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

BackgroundThe prevalence and mortality risk of depression in people with human immunodeficiency virus (HIV) infection receiving antiretroviral therapy (ART) is higher than in the general population, yet biomarkers for therapeutic targeting are unknown. In the current study, we aimed to identify plasma metabolites associated with depressive symptoms in people with HIV receiving ART.MethodsThis 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 2 independent cohorts (total n = 99) using liquid and gas chromatography and tandem mass spectrometry.ResultsParticipants with depressive symptoms had lower neuroactive steroids (dehydroepiandrosterone sulfate [DHEA-S], androstenediols, and pregnenolone sulfate) compared with those without depressive symptoms. The cortisol/DHEA-S ratio, an indicator of hypothalamic-pituitary-adrenal axis imbalance, was associated with depressive symptoms (P < .01) because of low DHEA-S levels, whereas cortisol was similar between groups. The odds of having depressive symptoms increased with higher cortisol/DHEA-S ratios (adjusted odds ratio, 2.5 per 1-unit increase in z score; 95% confidence interval, 1.3-4.7), independent of age and sex. The kynurenine-to-tryptophan ratio showed no significant associations.ConclusionsThese findings suggest that altered neuroactive steroid metabolism may contribute to the pathophysiological mechanisms of depression in ART-treated HIV-infected adults, representing a potential biological pathway for therapeutic targeting

Redox Mechanisms Influencing cGMP Signaling in Pulmonary Vascular Physiology and Pathophysiology

The soluble form of guanylate cyclase (sGC) and cGMP signaling are major regulators of pulmonary vasodilation and vascular remodeling that protect the pulmonary circulation from hypertension development. Nitric oxide, reactive oxygen species, thiol and heme redox, and heme biosynthesis control mechanisms regulating the production of cGMP by sGC. In addition, a cGMP-independent mechanism regulates protein kinase G through thiol oxidation in manner controlled by peroxide metabolism and NADPH redox. Multiple aspects of these regulatory processes contribute to physiological and pathophysiological regulation of the pulmonary circulation, and create potentially novel therapeutic targets for the treatment of pulmonary vascular disease