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Depressive DisorderPhase 2NCT05746546

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

A Phase 2 study testing Transdermal Nicotine patch in people with Depressive Disorder, run by Vanderbilt University Medical Center at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 60 years and older
Conditions the study is for
Depressive Disorder
What is being tested?
Transdermal Nicotine patch
Could I receive a placebo?
No, everyone receives an active treatment
How many people
25 participants
Where
1 siteUnited States
Study dates
15 Apr 2023to 9 Jul 2026
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 60 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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 8 weeks;
  • Severity: Montgomery-Asberg Depression Rating Scale (MADRS) score ≥ 15;
  • Cognition: Mini-Mental State Examination (MMSE) score ≥ 24;
  • Fluent in English

Who cannot join

  • 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 (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;
Show all 14Show fewer
  • 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.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Vanderbilt Psychiatric Hospital

    Nashville, Tennessee, 37212

Other trials in United States

About this study

Official title: Open Label Extension Study of Depressed Mood Improvement Through Nicotine (Depressed MIND3)

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.

Read the 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.

Being tested
Transdermal Nicotine patch
Keywords
Geriatrics, aging, elderly, cognition, memory, Transdermal Nicotine Patch, depression
Medical subject headings
Depressive Disorder, Depression

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Transdermal Nicotine patchDrug

    Also called Nicoderm CQ, Nicotrol

    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.

Study groups in NCT05746546
Study groupRoleWhat they receive
Transdermal Nicotine PatchExperimentalParticipants 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.
Receives: Drug: Transdermal Nicotine patch

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change in 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.

    Measured: Baseline to week 12

  2. Change in Continuous Performance Task (CPT) Performance

    Primary cognitive outcome, the CPT is a neuropsychological test that is conducted as part of the NIH EXAMINER Test Battery. Participants are asked to respond to a target image, and not to other images. This test is conducted at baseline and at week12. The specific primary outcome metric is standard error of change in the inter-stimulus hit reaction time or variability between different trials. There is not absolute range, but lower scores indicate decreased variability across trials and overall better performance.

    Measured: Baseline to Week 12

Secondary outcomes (13)

  1. NIH EXAMINER Test Battery

    Secondary Cognitive Outcome: This neuropsychological test battery assesses a range of executive functions. We will examine its Executive Composite Score and the three factor scores (Cognitive Control, Fluency, and Working Memory). Higher scores indicate better performance.

    Measured: Baseline to Week 12

  2. Selective Reminding Task

    Secondary cognitive outcome, Selective Reminding Task as a test of immediate and delayed verbal memory. This is an 8-trial, 16-word test where the interviewer reads unrelated words to the participant who must recall them. Any missed items are then repeated before the next attempt. Alternative word lists are available for repeated assessments. A delayed trial is administered after 20 minutes. Change in the recall, failure to recall and consistency over 12 weeks reflect the verbal memory function.

    Measured: Baseline to Week 12

  3. Trait Adjectives Task

    Participants view a series of randomized, rapidly presented positive and negative characteristics and quickly indicate whether each adjective does or does not apply to them. Positive and negative adjectives are balanced. Measures include number of adjectives endorsed or rejected, and RT for those trials. Task performance assesses self-referential negativity bias and is associated with antidepressant response. Anticipate increased endorsement of positive adjective and increased rejection of negative adjectives in the active arm.

    Measured: Baseline to Week 12

  4. Ruminative Response Scale

    Secondary mood outcome: Change in rumination measured by the Ruminative Response Scale total score measured at Screening visit, week 6 and week 12. This is a self-report scale with a range of 0-66, where higher scores indicate higher levels of rumination.

    Measured: Baseline to Week 12

  5. Apathy Evaluation Scale (AES)

    Secondary Mood Outcomes: Change in apathy as measured by the self-report AES, a questionnaire with a range of 0-54, where lower scores indicate greater apathy.

    Measured: Baseline to Week 12

  6. Insomnia Severity Index

    Secondary Mood Outcomes: Change in the severity of insomnia measures as self-report, a questionnaire with the range of 0-21, where higher scores indicate increase in severity.

    Measured: Baseline to Week 12

  7. Penn State Worry Questionnaire (PSWQ

    Secondary mood outcome: Change in anxiety and worry measured by PSWQ, a self-report questionnaire with a range of 16-80, where higher scores indicate greater anxiety and worry.

    Measured: Baseline to Week 12

  8. Fatigue Severity Scale

    Secondary fatigue out come :self-reported questionnaire that ranges from 0- 56;where higher scores indicate severe fatigue.

    Measured: Baseline to Week 12

  9. General Anxiety Disorder Scale (7 Item)

    Secondary Mood outcome: self-reported questionnaire to measure the severity of anxiety. Questionnaire ranges 0-24, higher scores indicates greater anxiety state.

    Measured: Baseline to Week 12

  10. PROMIS Applied Cognition Abilities Short

    Secondary Cognitive outcome:PROMIS (Patient reported outcome measurement information system) is a self-reported questionnaire to measure mental acuity, concentration, verbal and nonverbal memory, verbal fluency, and perceived changes in these cognitive functions, ranges from 0-32 , where higher scores indicate improvement.

    Measured: Baseline to Week 12

  11. Attentional Control Scale

    Secondary Cognitive outcome: The Attentional Control Scale (ACS) is a self-report questionnaire that has been developed to measure individual differences in attentional control. These findings are discussed in relation to previous studies on attentional and executive control in anxiety and depression. Higher scores indicative of better attentional control.

    Measured: Baseline to Week 12

  12. Monetary Incentive Delay Task

    Secondary cognitive outcome. This task assesses neural response during reward anticipation and receipt.

    On each trial, participants are presented with a cue indicating that trial's reward value ($0, $1, $2, or $4). After the cue, a delay period ensues as the participant waits for the target. Participants press a button as quickly as possible when the target is visible. A feedback screen then appears indicating the outcome ("Hit!" or "Miss!") for each trial, with a brief interval before the next trial. Target duration is continually adjusted during the session based on individual performance to keep success rate at 60%. Participants will complete trials over 15 minutes.

    Measured: Baseline to Week12

  13. Probabilistic Selection Task

    Secondary cognitive outcome to assess brain's reward system.Participants are instructed to choose between abstract stimuli via key press. The task is composed of two phases. During the first phase, subjects learn to associate 6 abstract visual stimuli with different reward probabilities. In phase 1, the various stimuli are always presented in pairs, where the sum of the two reward probabilities associated with each stimuli equal 100%. Participants learn that for each pair, choosing one stimuli over the other results in more reward. The subject is tested on this association in phase two. During phase two, the subject must decide between novel combinations of stimuli. Each stimuli is presented with the remaining four stimuli that it was not paired with in phase 1. Participants are instructed to win as many rewards as possible

    Measured: Baseline and at week 12

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted27 Feb 2023
  2. Study start15 Apr 2023
  3. Primary completion9 Jul 2026
  4. Study completion9 Jul 2026

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Basic science
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
25 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05746546
Sponsor's protocol ID
222009-EXT
Other IDs
4R33MH122464-03
Status last verified
Aug 2026
First submitted
14 Feb 2023
Last updated
6 Aug 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: This study will include clinical and cognitive, data from older depressed subjects. The final dataset will include clinical information about subject psychiatric diagnoses, psychiatric and medical history, cognitive data, and response to transdermal nicotine. We will share data via the National Institute for Mental Health Data Archive (NDA). NDA provides a secure platform for data-sharing allowing for communication of research data, tools, and supporting documents. As required by NDA, we will obtain a Global Unique Identifier (GUID) for each participant. We will additionally follow NDA requirements to certify and review data, as well as timeline requirements for data submission and data sharing. Sharing of neuroimaging data will also be facilitated by an XNAT system (xnat.org). XNAT is an open-source informatics software platform that assists in the management and archiving of imaging data.

Publications

  • 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.

    PubMed 30192444

  • 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.

    PubMed 25662104

  • 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.

    PubMed 28859996

  • 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.

    PubMed 19001356

  • 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.

    PubMed 22425432

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Transdermal Nicotine patch in people with Depressive Disorder, run by Vanderbilt University Medical Center at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 6 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in MADRS (Montgomery Asberg Depression Rating Scale) Score (time frame: Baseline to week 12). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05746546, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Aug 2026.

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