Depressed Mood Improvement Through Nicotine Dosing 3

NCT ID: NCT05746273

Last Updated: 2025-12-12

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-04-15
• Study Completion Date: 2026-09-30

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).

Conditions

Depressive Disorder

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Transdermal Nicotine Patch

Participants will be randomized to apply nicotine transdermal patches during waking hours. Active dose will titrate up from 3.5mg to 7mg in the first 3 weeks. Doses can be optionally titrated to a maximum of 14mg over 12 weeks, based on tolerability and perceived benefit. After 12 weeks, the patch dose will be tapered over 2-3 weeks.

Group Type: EXPERIMENTAL

Transdermal Nicotine Patch

Intervention Type: DRUG

Participants will wear nicotine transdermal patches daily for 12-15 weeks. They will apply a study patch each morning and remove at bedtime. Active dose will titrate up from 3.5mg to 7mg, and then can optionally be further titrated to a maximum dose of 14mg. After week12, the dose will be slowly tapered over 2-3 weeks.

Transdermal Placebo Patch

Participants will be randomized to apply placebo transdermal patches during waking hours. Placebo patch titration will mirror the active arm, increasing the dose will titrate up from 3.5mg to 7mg in the first 3 weeks. Doses can be optionally titrated to a maximum of 14mg over 12 weeks, based on tolerability and perceived benefit. After 12 weeks, the patch dose will be tapered over 2-3 weeks.

Group Type: PLACEBO_COMPARATOR

Transdermal Placebo Patch

Intervention Type: DRUG

Participants will wear placebo transdermal patches daily for 12-15 weeks. They will apply a study patch each morning and remove at bedtime. Placebo patch dose will titrate up from 3.5mg to 7mg, and then can optionally be further titrated to a maximum dose of 14mg. After week12, the dose will be slowly tapered over 2-3 weeks.

Interventions

Transdermal Nicotine Patch

Participants will wear nicotine transdermal patches daily for 12-15 weeks. They will apply a study patch each morning and remove at bedtime. Active dose will titrate up from 3.5mg to 7mg, and then can optionally be further titrated to a maximum dose of 14mg. After week12, the dose will be slowly tapered over 2-3 weeks.

Intervention Type: DRUG

Transdermal Placebo Patch

Participants will wear placebo transdermal patches daily for 12-15 weeks. They will apply a study patch each morning and remove at bedtime. Placebo patch dose will titrate up from 3.5mg to 7mg, and then can optionally be further titrated to a maximum dose of 14mg. After week12, the dose will be slowly tapered over 2-3 weeks.

Intervention Type: DRUG

Other Intervention Names

Nicoderm CQ; Nicotrol; Placebo Patches

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

• Minimum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Mental Health (NIMH)

NIH

Sponsor Role: collaborator

Vanderbilt University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Warren Taylor

Director, Division of General Psychiatry and Division of Geriatric Psychiatry

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Warren Taylor

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University Medical Center

Locations

Vanderbilt Psychiatric Hosptial

Nashville, Tennessee, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Sarah Siddiqi

Role: CONTACT

sarah.siddiqi@vumc.org

6159368297

Carrie Williams

Role: CONTACT

carrie.e.williams@vumc.org

6159362162

Facility Contacts

Sarah Siddiqi

Role: primary

sarah.siddiqi@vumc.org

16159368297

References

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.

Reference Type: BACKGROUND

PMID: 30192444 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25662104 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 28859996 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 19001356 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 22425432 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25251617 (View on PubMed)

Other Identifiers

4R33MH122464-03

Identifier Type: NIH

Identifier Source: secondary_id

View Link

222009

Identifier Type: -

Identifier Source: org_study_id