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

Study Overview
=================
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.

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.

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

Conditions
-----------------
Major Depressive Disorder

Intervention / Treatment
-----------------
* Drug: Escitalopram Pill
* Other: Placebo
* Drug: Levomilnacipran Pill


Participation Criteria
=================
Eligibility 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 MoCA-BLIND greater than or equal to 13 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

Ages Eligible for Study
-----------------
Minimum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Escitalopram Pill<br>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<br>* Double-blinded, randomly assigned<br>* Other names: Lexapro;|
| Placebo Comparator: Placebo<br>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<br>* Double-blinded, randomly assigned<br>|
| Other: Escitalopram Pill (Phase II)<br>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<br>* Double-blinded, randomly assigned<br>* Other names: Lexapro;|
| Active Comparator: Levomilnacipran Pill<br>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<br>* Double-blinded, randomly assigned<br>* Other names: Fetzima;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Montgomery Asberg Depression Rating Scale Score | Treatment response will be defined as either a MADRS score of less than 12 or 30% or greater reduction in MADRS score. | Change in Baseline MADRS score through Week 12 | 
| Change in Functional Connectivity | 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. | Change in Functional Connectivity through Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Styles Questionnaire- Rumination (RSQ-Rumination) | Examines propensity towards negative bias during thought. To be used as covariate in functional connectivity analysis. | Baseline, Week 1, and Week 12 | 
| Hamilton Anxiety Rating Scale (HARS) | Examines level of anxiety and somatization. To be used as covariate in functional connectivity analysis. | Baseline, Week 1, and Week 12 | 
| Neuropsychological evaluations | 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). | Baseline and Week 12 | 
| Antidepressant Treatment History Questionnaire (ATHF) | Investigators will examine prior treatment history and how this may affect treatment response in this study. | Baseline | 
| Medication Plasma Levels | Investigators will assess how blood levels of escitalopram and levomilnacipran may affect treatment response. | Weeks 1-12 | 
| Age of Onset | Investigators will assess how early vs. late onset depression (e.g., onset before/after age 60) may affect treatment response. | Baseline | 
| Duration of Illness | Investigators will assess how length of current episode and number of previous episodes affect treatment response. | Baseline | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Depression, fMRI, Escitalopram, Lexapro, Randomized Clinical Trial, Levomilnacipran, Fetzima