Neurophysin I: a reliable, novel, and robust biomarker for oxytocin.

Neurophysin I (NP-I), a stable byproduct of the oxytocin precursor, can serve as a reliable biomarker for oxytocin secretion when stimulated by MDMA. In a double-blind, placebo-controlled crossover study, 15 patients with hypothalamic-posterior-pituitary dysfunction and 15 matched healthy controls received a single 100 mg dose of MDMA or placebo. In healthy controls, MDMA caused an 8-fold increase in oxytocin (peak: 624 pM) and a 20-fold increase in NP-I (peak: 1508 pM). Patients showed no notable oxytocin increase (peak: 92 pM) and only a mild NP-I rise (peak: 263 pM). The difference in NP-I area under the curve between groups was significant (2340 pM·5 h; 95% CI, 1462-3218). NP-I measurement offers a way to assess oxytocin secretion, aiding research into conditions like autism, anxiety, and depression.

Study at a glance

Abstract

Oxytocin (OXT) deficiency is a recently identified novel psycho-neuroendocrine entity associated with anxiety and reduced prosocial behavior. However, diagnosis and clinical progress have been hindered by challenges in reliably measuring OXT. Neurophysin I (NP-I), an equimolarly co-released cleavage product of the OXT precursor peptide, offers a promising alternative biomarker due to its stability, although it requires validation. Analysis of a double-blind, placebo-controlled, cross-over study including 15 patients with hypothalamic-posterior-pituitary dysfunction and 15 healthy controls matched according to age (±3), sex, body mass index (±2), and menopause/hormonal contraceptives. Participants received a single oral dose of the strong OXT stimulator 3,4-methylenedioxymethamphetamine (MDMA, 100 mg) and placebo in random order, with a wash-out period of 2 weeks between both experimental sessions. NP-I and OXT levels were measured at 6 time points over 5 h after drug intake. Subjective drug effects were assessed using visual analog scales ranging from 0 = "not at all" to 100 = "extremely," or were bidirectionally ranging from -50 to +50 mm, with 0 being the neutral measure = "no effect." The primary endpoint-net incremental area under the curve (AUC) of NP-I from 0 to 300 min-was analyzed using a linear mixed-effects model. In healthy controls, MDMA induced an 8-fold increase in OXT (peak: 624 pM [235-959]) and a 20-fold increase in NP-I (peak: 1508 pM [911-2233]). In contrast, in patients, MDMA induced no notable increase in OXT (peak: 92 pM [79-110]) and only a mild increase in NP-I (peak: 263 pM [140-300]). The AUC of NP-I after MDMA was 2279 pM·5 h [1087-3696] and 97 pM·5 h [50-241] in healthy controls and patients, respectively, with a significant difference (2340 pM·5 h (95% CI, 1462-3218; P 0.5). These results validate NP-I as a biomarker for endogenous OXT secretion after stimulation with MDMA, addressing long-standing challenges in direct OXT measurement. NP-I offers novel opportunities for research in conditions where reduced OXT levels or disruptions in signaling are implicated, such as autism spectrum disorder, anxiety, and depression.