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

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $615,653

## Abstract

In this competing renewal (Year 11) of our R01 using fMRI to study late-life depression (LLD) pharmacotherapy
(R01MH076079), the primary aim is to characterize functional connectivity changes associated with initial
medication exposure (12-hour challenge). Our preliminary data suggests that these initial fMRI changes reflect
monoaminergic engagement, regardless of monoaminergic class (serotonergic or noradrenergic), and predict
later treatment response. In the proposed study we 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 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 24 hours of starting a new monoaminergic antidepressant1. For
this proposal, we 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. Our 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, we will also explore the
moderating role of vascular burden on the proposed association between CAN engagement and treatment
response. We will recruit 100 older adults with LLD who will be randomized to receive treatment with either a
very specific serotonin reuptake inhibitor (escitalopram) or a norepinephrine reuptake inhibitor
(levomilnacipram). A pair of fMRI scans one day apart will be used to measure FC associated with medication
titration. We propose to 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, our study will further our understanding of the acute neural system changes associated with
monoaminergic antidepressa...

## Key facts

- **NIH application ID:** 9848627
- **Project number:** 5R01MH076079-14
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** HOWARD J AIZENSTEIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $615,653
- **Award type:** 5
- **Project period:** 2017-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9848627

## Citation

> US National Institutes of Health, RePORTER application 9848627, Neural Mechanisms of Monoaminergic Engagement in Late-Life Depression Treatment Response (NEMO) (5R01MH076079-14). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9848627. Licensed CC0.

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