Kapogiannis D, Dobrowolny H, Tran J, et al. - In order to test their hypothesis of impairments of neuronal insulin signaling in drug-naive first-episode schizophrenia (DNFES), researchers analyzed peripheral blood extracellular vesicles enriched for neuronal origin (nEVs) to attain insight into neuronal insulin signaling in vivo. Plasma nEVs from 48 DNFES patients and healthy matched controls, after overnight fasting, were examined for phosphorylated insulin signal transduction serine-threonine kinases pS312-IRS-1, pY-IRS-1, pS473-AKT, pS9-GSK3β, pS2448-mTOR, pT389-p70S6K, and respective total protein levels. Reduction in upstream pS312-IRS-1 at trend level was observed (P = 0.071; this condition may amplify IRS-1 signaling). Exploratory omnibus analysis of downstream serine-threonine kinases (AKT, GSK3β, mTOR, p70S6K) revealed that DNFES vs controls had lower phosphorylated/total protein ratios (P = 0.013). This confirms reduced pathway activation. As per posthoc-tests, a reduced phosphorylation ratio of mTOR was evident particularly (P = 0.027). Diagnosis-dependent statistical interactions with insulin blood levels were evident with phosphorylation ratios of p70S6K (P = 0.029), GSK3β (P = 0.039), and at trend level AKT (P = 0.061). The phosphorylation ratio of AKT correlated inversely with PANSS-G and PANSS-total scores, and other ratios showed similar trends. Findings thereby strengthen the hypothesis of neuronal insulin resistance in DNFES, small sample sizes notwithstanding. Adaptive feedback mechanisms may explain the counterintuitive trend towards lowered pS312-IRS-1 in DNFES. The clinical implication of the observed changes in insulin signaling was suggested by their association with higher PANSS scores.