# A translational study of neuroinflammatory depression: Understanding mechanism and evaluation of a novel pharmacologic intervention

> **NIH NIH R01** · STATE UNIVERSITY NEW YORK STONY BROOK · 2021 · $21,899

## Abstract

Major depressive disorder (MDD) is one of the most heterogeneous disorders in psychiatry and first line
treatments are inadequate for the majority of patients, likely because they do not target an individual’s subtype.
Improving our understanding of MDD subtypes will allow us to (1) identify treatments that target subtype-specific
pathophysiology and (2) determine which subgroup of MDD patients will best respond to these treatments, thus
improving antidepressant outcomes. In a neuroinflammatory subtype, MDD may manifest via chronic
neuroinflammation. The translocator protein (TSPO), located on the outer mitochondrial membrane of microglia
and astrocytes, is regarded as a marker of this neuroinflammation and can be measured in vivo by positron
emission tomography (PET). In support of a neuroinflammatory subtype of MDD, TSPO, measured by PET, was
found to be elevated by 30% on average in the prefrontal cortex (PFC) in MDD relative to healthy individuals.
Further, we have preliminary data from a repeated social defeat stress mouse model that shows elevated PFC
TSPO and other elevated neuroinflammation markers in a subset of ‘depressed’, non-resilient mice, and that this
phenotype is reversed by elimination of TSPO expressing glial cells! To parallel this effect in humans, brain-
penetrant anti-inflammatory medications such as celecoxib can be used. Celecoxib has antidepressant effects
in MDD; however, the observed effect sizes are highly variable, likely reflecting the biological heterogeneity of
MDD. We hypothesize that anti-inflammatory treatments such as celecoxib will be most effective in those with
the neuroinflammatory subtype of MDD and that the mechanism of antidepressant action is through a reduction
of neuroinflammation. We will test these hypotheses in parallel studies in humans in rodents. For the human
aim, we will take advantage of an ongoing study of celecoxib efficacy currently being performed at Stony Brook
Medicine (PI: Parsey) by recruiting participants who are already being treated with celecoxib (8 weeks,
400mg/day). 53 MDD participants will be enrolled, with 42 expected to complete the study involving TSPO PET
imaging before and after treatment. We hypothesize that higher PFC TSPO (as measured by PET) prior to
treatment will be correlated with better response to celecoxib and further, that reductions in PFC TSPO will be
correlated to depression improvement after adjusting for covariates. In a parallel study in rodents, we
hypothesize that PFC TSPO and other CNS inflammation markers in our repeated social defeat stress mouse
model of depression will be elevated as measured by microPET, quantitative protein/mRNA level analysis, and
reactive microglial morphology, when compared to wild type mice. Further, we hypothesize that elevated PFC
TSPO and other neuroinflammatory markers will be reduced after celecoxib treatment. If mouse and human
studies do not agree, this suggests that TSPO PET provides a clinically relevant proxy of neu...

## Key facts

- **NIH application ID:** 10273563
- **Project number:** 3R01MH123093-01S1
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** Christine Delorenzo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $21,899
- **Award type:** 3
- **Project period:** 2020-05-05 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10273563

## Citation

> US National Institutes of Health, RePORTER application 10273563, A translational study of neuroinflammatory depression: Understanding mechanism and evaluation of a novel pharmacologic intervention (3R01MH123093-01S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10273563. Licensed CC0.

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