Depressive DisorderPhase 2DepMIND3NCT05746273
Depressed Mood Improvement Through Nicotine Dosing 3
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.
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?
- Yes, some participants may receive a placebo
- How many people
- 40 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 6 weeks;
- severity: at least mild active depression symptoms, defined as MADRS ≥ 15;
- cognition: MMSE ≥ 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;
- 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 15Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Vanderbilt Psychiatric Hosptial
Nashville, Tennessee, 37212
About this study
Official title: Nicotinic Modulation of the Cognitive Control System in Late-Life Depression (R33 Phase)
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.
Read the 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
- Being tested
- Transdermal Nicotine Patch, Transdermal Placebo Patch
- Keywords
- geriatrics, aging, elderly, cognition, memory, nicotine transdermal 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. 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 PatchDrug
Also called Placebo Patches
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Transdermal Placebo Patch |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
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.
Measured: Baseline to week 6.
Secondary outcomes (13)
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
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
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
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
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
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
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
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
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
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
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
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 and to week 12
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 to week 12
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Feb 2023
- Study start15 Apr 2023
- Primary completion9 Jul 2026
- Study completion9 Jul 2026
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Depressive DisorderStudies of the same condition, open and under way.
- More trials run by Vanderbilt University Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 40 participants (actual)
Sponsor and investigators
- Lead sponsor
- Vanderbilt University Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH), University of North Carolina, Chapel Hill
- Responsible party
- Principal investigator, Patricia Andrews, Vanderbilt University Medical Center
- Investigators
- Warren Taylor, Study director, Vanderbilt University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05746273
- Sponsor's protocol ID
- 222009
- Other IDs
- 4R33MH122464-03
- Acronym
- DepMIND3
- 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, cognitive, and neuroimaging 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 of 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 30192444Sutherland 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 25662104Gandelman 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 28859996Aizenstein 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 19001356Alexopoulos 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 22425432Taylor 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.
PubMed 25251617
Study at a glance
From the registry record, last updated by the sponsor on 6 Aug 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Nicotinic Modulation of the Cognitive Control System in Late-Life Depression (R33 Phase)
- ClinicalTrials.gov ID
- NCT05746273
- Acronym / sponsor ID
- DepMIND3 / 222009
- Conditions
- Depressive Disorder
- Keywords
- geriatrics, aging, elderly, cognition, memory, nicotine transdermal patch, depression
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 40 participants (actual)
- Lead sponsor
- Vanderbilt University Medical CenterUniversity, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH), University of North Carolina, Chapel Hill
- Study start
- 15 Apr 2023 (actual)
- Primary completion
- 9 Jul 2026 (actual)
- Study completion
- 9 Jul 2026 (actual)
- First posted
- 27 Feb 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Transdermal Nicotine Patch | Experimental | Drug: Transdermal Nicotine PatchParticipants 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. |
| Transdermal Placebo Patch | Placebo comparator | Drug: Transdermal Placebo PatchParticipants 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. |
Who may qualify
- Ages
- 60 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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;
Key exclusion criteria (15 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Transdermal Nicotine PatchAlso: Nicoderm CQ, NicotrolParticipants 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. | Drug | Transdermal Nicotine Patch |
| Transdermal Placebo PatchAlso: Placebo PatchesParticipants 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. | Drug | Transdermal Placebo Patch |
Primary outcome
MADRS (Montgomery Asberg Depression Rating Scale) Score
Time frame: Baseline to week 12
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.
Functional Magnetic Resonance Imaging (MRI)
Time frame: Baseline to week 6.
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.
13 secondary outcomes
NIH EXAMINER Test Battery
Time frame: Baseline to Week 12
Selective Reminding Task
Time frame: Baseline to Week 12
Trait Adjectives Task
Time frame: Baseline to Week 12
Ruminative Response Scale
Time frame: Baseline to Week 12
Apathy Evaluation Scale (AES)
Time frame: Baseline to Week 12
Insomnia Severity Index
Time frame: Baseline to Week 12
Penn State Worry Questionnaire (PSWQ)
Time frame: Baseline to Week 12
Fatigue Severity Scale
Time frame: Baseline to Week 12
General Anxiety Disorder Scale (7 Item)
Time frame: Baseline to Week 12
PROMIS Applied Cognition Abilities Short
Time frame: Baseline to Week 12
Attentional Control Scale
Time frame: Baseline to Week 12
Monetary Incentive Delay Task
Time frame: Baseline and to week 12
Probabilistic Selection Task
Time frame: Baseline and to week 12
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Aug 2026.
- Background: PubMed 30192444Gandelman 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.
- Background: PubMed 25662104Sutherland 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.
- Background: PubMed 28859996Gandelman 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.
- Background: PubMed 19001356Aizenstein 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.
- Background: PubMed 22425432Alexopoulos 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.
- Background: PubMed 25251617Taylor 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.
- Individual participant dataSharing planned: Yes. This study will include clinical, cognitive, and neuroimaging 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 of 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Warren Taylor study director
Vanderbilt University Medical Center
1 site in 1 country: see every site and its status.
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 15 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. Some participants in this study may receive a placebo. 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?
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 NCT05746273, which also lists 6 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.