Depressed Mood Improvement Through Nicotine Dosing (Depressed MIND Study)

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.

Inclusion Criteria:

- Age > 60 years;

- DSM-5 (Diagnostic and statistical manual-5) diagnosis of major depressive disorder,
single or recurrent episode;

- Subjective cognitive decline, defined as endorsing 20% of items on the Cognitive
Complaint Index (CCI);

- depression severity: MADRS (Montgomery-Asberg Depression Rating Scale) ≥ 15;

- cognition: MOCA (Montreal Cognitive Assessment) ≥ 24;

- fluent in English;

- intact hearing / vision allowing completion of study procedures;

- for individuals on antidepressants at study entry, they must be on a stable dose for
at least 6 weeks.

Exclusion Criteria:

- Other Axis I psychiatric disorders, except for anxiety symptoms occurring in a
depressive episode;

- History of alcohol or drug dependence or abuse in the last 3 years;

- Tobacco or nicotine use in last year;

- History of a developmental disorder or IQ score < 70;

- Acute suicidality;

- Acute grief (<1 month);

- Current or past psychosis;

- Primary neurological disorder, including dementia, stroke, brain tumors, etc.;

- Any MRI contraindication;

- Unstable medical illness;

- Allergy or hypersensitivity to nicotine patches;

- Regular use of drugs with centrally acting cholinergic or anticholinergic properties
in last 4 weeks, including acetylcholinesterase inhibitors;

- Current or planned psychotherapy;

- Electroconvulsive therapy (ECT) or transcranial magnetic stimulation (TMS) in last two
months.