# 1/2 Inflammation and Stress Response in Familial and Nonfamilial Youth Suicidal Behavior

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $365,758

## Abstract

Suicide is 2nd leading cause of death in the US youth, and rates have risen 33% in 17 years. Clinical risk factors
alone have disappointing predictive power and biological predictors show promise but rarely separated into long-
term and short-term predictors due to the challenge of detecting biological profiles shortly before suicide behavior
(SB). We propose a novel pragmatic approach of examining biological risk profiles immediately after an acute
suicidal crisis and then separating them into familial and nonfamilial risk profiles. Our collaborative work indicates
a stress responsive biological phenotype associated with more lethal and familial SB where inflammation
activates the kynurenine pathway depleting brain serotonin by shunting tryptophan away from serotonin toward
kynurenine synthesis. Inflammation and neuroinflammation can potentially result from HPA axis and
mitochondrial dysregulations. We also find HPA axis dysregulation and inflammation to be more pronounced in
those with SB and family history of SB. We hypothesize familial factors to be mostly long-term and nonfamilial
factors to be mostly short-term risk factors. We propose to examine short-term or proximal biological risk profiles
for suicidal behavior (SB) in stress response and inflammatory pathways, peripherally and in the brain, and
examine familial and nonfamilial biological mechanisms for SB in young adults. We will recruit 120 young adult
psychiatric inpatients or outpatients, aged 18-30 years, 80 at high-risk for SB defined as those presenting to the
emergency department (ED) or admitted for suicidal ideation (SI) with a plan and intent or SB in the last two
weeks; and 40 at lower risk with no SB or SI with plan/intent in past 3 months. Groups will be frequency-matched
on familial risk. We will collect: 1) clinical data; 2) hair to measure hair cortisol concentrations (HCC); 3) conduct
the Trier Social Stress Task (TSST) to measure cortisol, peripheral inflammation (cytokines, kynurenine
metabolites) and circulating cell free mitochondrial DNA (ccf-mtDNA); 4) PET imaging using [11C]ER176 ligand
to measure neuroinflammation; and 5) near-infrared spectroscopy (NIRS) to measure in PFC oxidation state of
cytochrome-c-oxidase (oxCOX), a brain marker of mitochondrial function. Patients will be followed up at 1, 3,
and 12 months. The year post-hospital/ED discharge is a high-risk period for SB and the first 3 months is the
highest risk period. We hypothesize high-risk patients will show higher [11C]ER176 PET binding and lower oxCOX
at baseline. They will also show lower HCC and higher cortisol response to stress and higher inflammation and
ccf-mtDNA prior and in response to stress at baseline. Offspring of attempters will show more severe biological
profiles due to the contribution of short and longer-term risk factors. We will also examine the relationships
between peripheral and brain measures and explore whether they predict SB. This study will improve our
understanding of ...

## Key facts

- **NIH application ID:** 10366252
- **Project number:** 2R01MH108039-06A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Nadine M. Melhem
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $365,758
- **Award type:** 2
- **Project period:** 2015-08-20 → 2026-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10366252

## Citation

> US National Institutes of Health, RePORTER application 10366252, 1/2 Inflammation and Stress Response in Familial and Nonfamilial Youth Suicidal Behavior (2R01MH108039-06A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10366252. Licensed CC0.

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