Depressed Mood Improvement Through Nicotine Dosing 2

Deficits in cognitive control are core features of late-life depression, contributing both to emotion dysregulation and problems with inhibiting irrelevant information, conflict detection, and working memory. Clinically characterized as executive dysfunction, these deficits are associated with poor response to antidepressants and higher levels of disability. Improvement of cognitive control network (CCN) dysfunction may benefit both mood and cognitive performance, however no current pharmacotherapy improves CCN deficits in LLD. Supported by pilot data, Investigators propose that nicotine acetylcholine receptor agonists enhance CCN function and resultantly improve mood and cognitive performance in late-life depression. The objective of this initial R61-phase trial is to first determine whether transdermal nicotine enhances CCN neural activity in an exposure-dependent fashion during an emotional response inhibition task (the emotional Stroop task). Investigator's approach for the R61 phase is to examine in 36 older adults with Major Depressive Disorder whether transdermal nicotine patches enhance CCN activity over 12 weeks as measured during fMRI with the emotional Stroop task while measuring nicotine and nicotine metabolite levels. Transdermal nicotine has a mechanism of action that is distinct from current antidepressants, potentially making it a potentially important antidepressant augmentation agent. If hypotheses are correct, as patches are commercially available, this approach could be rapidly moved into definitive studies and may have applicability to other psychiatric disorders characterized by CCN dysfunction.

Late-life depression (LLD) is characterized both by affective symptoms and broad cognitive deficits. The co-occurrence of cognitive deficits in LLD, particularly executive dysfunction, is a clinically relevant phenotype characterized by significant disability and poor antidepressant response. Cognitive deficits can persist even with successful antidepressant treatment and increase the risk of depression relapse. Despite the clinical importance of cognitive deficits in LLD, there are no established treatments that specifically target cognition in this population. This is particularly important, as the cognitive deficits appear to directly contribute to disability and poor antidepressant treatment outcomes. The lack of clear pharmacologic targets and therapies aimed at improving cognitive deficits in depression is a substantial deficiency in current therapeutics.

Modulation of the cholinergic system by nicotinic receptor stimulation may improve both mood and cognition in depressed elders. Clinically, transdermal nicotine improves mood in smokers and a placebo-controlled pilot trial in nonsmoking adults found that transdermal nicotine significantly improved mood. As observed in smokers, nicotine's effect to increase cognitive control network activity while reducing default mode network activity will reduce depression's characteristic bias to negatively valenced stimuli and decrease rumination. Supporting this theory, nicotinic receptor activity stimulates serotonin release and protects against worsening mood with tryptophan depletion.

The Depressed Mind 2 Study examines whether enhancement of CCN function by nicotinic acetylcholine receptor agonists will improve mood and cognitive symptoms in LLD. This is supported by pilot data demonstrating that open-label administration of transdermal nicotine (TDN) patches safely improved depression severity. The investigators also observed trends suggesting that TDN may provide benefit for cognitive performance, specifically in domains of episodic memory, working memory, and attention. In other pilot data using an emotional Stroop task, TDN reduces the differences in functional magnetic resonance imaging (fMRI) activation in the cognitive control network (CCN) between Stroop conditions. Importantly, this activation change was associated with a corresponding reduction in depression severity. Based on these data, investigators hypothesize that nicotinic receptor agonists enhance CCN function in LLD and in turn this may improve depressive symptoms.

Thirty-six participants will be enrolled to test for target engagement, defined as TDN exposure dependent effect in CCN activation. Based on pilot data, the study will test for enhancement of CCN function by examining the Stroop fMRI response, or the reduction in CCN activation between incongruent and congruent conditions of the emotional Stroop task during fMRI. Investigators will assess the effects of variability in nicotine exposure on target engagement by measuring nicotine blood levels in conjunction with repeat MRI.

Primary aim: To test CCN engagement over 12 weeks of Open labeled Transdermal Nicotine(TDN).

Hypothesis1A(Target Engagement): TDN will enhance CCN function, measured as a reduction in the middle or superior frontal gyri (M/SFG) Stroop functional MRI response (the activation difference between incongruent and congruent conditions of the emotional Stroop task). 60% or more of subjects will exhibit a M/SFG z-score reduction of 0.5 or greater.

Hypothesis1B (Exposure): Higher nicotine exposure measured by patch dose or nicotine metabolite levels will be associated with a greater reduction in the M/SFG Stroop fMRI response.

Eligibility Criteria:
Inclusion Criteria:

1. Age \> 60 years;
2. Diagnosis of major depressive disorder, single or recurrent episode (DSM5);
3. On a stable therapeutic dose of an allowed selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) for at least 8 weeks;
4. Severity: Montgomery-Asberg Depression Rating Scale (MADRS) score ≥ 15;
5. Cognition: Mini-Mental State Examination (MMSE) score ≥ 24;
6. Fluent in English

Exclusion Criteria:

1. Other Axis I psychiatric disorders, except for generalized anxiety disorder (GAD) symptoms occurring in a depressive episode;
2. Use of other medications for depression, e.g., bupropion or augmenting agents, although short-acting sedatives are allowed (see below);
3. Any use of tobacco or nicotine in the last year;
4. Living with a smoker or regular exposure to secondhand smoke;
5. History of alcohol use disorder or substance use disorder of moderate or greater severity (endorsing 4 or more of the 12 criteria) in the last 12 months;
6. Acute suicidality;
7. Acute grief (\<1 month);
8. Current or past psychosis;
9. Primary neurological disorder, including dementia, stroke, epilepsy, etc.;
10. MRI contraindication;
11. Electroconvulsive therapy or transcranial magnetic stimulation in last 2 months;
12. Current or planned psychotherapy;
13. Allergy or hypersensitivity to nicotine patches;
14. In the last 4 weeks, regular use of drugs with central cholinergic or anticholinergic properties or moderate / severe CYP2A6 inhibitors /inducers.