<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04433767</url>
  </required_header>
  <id_info>
    <org_study_id>200457</org_study_id>
    <nct_id>NCT04433767</nct_id>
  </id_info>
  <brief_title>Depressed Mood Improvement Through Nicotine Dosing 2</brief_title>
  <acronym>DepMIND2</acronym>
  <official_title>Nicotinic Modulation of the Cognitive Control System in Late-life Depression</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vanderbilt University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Vanderbilt University Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Deficits in cognitive control are core features of late-life depression, contributing both to&#xD;
      emotion dysregulation and problems with inhibiting irrelevant information, conflict&#xD;
      detection, and working memory. Clinically characterized as executive dysfunction, these&#xD;
      deficits are associated with poor response to antidepressants and higher levels of&#xD;
      disability. Improvement of cognitive control network (CCN) dysfunction may benefit both mood&#xD;
      and cognitive performance, however no current pharmacotherapy improves CCN deficits in LLD.&#xD;
      Supported by pilot data, Investigators propose that nicotine acetylcholine receptor agonists&#xD;
      enhance CCN function and resultantly improve mood and cognitive performance in late-life&#xD;
      depression. The objective of this initial R61-phase trial is to first determine whether&#xD;
      transdermal nicotine enhances CCN neural activity in an exposure-dependent fashion during an&#xD;
      emotional response inhibition task (the emotional Stroop task). Investigator's approach for&#xD;
      the R61 phase is to examine in 36 older adults with Major Depressive Disorder whether&#xD;
      transdermal nicotine patches enhance CCN activity over 12 weeks as measured during fMRI with&#xD;
      the emotional Stroop task while measuring nicotine and nicotine metabolite levels.&#xD;
      Transdermal nicotine has a mechanism of action that is distinct from current antidepressants,&#xD;
      potentially making it a potentially important antidepressant augmentation agent. If&#xD;
      hypotheses are correct, as patches are commercially available, this approach could be rapidly&#xD;
      moved into definitive studies and may have applicability to other psychiatric disorders&#xD;
      characterized by CCN dysfunction.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Late-life depression (LLD) is characterized both by affective symptoms and broad cognitive&#xD;
      deficits. The co-occurrence of cognitive deficits in LLD, particularly executive dysfunction,&#xD;
      is a clinically relevant phenotype characterized by significant disability and poor&#xD;
      antidepressant response. Cognitive deficits can persist even with successful antidepressant&#xD;
      treatment and increase the risk of depression relapse. Despite the clinical importance of&#xD;
      cognitive deficits in LLD, there are no established treatments that specifically target&#xD;
      cognition in this population. This is particularly important, as the cognitive deficits&#xD;
      appear to directly contribute to disability and poor antidepressant treatment outcomes. The&#xD;
      lack of clear pharmacologic targets and therapies aimed at improving cognitive deficits in&#xD;
      depression is a substantial deficiency in current therapeutics.&#xD;
&#xD;
      Modulation of the cholinergic system by nicotinic receptor stimulation may improve both mood&#xD;
      and cognition in depressed elders. Clinically, transdermal nicotine improves mood in smokers&#xD;
      and a placebo-controlled pilot trial in nonsmoking adults found that transdermal nicotine&#xD;
      significantly improved mood. As observed in smokers, nicotine's effect to increase cognitive&#xD;
      control network activity while reducing default mode network activity will reduce&#xD;
      depression's characteristic bias to negatively valenced stimuli and decrease rumination.&#xD;
      Supporting this theory, nicotinic receptor activity stimulates serotonin release and protects&#xD;
      against worsening mood with tryptophan depletion.&#xD;
&#xD;
      The Depressed Mind 2 Study examines whether enhancement of CCN function by nicotinic&#xD;
      acetylcholine receptor agonists will improve mood and cognitive symptoms in LLD. This is&#xD;
      supported by pilot data demonstrating that open-label administration of transdermal nicotine&#xD;
      (TDN) patches safely improved depression severity. The investigators also observed trends&#xD;
      suggesting that TDN may provide benefit for cognitive performance, specifically in domains of&#xD;
      episodic memory, working memory, and attention. In other pilot data using an emotional Stroop&#xD;
      task, TDN reduces the differences in functional magnetic resonance imaging (fMRI) activation&#xD;
      in the cognitive control network (CCN) between Stroop conditions. Importantly, this&#xD;
      activation change was associated with a corresponding reduction in depression severity. Based&#xD;
      on these data, investigators hypothesize that nicotinic receptor agonists enhance CCN&#xD;
      function in LLD and in turn this may improve depressive symptoms.&#xD;
&#xD;
      Thirty-six participants will be enrolled to test for target engagement, defined as TDN&#xD;
      exposure dependent effect in CCN activation. Based on pilot data, the study will test for&#xD;
      enhancement of CCN function by examining the Stroop fMRI response, or the reduction in CCN&#xD;
      activation between incongruent and congruent conditions of the emotional Stroop task during&#xD;
      fMRI. Investigators will assess the effects of variability in nicotine exposure on target&#xD;
      engagement by measuring nicotine blood levels in conjunction with repeat MRI.&#xD;
&#xD;
      Primary aim: To test CCN engagement over 12 weeks of Open labeled Transdermal Nicotine(TDN).&#xD;
&#xD;
      Hypothesis1A(Target Engagement): TDN will enhance CCN function, measured as a reduction in&#xD;
      the M/SFG Stroop BOLD response (the activation difference between incongruent and congruent&#xD;
      conditions of the emotional Stroop task). 60% or more of subjects will exhibit a M/SFG&#xD;
      z-score reduction of 0.5 or greater.&#xD;
&#xD;
      Hypothesis1B (Exposure): Higher nicotine exposure measured by patch dose or nicotine&#xD;
      metabolite levels will be associated with a greater reduction in the M/SFG Stroop BOLD&#xD;
      response.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 15, 2020</start_date>
  <completion_date type="Actual">October 7, 2022</completion_date>
  <primary_completion_date type="Actual">October 7, 2022</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>MADRS (Montgomery Asberg Depression Rating Scale) Score</measure>
    <time_frame>Baseline to week 12</time_frame>
    <description>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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Functional Magnetic Resonance Imaging (MRI)</measure>
    <time_frame>Baseline, week 6, week 12</time_frame>
    <description>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 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.&#xD;
The primary outcome will be change in activation difference from baseline to week 12. 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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Continuous Performance Task (CPT) Performance</measure>
    <time_frame>Baseline to week 12</time_frame>
    <description>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 &quot;X&quot;. 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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>NIH EXAMINER Test Battery</measure>
    <time_frame>Baseline to week 12</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Choice Reaction Time (CRT) Performance</measure>
    <time_frame>Baseline to week 12</time_frame>
    <description>Secondary cognitive outcome, a neuropsychological test measure of attention. We will examine the total response time for the CRT. Lower scores indicate better performance.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Selective Reminding Task</measure>
    <time_frame>Baseline to week12</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Trait Adjectives Task</measure>
    <time_frame>Baseline to week 12</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ruminative Response Scale</measure>
    <time_frame>Baseline to week12</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Apathy Evaluation Scale (AES)</measure>
    <time_frame>Baseline to week12</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Insomnia Severity Index</measure>
    <time_frame>Baseline to week 12</time_frame>
    <description>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 .</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Penn State Worry Questionnaire (PSWQ)</measure>
    <time_frame>Baseline to week 12</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fatigue Severity Scale</measure>
    <time_frame>Baseline to week12</time_frame>
    <description>Secondary fatigue out come :self-reported questionnaire that ranges from 0- 56;where higher scores indicate severe fatigue.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Snaith-Hamilton Pleasure Scale (SHAPS)</measure>
    <time_frame>Baseline to week 12</time_frame>
    <description>Secondary mood outcome: Change in anhedonia measured by SHAPS, a self-report questionnaire that ranges from 0-42, where higher scores indicate greater anhedonia.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>General Anxiety Disorder</measure>
    <time_frame>Baseline to week 12</time_frame>
    <description>Secondary Mood outcome: self-reported questionnaire to measure the severity of anxiety. Questionnaire ranges 0-24, higher scores indicates greater anxiety state.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PROMIS Applied Cognition Abilities Short</measure>
    <time_frame>Baseline to week12</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Attentional Control Scale</measure>
    <time_frame>Baseline to week 12</time_frame>
    <description>Secondary Attention 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</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">34</enrollment>
  <condition>Depressive Disorder</condition>
  <arm_group>
    <arm_group_label>Transdermal Nicotine Patch</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Transdermal Nicotine patch</intervention_name>
    <description>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.&#xD;
After week 12 , dose will be slowly tapered over 3 weeks.</description>
    <arm_group_label>Transdermal Nicotine Patch</arm_group_label>
    <other_name>Nicoderm CQ</other_name>
    <other_name>Nicotrol</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age &gt; 60 years;&#xD;
&#xD;
          2. Diagnosis of major depressive disorder, single or recurrent episode (DSM5);&#xD;
&#xD;
          3. On a stable therapeutic dose of an allowed SSRI or SNRI for at least 8 weeks;&#xD;
&#xD;
          4. Severity: Montgomery-Asberg Depression Rating Scale (MADRS) score ≥ 15;&#xD;
&#xD;
          5. Cognition: Mini-Mental State Examination (MMSE) score ≥ 24;&#xD;
&#xD;
          6. Fluent in English&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Other Axis I psychiatric disorders, except for generalized anxiety disorder (GAD)&#xD;
             symptoms occurring in a depressive episode;&#xD;
&#xD;
          2. Use of other medications for depression, e.g., bupropion or augmenting agents,&#xD;
             although short-acting sedatives are allowed (see below);&#xD;
&#xD;
          3. Any use of tobacco or nicotine in the last year;&#xD;
&#xD;
          4. Living with a smoker or regular exposure to secondhand smoke;&#xD;
&#xD;
          5. History of alcohol use disorder or substance use disorder of moderate or greater&#xD;
             severity (endorsing 4 or more of the 12 criteria) in the last 12 months;&#xD;
&#xD;
          6. Acute suicidality;&#xD;
&#xD;
          7. Acute grief (&lt;1 month);&#xD;
&#xD;
          8. Current or past psychosis;&#xD;
&#xD;
          9. Primary neurological disorder, including dementia, stroke, epilepsy, etc.;&#xD;
&#xD;
         10. MRI contraindication;&#xD;
&#xD;
         11. Electroconvulsive therapy or transcranial magnetic stimulation in last 2 months;&#xD;
&#xD;
         12. Current or planned psychotherapy;&#xD;
&#xD;
         13. Allergy or hypersensitivity to nicotine patches;&#xD;
&#xD;
         14. In the last 4 weeks, regular use of drugs with central cholinergic or anticholinergic&#xD;
             properties or moderate / severe CYP2A6 inhibitors /inducers.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>60 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Warren D Taylor, MD,MHSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>Vanderbilt University Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Vanderbilt Psychiatric Hospital</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37212</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <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.</citation>
    <PMID>30192444</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>25662104</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>28859996</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>19001356</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>22425432</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>25251617</PMID>
  </reference>
  <verification_date>December 2022</verification_date>
  <study_first_submitted>June 12, 2020</study_first_submitted>
  <study_first_submitted_qc>June 12, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 16, 2020</study_first_posted>
  <last_update_submitted>December 6, 2022</last_update_submitted>
  <last_update_submitted_qc>December 6, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 9, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Vanderbilt University Medical Center</investigator_affiliation>
    <investigator_full_name>Warren Taylor</investigator_full_name>
    <investigator_title>Professor of Psychiatry</investigator_title>
  </responsible_party>
  <keyword>geriatrics</keyword>
  <keyword>aging</keyword>
  <keyword>elderly</keyword>
  <keyword>cognition</keyword>
  <keyword>memory</keyword>
  <keyword>nicotine transdermal patch</keyword>
  <keyword>depression</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Depressive Disorder</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nicotine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>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.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_time_frame>Data will be shared according to policies from the NDCT and NDA (NIMH Data Archive). Descriptive data, outcome measures and analyzed data will be shared will be shared within 4 months of when a publication is accepted. Study data will be shared through the NDCT indefinitely.</ipd_time_frame>
    <ipd_access_criteria>The NIH will provide access to scientific investigators for research purposes. Qualified researchers who have completed a Data Use Certification and received approval from the NDA Data Access Committee (DAC) may be approved to access broadly shared data. A separate request process exists for access to data in federated sources. Additionally, the DAC and support staff at NIH have access to NDA shared data.</ipd_access_criteria>
    <ipd_url>https://nda.nih.gov</ipd_url>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>May 6, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/67/NCT04433767/Prot_SAP_001.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>December 20, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/67/NCT04433767/ICF_002.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04433767
org study id: 200457
nct id: NCT04433767
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
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.
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 M/SFG Stroop BOLD 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 BOLD
      response.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: MADRS (Montgomery Asberg Depression Rating Scale) Score
time frame: Baseline to week 12
description: 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.
measure: Functional Magnetic Resonance Imaging (MRI)
time frame: Baseline, week 6, week 12
description: 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 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 12. 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.
measure: Continuous Performance Task (CPT) Performance
time frame: Baseline to week 12
description: 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.
measure: NIH EXAMINER Test Battery
time frame: Baseline to week 12
description: 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.
measure: Choice Reaction Time (CRT) Performance
time frame: Baseline to week 12
description: Secondary cognitive outcome, a neuropsychological test measure of attention. We will examine the total response time for the CRT. Lower scores indicate better performance.
measure: Selective Reminding Task
time frame: Baseline to week12
description: 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.
measure: Trait Adjectives Task
time frame: Baseline to week 12
description: 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.
measure: Ruminative Response Scale
time frame: Baseline to week12
description: 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
measure: Apathy Evaluation Scale (AES)
time frame: Baseline to week12
description: 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.
measure: Insomnia Severity Index
time frame: Baseline to week 12
description: 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 .
measure: Penn State Worry Questionnaire (PSWQ)
time frame: Baseline to week 12
description: 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.
measure: Fatigue Severity Scale
time frame: Baseline to week12
description: Secondary fatigue out come :self-reported questionnaire that ranges from 0- 56;where higher scores indicate severe fatigue.
measure: Snaith-Hamilton Pleasure Scale (SHAPS)
time frame: Baseline to week 12
description: Secondary mood outcome: Change in anhedonia measured by SHAPS, a self-report questionnaire that ranges from 0-42, where higher scores indicate greater anhedonia.
measure: General Anxiety Disorder
time frame: Baseline to week 12
description: Secondary Mood outcome: self-reported questionnaire to measure the severity of anxiety. Questionnaire ranges 0-24, higher scores indicates greater anxiety state.
measure: PROMIS Applied Cognition Abilities Short
time frame: Baseline to week12
description: 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.
measure: Attentional Control Scale
time frame: Baseline to week 12
description: Secondary Attention 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
arm group label: Transdermal Nicotine Patch
arm group type: Experimental
description: 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.
intervention type: Drug
intervention name: Transdermal Nicotine patch
description: 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.
arm group label: Transdermal Nicotine Patch
other name: Nicoderm CQ
other name: Nicotrol
criteria: 
gender: All
minimum age: 60 Years
maximum age: N/A
healthy volunteers: No
last name: Warren D Taylor, MD,MHSc
role: Principal Investigator
affiliation: Vanderbilt University Medical Center
facility: 
country: United States
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.
PMID: 30192444
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.
PMID: 25662104
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.
PMID: 28859996
citation: 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.
PMID: 19001356
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.
PMID: 22425432
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.
PMID: 25251617
responsible party type: Principal Investigator
investigator affiliation: Vanderbilt University Medical Center
investigator full name: Warren Taylor
investigator title: Professor of Psychiatry
mesh term: Depressive Disorder
mesh term: Nicotine
sharing ipd: Yes
ipd description: 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.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd time frame: Data will be shared according to policies from the NDCT and NDA (NIMH Data Archive). Descriptive data, outcome measures and analyzed data will be shared will be shared within 4 months of when a publication is accepted. Study data will be shared through the NDCT indefinitely.
ipd access criteria: The NIH will provide access to scientific investigators for research purposes. Qualified researchers who have completed a Data Use Certification and received approval from the NDA Data Access Committee (DAC) may be approved to access broadly shared data. A separate request process exists for access to data in federated sources. Additionally, the DAC and support staff at NIH have access to NDA shared data.
ipd url: https://nda.nih.gov
provided document: 
provided document: 