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Late-life depression is characterized by both affective (mood) symptoms and cognitive deficits. There is currently no intervention that may provide consistent benefits to both mood and cognitive performance. Agonist activity at the nicotinic acetylcholine receptors via transdermal nicotine patches may provide benefit to both mood and cognition, working through nicotine's effects on brain neural networks, specifically the cognitive control network and default mode network.
In this initial pilot project, the investigators will test this hypotheses in 15 nonsmoking depressed elders with subjective cognitive impairment. Following baseline neuroimaging and cognitive testing, participants will receive 12 weeks of open-label transdermal nicotine. Afterwards, participants will repeat neuroimaging and cognitive assessments.
Late-life depression (LLD) is characterized both by affective symptoms and 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 treatments that improve cognitive deficits in depression is a 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. In a previous trial examining Mild Cognitive Impairment, transdermal nicotine safely improved cognitive function on tests of attention, episodic memory, and processing speed. These same cognitive domains are impaired in LLD. The investigators hypothesize that these effects on mood and cognition are mediated through nicotine's effect to increase cognitive control network activity and reduce default mode network (DMN) activity. This pattern of network activity during tasks demanding external attention is associated with better task performance. Furthermore, as seen in smokers, nicotine's effect on these networks reduces depression's bias to negatively valenced stimuli and decreases rumination.
The central hypothesis is that in LLD, transdermal nicotine will safely improve depression by increasing activity in cognitive control regions and decreasing activity in DMN regions. This will result in a decreased attentional bias to and reactivity to negative stimuli. A secondary hypothesis is that transdermal nicotine will also improve subjective and objective cognitive performance through these same network effects.
Primary Aim 1: To determine whether administration of transdermal nicotine over 12 weeks improves clinical symptoms in patients with LLD with subjective cognitive impairment (SCI).
Hypothesis 1: Transdermal nicotine administration will result in reductions in depression severity measured by the Montgomery-Asberg Depression Rating Scale (MADRS; primary mood outcome). It will also result in improvement in broader assessments of depressive symptomatology, including anhedonia, apathy, fatigue, sleep, and rumination (secondary outcomes).
Hypothesis 2: Transdermal nicotine administration will result in improvements in attentional performance on the Conner's Continuous Performance Task (CPT; primary cognitive outcome). It will also result in improvement in subjective and objective cognitive performance on other tasks measuring attention, episodic memory, working memory, processing speed, and executive function (secondary outcomes).
Secondary Aim 2: To determine whether administration of transdermal nicotine over 12 weeks modulates canonical intrinsic functional network activity in LLD with SCI.
Hypothesis 3: On repeat administration of the Posner task of external attention, transdermal nicotine administration will result in increased activity within the cognitive control network and decreased activity within the default mode network.
Hypothesis 4: Transdermal nicotine administration will result in increased functional connectivity within the cognitive control network and decreased connectivity within the default mode network at rest.
Hypothesis 5: Changes in intrinsic network activity / connectivity with transdermal nicotine administration will be associated with changes in mood symptoms and subjective and objective cognitive performance.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Transdermal nicotine patch | Experimental | Transdermal nicotine patch, administered on awakening and removed at bedtime (16h/d). Dosing 3.5mg patch/daily, titrated over study to maximum dose of 21mg patch/daily. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Nicotine | Drug | Open-label transdermal nicotine patch |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change in Total MADRS (Montgomery Asberg Depression Rating Scale) Score | Primary mood outcome measured by the total score of the clinician-rated MADRS. MADRS was measured every 3 weeks (baseline, week 3, week 6, week 9, and week 12). MADRS total score range is 0-60, where higher scores indicate greater depression severity. | Baseline to week 12 |
| Change in Continuous Performance Task (CPT) Performance | Primary cognitive outcome, the CPT is a neuropsychological test that measures attention. In this 14-minute test, participants are asked to respond when any letter appears, except the non-target letter "X". This test is conducted at baseline and at week 12. The specific primary outcome metric is standard error of change in the inter-stimulus hit reaction time, or variability between different trials. There is no absolute range, but lower scores indicate decreased variability across trials and overall better performance. | Baseline to week 12 |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Snaith-Hamilton Pleasure Scale (SHAPS) Score | Secondary mood outcome: Change in anhedonia measured by SHAPS, a self-report questionnaire that ranges from 0-42, where higher scores indicate greater anhedonia. | Baseline to week 12 |
| Change in Penn State Worry Questionnaire (PSWQ) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Warren D Taylor, MD, MHSc | Vanderbilt University Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Vanderbilt Psychiatric Hospital | Nashville | Tennessee | 37212 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 30192444 | Derived | 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. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Transdermal Nicotine Patch | Transdermal nicotine patch, administered on awakening and removed at bedtime (16h/d). Dosing began at 3.5mg patch/daily, titrated over study to maximum dose of 21mg patch/daily. Dose could be reduced to the prior level or an intermediate level for tolerability. Titration schedule: 3.5mg patch x 1 week, 7mg patch x 2 weeks, 14mg patch x 3 weeks, 21mg patch x 6 weeks. Nicotine: Open-label transdermal nicotine patch |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Transdermal Nicotine Patch | Transdermal nicotine patch, administered on awakening and removed at bedtime (16h/d). Dosing began at 3.5mg patch/daily, titrated over study to maximum dose of 21mg patch/daily. Dose could be reduced to the prior level or an intermediate level for tolerability. Titration schedule: 3.5mg patch x 1 week, 7mg patch x 2 weeks, 14mg patch x 3 weeks, 21mg patch x 6 weeks. Nicotine: Open-label transdermal nicotine patch |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Total MADRS (Montgomery Asberg Depression Rating Scale) Score | Primary mood outcome measured by the total score of the clinician-rated MADRS. MADRS was 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. | Analyses included all participants, including the one subject who withdrew early. Missing values were imputed using the mean value of the sample at that time point. | Posted | Mean | Standard Deviation | units on a scale | Baseline to week 12 |
|
12 weeks
Adverse events collected through query of subjects about any new or worsening problems or side effects, conducted at each contact.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Transdermal Nicotine Patch | Transdermal nicotine patch, administered on awakening and removed at bedtime (16h/d). Dosing began at 3.5mg patch/daily, titrated over study to maximum dose of 21mg patch/daily. Dose could be reduced to the prior level or an intermediate level for tolerability. Titration schedule: 3.5mg patch x 1 week, 7mg patch x 2 weeks, 14mg patch x 3 weeks, 21mg patch x 6 weeks. Nicotine: Open-label transdermal nicotine patch |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea | Gastrointestinal disorders | Non-systematic Assessment |
Open label trial design Only 8/14 participants who completed the study could tolerate the maximum patch dose of 21mg. The other 6 could only tolerate a maximum dose of 10.5mg, primarily due to adverse events.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Warren D. Taylor, MD | Vanderbilt University Medical Center | 6153221073 | warren.d.taylor@vanderbilt.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Apr 13, 2017 | Jun 26, 2018 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D003865 | Depressive Disorder, Major |
| D003863 | Depression |
| ID | Term |
|---|---|
| D003866 | Depressive Disorder |
| D019964 | Mood Disorders |
| D001523 | Mental Disorders |
| D001526 | Behavioral Symptoms |
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| ID | Term |
|---|---|
| D009538 | Nicotine |
| ID | Term |
|---|---|
| D012991 | Solanaceous Alkaloids |
| D000470 | Alkaloids |
| D006571 | Heterocyclic Compounds |
| D011725 | Pyridines |
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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. |
| Baseline to week 12 |
| Change in Ruminative Response Scale Total Score | Secondary mood outcome: Change in rumination measured by the Ruminative Response Scale total score measured at baseline and week 12. This is a self-report scale with a range of 0-66, where higher scores indicate higher levels of rumination. | Baseline to week 12 |
| Change in 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. | Baseline to 12 weeks |
| Change in MFQ (Memory Frequency Questionnaire) Score | Secondary cognitive outcome: Change in subjective cognitive performance as measured by MFQ, a self-report scale ranging from 64-448. Higher scores indicate better subjective memory function, while lower scores indicate poorer subjective memory function. | Baseline to week 12 |
| Change in Choice Reaction Time (CRT) Performance | Secondary cognitive outcome, a neuropsychological test measure of attention. We examined the total response time for the CRT. Lower scores indicate better performance. | Baseline to week 12 |
| Change in One-back Test Performance | Secondary cognitive outcome examining change in speed of responses ton the one-back test, no absolute range. In this variant of the "N-back" task, participants view a series of cards, and indicate whether the card they are currently viewing is identical to the previously viewed card. Lower scores indicate better performance. | Baseline to week 12 |
| Change in NYU (New York University) Paragraph Recall Performance | Secondary cognitive outcome of a neuropsychological test examining episodic memory performance using the NYU Paragraph Recall test. No absolute range. Higher scores indicate better performance. | Baseline to week 12 |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Past smoker (defined as smoking at least 1 cigarette daily for at least 6 months over the lifetime) | Count of Participants | Participants |
|
| Depression severity (measured by Montgomery Asberg Depression Rating Scale total score) | The Montgomery-Asberg Depression Rating Scale (MADRS) is a clinician-rated measure of depression severity with a total score ranging from 0 to 60, where higher scores indicate greater depression severity. | Mean | Standard Deviation | units on a scale |
|
|
|
|
| Primary | Change in Continuous Performance Task (CPT) Performance | Primary cognitive outcome, the CPT is a neuropsychological test that measures attention. In this 14-minute test, participants are asked to respond when any letter appears, except the non-target letter "X". This test is conducted at baseline and at week 12. The specific primary outcome metric is standard error of change in the inter-stimulus hit reaction time, or variability between different trials. There is no absolute range, but lower scores indicate decreased variability across trials and overall better performance. | Subject who withdrew early not included due to no 12-week data. | Posted | Mean | Standard Deviation | milliseconds | Baseline to week 12 |
|
|
|
|
| Secondary | Change in Snaith-Hamilton Pleasure Scale (SHAPS) Score | Secondary mood outcome: Change in anhedonia measured by SHAPS, a self-report questionnaire that ranges from 0-42, where higher scores indicate greater anhedonia. | One subject not included due to early withdrawal | Posted | Mean | Standard Deviation | units on a scale | Baseline to week 12 |
|
|
|
|
| Secondary | Change in 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. | One participant not included due to early withdrawal. | Posted | Mean | Standard Deviation | units on a scale | Baseline to week 12 |
|
|
|
|
| Secondary | Change in Ruminative Response Scale Total Score | Secondary mood outcome: Change in rumination measured by the Ruminative Response Scale total score measured at baseline and week 12. This is a self-report scale with a range of 0-66, where higher scores indicate higher levels of rumination. | Subject who withdrew early not included due to no 12-week data. | Posted | Mean | Standard Deviation | units on a scale | Baseline to week 12 |
|
|
|
|
| Secondary | Change in 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. | Subject who withdrew early not included due to no 12-week data. | Posted | Mean | Standard Deviation | units on a scale | Baseline to 12 weeks |
|
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|
| Secondary | Change in MFQ (Memory Frequency Questionnaire) Score | Secondary cognitive outcome: Change in subjective cognitive performance as measured by MFQ, a self-report scale ranging from 64-448. Higher scores indicate better subjective memory function, while lower scores indicate poorer subjective memory function. | Subject who withdrew early not included due to no 12-week data. | Posted | Mean | Standard Deviation | units on a scale | Baseline to week 12 |
|
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|
| Secondary | Change in Choice Reaction Time (CRT) Performance | Secondary cognitive outcome, a neuropsychological test measure of attention. We examined the total response time for the CRT. Lower scores indicate better performance. | Subject who withdrew early not included due to no 12-week data. | Posted | Mean | Standard Error | milliseconds | Baseline to week 12 |
|
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|
| Secondary | Change in One-back Test Performance | Secondary cognitive outcome examining change in speed of responses ton the one-back test, no absolute range. In this variant of the "N-back" task, participants view a series of cards, and indicate whether the card they are currently viewing is identical to the previously viewed card. Lower scores indicate better performance. | Subject who withdrew early not included due to no 12-week data. | Posted | Mean | Standard Deviation | milliseconds | Baseline to week 12 |
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| Secondary | Change in NYU (New York University) Paragraph Recall Performance | Secondary cognitive outcome of a neuropsychological test examining episodic memory performance using the NYU Paragraph Recall test. No absolute range. Higher scores indicate better performance. | Subject who withdrew early not included due to no 12-week data. | Posted | Mean | Standard Error | Items correct | Baseline to week 12 |
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| 0 |
| 15 |
| 0 |
| 15 |
| 14 |
| 15 |
| Dizziness | Nervous system disorders | Non-systematic Assessment | Symptoms included feelings of dizziness or lightheadedness |
|
| Anxiety | Psychiatric disorders | Non-systematic Assessment | Increases in subjective anxiety or tension |
|
| Headache | Nervous system disorders | Non-systematic Assessment | New onset of headaches or worsening pre-existing headache problem |
|
| Vivid Dreams | Nervous system disorders | Non-systematic Assessment | Increase frequency / intensity of "vivid" or lifelike dreams |
|
| Patch site reaction | Skin and subcutaneous tissue disorders | Non-systematic Assessment | Rash or pruritus at site where nicotine patch was applied |
|
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| D001519 |
| Behavior |
| D006573 |
| Heterocyclic Compounds, 1-Ring |