Oxytocin substitution therapy in patients with AVP deficiency (central diabetes insipidus): study protocol of a double-blind, randomised placebo-controlled trial.
This paper describes the protocol for a double-blind, randomised placebo-controlled trial investigating whether intranasal oxytocin substitution therapy (24 IU twice daily for 28 days) improves anxiety and emotion recognition in patients with AVP deficiency (central diabetes insipidus).
Key Findings
Background
AVP deficiency (central diabetes insipidus) may be associated with co-occurring oxytocin deficiency due to the anatomical proximity of AVP and OXT systems in the posterior pituitary.
Both arginine vasopressin (AVP) and oxytocin (OXT) are released from the posterior pituitary gland.
Disruptions of the AVP system may also affect the OXT system given their anatomical proximity.
OXT deficiency in patients with AVP-D was identified using 3,4-methylenedioxymethamphetamine (MDMA) stimulation tests.
OXT deficiency in AVP-D patients was linked to increased anxiety and impaired emotion recognition.
Methods
The trial uses a randomised, double-blind, placebo-controlled, parallel-group design enrolling adults with AVP deficiency.
Participants are randomised 1:1 to receive intranasal OXT (Syntocinon, 24 IU twice daily) or placebo for 28 days.
The study is conducted in Switzerland and the European Union.
Ethical approval was granted by Ethikkommission Nordwest- und Zentralschweiz (EKNZ), project number EKNZ 2023-01010, and the Erasmus MC MERC, EU-CT number 2024-516 813-19-00.
The trial is registered under NCT06036004.
Analyses will follow the intention-to-treat principle.
Methods
The primary endpoint is a composite binary outcome defined as clinically meaningful improvement in either trait anxiety or emotion recognition.
Clinically meaningful improvement in trait anxiety is defined as a ≥5-point reduction in State-Trait Anxiety Inventory-Trait (STAI-T) Score.
Clinically meaningful improvement in emotion recognition is defined as a ≥4-point increase in EmBody/EmFace task performance.
Fisher's exact test will be used for the primary outcome analysis.
Mixed-effects models will be used for secondary endpoints.
Methods
Secondary outcomes encompass a broad range of psychological, neuroimaging, metabolic, and safety measures.
Secondary outcomes include empathy, stress reactivity, and neuroimaging markers of amygdala activity.
Additional psychological measures and metabolic parameters are also included as secondary outcomes.
Safety outcomes specifically include monitoring for hyponatraemia, a known potential adverse effect of oxytocin.
OXT replacement therapy is not currently established as a treatment for AVP-D, and long-term replacement therapy remains unexplored.
What This Means
This research describes the design of a clinical trial testing whether a nasal spray containing oxytocin—a hormone sometimes called the 'bonding hormone'—can help patients with a condition called central diabetes insipidus (also known as AVP deficiency). This condition damages the back part of the pituitary gland, which normally produces two related hormones: one that controls water balance (AVP) and one involved in social and emotional functioning (oxytocin). Previous research using a stimulation test suggested that patients with this condition often have low oxytocin levels, which may explain why they tend to experience higher anxiety and difficulty recognizing emotions in others.
The trial will randomly assign adult patients to receive either an oxytocin nasal spray (24 units, twice a day) or an identical-looking placebo spray for 28 days, with neither patients nor researchers knowing who receives which treatment. The main goal is to see whether treatment leads to a meaningful improvement in either anxiety levels (measured by a standard questionnaire) or the ability to recognize emotions (measured by a computerized task). The study will also look at brain activity, stress responses, empathy, and various safety measures including salt levels in the blood, since oxytocin can sometimes affect sodium balance.
This research matters because patients with AVP deficiency often report significant impacts on their quality of life related to mood and social functioning, yet current treatment only addresses the water balance problem and not the potential oxytocin deficit. If oxytocin replacement proves effective and safe, it could open a new avenue of treatment for the psychological symptoms experienced by these patients. Results will be made publicly available through open-access publication.
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Atila C, Leibnitz S, Nikaj A, Liechti M, De Quervain D, Christ-Crain M. (2026). Oxytocin substitution therapy in patients with AVP deficiency (central diabetes insipidus): study protocol of a double-blind, randomised placebo-controlled trial.. BMJ open. https://doi.org/10.1136/bmjopen-2025-109940