Nicotinic Modulation of the Cognitive Control System in Late-life Depression
Overview
- Phase
- Phase 2
- Intervention
- Transdermal Nicotine patch
- Conditions
- Depressive Disorder
- Sponsor
- Vanderbilt University Medical Center
- Enrollment
- 29
- Locations
- 1
- Primary Endpoint
- MADRS (Montgomery Asberg Depression Rating Scale) Score Change
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
Deficits in cognitive control are core features of late-life depression, contributing both to emotion dysregulation and problems with inhibiting irrelevant information, conflict detection, and working memory. Clinically characterized as executive dysfunction, these deficits are associated with poor response to antidepressants and higher levels of disability. Improvement of cognitive control network (CCN) dysfunction may benefit both mood and cognitive performance, however no current pharmacotherapy improves CCN deficits in LLD. Supported by pilot data, Investigators propose that nicotine acetylcholine receptor agonists enhance CCN function and resultantly improve mood and cognitive performance in late-life depression. The objective of this initial R61-phase trial is to first determine whether transdermal nicotine enhances CCN neural activity in an exposure-dependent fashion during an emotional response inhibition task (the emotional Stroop task). Investigator's approach for the R61 phase is to examine in 36 older adults with Major Depressive Disorder whether transdermal nicotine patches enhance CCN activity over 12 weeks as measured during fMRI with the emotional Stroop task while measuring nicotine and nicotine metabolite levels. Transdermal nicotine has a mechanism of action that is distinct from current antidepressants, potentially making it a potentially important antidepressant augmentation agent. If hypotheses are correct, as patches are commercially available, this approach could be rapidly moved into definitive studies and may have applicability to other psychiatric disorders characterized by CCN dysfunction.
Detailed Description
Late-life depression (LLD) is characterized both by affective symptoms and broad cognitive deficits. The co-occurrence of cognitive deficits in LLD, particularly executive dysfunction, is a clinically relevant phenotype characterized by significant disability and poor antidepressant response. Cognitive deficits can persist even with successful antidepressant treatment and increase the risk of depression relapse. Despite the clinical importance of cognitive deficits in LLD, there are no established treatments that specifically target cognition in this population. This is particularly important, as the cognitive deficits appear to directly contribute to disability and poor antidepressant treatment outcomes. The lack of clear pharmacologic targets and therapies aimed at improving cognitive deficits in depression is a substantial deficiency in current therapeutics. Modulation of the cholinergic system by nicotinic receptor stimulation may improve both mood and cognition in depressed elders. Clinically, transdermal nicotine improves mood in smokers and a placebo-controlled pilot trial in nonsmoking adults found that transdermal nicotine significantly improved mood. As observed in smokers, nicotine's effect to increase cognitive control network activity while reducing default mode network activity will reduce depression's characteristic bias to negatively valenced stimuli and decrease rumination. Supporting this theory, nicotinic receptor activity stimulates serotonin release and protects against worsening mood with tryptophan depletion. The Depressed Mind 2 Study examines whether enhancement of CCN function by nicotinic acetylcholine receptor agonists will improve mood and cognitive symptoms in LLD. This is supported by pilot data demonstrating that open-label administration of transdermal nicotine (TDN) patches safely improved depression severity. The investigators also observed trends suggesting that TDN may provide benefit for cognitive performance, specifically in domains of episodic memory, working memory, and attention. In other pilot data using an emotional Stroop task, TDN reduces the differences in functional magnetic resonance imaging (fMRI) activation in the cognitive control network (CCN) between Stroop conditions. Importantly, this activation change was associated with a corresponding reduction in depression severity. Based on these data, investigators hypothesize that nicotinic receptor agonists enhance CCN function in LLD and in turn this may improve depressive symptoms. Thirty-six participants will be enrolled to test for target engagement, defined as TDN exposure dependent effect in CCN activation. Based on pilot data, the study will test for enhancement of CCN function by examining the Stroop fMRI response, or the reduction in CCN activation between incongruent and congruent conditions of the emotional Stroop task during fMRI. Investigators will assess the effects of variability in nicotine exposure on target engagement by measuring nicotine blood levels in conjunction with repeat MRI. Primary aim: To test CCN engagement over 12 weeks of Open labeled Transdermal Nicotine(TDN). Hypothesis1A(Target Engagement): TDN will enhance CCN function, measured as a reduction in the middle or superior frontal gyri (M/SFG) Stroop functional MRI response (the activation difference between incongruent and congruent conditions of the emotional Stroop task). 60% or more of subjects will exhibit a M/SFG z-score reduction of 0.5 or greater. Hypothesis1B (Exposure): Higher nicotine exposure measured by patch dose or nicotine metabolite levels will be associated with a greater reduction in the M/SFG Stroop fMRI response.
Investigators
Warren Taylor
Professor of Psychiatry
Vanderbilt University Medical Center
Eligibility Criteria
Inclusion Criteria
- •Age \> 60 years;
- •Diagnosis of major depressive disorder, single or recurrent episode (DSM5);
- •On a stable therapeutic dose of an allowed selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) for at least 8 weeks;
- •Severity: Montgomery-Asberg Depression Rating Scale (MADRS) score ≥ 15;
- •Cognition: Mini-Mental State Examination (MMSE) score ≥ 24;
- •Fluent in English
Exclusion Criteria
- •Other Axis I psychiatric disorders, except for generalized anxiety disorder (GAD) symptoms occurring in a depressive episode;
- •Use of other medications for depression, e.g., bupropion or augmenting agents, although short-acting sedatives are allowed (see below);
- •Any use of tobacco or nicotine in the last year;
- •Living with a smoker or regular exposure to secondhand smoke;
- •History of alcohol use disorder or substance use disorder of moderate or greater severity (endorsing 4 or more of the 12 criteria) in the last 12 months;
- •Acute suicidality;
- •Acute grief (\<1 month);
- •Current or past psychosis;
- •Primary neurological disorder, including dementia, stroke, epilepsy, etc.;
- •MRI contraindication;
Arms & Interventions
Transdermal Nicotine Patch
Participants will wear open label transdermal nicotine patch daily for 12-15 weeks. They will apply study patch each morning and remove at bedtime. Dosage will begin at 3.5mg patch / day, increasing to a possible maximum of 21mg patch / day.
Intervention: Transdermal Nicotine patch
Outcomes
Primary Outcomes
MADRS (Montgomery Asberg Depression Rating Scale) Score Change
Time Frame: Baseline to week 12
Primary mood outcome measured by the total score of the clinician rated MADRS. MADRS will be measured every 3 weeks (baseline, week 3, week 6, week 9, and week 12). MADRS total score range is 0-60, where higher scores indicate greater depression severity. Change is calculated as the difference between week 12 and baseline.
Number of Participants Exhibiting Reduction in Frontal Activation During the Emotional Stroop Task During Functional Magnetic Resonance Imaging (MRI)
Time Frame: Baseline, week 6, week 12
MRI scans will be performed at baseline, week 6 and week 12. MRI will measure cognitive control network function, operationalized as a reduction in the emotional Stroop task functional MRI response in the middle and superior frontal gyri. The Stroop functional MRI response is calculated as the activation difference between incongruent and congruent conditions of the emotional Stroop task. The primary outcome is change in activation difference across the three time points. This is examined as a categorical variable, operationalized as those subjects who exhibit a middle / superior frontal gyri z-score reduction in activation over time of 0.5 or greater, relative to baseline at either week 6 and/or week 12. The a priori threshold being tested was that 60% or more of participants would exhibit a z-score reduction of 0.5 or greater, examined separately in the left and right middle and superior frontal gyri.
Secondary Outcomes
- Selective Reminding Task Performance Change(Baseline to week12)
- Trait Adjectives Task, Change in Positive Items Endorsed(Assessed at baseline, week 6, and week 12, change from baseline to week 12 reported)
- NIH EXAMINER Test Battery Executive Composite Score Change(Baseline to week 12)
- NIH EXAMINER Test Battery Cognitive Control Factor Change(Baseline to week 12)
- NIH EXAMINER Test Battery Fluency Factor Change(Baseline to week 12)
- NIH EXAMINER Test Battery Working Memory Factor Change(Baseline to week 12)
- Choice Reaction Time (CRT) Performance Change(Baseline to week 12)
- Trait Adjectives Task, Change in Negative Items Rejected(Assessed at baseline, week 6, and week 12, change from baseline to week 12 reported)
- Ruminative Response Scale Score Change(Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.)
- Trait Adjectives Task, Change in Reaction Time to Endorse Positive Items(Assessed at baseline, week 6, and week 12, change from baseline to week 12 reported)
- Trait Adjectives Task, Change in Reaction Time to Reject Negative Items(Assessed at baseline, week 6, and week 12, change from baseline to week 12 reported)
- Apathy Evaluation Scale (AES) Score Change(Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.)
- Insomnia Severity Index Score Change(Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.)
- Penn State Worry Questionnaire (PSWQ) Score Change(Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.)
- Fatigue Severity Scale Score Change(Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.)
- Dimensional Anhedonia Rating Scale (DARS) Score Change(Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.)
- General Anxiety Disorder-7 Item Scale (GAD7) Score Change(Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.)
- Patient Reported Outcome Measurement Information System (PROMIS) Applied Cognition Abilities Short Form Score Change(Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.)
- Attentional Control Scale Score Change(Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.)
- Anxiety Sensitivity Index 3 (ASI-3) Score Change(Assessed at baseline, Week 6, and Week 12; only baseline to week 12 reported.)