Depressive DisorderPhase 2DepMIND2NCT04433767
Depressed Mood Improvement Through Nicotine Dosing 2
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, 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
- 29 participants
- Where
- 1 siteUnited States
- Study dates
- 15 Dec 2020to 7 Oct 2022
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 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
Who cannot join
- 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;
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
About this study
Official title: Nicotinic Modulation of the Cognitive Control System in Late-life Depression
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.
Read the detailed description
Late-life depression (LLD) is characterized both by affective symptoms and broad cognitive deficits. The co-occurrence of cognitive deficits in LLD, particularly executive dysfunction, 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. This is particularly important, as the cognitive deficits appear to directly contribute to disability and poor antidepressant treatment outcomes. The lack of clear pharmacologic targets and therapies aimed at improving cognitive deficits in depression is a substantial deficiency in current therapeutics.
Modulation of the cholinergic system by nicotinic receptor stimulation may improve both mood and cognition in depressed elders. Clinically, transdermal nicotine improves mood in smokers and a placebo-controlled pilot trial in nonsmoking adults found that transdermal nicotine significantly improved mood. As observed in smokers, nicotine's effect to increase cognitive control network activity while reducing default mode network activity will reduce depression's characteristic bias to negatively valenced stimuli and decrease rumination. Supporting this theory, nicotinic receptor activity stimulates serotonin release and protects against worsening mood with tryptophan depletion.
The Depressed Mind 2 Study examines whether enhancement of CCN function by nicotinic acetylcholine receptor agonists will improve mood and cognitive symptoms in LLD. This is supported by pilot data demonstrating that open-label administration of transdermal nicotine (TDN) patches safely improved depression severity. The investigators also observed trends suggesting that TDN may provide benefit for cognitive performance, specifically in domains of episodic memory, working memory, and attention. In other pilot data using an emotional Stroop task, TDN reduces the differences in functional magnetic resonance imaging (fMRI) activation in the cognitive control network (CCN) between Stroop conditions. Importantly, this activation change was associated with a corresponding reduction in depression severity. Based on these data, investigators hypothesize that nicotinic receptor agonists enhance CCN function in LLD and in turn this may improve depressive symptoms.
Thirty-six participants will be enrolled to test for target engagement, defined as TDN exposure dependent effect in CCN activation. Based on pilot data, the study will test for enhancement of CCN function by examining the Stroop fMRI response, or the reduction in CCN activation between incongruent and congruent conditions of the emotional Stroop task during fMRI. Investigators will assess the effects of variability in nicotine exposure on target engagement by measuring nicotine blood levels in conjunction with repeat MRI.
Primary aim: To test CCN engagement over 12 weeks of Open labeled Transdermal Nicotine(TDN).
Hypothesis1A(Target Engagement): TDN will enhance CCN function, measured as a reduction in the middle or superior frontal gyri (M/SFG) Stroop functional MRI response (the activation difference between incongruent and congruent conditions of the emotional Stroop task). 60% or more of subjects will exhibit a M/SFG z-score reduction of 0.5 or greater.
Hypothesis1B (Exposure): Higher nicotine exposure measured by patch dose or nicotine metabolite levels will be associated with a greater reduction in the M/SFG Stroop fMRI response.
- Conditions
- Depressive Disorder
- Being tested
- Transdermal Nicotine 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 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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Transdermal Nicotine 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 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.
Measured: 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.
Measured: Baseline, week 6, week 12
Secondary outcomes (20)
NIH EXAMINER Test Battery Executive Composite Score Change
Secondary Cognitive Outcome: This neuropsychological test battery assesses a range of executive functions. Its Executive Composite Score is a single score that represents overall executive function performance across multiple individual neuropsychological tests, including the Dot counting test, the N-back test, the Flanker task, a continuous performance test, anti-saccades test, a set shifting test, and fluency tests. Higher scores indicate better executive function, with a range of -3.0 to 3.0. This composite is generated separately from EXAMINER sub scales.
Measured: Baseline to week 12
NIH EXAMINER Test Battery Cognitive Control Factor Change
Secondary Cognitive Outcome: This neuropsychological test battery assesses a range of executive functions. Its Cognitive Control Factor Score is a single score that represents cognitive control function performance across multiple individual neuropsychological tests, including the Flanker task, a continuous performance test, anti-saccades test, and a set shifting test. Higher scores indicate better executive function, with a range of -3.0 to 3.0. This is calculated independently of the executive composite or other factor scores.
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
NIH EXAMINER Test Battery Fluency Factor Change
Secondary Cognitive Outcome: This neuropsychological test battery assesses a range of executive functions. Its Fluency Factor Score is a single score that represents verbal fluency performance across phonemic and categorical fluency assessments. Higher scores indicate better executive function, with a range of -3.0 to 3.0. This is calculated independently of the executive composite or other factor scores.
Measured: Baseline to week 12
NIH EXAMINER Test Battery Working Memory Factor Change
Secondary Cognitive Outcome: The EXAMINER test battery Working Memory Factor Score is a single score that represents working memory performance across multiple individual neuropsychological tests, including the Dot counting and n-back tests. Higher scores indicate better executive function, with a range of -3.0 to 3.0. This is calculated independently of the executive composite or other factor scores.
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
Choice Reaction Time (CRT) Performance Change
Secondary cognitive outcome, a neuropsychological test measure of attention. We will examine change in total reaction time for the CRT. Lower reaction time indicates better performance.
Measured: Baseline to week 12
Selective Reminding Task Performance Change
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. Scores range from 0-60, with higher scores indicating better performance. Change in the recall over 12 weeks reflect the verbal memory function, with higher scores indicating better verbal memory performance.
Measured: Baseline to week12
Trait Adjectives Task, Change in Positive Items Endorsed
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. These are assessed separately for positive items endorsed and negative items rejected. Task performance assesses self-referential negativity bias and is associated with antidepressant response. Task completed at baseline, week 6, and week 12. Scores for positive items endorsed range from 0 to 24, with higher scores indicating more positive items being endorsed, so a reduction in negativity bias.
Measured: Assessed at baseline, week 6, and week 12, change from baseline to week 12 reported
Trait Adjectives Task, Change in Negative Items Rejected
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. These are assessed separately for positive items endorsed and negative items rejected. Task performance assesses self-referential negativity bias and is associated with antidepressant response. Task completed at baseline, week 6, and week 12. Scores for negative items rejected range from 0 to 24, with higher scores indicating that more negative items are rejected, thus a reduction in negativity bias.
Measured: Assessed at baseline, week 6, and week 12, change from baseline to week 12 reported
Trait Adjectives Task, Change in Reaction Time to Endorse Positive Items
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. These are assessed separately for positive items endorsed and negative items rejected. Task performance assesses self-referential negativity bias and is associated with antidepressant response. Task completed at baseline, week 6, and week 12. A score reduction represents increased reaction time.
Measured: Assessed at baseline, week 6, and week 12, change from baseline to week 12 reported
Trait Adjectives Task, Change in Reaction Time to Reject Negative Items
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. These are assessed separately for positive items endorsed and negative items rejected. Task performance assesses self-referential negativity bias and is associated with antidepressant response. Task completed at baseline, week 6, and week 12. A reduction in score indicates a faster reaction time.
Measured: Assessed at baseline, week 6, and week 12, change from baseline to week 12 reported
Ruminative Response Scale Score Change
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: Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.
Apathy Evaluation Scale (AES) Score Change
Secondary Mood Outcomes: Change in apathy as measured by the self-report AES, a questionnaire with a range of 0-54, where higher scores indicate greater apathy. Measured at baseline, week 6, and week 12.
Measured: Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.
Insomnia Severity Index Score Change
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. Assessed at baseline, week 6, and week 12.
Measured: Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.
Penn State Worry Questionnaire (PSWQ) Score Change
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. Assessed at baseline, week 6, and week 12.
Measured: Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.
Fatigue Severity Scale Score Change
Secondary outcome examining fatigue using a self-report questionnaire that ranges from 0- 56, where higher scores indicate more severe fatigue. Questionnaire administered at baseline, week 6, and week 12.
Measured: Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.
Dimensional Anhedonia Rating Scale (DARS) Score Change
Secondary mood outcome: Change in anhedonia measured by DARS, a self-report questionnaire that ranges from 0-68, where lower scores indicate greater anhedonia. Conversely, higher scores indicate greater ability to enjoy activities. Assessed at baseline, week 6, and week 12.
Measured: Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.
General Anxiety Disorder-7 Item Scale (GAD7) Score Change
Secondary Mood outcome: self-reported questionnaire to measure the severity of anxiety. Questionnaire ranges 0-24, higher scores indicates greater anxiety state. Assessed at baseline, week 6, and week 12.
Measured: Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.
Patient Reported Outcome Measurement Information System (PROMIS) Applied Cognition Abilities Short Form Score Change
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. Assessed at baseline, week 6, and week 12.
Measured: Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.
Attentional Control Scale Score Change
Secondary Attention outcome: The Attentional Control Scale (ACS) is a self-report questionnaire that has been developed to measure individual differences in attentional control. The scale ranges from 0-80, with higher scores indicative of better attentional control, and a positive change indicated improved attentional control. Assessed at baseline, week 6, and week 12.
Measured: Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.
Anxiety Sensitivity Index 3 (ASI-3) Score Change
The ASI-3 is a self-report questionnaire assesses anxiety sensitivity, or the fear of arousal-related sensations. Specifically these derive from the belief that anxiety- or arousal-based sensations have negative consequences. This self-report scale includes 18 items with scores ranging from 0 to 72, where higher scores indicate greater anxiety sensitivity.
Measured: Assessed at baseline, Week 6, and Week 12; only baseline to week 12 reported.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Jun 2020
- Study start15 Dec 2020
- Primary completion7 Oct 2022
- Study completion7 Oct 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (7)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
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 29 participants (actual)
Sponsor and investigators
- Lead sponsor
- Vanderbilt University Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Warren Taylor, Vanderbilt University Medical Center
- Investigators
- Warren D Taylor, MD,MHSc, Principal investigator, Vanderbilt University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04433767
- Sponsor's protocol ID
- 200457
- Acronym
- DepMIND2
- Status last verified
- Nov 2023
- First submitted
- 12 Jun 2020
- Last updated
- 6 Dec 2023
- Results posted
- Yes, on ClinicalTrials.gov
- 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 Database for Clinical Trials related to Mental Illness (NDCT). NDCT provides a secure platform for data-sharing allowing for communication of research data, tools, and supporting documents. As required by NDCT, we will obtain a Global Unique Identifier (GUID) for each participant. We will additionally follow NDCT 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 25251617Andrews 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.
PubMed 39009312
Study at a glance
From the registry record, last updated by the sponsor on 6 Dec 2023. 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
- ClinicalTrials.gov ID
- NCT04433767
- Acronym / sponsor ID
- DepMIND2 / 200457
- Conditions
- Depressive Disorder
- Keywords
- geriatrics, aging, elderly, cognition, memory, nicotine transdermal patch, depression
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 29 participants (actual)
- Lead sponsor
- Vanderbilt University Medical CenterUniversity, hospital or other
- Study start
- 15 Dec 2020 (actual)
- Primary completion
- 7 Oct 2022 (actual)
- Study completion
- 7 Oct 2022 (actual)
- First posted
- 16 Jun 2020 (actual)
- Results
- Posted 6 Dec 2023
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, 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.
Detailed description
Late-life depression (LLD) is characterized both by affective symptoms and broad cognitive deficits. The co-occurrence of cognitive deficits in LLD, particularly executive dysfunction, 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. This is particularly important, as the cognitive deficits appear to directly contribute to disability and poor antidepressant treatment outcomes. The lack of clear pharmacologic targets and therapies aimed at improving cognitive deficits in depression is a substantial deficiency in current therapeutics.
Modulation of the cholinergic system by nicotinic receptor stimulation may improve both mood and cognition in depressed elders. Clinically, transdermal nicotine improves mood in smokers and a placebo-controlled pilot trial in nonsmoking adults found that transdermal nicotine significantly improved mood. As observed in smokers, nicotine's effect to increase cognitive control network activity while reducing default mode network activity will reduce depression's characteristic bias to negatively valenced stimuli and decrease rumination. Supporting this theory, nicotinic receptor activity stimulates serotonin release and protects against worsening mood with tryptophan depletion.
The Depressed Mind 2 Study examines whether enhancement of CCN function by nicotinic acetylcholine receptor agonists will improve mood and cognitive symptoms in LLD. This is supported by pilot data demonstrating that open-label administration of transdermal nicotine (TDN) patches safely improved depression severity. The investigators also observed trends suggesting that TDN may provide benefit for cognitive performance, specifically in domains of episodic memory, working memory, and attention. In other pilot data using an emotional Stroop task, TDN reduces the differences in functional magnetic resonance imaging (fMRI) activation in the cognitive control network (CCN) between Stroop conditions. Importantly, this activation change was associated with a corresponding reduction in depression severity. Based on these data, investigators hypothesize that nicotinic receptor agonists enhance CCN function in LLD and in turn this may improve depressive symptoms.
Thirty-six participants will be enrolled to test for target engagement, defined as TDN exposure dependent effect in CCN activation. Based on pilot data, the study will test for enhancement of CCN function by examining the Stroop fMRI response, or the reduction in CCN activation between incongruent and congruent conditions of the emotional Stroop task during fMRI. Investigators will assess the effects of variability in nicotine exposure on target engagement by measuring nicotine blood levels in conjunction with repeat MRI.
Primary aim: To test CCN engagement over 12 weeks of Open labeled Transdermal Nicotine(TDN).
Hypothesis1A(Target Engagement): TDN will enhance CCN function, measured as a reduction in the middle or superior frontal gyri (M/SFG) Stroop functional MRI response (the activation difference between incongruent and congruent conditions of the emotional Stroop task). 60% or more of subjects will exhibit a M/SFG z-score reduction of 0.5 or greater.
Hypothesis1B (Exposure): Higher nicotine exposure measured by patch dose or nicotine metabolite levels will be associated with a greater reduction in the M/SFG Stroop fMRI response.
Study design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Transdermal Nicotine Patch | Experimental | Drug: Transdermal Nicotine patchParticipants 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. |
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 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;
Key exclusion criteria (14 listed)
- 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;
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 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. | Drug | Transdermal Nicotine Patch |
Primary outcome
MADRS (Montgomery Asberg Depression Rating Scale) Score Change
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. Change is calculated as the difference between week 12 and baseline.
Number of Participants Exhibiting Reduction in Frontal Activation During the Emotional Stroop Task During Functional Magnetic Resonance Imaging (MRI)
Time frame: Baseline, week 6, week 12
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.
20 secondary outcomes
NIH EXAMINER Test Battery Executive Composite Score Change
Time frame: Baseline to week 12
NIH EXAMINER Test Battery Cognitive Control Factor Change
Time frame: Baseline to week 12
NIH EXAMINER Test Battery Fluency Factor Change
Time frame: Baseline to week 12
NIH EXAMINER Test Battery Working Memory Factor Change
Time frame: Baseline to week 12
Choice Reaction Time (CRT) Performance Change
Time frame: Baseline to week 12
Selective Reminding Task Performance Change
Time frame: Baseline to week12
Trait Adjectives Task, Change in Positive Items Endorsed
Time frame: Assessed at baseline, week 6, and week 12, change from baseline to week 12 reported
Trait Adjectives Task, Change in Negative Items Rejected
Time frame: Assessed at baseline, week 6, and week 12, change from baseline to week 12 reported
Trait Adjectives Task, Change in Reaction Time to Endorse Positive Items
Time frame: Assessed at baseline, week 6, and week 12, change from baseline to week 12 reported
Trait Adjectives Task, Change in Reaction Time to Reject Negative Items
Time frame: Assessed at baseline, week 6, and week 12, change from baseline to week 12 reported
Ruminative Response Scale Score Change
Time frame: Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.
Apathy Evaluation Scale (AES) Score Change
Time frame: Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.
Insomnia Severity Index Score Change
Time frame: Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.
Penn State Worry Questionnaire (PSWQ) Score Change
Time frame: Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.
Fatigue Severity Scale Score Change
Time frame: Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.
Dimensional Anhedonia Rating Scale (DARS) Score Change
Time frame: Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.
General Anxiety Disorder-7 Item Scale (GAD7) Score Change
Time frame: Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.
Patient Reported Outcome Measurement Information System (PROMIS) Applied Cognition Abilities Short Form Score Change
Time frame: Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.
Attentional Control Scale Score Change
Time frame: Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.
Anxiety Sensitivity Index 3 (ASI-3) Score Change
Time frame: Assessed at baseline, Week 6, and Week 12; only baseline to week 12 reported.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Dec 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- 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.
- Derived from this study: PubMed 39009312Andrews 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.
- 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 Database for Clinical Trials related to Mental Illness (NDCT). NDCT provides a secure platform for data-sharing allowing for communication of research data, tools, and supporting documents. As required by NDCT, we will obtain a Global Unique Identifier (GUID) for each participant. We will additionally follow NDCT 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 D Taylor, MD,MHSc principal investigator
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 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 Dec 2023. 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?
Yes. Results are posted in the registry (first posted 6 Dec 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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 Change (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 NCT04433767, which also lists 7 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 Dec 2023.