Pittsburgh, Pennsylvania 15213

  • Major Depressive Disorder

Purpose:

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.


Study summary:

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.


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


Study is Available At:


Original ID:

STUDY19120137


NCT ID:

NCT03128021


Secondary ID:

R01MH076079


Study Acronym:

NEMO


Brief Title:

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


Official Title:

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


Overall Status:

Recruiting


Study Phase:

Phase 4


Genders:

N/A


Minimum Age:

60 Years


Maximum Age:

N/A


Quick Facts

Healthy Volunteers
Oversight Has DMC
Study Is FDA Regulated
Study Is Section 801
Has Expanded Access

Study Source:

University of Pittsburgh


Oversight Authority:

There was an error processing this request


Reasons Why Stopped:


Study Type:

Interventional


Study Design:


Number of Arms:

4


Number of Groups:

0


Total Enrollment:

140


Enrollment Type:

Anticipated


Overall Contact Information

Official Name:Howard J Aizenstein, MD, Ph.D.
Principal Investigator
Charles F. Reynolds III and Ellen G. Detlefsen Endowed Chair in Geriatric Psychiatry and Associate P
Primary Contact:Rachel Berta, BA
412-246-5685
goodra@upmc.edu

Study Dates

Start Date:May 24, 2017
Completion Date:December 31, 2022
Completion Type:Anticipated
Primary Completion Date:December 31, 2022
Primary Completion Type:Anticipated
Verification Date:January 2022
Last Changed Date:January 5, 2022
First Received Date:April 4, 2017

Study Outcomes

Outcome Type:Primary Outcome
Measure:Change in Montgomery Asberg Depression Rating Scale Score
Time Frame:Change in Baseline MADRS score through Week 12
Safety Issues:False
Description:Treatment response will be defined as either a MADRS score of less than 12 or 30% or greater reduction in MADRS score.
Outcome Type:Primary Outcome
Measure:Change in Functional Connectivity
Time Frame:Change in Functional Connectivity through Week 12
Safety Issues:False
Description: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.
Outcome Type:Secondary Outcome
Measure:Response Styles Questionnaire- Rumination (RSQ-Rumination)
Time Frame:Baseline, Week 1, and Week 12
Safety Issues:False
Description:Examines propensity towards negative bias during thought. To be used as covariate in functional connectivity analysis.
Outcome Type:Secondary Outcome
Measure:Hamilton Anxiety Rating Scale (HARS)
Time Frame:Baseline, Week 1, and Week 12
Safety Issues:False
Description:Examines level of anxiety and somatization. To be used as covariate in functional connectivity analysis.
Outcome Type:Secondary Outcome
Measure:Neuropsychological evaluations
Time Frame:Baseline and Week 12
Safety Issues:False
Description: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) (
Outcome Type:Secondary Outcome
Measure:Antidepressant Treatment History Questionnaire (ATHF)
Time Frame:Baseline
Safety Issues:False
Description:Investigators will examine prior treatment history and how this may affect treatment response in this study.
Outcome Type:Secondary Outcome
Measure:Medication Plasma Levels
Time Frame:Weeks 1-12
Safety Issues:False
Description:Investigators will assess how blood levels of escitalopram and levomilnacipran may affect treatment response.
Outcome Type:Secondary Outcome
Measure:Age of Onset
Time Frame:Baseline
Safety Issues:False
Description:Investigators will assess how early vs. late onset depression (e.g., onset before/after age 60) may affect treatment response.
Outcome Type:Secondary Outcome
Measure:Duration of Illness
Time Frame:Baseline
Safety Issues:False
Description:Investigators will assess how length of current episode and number of previous episodes affect treatment response.

Study Interventions

Intervention Type:Drug
Name:Escitalopram Pill
Description:Double-blinded, randomly assigned
Arm Name:Escitalopram Pill
Other Name:Lexapro
Intervention Type:Other
Name:Placebo
Description:Double-blinded, randomly assigned
Arm Name:Placebo
Intervention Type:Drug
Name:Levomilnacipran Pill
Description:Double-blinded, randomly assigned
Arm Name:Levomilnacipran Pill
Other Name:Fetzima

Study Arms

Study Arm Type:Active Comparator
Arm Name:Escitalopram Pill
Description: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.
Study Arm Type:Placebo Comparator
Arm Name:Placebo
Description: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.
Study Arm Type:Other
Arm Name:Escitalopram Pill (Phase II)
Description: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
Study Arm Type:Active Comparator
Arm Name:Levomilnacipran Pill
Description: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.

Study Agencies

Agency Class:Other
Agency Type:Lead Sponsor
Agency Name:Howard Aizenstein
Agency Class:Other
Agency Type:Collaborator
Agency Name:Weill Cornell Institute of Geriatric Psychiatry

Sample and Retention Information

There are no available Sample and Retention Information

Study References

Reference Type:Reference
Citation:Isella V, Villa L, Russo A, Regazzoni R, Ferrarese C, Appollonio IM. Discriminative and predictive power of an informant report in mild cognitive impairment. J Neurol Neurosurg Psychiatry. 2006 Feb;77(2):166-71.
PMID:16421116
Reference Type:Reference
Citation:Tomaszewski Farias S, Mungas D, Harvey DJ, Simmons A, Reed BR, Decarli C. The measurement of everyday cognition: development and validation of a short form of the Everyday Cognition scales. Alzheimers Dement. 2011 Nov;7(6):593-601. doi: 10.1016/j.jalz.2011.02.007.
PMID:22055976
Reference Type:Reference
Citation:Randolph C, Tierney MC, Mohr E, Chase TN. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): preliminary clinical validity. J Clin Exp Neuropsychol. 1998 Jun;20(3):310-9.
PMID:9845158
Reference Type:Reference
Citation:Delis DC, Kaplan, E., Kramer, J.H. Delis Kaplan Executive Funciton System Examiner's Manual. The Psychological Corporation; 2001.
Reference Type:Reference
Citation:Andreescu C, Reynolds CF 3rd. Late-life depression: evidence-based treatment and promising new directions for research and clinical practice. Psychiatr Clin North Am. 2011 Jun;34(2):335-55, vii-iii. doi: 10.1016/j.psc.2011.02.005. Review.
PMID:21536162

Data Source: ClinicalTrials.gov

Date Processed: August 16, 2022

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