This study aims to investigate the potential beneficial effects of intranasal oxytocin compared to placebo on emotion recognition and acute psychosocial stress in patients with arginine vasopressin deficiency compared to matched healthy controls.

Arginine vasopressin (AVP) and oxytocin are both nine-amino acid neuropeptides produced in the hypothalamus and are released into circulation from axon terminals projecting to the posterior pituitary. Disruption of the hypothalamic-pituitary axis due to inflammation, tumours, or head trauma may cause AVP deficiency, formerly known as central diabetes insipidus, a condition characterised by polyuria and polydipsia. Once diagnosed with AVP deficiency, desmopressin (AVP receptor 2 analogue) is prescribed to overcome polyuria and polydipsia symptoms. However, despite adequate treatment with desmopressin, patients often report residual psychological symptoms such as heightened anxiety, impairment in identifying and expressing emotions, lower levels of empathy, and increased stress-related behaviour. Oxytocin regulates complex socio-emotional functioning, including attachment and pair bonding, fear extinction, emotion recognition, and empathy. In line with this, oxytocin acts as a stress-buffering hormone as it reduces cortisol in response to stress and has anxiolytic effects. In addition to its release from axonal terminals, there is dendritic release of oxytocin into the brain, including key regions engaged in social-emotional behaviour such as the amygdala, hippocampus, insula. Specifically, it has been supposed that the prosocial effect of oxytocin might be secondary to an anxiolytic effect that involves modulation of amygdala responsivity and by improving emotion recognition. Due to the anatomical proximity, disruption of the AVP system leading to AVP deficiency could also disturb the oxytocin system leading to an additional oxytocin deficiency. Therefore, the psychopathological findings in patients may be caused by an additional oxytocin deficiency. Established pituitary provocation tests, however, failed to show a consistent increase in oxytocin levels. Several studies documented marked acute increases in circulating oxytocin levels in response to 3,4-methylenedioxymethamphetamine (MDMA, known as 'ecstasy') in healthy individuals explaining the empathic feelings and prosocial and anxiolytic effects of MDMA. Based on these results, the study team recently investigated MDMA as a novel provocation test for oxytocin deficiency in patients with AVP deficiency. The study team thereby demonstrated an additional oxytocin deficiency in patients with AVP deficiency using this novel stimulation test with MDMA. Results from this study demonstrate no or only minimal increase in oxytocin after MDMA intake in AVP deficiency while an almost 8-fold increase from baseline values in healthy controls. Acute oxytocin-induced effects under MDMA, such as increased trust, closeness, and openness to others, identification of facial emotions, and fear extinction, were significantly lower in patients compared to healthy controls. Based on this, the additional oxytocin deficiency could explain the psychopathology in patients. Given these data and evidence, oxytocin treatment to improve emotion recognition, decrease anxiety, and buffer effusive stress-induced cortisol increase would have great clinical implications. To date, the central effects of intranasal oxytocin in patients with AVP deficiency have not been addressed, and whether oxytocin administration in these patients can improve the psychological symptoms and provide a novel treatment option needs to be answered. Therefore, this case-control trial with randomized, placebo-controlled, double-blind, cross-over design aims to investigate the effects of a single dose of intranasal oxytocin compared to intranasal placebo on emotion recognition, and acute anxiety and cortisol in response to acute psychosocial stress in patients with AVP deficiency compared to healthy controls.

Inclusion criteria healthy controls

1. Adult healthy volunteers
2. Matched for age, sex, BMI, and oestrogen replacement/menopause/hormonal contraceptives to patients.
3. No medication, except hormonal contraception

Inclusion criteria

1. Adult patients with a confirmed diagnosis of AVP deficiency based on accepted criteria6
2. Stable hormone replacement therapy for at least three months with desmopressin and, in case of additional anterior pituitary deficiencies, with the respective substitution therapies.

Exclusion criteria

1. Participation in a trial with investigational drugs within 30 days
2. Active substance use disorder within the last six months
3. Consumption of alcoholic beverages >15 drinks/week
4. Current or previous psychotic disorder (e.g., schizophrenia spectrum disorder)
5. Pregnancy and breastfeeding within the last eight weeks