Depressive Disorder Clinical Trial
— DepMIND3Official 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.
Status | Recruiting |
Enrollment | 60 |
Est. completion date | September 30, 2026 |
Est. primary completion date | October 31, 2025 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 60 Years and older |
Eligibility | Inclusion Criteria: 1. Age = 60 years; 2. diagnosis of major depressive disorder, single or recurrent episode (DSM5); 3. On a stable therapeutic dose of an allowed SSRI or SNRI for at least 6 weeks; 4. severity: at least mild active depression symptoms, defined as MADRS = 15; 5. cognition: MMSE = 24; 6. fluent in English Exclusion Criteria: 1. 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); 2. 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; 3. Any use of tobacco or nicotine in the last year. 4. Living with a smoker or regular exposure to secondhand smoke. 5. 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. 6. Acute suicidality. 7. Acute grief (<1 month); 8. Current or past psychosis. 9. Primary central nervous system neurological disorder, including dementia, stroke, epilepsy, etc.; 10. Presence of unstable medical illness requiring urgent treatment or intervention; 11. MRI contraindication. 12. Electroconvulsive therapy or transcranial magnetic stimulation in last 2 months; 13. Current or planned psychotherapy where the potential participant does not want to pause therapy for the duration of the study; 14. Allergy or hypersensitivity to nicotine patches; 15. In the last 4 weeks, regular use of drugs with central cholinergic or anticholinergic properties or moderate / severe CYP2A6 inhibitors /inducers |
Country | Name | City | State |
---|---|---|---|
United States | Vanderbilt Psychiatric Hosptial | Nashville | Tennessee |
Lead Sponsor | Collaborator |
---|---|
Vanderbilt University Medical Center | National Institute of Mental Health (NIMH) |
United States,
Aizenstein HJ, Butters MA, Wu M, Mazurkewicz LM, Stenger VA, Gianaros PJ, Becker JT, Reynolds CF 3rd, Carter CS. Altered functioning of the executive control circuit in late-life depression: episodic and persistent phenomena. Am J Geriatr Psychiatry. 2009 Jan;17(1):30-42. doi: 10.1097/JGP.0b013e31817b60af. — View Citation
Alexopoulos GS, Hoptman MJ, Kanellopoulos D, Murphy CF, Lim KO, Gunning FM. Functional connectivity in the cognitive control network and the default mode network in late-life depression. J Affect Disord. 2012 Jun;139(1):56-65. doi: 10.1016/j.jad.2011.12.002. Epub 2012 Mar 15. — View Citation
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. — View Citation
Gandelman JA, Newhouse P, Taylor WD. Nicotine and networks: Potential for enhancement of mood and cognition in late-life depression. Neurosci Biobehav Rev. 2018 Jan;84:289-298. doi: 10.1016/j.neubiorev.2017.08.018. Epub 2017 Aug 30. — View Citation
Sutherland MT, Ray KL, Riedel MC, Yanes JA, Stein EA, Laird AR. Neurobiological impact of nicotinic acetylcholine receptor agonists: an activation likelihood estimation meta-analysis of pharmacologic neuroimaging studies. Biol Psychiatry. 2015 Nov 15;78(10):711-20. doi: 10.1016/j.biopsych.2014.12.021. Epub 2015 Jan 7. — View Citation
Taylor WD. Clinical practice. Depression in the elderly. N Engl J Med. 2014 Sep 25;371(13):1228-36. doi: 10.1056/NEJMcp1402180. No abstract available. — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | 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. | Baseline to week 12 | |
Primary | 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. | Baseline to week 6. | |
Primary | Continuous Performance Task (CPT) Performance | Primary cognitive outcome, the CPT is a neuropsychological test that measures attention conducted as part of the NIH EXAMINER Test Battery. In this test, participants are asked to respond to a target image and not to other images. This test is conducted at baseline and at week12. The specific primary outcome metric is standard error of change in the inter-stimulus hit reaction time or variability between different trials. There is not absolute range, but lower scores indicate decreased variability across trials and overall better performance. | Baseline to Week 12 | |
Secondary | 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. | Baseline to Week 12 | |
Secondary | Choice Reaction Time (CRT) Performance | Secondary cognitive outcome, a neuropsychological test measure of attention. We will examine the total response time for the CRT. Lower scores indicate better performance. | Baseline to Week 12 | |
Secondary | 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. | Baseline to Week 12 | |
Secondary | 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. | Baseline to Week 12 | |
Secondary | 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. | Baseline to Week 12 | |
Secondary | 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 Week 12 | |
Secondary | 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. | Baseline to Week 12 | |
Secondary | 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. | Baseline to Week 12 | |
Secondary | Fatigue Severity Scale | Secondary fatigue out come :self-reported questionnaire that ranges from 0- 56;where higher scores indicate severe fatigue. | Baseline to Week 12 | |
Secondary | 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. | Baseline to Week 12 | |
Secondary | 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. | Baseline to Week 12 | |
Secondary | 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. | Baseline to Week 12 |
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