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

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.