The prevalence and mortality risk of depression in people with Human Immunodeficiency Virus 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.
This is a prospective study of 99 ART-treated HIV-infected adults (94% with plasma VL < 200 copies/ml) with or without depressive symptoms assessed using the Beck Depression Inventory (BDI) from the NNTC and HNRC cohorts. Participants with BDI scores > 20 were classified as having high depressive symptoms. Plasma metabolite profiles from 55 participants comprised the discovery set; profiles from 44 additional participants were used to validate the accuracy of models. Metabolite profiling was performed using ultra high-performance liquid chromatography and tandem mass spectrometry (UHLC/MS/MS2) and gas chromatography/MS.
Median age, CD4+ T-cell count, and nadir CD4+ T-cell count were 50y, 373 cells/μl, and 66 cells/μl in the discovery cohort and statistically similar to the validation set. Seventeen (31%; median BDI 32) and 18 (41%; median BDI 23) participants were classified as having high depressive symptoms in the discovery and validation cohort, respectively. 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 due to low DHEA-S (Figure), and discriminated between participants with high vs. low depressive symptoms with AUC of 0.70 (P=0.03, discovery) and 0.80 (P=0.02, validation). When cortisol/DHEA-S was coupled with androstenediol and pregnenolone sulfate, discrimination improved with AUC of 0.81 (discovery) and 0.85 (validation). 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.
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.