Depressed Mood Improvement Through Nicotine Dosing 2

NCT04433767 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: 200457
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 1

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.

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 Change

  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.

  Baseline to week 12

• Number of Participants Exhibiting Reduction in Frontal Activation During the Emotional Stroop Task During Functional Magnetic Resonance Imaging (MRI)

  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.

  Baseline, week 6, week 12

Secondary Outcomes (20)

• 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

Study Arms (1)

Transdermal Nicotine Patch

EXPERIMENTAL

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.

Drug: Transdermal Nicotine patch

Interventions

Transdermal Nicotine patch DRUG

Participants will begin a 12- week open label trial of transdermal nicotine patch during the day and remove it at night (16 hours). Dose titration starting at 3.5 mg patch/daily to maximum of 21mg patch/daily. After week 12 , dose will be slowly tapered over 3 weeks.

Also known as: Nicoderm CQ, Nicotrol

Transdermal Nicotine 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 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

You may not qualify if:

• 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;
• Electroconvulsive therapy or transcranial magnetic stimulation in last 2 months;
• Current or planned psychotherapy;
• 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

• Vanderbilt University Medical Center: lead

Study Sites (1)

Vanderbilt Psychiatric Hospital

Nashville, Tennessee, 37212, United States

Location

Related Publications (7)

• 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

• Andrews P, Vega JN, Szymkowicz SM, Newhouse P, Tyndale R, Elson D, Kang H, Siddiqi S, Tyner EB, Mather K, Gunning FM, Taylor WD. Effects of open-label transdermal nicotine antidepressant augmentation on affective symptoms and executive function in late-life depression. J Affect Disord. 2024 Oct 1;362:416-424. doi: 10.1016/j.jad.2024.07.025. Epub 2024 Jul 14.

  PMID: 39009312 DERIVED

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

Limitations and Caveats

Small, open-label study design

Results Point of Contact

• Title: Warren Taylor, MD, Director of the DIvision of Geriatric Psychiatry
• Organization: Vanderbilt University Medical Cdenter

warren.d.taylor@vumc.org

615-322-1073

Study Officials

• Warren D Taylor, MD,MHSc

  Vanderbilt University Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Psychiatry

Study Record Dates

• First Submitted: June 12, 2020
• First Posted: June 16, 2020
• Study Start: December 15, 2020
• Primary Completion: October 7, 2022
• Study Completion: October 7, 2022
• Last Updated: December 6, 2023
• Results First Posted: December 6, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data will be shared according to policies from the NDCT and the NIMH Data Archive (NDA). 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 NDCT 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)