Intranasal oxytocin increases heart-rate variability in men at clinical high risk for psychosis: a proof-of-concept study

Abstract

Autonomic nervous system (ANS) dysfunction (i.e., increased sympathetic and/or decreased parasympathetic activity) has been proposed to contribute to psychosis vulnerability. Yet, we still lack directed therapeutic strategies that improve ANS regulation in psychosis or at-risk states. The oxytocin system constitutes a potential therapeutic target, given its role in ANS regulation. However, whether intranasal oxytocin ameliorates autonomic regulation during emerging psychosis is currently unknown. We pooled together two datasets, one of 30 men at clinical high risk for psychosis (CHR-P), and another of 17 healthy men, who had participated in two double-blinded, placebo-controlled, randomised, crossover MRI studies with similar protocols. All participants self-administered 40 IU of intranasal oxytocin or placebo using a nasal spray. We recorded pulse plethysmography during a period of 8 min at about 1 h post dosing and estimated heart rate (HR) and high-frequency HR variability (HF-HRV), an index of cardio-parasympathetic activity. CHR-P and healthy men did not differ at resting HR or HF-HRV under placebo. We found a significant condition × treatment effect for HF-HRV, showing that intranasal oxytocin, compared with placebo, increased HF-HRV in CHR-P but not in healthy men. The main effects of treatment and condition were not significant. In this proof-of-concept study, we show that intranasal oxytocin increases cardio-parasympathetic activity in CHR-P men, highlighting its therapeutic potential to improve autonomic regulation in this clinical group. Our findings support the need for further research on the preventive and therapeutic potential of intranasal oxytocin during emerging psychosis, where we lack effective treatments.

Tracking transient changes in the intrinsic neural frequency architecture: Oxytocin facilitates non-harmonic relationships between alpha and theta rhythms in the resting brain

“…Interestingly, the demonstrated OT-related changes in cross-frequency dynamics were shown to be paralleled by changes in ANS function, indicating a significant increase in high-frequency HRVan established marker of parasympathetic nervous system (PNS) 'rest-and-digest' autonomic function -as well as a decrease in low-frequency HRV -influenced by a mix of vagal, sympathetic nervous system (SNS) activity, and baroreflex mechanisms (Shaffer et al, 2014). These observations are in line with four prior studies, showing an increase in resting-state high-frequency HRV after a singledose of OT (Jain et al, 2017;Kemp et al, 2012;Martins et al, 2020;Norman et al, 2011). One study with chronic back pain patients showed no effect of OT on rest HRV, but here, small decreases in both high-and low-frequency HRV were noted during a mental arithmetic task, suggesting that OT differentially impacted HRV depending on whether the task context entailed a resting state or a state of (mild) cognitive stress (Tracy et al, 2018).…”

“…This notion is important, considering that context and state-dependent changes are highlighted as important factors for inducing variations in OT's neuromodulatory effects (e.g. differential effects on rest (Jain et al, 2017;Kemp et al, 2012;Martins et al, 2020;Norman et al, 2011) versus task-related HRV (Tracy et al, 2018)). In this view, it has been suggested that OT may primarily promote the restoration of autonomic balance (enhanced PNS drive) in the relative absence of acute stressors, but that opposite effects may be induced in task contexts that induce (mild) states of acute stress, in which case a facilitation of SNS-driven arousal and attentional salience may be evident (Carter, 2014).…”

“…As an additional outcome, effects of OT on resting-state heart rate variability (HRV) were also obtained to examine whether OT's effects on EEG cross-frequency dynamics are paralleled by changes in high-and/or low-frequency HRV (both established markers of autonomic nervous system (ANS) activity). These examinations will allow exploring how OT's neural effects on intrinsic coupling/decoupling relate to prior observations of a homeostatic role of OT in terms of enhancing intrinsic ANS parasympathetic tone (i.e., OT-induced increases in high-frequency HRV) (Jain et al, 2017;Kemp et al, 2012;Martins et al, 2020;Norman et al, 2011). and NCT04443647), assessing the effect of OT on stress neurophysiology (e.g., skin conductance) (Daniels et al, 2020;Soriano et al, 2020).…”

Advances and Challenges in Intranasal Delivery of Antipsychotic Agents Targeting the Central Nervous System

“…However, intranasal oxytocin increased HF-HRV in CHR-P only. These findings support the need for further research to investigate the therapeutic potential of intranasal oxytocin ( Martins et al, 2020 ). Hippocampal dysfunction (HD) was investigated as a crucial factor for psychosis onset.…”

Neural Functions of Hypothalamic Oxytocin and its Regulation

“…In women at the third trimester of pregnancy and during low-risk labor, application of OT increases vagally mediated activity ( Reyes-Lagos et al, 2015 ). IAO increases high frequency HRV (an index of cardio-parasympathetic activity) in men at clinical high risk for psychosis ( Martins et al, 2020 ) and with 38 men either receiving 24 IU OT intranasally or a placebo spray. While accomplishing an emotion classification task, electrodermal responses are measured as an index of sympathetic activity.…”