Advances in the field of intranasal oxytocin research: lessons learned and future directions for clinical research

Abstract

Reports on the modulatory role of the neuropeptide oxytocin on social cognition and behavior have steadily increased over the last two decades, stimulating considerable interest in its psychiatric application. Basic and clinical research in humans primarily employs intranasal application protocols. This approach assumes that intranasal administration increases oxytocin levels in the central nervous system via a direct nose-to-brain route, which in turn acts upon centrally-located oxytocin receptors to exert its behavioral effects. However, debates have emerged on whether intranasally administered oxytocin enters the brain via the nose-to-brain route and whether this route leads to functionally relevant increases in central oxytocin levels. In this review we outline recent advances from human and animal research that provide converging evidence for functionally relevant effects of the intranasal oxytocin administration route, suggesting that direct nose-to-brain delivery underlies the behavioral effects of oxytocin on social cognition and behavior. Moreover, advances in previously debated methodological issues, such as pre-registration, reproducibility, statistical power, interpretation of non-significant results, dosage, and sex differences are discussed and integrated with suggestions for the next steps in translating intranasal oxytocin into psychiatric applications.

Fig. 1. Endogenous oxytocin administration and endogenous oxytocin production.

Endogenous oxytocin is primarily produced in the hypothalamus, within the supraoptic (SON) and paraventricular (PVN) nuclei (right inset). Synthesized oxytocin is stored for peripheral release in the posterior pituitary and also secreted within the brain via axonal and dendritic release mechanisms. Intranasally administered exogenous oxytocin travels both to the brain, via olfactory and trigeminal nerve fibers, and the periphery via the highly vascularized nasal cavity. Only very small amounts of peripherally circulating oxytocin are thought to cross the blood-brain barrier owing to an endothelial barrier with tight junctions (left inset), however, these amounts might still be biologically relevant. Image created with BioRender.com.

Fig. 2. Minor changes in study design can dramatically reduce the resources required to achieve desired statistical power for intranasal oxytocin studies.

Four power contour plots are presented for different study designs, which all detect an effect size of δ = 0.2 with a Type I error rate of α = 0.05 and 80% power. Power contour plots demonstrate how the sensitivity of a test changes with the hypothetical effect size and sample size. The most efficient use of resources from these examples is a within-participants design using a one-tailed test. With this research design, a sample size of 156 participants is required to reliably detect (with a probability greater than 80%) an effect size of δ ≥ 0.2. In other words, this design requires the resources to support 312 laboratory visits in total. In comparison, the a between-participants design with a two-tailed test with the same parameters requires 788 laboratory visits in total.