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

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.