Depressed Mood Improvement Through Nicotine Dosing-3 (Depressed MIND3) Extension

NCT ID: NCT05746546

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: 2026-10-31

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 is an open-label, extension to the blinded Depressed MIND 3 (Depressed Mood Improvement through nicotine dosing) study. It will evaluate longer-term safety and efficacy of Transdermal Nicotine Patches for potential benefit in cognitive and depression outcomes in elderly depressed participants. Subjects complete blinded randomized trial of Depressed MIND-3 will be eligible for continuation in this extension. This extension study will consist of up to 12 weeks of treatment and a 3 -week safety follow-up period.

Detailed Description

The purpose of this open-label extension to the Depressed MIND 3 study will be to gather data on longer-term benefits and safety in patients with late-life depression (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.

Investigators 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 an open-label extension of a randomized double blind placebo control trial that will enroll 80 participants over a 3-year period. After randomization and completion of the blinded study phase, participants will be eligible for this 12-week extension.

At the completion of Week-12 visit of the Depressed MIND -3, all eligible subjects will be offered enrollment in the open label extension study. Study visits during the treatment period for all subjects will occur approximately 3 weeks with flexible dose titration. This will be followed by a 1-3 week taper phase. The total duration of study participation will be approximately 15 weeks.

Conditions

Depressive Disorder

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Transdermal Nicotine Patch

Participants will wear nicotine transdermal patches daily for 12-15 weeks. Participants 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.

Group Type: EXPERIMENTAL

Transdermal Nicotine patch

Intervention Type: DRUG

Participants will wear nicotine transdermal patches daily for 12-15 weeks. Participants 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.

Interventions

Transdermal Nicotine patch

Participants will wear nicotine transdermal patches daily for 12-15 weeks. Participants 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

Other Intervention Names

Nicoderm CQ; Nicotrol

Eligibility Criteria

Inclusion Criteria

Eligibility criteria for the blinded phase includes:

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 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) 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 (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.

• 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 D Taylor

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University Medical Center

Locations

Vanderbilt Psychiatric Hospital

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

(615)936-2162

Facility Contacts

Carrie Williams

Role: primary

carrie.e.williams@vumc.org

(615) 936-2162

Sarah Sarah, BA

Role: backup

sarah.siddiqi@vumc.org

615-936-8297

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)

Other Identifiers

4R33MH122464-03

Identifier Type: NIH

Identifier Source: secondary_id

View Link

222009-EXT

Identifier Type: -

Identifier Source: org_study_id