Young first-episode psychosis patients exhibit impaired microvascular function in the skin and low systemic nitric oxide availability, independent of classical cardiovascular risk factors.

Impaired endothelial function in patients with psychotic disorders may contribute to increased cardiovascular mortality, but the mechanisms involved remain unclear. Here, we comprehensively analyzed endothelial function in 33 young (median age 18: IQR 17-27) patients diagnosed with first-episode psychosis (FEP), examining large vessels (flow-mediated dilation; FMD) and the microcirculation in peripheral vessels (peripheral arterial tonometry following reactive hyperemia; RH-PAT) and in the skin (flow-mediated skin fluorescence; FMSF). We also measured the plasma concentration of nitric oxide (NO) metabolites (nitrite/nitrate) and 18 biomarkers related to endothelial function, including those representative of glycocalyx damage (SDC-1), endothelial inflammation (sVCAM-1), disrupted endothelial permeability (Angpt-1, Angpt-2), and hemostasis (TAFI, THBS-1). In FEP patients, FMD and RH-PAT remained largely unchanged, but skin microcirculation measured by FMSF was impaired, with pronounced alterations in baseline microvascular oscillations and reactive hyperemic response. Plasma nitrite concentration in FEP patients was significantly lowered, but the profile of biomarkers did not display typical pattern of pro-inflammatory and pro-thrombotic changes associated with endothelial dysfunction, but prominent lowering of adrenomedullin and annexin A5 levels. FEP patients had higher white blood cell counts, total cholesterol, and triglycerides levels, but these parameters did not correlate with any of the vascular readouts. In conclusion, young FEP patients displayed a distinct endotype of endothelial dysfunction with impaired systemic NO bioavailability and prominent functional alterations in the microcirculation of the skin. These results indicate that the assessment of functional changes in skin microcirculation by FMSF may provide novel insights into the early negative effects of psychosis on the microvasculature.