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Neural Mechanisms of Monoaminergic Engagement in Late-life Depression Treatment Response (NEMO) (NEMO)

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ClinicalTrials.gov Identifier: NCT03128021
Recruitment Status : Recruiting
First Posted : April 25, 2017
Last Update Posted : November 3, 2020
Sponsor:
Collaborators:
Weill Cornell Institute of Geriatric Psychiatry
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
Howard Aizenstein, University of Pittsburgh

Brief Summary:

The Department of Psychiatry at the University of Pittsburgh is conducting a research study to learn about the changes that occur in the brain when individuals suffer from and then are treated for depression. The NEMO study has two main purposes. The first is to provide medication treatment to individuals ages 60 and older who are currently depressed.

The second part of the study involves completing a series of 4 MRIs, which assess changes in brain function over the course of treatment. This research may help investigators to develop faster and more effective treatment plans in the future, as brain responses that are detected early in treatment may predict how well an individual will respond to antidepressant medication.


Condition or disease Intervention/treatment Phase
Major Depressive Disorder Drug: Escitalopram Pill Other: Placebo Drug: Levomilnacipran Pill Phase 4

Detailed Description:

In this competing renewal (Year 11) of the investigators' R01 which has used functional magnetic resonance imaging (fMRI) to study late-life depression (LLD) pharmacotherapy (R01MH076079), the primary aim of this study is to characterize functional connectivity changes associated with initial medication exposure (12-hour challenge). Preliminary data suggests that these initial fMRI changes reflect monoaminergic engagement, regardless of monoaminergic class, and predict later treatment response. This study will test a neural systems level model that response in LLD is mediated by acute pharmacologically-induced changes in cognitive and affective large scale network.

Depression in older adults is frequently disabling and is often resistant to first-line treatments, requiring more prolonged treatment trials than in younger adults, mainly due to its heterogeneous pathophysiology (e.g. vascular and degenerative brain changes). Currently, there is little neurobiological data to guide changing or augmenting antidepressant medications. Thus, there has been a heightened focus on tailoring treatment to optimize outcome as described in the 2015 National Institute of Mental Health (NIMH) draft strategic plan (strategy 3.2). While antidepressant clinical response may take up to 8 weeks, recent studies suggest that physiologic changes, as measured with pharmacologic fMRI (phMRI) are seen within 12 hours of starting a new monoaminergic antidepressant (1).

For this proposal, investigators focus on three major Cognitive and Affective Networks (CAN): the Default Mode Network (DMN), the Salience Network (SN) and the Executive Control Network (ECN). The proposed model suggests that monoaminergic engagement leads to core CAN changes, changes that subsequently are related to overall clinical response as well as response in specific symptom clusters such as negative bias, somatizations/anxiety and cognitive control. The same networks that are functionally connected while individuals are at rest, are also selectively engaged during tasks. Investigators' prior work shows that pharmacotherapy - regardless of type of antidepressant used - engages these specific networks at rest and during standard cognitive and affective tasks. Given the role of cerebrovascular disease in LLD treatment response, the moderating role of vascular burden on the proposed association between CAN engagement and treatment response will also be explored.

The University of Pittsburgh will recruit 100 older adults with LLD that will be randomized to receive treatment with either a very specific serotonin reuptake inhibitor (escitalopram) or a norepinephrine reuptake inhibitor (levomilnacipran). A pair of fMRI scans one day apart will be used to measure functional connectivity (FC) associated with medication titration. Investigators will use a very early (12 hours after initiation of treatment) biomarker of treatment response, which, when validated, would decrease substantially the waiting time between medication changes. Additionally, this study will further increase knowledge of the acute neural system changes associated with monoaminergic antidepressants; this knowledge of mechanism is essential for both guiding LLD treatment research, and serving as an engagement target in LLD treatment research.

Note: The original study design involved randomization to escitalopram or placebo (instead of escitalopram and levomilnacipran). Therefore a subset of participants will complete the study according to this design.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 140 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Participants will be randomly assigned to take either escitalopram or levomilnacipran throughout the 12-week trial.

The following information applies to the original study design. Enrollment according to this design was complete as of April 2018: During Phase I, participants will be randomly assigned to take escitalopram or placebo daily for 6 weeks. After 6 weeks, participants who are randomly assigned to placebo will be given the option to have an open-label of escitalopram for Phase II. Those who did not respond to escitalopram in Phase I will be referred for alternate treatment. All participants, regardless of outcome will be asked to return for follow-up procedures.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Although this is a double-blinded study, one staff member will be unblinded regarding study randomization. Should the need ever arise, the blind can be instantly broken for the participant's safety and well-being.
Primary Purpose: Treatment
Official Title: Neural Mechanisms of Monoaminergic Engagement in Late-life Depression Treatment Response (NEMO)
Actual Study Start Date : May 24, 2017
Estimated Primary Completion Date : April 2022
Estimated Study Completion Date : July 2022


Arm Intervention/treatment
Active Comparator: Escitalopram Pill
Participants in this arm will receive an initial dose of 5 mg. Further titrations will be decided based on clinical response and tolerability (maximum dose of 20 mg). The medication will be taken by mouth in pill form, once daily.
Drug: Escitalopram Pill
Double-blinded, randomly assigned
Other Name: Lexapro

Placebo Comparator: Placebo

Participants will be given a sugar pill (placebo) to be taken by mouth once daily for the 6 week duration of Phase I. As this arm is also double-blinded, participants will receive an initial dose of 5 mg and further titrations (maximum dose of 20 mg) will be decided based on clinical response and tolerability.

Note: This arm no longer applies as of 5/16/18. Participants are now randomly assigned to Lexapro or Fetzima.

Other: Placebo
Double-blinded, randomly assigned

Escitalopram Pill (Phase II)

Participants who were in the placebo arm for Phase I who do not show signs of response to treatment by week 6 (defined as either a MADRS score of greater than 12 or less than a 30% reduction in MADRS score to be deemed a non-responder) will be given the option to have an open-label trial of escitalopram in Phase II.

Participants in this arm will receive an initial dose of 5 mg. Further titrations throughout the 6 week duration of Phase 2 (maximum dose of 20 mg) will be decided based on clinical response and tolerability. The medication will be taken by mouth in pill form, once daily.

Note: This arm no longer applies as of 5/16/18. Participants are now randomly assigned to Lexapro or Fetzima and the assignment does not change throughout the study.

Drug: Escitalopram Pill
Double-blinded, randomly assigned
Other Name: Lexapro

Active Comparator: Levomilnacipran Pill
Participants will receive an initial dose of 20 mg blinded levomilnacipran. At day 7, the doses will be titrated to 40 mg of levomilnacipran. Further titrations (maximum dose of 120 mg of levomilnacipran) will be decided based on clinical response and tolerability. The medication will be taken by mouth in pill form, once daily.
Drug: Levomilnacipran Pill
Double-blinded, randomly assigned
Other Name: Fetzima




Primary Outcome Measures :
  1. Change in Montgomery Asberg Depression Rating Scale Score [ Time Frame: Change in Baseline MADRS score through Week 12 ]
    Treatment response will be defined as either a MADRS score of less than 12 or 30% or greater reduction in MADRS score.

  2. Change in Functional Connectivity [ Time Frame: Change in Functional Connectivity through Week 12 ]
    The primary analysis will consist of linear mixed effects models with functional connectivity (for each region of interest) as the outcome measure and group (R [responder]/NR[non-responder], as defined by MADRS), time and their interaction.


Secondary Outcome Measures :
  1. Response Styles Questionnaire- Rumination (RSQ-Rumination) [ Time Frame: Baseline, Week 1, and Week 12 ]
    Examines propensity towards negative bias during thought. To be used as covariate in functional connectivity analysis.

  2. Hamilton Anxiety Rating Scale (HARS) [ Time Frame: Baseline, Week 1, and Week 12 ]
    Examines level of anxiety and somatization. To be used as covariate in functional connectivity analysis.

  3. Neuropsychological evaluations [ Time Frame: Baseline and Week 12 ]
    The neuropsychological testing battery, developed and applied by Co-I Meryl Butters, Ph.D., includes components of the Delis-Kaplan Executive Function Scale (D-KEFS) (2), and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) (3). The E-Cog (short form) (4), which detects decline in daily function, will require phone contact with a family member that can provide input regarding the participant's ability to perform certain tasks. The Performance Assessment of Self-Care Skills (PASS) will be used to detect deficits in the cognitive instrumental activities of daily living (e.g., paying bills, medication management, appliances repair (5).

  4. Antidepressant Treatment History Questionnaire (ATHF) [ Time Frame: Baseline ]
    Investigators will examine prior treatment history and how this may affect treatment response in this study.

  5. Medication Plasma Levels [ Time Frame: Weeks 1-12 ]
    Investigators will assess how blood levels of escitalopram and levomilnacipran may affect treatment response.

  6. Age of Onset [ Time Frame: Baseline ]
    Investigators will assess how early vs. late onset depression (e.g., onset before/after age 60) may affect treatment response.

  7. Duration of Illness [ Time Frame: Baseline ]
    Investigators will assess how length of current episode and number of previous episodes affect treatment response.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   60 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age greater than or equal to 60 years old
  • Current Major Depressive Episode or Current Depressive Disorder Not Otherwise Specified or Dysthymic Disorder
  • Montgomery-Asberg Depression Rating Scale (MADRS) greater than or equal to 12
  • Modified Mini-Mental State (3MS) score greater than or equal to 84

Exclusion Criteria:

  • History of Mania or Psychosis
  • Current suicidal ideation that cannot be safely managed within the confines of a clinical trial
  • Alcohol or Substance Abuse (current or past 3 months) endorsed via phone screening interview or diagnosed by Structured Clinical Interview for the Diagnostic and Statistical Manual for Mental Disorders (SCID)
  • Dementia of any etiology endorsed via phone screening interview or diagnosed by SCID
  • Medical conditions with known significant effects on mood (e.g., stroke, current hypothyroid state) as well as unstable medical illness, including delirium, uncontrolled diabetes mellitus, hypertension, hyperlipidemia, or cardiovascular risk factors that are not under medical management Unwilling or clinically determined to be unable to taper from high doses of benzodiazepines (equivalent to > 2 mg lorazepam/day) or other anti-depressant/anti-anxiety medications at time of screening. However, for participants who are prescribed low dose psychotropics for pain, sleep disturbances, and/or medical conditions (e.g. amitriptyline for peripheral neuropathy, low dose trazodone as a sleep aid), these will be allowed in most circumstances. We will include participants on certain dosages of the most commonly prescribed antidepressants (for medical reasons) as follows: amitriptyline up to 50 mg/d, doxepin up to 50 mg/d, trazodone up to 100 mg/d, and imipramine up to 50 mg/d. Participants will also be able to continue taking buspirone, an antianxiety medication. As per the examples above, the PI will decide if the participants are eligible for the study and if they may continue the current medication. Justification regarding all decisions will be documented in the research record.
  • Inability to complete required assessments including brain MRI and blood draw
  • Hearing/vision impairment precluding neuropsychological testing
  • Difficulty conversing in English
  • Clinical contraindication to use of escitalopram or levomilnacipran or history of treatment resistance to escitalopram or levomilnacipran
  • Unable or unwilling to provide a secondary/emergency contact person
  • History of stroke with residual symptoms, current epilepsy, or current post-concussive symptoms
  • Clinically relevant hyponatremia (below 130 mEq/L)
  • Significant renal impairment

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03128021


Contacts
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Contact: Dana Williams, MS 412-246-5924 barvdm@upmc.edu
Contact: Rachel Berta, BA 412-246-5685

Locations
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United States, Pennsylvania
University of Pittsburgh Recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: Dana Williams, MS    412-246-5924    barvdm@upmc.edu   
Contact: Rachel Berta, BA    412-246-5685    goodra@upmc.edu   
Sub-Investigator: Meryl A Butters, Ph.D.         
Sub-Investigator: Tae Kim, Ph.D.         
Sub-Investigator: Dana Tudorascu, Ph.D.         
Principal Investigator: Howard Aizenstein, M.D., Ph.D.         
Principal Investigator: Carmen Andreescu, M.D.         
Sponsors and Collaborators
Howard Aizenstein
Weill Cornell Institute of Geriatric Psychiatry
National Institute of Mental Health (NIMH)
Investigators
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Principal Investigator: Howard J Aizenstein, MD, Ph.D. Charles F. Reynolds III and Ellen G. Detlefsen Endowed Chair in Geriatric Psychiatry and Associate Professor of Bioengineering and Clinical and Translational Science
Principal Investigator: Carmen Andreescu, MD Assistant Professor of Psychiatry
  Study Documents (Full-Text)

Documents provided by Howard Aizenstein, University of Pittsburgh:
Additional Information:
Publications:
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Responsible Party: Howard Aizenstein, Charles F. Reynolds III and Ellen G. Detlefsen Endowed Chair in Geriatric Psychiatry and Associate Professor of Bioengineering and Clinical and Translational Science, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT03128021    
Other Study ID Numbers: STUDY19120137
R01MH076079 ( U.S. NIH Grant/Contract )
First Posted: April 25, 2017    Key Record Dates
Last Update Posted: November 3, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant data (IPD) will be shared through the NIMH Data Archive.
Time Frame: Data collected to date is submitted twice annually (January and July) and is shared within 4 months of submission.
Access Criteria: NIH will provide access to scientific investigators for research purposes.
URL: https://ndar.nih.gov/edit_collection.html?id=2583

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Howard Aizenstein, University of Pittsburgh:
Depression
fMRI
Escitalopram
Lexapro
Randomized Clinical Trial
Levomilnacipran
Fetzima
Additional relevant MeSH terms:
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Depression
Depressive Disorder
Depressive Disorder, Major
Behavioral Symptoms
Mood Disorders
Mental Disorders
Milnacipran
Citalopram
Levomilnacipran
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Serotonin Agents
Physiological Effects of Drugs
Antidepressive Agents, Second-Generation
Antidepressive Agents
Psychotropic Drugs
Peripheral Nervous System Agents
Serotonin and Noradrenaline Reuptake Inhibitors
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents