# BLRD Research Career Scientist Award Application

> **NIH VA IK6** · JESSE BROWN VA MEDICAL CENTER · 2024 · —

## Abstract

Every day, 44 veterans or active-duty troops complete suicide, primarily due to the ramifications of untreated
depression. Due to fear and stigma, many do not seek treatment. For those who do, about one third of the
time, no drug offers relief and even those antidepressants that do work often require 6-8 weeks before
therapeutic onset. Unfortunately, no unifying hypothesis for a molecular/cellular basis of action for
antidepressant drugs (or depressive disorders) has emerged. Over the last several years, we have suggested
that, in addition to presynaptic targets (uptake sites), antidepressant drugs have a post-synaptic mechanism of
action. Toward this end, we have observed that chronic treatment (3-5 days) of cultured neural or glial cells
with several chemically diverse antidepressant compounds, translocates the heterotrimeric G protein Gsα out
of lipid rafts and into a closer association with adenylyl cyclase. Post-mortem tissue from depressed suicides
shows just the opposite, with an increased proportion of Gsα ensconced in lipid rafts and preliminary data
suggest that this is also observed in blood cells, where the extent of Gsα in lipid rafts correlates with both
depression and clinical response to antidepressants. Furthermore, several experimental compounds may have
antidepressant effects as well as shorter therapeutic onset, and the proposed studies will search for a cellular
“biosignature” for antidepressant action. Proposed studies will also attempt to establish a mechanistic
understanding for the translocation of Gsα from lipid rafts as a hallmark of depression and as a conduit for
antidepressant action. One aspect of this involves an investigation of the interactions between
antidepressants and lipids, particularly the omega 3 polyunsaturated fatty acids from fish oil (DHA and EPA).
Another aim involved the possibility that tubulin forms the anchor for Gsα in lipid rafts. One potential
application of the proposed studies is to develop a platform that can provide a cell-based screen for putative
antidepressant compounds as well as a screening tool to indicate personalized antidepressant choice. Another
intent of these studies is to provide a peripheral tissue biological marker for depression and an early (< 1
week) indicator of successful antidepressant treatment that can be developed into a clinically useful,
inexpensive and readily available biomarker for clinical use. The identification of a pathway for antidepressant
action might lead to novel antidepressant drugs, while the assignation of a quantitative value for depression
may help overcome stigma and encourage thousands of depressed veterans to seek treatment. Toward this
end, we have developed a new collaboration with the Greater Los Angeles VAMC to do a clinical study that will
help to extend the clinical utility of our depression biomarker in a veteran population.

## Key facts

- **NIH application ID:** 10806822
- **Project number:** 2IK6BX004475-06
- **Recipient organization:** JESSE BROWN VA MEDICAL CENTER
- **Principal Investigator:** MARK M. RASENICK
- **Activity code:** IK6 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2018-10-01 → 2028-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10806822

## Citation

> US National Institutes of Health, RePORTER application 10806822, BLRD Research Career Scientist Award Application (2IK6BX004475-06). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10806822. Licensed CC0.

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