# In Vivo Targeting of Neuroactive Steroid and Immune Networks for Depression in People Living with HIV.

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $755,637

## Abstract

Project Summary
 The prevalence of depression in people living with HIV (PLWH) is estimated at 20-45% despite
antiretroviral therapy with two-thirds of adults inadequately treated, and only one-third of adults achieving
remission. Hypothalamic-pituitary-adrenal axis dysfunction and chronic inflammation contribute to
depressive symptoms in PLWH and represent alternative pathways for targeting. Neuroactive steroids
can improve depressive symptoms in psychiatric conditions and are effective in chronic pain. In human
studies, the effect was mediated by pregnenolone, the first neuroactive steroid derived from cholesterol.
In this proposal, we hypothesize that a central mechanism of pathogenesis in neuropsychological disease
is a relative deficiency of neuroactive steroids that defines a biological subtype of depressed mood in
PLWH. Changes in neuroactive steroids promote neurological functioning by several means that include
increasing GABAergic neurotransmission and reducing systemic inflammation. To address our
hypothesis, we will perform a 3:1 double-blind trial enrolling 120 PLWH on ART with depression,
randomized to pregnenolone or placebo, as add-on therapy, for 8 weeks, and will systematically
investigate GABA-mediated inhibition and peripheral immune responses as they relate to depressed
mood. This project utilizes magnetic resonance spectroscopy and task-based functional magnetic
resonance imaging to probe the behavioral and neural responses after pregnenolone. We will
longitudinally profile immune cell populations and investigate the transcriptional responses in monocytes
to identify genes associated with clinical response. Finally, we will use baseline predictors to model
whether levels of neuroactive steroids predict clinical improvement among PLWH receiving
pregnenolone. This proposal leverages an extensive neuroimaging, and immune profiling infrastructure
and the extensive scientific expertise of collaborating investigators and laboratories. Our approach may
define novel relationships between pregnenolone and mechanisms of depression, potentially suggesting
new therapeutic targets based on the biology of neuroactive steroids, to address a critical unmet need in
PLWH.

## Key facts

- **NIH application ID:** 10914089
- **Project number:** 5R01MH131194-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Shibani Sharon Mukerji
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $755,637
- **Award type:** 5
- **Project period:** 2022-09-08 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10914089

## Citation

> US National Institutes of Health, RePORTER application 10914089, In Vivo Targeting of Neuroactive Steroid and Immune Networks for Depression in People Living with HIV. (5R01MH131194-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10914089. Licensed CC0.

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