Oxytocin substitution therapy in patients with AVP deficiency (central diabetes insipidus): study protocol of a double-blind, randomised placebo-controlled trial

Abstract

Introduction: Arginine vasopressin (AVP) and oxytocin (OXT) are both hormones released from the posterior pituitary. While AVP primarily regulates water reabsorption in the kidneys, OXT plays a key role in socioemotional functioning. Due to the anatomical proximity, disruptions of the AVP system leading to AVP deficiency (AVP-D) may also affect the OXT system, possibly resulting in an additional OXT deficiency. This hypothesis was recently proven by using the 3,4-methylenedioxymethamphetamine stimulation tests and identifying OXT deficiency in patients with AVP-D, linked to increased anxiety and impaired emotion recognition. Despite these findings, OXT replacement therapy is not currently established as a treatment for AVP-D and long-term replacement therapy remains unexplored. Methods and analysis: This is a randomised, double-blind, placebo-controlled, parallel-group trial enrolling adults with AVP-D. Participants are randomised 1:1 to receive intranasal OXT (Syntocinon, 24 IU twice daily) or placebo for 28 days. The primary endpoint is a composite binary outcome defined as a clinically meaningful improvement in either trait anxiety (≥5-point reduction in State-Trait Anxiety Inventory-Trait Score) or emotion recognition (≥4-point increase in EmBody/EmFace task performance). Secondary outcomes include empathy, stress reactivity, neuroimaging markers of amygdala activity, additional psychological measures, metabolic parameters and safety outcomes, including hyponatraemia. Analyses will follow the intention-to-treat principle, with Fisher’s exact test used for the primary outcome and mixed-effects models for secondary endpoints. Ethics and dissemination: The study has been approved by the competent ethics committees and regulatory authorities in Switzerland and the European Union. The following institutions granted ethical approval: Ethikkommission Nordwest- und Zentralschweiz (EKNZ), project number EKNZ 2023–01010 and the Erasmus MC MERC, EU-CT number 2024–5 16 813-19-00. Results will be published in open-access, peer-reviewed journals and disseminated via scientific meetings, media communication and lay summaries provided to participants. De-identified individual participant data will be made available on reasonable request following publication. Trial registration number: NCT06036004.