Depressed Mood Improvement Through Nicotine Dosing 3

NCT05746273 | Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: 2220094R33MH122464-03
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

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.

Conditions

Depressive Disorder

Keywords

geriatrics; aging; elderly; cognition; memory; nicotine transdermal patch; depression

Outcome Measures

Primary Outcomes (2)

• MADRS (Montgomery Asberg Depression Rating Scale) Score

  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.

  Baseline to week 12

• Functional Magnetic Resonance Imaging (MRI)

  MRI scans will be performed at baseline and week 6. MRI will measure cognitive control network function, operationalized as a reduction in the Stroop BOLD response in the middle and superior frontal gyri. The Stroop BOLD response is calculated as the activation difference between incongruent and congruent conditions of the emotional Stroop task. The primary outcome will be change in activation difference from baseline to week 6. This will be examined as both a continuous variable and a categorical variable, operationalized as those subjects will exhibit a middle / superior frontal gyri z-score reduction in activation over time of 0.5 or greater.

  Baseline to week 6.

Secondary Outcomes (13)

• NIH EXAMINER Test Battery

  Baseline to Week 12

• Selective Reminding Task

  Baseline to Week 12

• Trait Adjectives Task

  Baseline to Week 12

• Ruminative Response Scale

  Baseline to Week 12

• Apathy Evaluation Scale (AES)

  Baseline to Week 12

Study Arms (2)

Transdermal Nicotine Patch

EXPERIMENTAL

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.

Drug: Transdermal Nicotine Patch

Transdermal Placebo Patch

PLACEBO COMPARATOR

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.

Drug: Transdermal Placebo Patch

Interventions

Transdermal Nicotine Patch 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.

Also known as: Nicoderm CQ, Nicotrol

Transdermal Nicotine Patch

Transdermal Placebo Patch 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.

Also known as: Placebo Patches

Transdermal Placebo Patch

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 60 years;
• diagnosis of major depressive disorder, single or recurrent episode (DSM5);
• On a stable therapeutic dose of an allowed SSRI or SNRI for at least 6 weeks;
• severity: at least mild active depression symptoms, defined as MADRS ≥ 15;
• cognition: MMSE ≥ 24;
• fluent in English

You may not qualify if:

• 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);
• 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;
• 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 central nervous system neurological disorder, including dementia, stroke, epilepsy, etc.;
• Presence of unstable medical illness requiring urgent treatment or intervention;
• MRI contraindication.
• Electroconvulsive therapy or transcranial magnetic stimulation in last 2 months;
• Current or planned psychotherapy where the potential participant does not want to pause therapy for the duration of the study;
• Allergy or hypersensitivity to nicotine patches;
• In the last 4 weeks, regular use of drugs with central cholinergic or anticholinergic properties or moderate / severe CYP2A6 inhibitors /inducers

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: collaborator
• Vanderbilt University Medical Center: lead
• National Institute of Mental Health (NIMH): collaborator

Study Sites (1)

Vanderbilt Psychiatric Hosptial

Nashville, Tennessee, 37212, United States

RECRUITING

Related Publications (6)

• 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.

  PMID: 30192444 BACKGROUND

• 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.

  PMID: 25662104 BACKGROUND

• 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.

  PMID: 28859996 BACKGROUND

• 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.

  PMID: 19001356 BACKGROUND

• 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.

  PMID: 22425432 BACKGROUND

• 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.

  PMID: 25251617 BACKGROUND

MeSH Terms

Conditions

Depressive Disorder; Depression

Interventions

Tobacco Use Cessation Devices; Nicotine

Condition Hierarchy (Ancestors)

Mood Disorders; Mental Disorders; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Therapeutics; Solanaceous Alkaloids; Alkaloids; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

Study Officials

• Warren Taylor

  Vanderbilt University Medical Center

  STUDY DIRECTOR

Central Study Contacts

Patricia Andrews, MD

CONTACT

(615) 936-3555; patricia.andrews@vumc.org

Carrie Williams

CONTACT

6159362162; carrie.e.williams@vumc.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double Blinded, using matching placebo patches.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director, Division of General Psychiatry and Division of Geriatric Psychiatry

Study Record Dates

• First Submitted: February 14, 2023
• First Posted: February 27, 2023
• Study Start: April 15, 2023
• Primary Completion (Estimated): July 31, 2026
• Study Completion (Estimated): September 30, 2026
• Last Updated: February 6, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data will be shared according to policies from the NDA (NIMH Data Archive). Descriptive data, outcome measures and analyzed data will be shared will be shared within 4 months of when a publication is accepted. Study data will be shared through the NDA indefinitely.
• Access Criteria: The NIH will provide access to scientific investigators for research purposes. Qualified researchers who have completed a Data Use Certification and received approval from the NDA Data Access Committee (DAC) may be approved to access broadly shared data. A separate request process exists for access to data in federated sources. Additionally, the DAC and support staff at NIH have access to NDA shared data.

Locations

US (1)