Low Neuroactive Steroids Identifies a Biological Subtype of Depression in Adults with Human Immunodeficiency Virus on Suppressive Antiretroviral Therapy.

BACKGROUND: The prevalence and mortality risk of depression in people with Human Immunodeficiency Virus (HIV)-infection (PWH) on antiretroviral therapy (ART) is higher than in the general population, yet biomarkers for therapeutic targeting are unknown. Here, we aimed to identify plasma metabolites associated with depressive symptoms in PWH on ART. METHODS: This is a prospective study of ART-treated HIV-infected adults with or without depressive symptoms assessed using longitudinal Beck Depression Inventory scores. Plasma metabolite profiling was performed in two independent cohorts (total n=99) using liquid and gas chromatography and tandem mass spectrometry. RESULTS: Participants with depressive symptoms had lower neuroactive steroids (dehydroepiandrosterone sulfate (DHEA-S), androstenediols, pregnenolone sulfate) compared to those without depressive symptoms. Cortisol/DHEA-S ratio, an indicator of hypothalamic-pituitary-adrenal axis imbalance, was associated with depressive symptoms (p<0.01) due to low DHEA-S, while cortisol was similar between groups. The odds of having depressive symptoms increased with higher cortisol/DHEA-S ratios [odds 2.5 per z-score, 95% confidence interval 1.3-4.7], independent of age and gender. Kynurenine to tryptophan ratio showed no significant associations. CONCLUSIONS: These findings suggest that altered neuroactive steroid metabolism may contribute to the pathophysiology of depression in ART-treated HIV-infected adults, representing a potential biological pathway for therapeutic targeting.