Clinical trial NCT05746273: Depressed Mood Improvement Through Nicotine Dosing 3
Official title: Nicotinic Modulation of the Cognitive Control System in Late-Life Depression (R33 Phase)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Depressive Disorder
Keywords: geriatrics
aging
elderly
cognition
memory
nicotine transdermal patch
depression
Lead sponsor: Vanderbilt University Medical Center
Sponsor class: OTHER
Collaborators: name: National Institute of Mental Health (NIMH)
First posted: 2023-02-27
Enrollment: 60
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Deficits in cognitive control are core features of late-life depression (LLD), 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 Cognitive Control Network deficits in LLD.

The study examines the hypothesis that nicotine acetylcholine receptor agonists enhance Cognitive Control Network function. This effect may resultantly improve mood and cognitive performance in LLD. Small, open-label studies of transdermal nicotine (TDN) patches have supported potential clinical benefit and provided support that transdermal nicotine administration engages the Cognitive Control Network.

This blinded study will expand past open-label trials supporting potential benefit in LLD. It will examine TDN's effect on depression severity and cognitive control functions measured by neuropsychological testing. The study will evaluate 60 eligible and enrolled participants over a 3-year period.

Detailed description: The purpose of the Depressed MIND3 study is to determine whether blinded, placebo-controlled administration of transdermal nicotine results in significant cognitive, clinical and functional improvement in participants with LLD. Neuronal nicotinic receptors have long been known to play a critical role in memory function in preclinical studies, with nicotine improving attention, learning, and memory function. This may be particularly relevant in LLD, which is characterized both by affective symptoms and broad 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 clear pharmacologic targets and therapies aimed at improving cognitive deficits in depression is a substantial deficiency in current therapeutics.

We propose that modulation of the cognitive control network by stimulation of cholinergic system nicotinic acetylcholine receptors will improve both mood and cognition in depressed elders. The study is a randomized double blind placebo control trial that will enroll 80 participants over a 3-year period. Participants will be randomized (2:1) to receive either active transdermal nicotine (TDN) patches or matching placebo patches. Participants will apply patches daily for 12 weeks, followed by a 3-week taper period.

The Aims of this blinded trial are to: 1) validate target engagement and determine whether change in brain activation to an emotional Stroop task is related to improvement in depression severity and cognitive performance; and 2) determine the specificity of TDN's effects by examining whether changes in the default mode network (DMN) or other regions occur with TDN and if so, are they related to change in clinical measures.

AIM 1: Examine how TDN's neural circuit changes affect depressive symptoms in a blinded RCT.

Hyp 1A: Compared with placebo, TDN administration will significantly reduce the Stroop BOLD response on functional Magnetic Resonance Imaging. This change will be associated with reduction in depression severity by the Montgomery-Asberg Depression Rating Scale (MADRS).

Hyp 1B: Change in the Stroop BOLD response of other brain regions with TDN administration, specifically the DMN, will not be significantly associated with change in depression severity.

Hyp 1C: Compared with placebo, TDN will improve depression severity measured by MADRS (primary clinical outcome), reduce apathy and rumination measured by self-report, and reduce negative self-referential thinking measured by the Trait Adjectives Task (secondary outcomes).

AIM 2: Examine how TDN's circuit changes affect CCN-mediated cognitive performance.

Hyp 2A: Reduction in the Stroop BOLD response will be associated with improvement in attention, working memory, and episodic memory performance. Change in the Stroop BOLD response of other regions, specifically the DMN, will not be associated with change in task performance.

Hyp 2B: Compared with placebo, nicotine will improve performance on tasks of attention, working memory, and episodic memory (secondary outcomes).

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 SSRI or SNRI for at least 6 weeks;
4. severity: at least mild active depression symptoms, defined as MADRS ≥ 15;
5. cognition: MMSE ≥ 24;
6. fluent in English

Exclusion Criteria:

1. Other Axis I psychiatric disorders, except for generalized anxiety disorder (GAD) or social phobia symptoms occurring in a depressive episode or diagnosis of an attentional disorder, such as Attention Deficit Hyperactivity Disorder (ADHD);
2. Use of other augmentation medication treatments for depression or ADHD e.g., stimulant medications (e.g., adjunctive bupropion or other augmenting agents) that the participant does not want to stop, although short-acting sedatives are allowed;
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 central nervous system neurological disorder, including dementia, stroke, epilepsy, etc.;
10. Presence of unstable medical illness requiring urgent treatment or intervention;
11. MRI contraindication.
12. Electroconvulsive therapy or transcranial magnetic stimulation in last 2 months;
13. Current or planned psychotherapy where the potential participant does not want to pause therapy for the duration of the study;
14. Allergy or hypersensitivity to nicotine patches;
15. In the last 4 weeks, regular use of drugs with central cholinergic or anticholinergic properties or moderate / severe CYP2A6 inhibitors /inducers

Primary outcomes:
measure: MADRS (Montgomery Asberg Depression Rating Scale) Score
timeFrame: Baseline to week 12
measure: Functional Magnetic Resonance Imaging (MRI)
timeFrame: Baseline to week 6.
measure: Continuous Performance Task (CPT) Performance
timeFrame: Baseline to Week 12
Secondary outcomes:
measure: NIH EXAMINER Test Battery
timeFrame: Baseline to Week 12
measure: Selective Reminding Task
timeFrame: Baseline to Week 12
measure: Trait Adjectives Task
timeFrame: Baseline to Week 12
measure: Ruminative Response Scale
timeFrame: Baseline to Week 12
measure: Apathy Evaluation Scale (AES)
timeFrame: Baseline to Week 12
measure: Insomnia Severity Index
timeFrame: Baseline to Week 12
measure: Penn State Worry Questionnaire (PSWQ)
timeFrame: Baseline to Week 12
measure: Fatigue Severity Scale
timeFrame: Baseline to Week 12
measure: General Anxiety Disorder Scale (7 Item)
timeFrame: Baseline to Week 12
measure: PROMIS Applied Cognition Abilities Short
timeFrame: Baseline to Week 12
measure: Attentional Control Scale
timeFrame: Baseline to Week 12
Other outcomes:
Locations:
city: Nashville
country: United States
facility: Vanderbilt Psychiatric Hosptial
state: Tennessee
Study officials:
affiliation: Vanderbilt University Medical Center
name: Warren Taylor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gandelman JA, Kang H, Antal A, Albert K, Boyd BD, Conley AC, Newhouse P, Taylor WD. Transdermal Nicotine for the Treatment of Mood and Cognitive Symptoms in Nonsmokers With Late-Life Depression. J Clin Psychiatry. 2018 Aug 28;79(5):18m12137. doi: 10.4088/JCP.18m12137.
citation: 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 Nov 15;78(10):711-20. doi: 10.1016/j.biopsych.2014.12.021. Epub 2015 Jan 7.
citation: Gandelman JA, Newhouse P, Taylor WD. Nicotine and networks: Potential for enhancement of mood and cognition in late-life depression. Neurosci Biobehav Rev. 2018 Jan;84:289-298. doi: 10.1016/j.neubiorev.2017.08.018. Epub 2017 Aug 30.
citation: Aizenstein HJ, Butters MA, Wu M, Mazurkewicz LM, Stenger VA, Gianaros PJ, Becker JT, Reynolds CF 3rd, Carter CS. Altered functioning of the executive control circuit in late-life depression: episodic and persistent phenomena. Am J Geriatr Psychiatry. 2009 Jan;17(1):30-42. doi: 10.1097/JGP.0b013e31817b60af.
citation: Alexopoulos GS, Hoptman MJ, Kanellopoulos D, Murphy CF, Lim KO, Gunning FM. Functional connectivity in the cognitive control network and the default mode network in late-life depression. J Affect Disord. 2012 Jun;139(1):56-65. doi: 10.1016/j.jad.2011.12.002. Epub 2012 Mar 15.
citation: Taylor WD. Clinical practice. Depression in the elderly. N Engl J Med. 2014 Sep 25;371(13):1228-36. doi: 10.1056/NEJMcp1402180. No abstract available.