCID: PMC3466669. 
69.  Potter AS, Newhouse PA. Effects of acute nicotine administration on behavioral inhibition in adolescents 
with attention-deficit/hyperactivity disorder. Psychopharmacology (Berl). 2004;176(2):182-94. 
70.  Potter AS, Newhouse PA. Acute nicotine improves cognitive deficits in young adults with attention-
deficit/hyperactivity disorder. Pharmacol Biochem Behav. 2008;88(4):407-17. 
71.  Conners CK, Levin ED, Sparrow E, Hinton SC, Erhardt D, Meck WH, Rose JE, March J. Nicotine and 
attention in adult attention deficit hyperactivity disorder (ADHD). Psychopharmacol Bull. 1996;32(1):67-73. 
72.  Gehricke JG, Hong N, Whalen CK, Steinhoff K, Wigal TL. Effects of transdermal nicotine on symptoms, 
moods, and cardiovascular activity in the everyday lives of smokers and nonsmokers with attention-
deficit/hyperactivity disorder. Psychol Addict Behav. 2009;23(4):644-55. 
73.  Levin ED, Conners CK, Sparrow E, Hinton SC, Erhardt D, Meck WH, Rose JE, March J. Nicotine effects on 
adults with attention-deficit/hyperactivity disorder. Psychopharmacology (Berl). 1996;123(1):55-63. 
74.  Poltavski DV, Petros T. Effects of transdermal nicotine on attention in adult non-smokers with and without 
attentional deficits. Physiol Behav. 2006;87(3):614-24. 
75.  Shytle RD, Silver AA, Wilkinson BJ, Sanberg PR. A pilot controlled trial of transdermal nicotine in the 
treatment of attention deficit hyperactivity disorder. World J Biol Psychiatry. 2002;3(3):150-5. 
76.  Wilens TE, Decker MW. Neuronal nicotinic receptor agonists for the treatment of attention-
deficit/hyperactivity disorder: focus on cognition. Biochem Pharmacol. 2007;74(8):1212-23. 
77.  Wilens TE, Biederman J, Spencer TJ, Bostic J, Prince J, Monuteaux MC, Soriano J, Fine C, Abrams A, Rater 
M, Polisner D. A pilot controlled clinical trial of ABT-418, a cholinergic agonist, in the treatment of adults with 
attention deficit hyperactivity disorder. Am J Psychiatry. 1999;156(12):1931-7. 
78.  Wilens TE, Verlinden MH, Adler LA, Wozniak PJ, West SA. ABT-089, a neuronal nicotinic receptor partial 
agonist, for the treatment of attention-deficit/hyperactivity disorder in adults: results of a pilot study. Biological 
Psychiatry. 2006;59(11):1065-70. 
79.  Wignall ND, de Wit H. Effects of nicotine on attention and inhibitory control in healthy nonsmokers. 
Experimental and clinical psychopharmacology. 2011;19(3):183-91. 
80.  Thiel CM. Cholinergic modulation of learning and memory in the human brain as detected with functional 
neuroimaging. Neurobiol Learn Mem. 2003;80(3):234-44. 


 
Protocol Version #: 1.3 
 
 
Protocol Date:04/13/2017 
21
81.  Newhouse PA, Potter AS, Dumas JA, Thiel CM. Functional brain imaging of nicotinic effects on higher 
cognitive processes. Biochemical pharmacology. 2011;82(8):943-51. PMCID: PMC3162085. 
82.  Hasselmo ME, Sarter M. Modes and Models of Forebrain Cholinergic Neuromodulation of Cognition. 
Neuropsychopharmacology. 2010. 
83.  Dumas JA, Newhouse PA. The cholinergic hypothesis of cognitive aging revisited again: cholinergic 
functional compensation. Pharmacol Biochem Behav. 2011;99(2):254-61. PMCID: PMC3114182. 
84.  Mattay VS, Fera F, Tessitore A, Hariri AR, Berman KF, Das S, Meyer-Lindenberg A, Goldberg TE, Callicot 
JH, Weinberger DR. Neuropsychological corelates of age-related changes in working memory capacity. 
Neuroscience Letters. 2006;392(1-2):32-7. 
85.  Rypma B, D'Esposito M. Isolating the neural mechanisms of age-related changes in human working 
memory. Nature Neuroscience. 2000;3(5):509-15. 
86.  Sutherland MT, Ray KL, Riedel MC, Yanes JA, Stein EA, Laird AR. Neurobiological impact of nicotinic 
acetylcholine receptor agonists: an activation likelihood estimation meta-analysis of pharmacologic 
neuroimaging studies. Biol Psychiatry. 2015;78(10):711-20. PMCID: PMCPMC4494985. 
87.  Buckner RL, Andrews-Hanna JR, Schacter DL. The brain's default network: anatomy, function, and 
relevance to disease. Ann N Y Acad Sci. 2008;1124:1-38. 
88.  Kumari V, Gray JA, ffytche DH, Mitterschiffthaler MT, Das M, Zachariah E, Vythelingum GN, Williams SC, 
Simmons A, Sharma T. Cognitive effects of nicotine in humans: an fMRI study. Neuroimage. 2003;19(3):1002-
13. 
89.  Cohen JD, Perlstein WM, Braver TS, Nystrom LE, Noll DC, Jonides J, Smith EE. Temporal dynamics of 
brain activation during a working memory task. Nature. 1997;386(6625):604-8. 
90.  Hahn B, Ross TJ, Wolkenberg FA, Shakleya DM, Huestis MA, Stein EA. Performance effects of nicotine 
during selective attention, divided attention, and simple stimulus detection: an fMRI study. Cereb Cortex. 
2009;19(9):1990-2000. PMCID: PMC2733682. 
91.  Ernst M, Matochik JA, Heishman SJ, Van Horn JD, Jons PH, Henningfield JE, London ED. Effect of nicotine 
on brain activation during performance of a working memory task. Proc Natl Acad Sci U S A. 2001;98(8):4728-
33. PMCID: PMC31902. 
92.  Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 
1979;134:382-9. 
93.  Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker RW, Dunbar GC. 
The Mini-International Neuropsychiatric Inventory (M.I.N.I.): the development and validation of a structured 
diagnostic interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;Suppl 20:22-33. 
94.  Sheehan DV, Lecrubier Y, Sheehan KH, Janavs J, Weiller E, Keskiner A, Schinka J, Knapp E, Sheehan MF, 
Dunbar GC. The validity of the Mini International Neuropsychiatric Interview (MINI) according to the SCID-P 
and its reliability. Eur Psychiatry. 1997;5:232-41. 
95.  Keller MB, Lavori PW, Friedman DS, Nielsen E, Endicott J, McDonald-Scott P, Andreasen NC. The 
longitudinal interval follow-up evaluation. A comprehensive method for assessing outcome in prospective 
longitudinal studies. Arch Gen Psychiatry. 1987;44:540-8. 
96.  Sackeim HA, Prudic J, Devanand DP, Decina P, Kerr B, Malitz S. The impact of medication resistance and 
continuation pharmacotherapy on relapse following response to electroconvulsive therapy in major depression. 
J Clin Psychopharmacol. 1990;10:96-104. 
97.  Nolen-Hoeksema S, Morrow J, Fredrickson BL. Response styles and the duration of episodes of depressed 
mood. J Abnorm Psychol. 1993;102(1):20-8. 
98.  Cohen S, Kamarck T, Mermelstein R. A global measure of perceived stress. J Health Soc Behav. 
1983;24:385-96. 
99.  Miller MD, Paradis CF, Houck PR, Mazumdar S, Stack JA, Rifai AH, Mulsant B, Reynolds CF. Rating chronic 
medical illness burden in geropsychiatric practice and research: application of the Cumulative Illness Rating 
Scale. Psychiatry Res. 1992;41:237-48. 
100.  Wisniewski SR, Rush AJ, Balasubramani GK, Trivedi MH, Nierenberg AA. Self-rated global measure of the 
frequency, intensity, and burden of side effects. Journal of Psychiatric Practice. 2006;12(2):71-9. 


 
Protocol Version #: 1.3 
 
 
Protocol Date:04/13/2017 
22
101.  Morisky DE, Green LW, Levine DM. Concurrent and predictive validity of a self-reported measure of 
medication adherence. Med Care. 1986;24(1):67-74. 
102.  Conners CK. The Conners Continuous Performance Test. Toronto, Canada: Multi-Health Systems; 1994. 
103.  Jucaite A, Ohd J, Potter AS, Jaeger J, Karlsson P, Hannesdottir K, Bostrom E, Newhouse PA, Paulsson B. 
A randomized, double-blind, placebo-controlled crossover study of alphabeta * nicotinic acetylcholine receptor 
agonist AZD1446 (TC-6683) in adults with attention-deficit/hyperactivity disorder. Psychopharmacology (Berl). 
2013. 
104.  Trivedi MH, Rush AJ, Wisniewski S, Nierenberg AA, Warden D, Ritz L, Norquist G, Howland RH, Lebowitz 
B, McGrath PJ, Shores-Wilson K, Biggs MM, Balasubramani GK, Fava M, Team SDS. Evaluation of outcomes 
with citalopram for depression using measurement-based care in STAR*D: Implications for clinical practice. Am 
J Psychiatry. 2006;163:28-40. 
105.  Posner MI. Orienting of attention. The Quarterly journal of experimental psychology. 1980;32(1):3-25. 
106.  Thiel CM, Fink GR. Effects of the cholinergic agonist nicotine on reorienting of visual spatial attention and 
top-down attentional control. Neuroscience. 2008;152(2):381-90. 
107.  Thiel CM, Zilles K, Fink GR. Nicotine modulates reorienting of visuospatial attention and neural activity in 
human parietal cortex. Neuropsychopharmacology. 2005;30(4):810-20. 
108.  Vossel S, Thiel CM, Fink GR. Behavioral and neural effects of nicotine on visuospatial attentional 
reorienting in non-smoking subjects. Neuropsychopharmacology. 2008;33(4):731-8. 
109.  Etkin A, Egner T, Peraza DM, Kandel ER, Hirsch J. Resolving emotional conflict: a role for the rostral 
anterior cingulate cortex in modulating activity in the amygdala. Neuron. 2006;51(6):871-82. 
110.  Egner T, Etkin A, Gale S, Hirsch J. Dissociable neural systems resolve conflict from emotional versus 
nonemotional distracters. Cereb Cortex. 2008;18(6):1475-84. 
111.  http://www.fil.ion.ucl.ac.uk/spm/software/spm8/  [January 15, 2013]. 
112.  Kohler S, Ashton CH, Marsh R, Thomas AJ, Barnett NA, O'Brien JT. Electrophysiological changes in late 
life depression and their relation to structural brain changes. Int Psychogeriatr. 2011;23(1):141-8. 
113.  Zhang BW, Xu J, Chang Y. The Effect of Aging in Inhibitory Control of Major Depressive Disorder 
Revealed by Event-Related Potentials. Front Hum Neurosci. 2016;10:116. PMCID: PMCPMC4811904. 
114.  Hindmarch I. Psychological performance models as indicators of the effects of hypnotic drugs on sleep. 
Psychopharmacology Suppl. 1984;1:58-68. 
115.  Key AP, Dykens EM. Event-related potential index of age-related differences in memory processes in 
adults with Down syndrome. Neurobiol Aging. 2014;35(1):247-53. PMCID: PMCPMC3849808. 
116.  Srinivasan R, Nunez PL, Tucker DM, Silberstein RB, Cadusch PJ. Spatial sampling and filtering of EEG 
with spline laplacians to estimate cortical potentials. Brain Topogr. 1996;8(4):355-66. 
117.  Greenland S, Satterfield MH, Lanes SF. A meta-analysis to assess the incidence of adverse effects 
associated with the transdermal nicotine patch. Drug Safety. 1998;18(4):297-308. 
118.  Spyker DA, Alderfer RJ, Goetsch RA, Longmire AW, Kramer ED. Adverse Events and Prolonged Use of 
Nicotine Gum and Patch. In: Benowitz NL, editor. Nicotine Safety and Toxicity: Oxford University Press; 1998. 
p. 167-72. 
119.  Benowitz NL. Cardiovascular Toxicity of Nicotine: Pharmacokinetic and Pharmacodynamic Considerations. 
In: Benowitz NL, editor. Nicotine Safety and Toxicity. New York: Oxford University Press; 1998. p. 19-27. 
120.  Murray RP, Daniels K. Long-Term Nicotine Therapy. In: Benowitz NL, editor. Nicotine Safety and Toxicity: 
Oxford University Press; 1998. p. 173-82. 
121.  Rhodes J, Green J, Thomas G. Nicotine and the Gastrointestinal Tract. In: Benowitz NL, editor. Nicotine 
Safety and Toxicity: Oxford University Press; 1998. p. 161-6. 
122.  Haustein KO, Haffner S, Woodcock BG. A review of the pharmaological and psychopharmacological 
aspects of smoking and smoking cessation in psychiatric patients. International Journal of Clinical 
Pharmacology and Therapeutics. 2002;40(9):404-18. 
123.  Rennard SI, Daughton D, Windle J. Toxicity of Nicotine Replacement in Patients with Coronary Artery 
Disease. In: Benowitz NL, editor. Nicotine Safety and Toxicity: Oxford University Press; 1998. p. 49-53. 
124.  Hawkins BT, Brown RC, Davis TP. Smoking and ischemic stroke: a role for nicotine? Trends in 
Pharmacological Sciences. 2002;23(2):78-82. 


 
Protocol Version #: 1.3 
 
 
Protocol Date:04/13/2017 
23
125.  Gerzanich V, Zhang F, West GA, Simard JM. Chronic nicotine alters NO signaling of Ca(2+) channels in 
cerebral arterioles. Circ Res. 2001;88(3):359-65. 
126.  Hawkins BT, Brown RC, Davis TP. Smoking and ischemic stroke: a role for nicotine? Trends Pharmacol 
Sci. 2002;23(2):78-82. 
127.  Zidovetzki R, Chen P, Fisher M, Hofman FM, Faraci FM. Nicotine increases plasminogen activator 
inhibitor-1 production by human brain endothelial cells via protein kinase C-associated pathway. Stroke. 
1999;30(3):651-5. 
128.  Mikhailidis DP, Papadakis JA, Ganotakis ES. Smoking, diabetes and hyperlipidaemia. Journal of the Royal 
Society of Health. 1998;118(2):91-3. 
129.  Henkin L, Zaccaro D, Haffner S, Karter A, Rewers M, Sholinsky P, Wagenknecht L. Cigarette smoking, 
environmental tobacco smoke exposure and insulin sensitivity: the Insulin Resistance Atherosclerosis Study. 
Annals of Epidemiology. 1999;9(5):290-6. 
130.  Targher G, Alberiche M, Zenere MB, Bonadonna RC, Muggeo M, Bonora E. Cigarette smoking and insulin 
resistance in patients with noninsulin-dependent diabetes mellitus. Journal of Clinical Endocrinology & 
Metabolism. 1997;82(11):3619-24. 
131.  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. 
132.  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. 
133.  Benowitz NL. Risks and benefits of nicotine. In: Benowitz NL, editor. Nicotine Safety and Toxicity. New 
York: Oxford University Press; 1998. p. 185-94. 
134.  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. 
135.  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. 
136.  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. 
137.  Kelton MC, Kahn HJ, Conrath CL, Newhouse PA. The effects of nicotine on Parkinson's disease. Brain and 
Cognition. 2000;43:274-82. 
138.  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. 
139.  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. 
140.  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. 
141.  Fagerstrom KO, Pomerleau O, Giordani B, Stelson F. Nicotine may relieve symptoms of Parkinson's 
disease. Psychopharmacology. 1994;116:117-9. 
142.  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. 
143.  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. 
144.  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. 
145.  Farre M, Cami J. Pharmacokinetic considerations in abuse liability evaluation. British Journal of Addiction. 
1991;86(12):1601-6. 


 
Protocol Version #: 1.3 
 
 
Protocol Date:04/13/2017 
24
146.  Henningfield JE, Keenan RM. Nicotine delivery kinetics and abuse liability. Journal of Consulting & Clinical 
Psychology. 1993;61(5):743-50. 
147.  Henningfield JE, Keenan RM. Nicotine delivery kinetics and abuse liability. J Consult Clin Psychol. 
1993;61(5):743-50. 
148.  Pomerleau OF. Nicotine and the central nervous system: biobehavioral effects of cigarette smoking. 
American Journal of Medicine. 1992;93(1A):2S-7S. 
149.  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. 
150.  Rose JE, Westman EC, Behm FM. Nicotine/mecamylamine combination treatment for smoking cessation. 
Drug Development Research. 1996;38(3/4):243-56. 
151.  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. 
152.  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.