Patients with arginine vasopressin deficiency (AVP-D) appear to also be deficient in oxytocin, the "love hormone," suggesting a possible pathway for treating the psychological symptoms associated with the illness.
Formerly known as central diabetes insipidus, AVP-D is a rare neuroendocrine condition in which fluid isn't regulated, leading to polydipsia and polyuria. The vasopressin receptor 2 agonist desmopressin treats those symptoms, but patients often also experience psychopathologic problems, such as increased anxiety, depression, and emotional withdrawal.
It has been hypothesized that those symptoms are due to a concurrent deficiency of the so-called "love hormone" oxytocin, given the anatomic proximity of vasopressin and oxytocin production in the brain.
Now, for the first time, researchers have demonstrated evidence of that phenomenon using 3,4-methylenedioxymethamphetamine (MDMA, also known as "ecstasy") to provoke oxytocin release. In individuals without AVP-D, use of MDMA resulted in large increases in plasma oxytocin concentrations, whereas there was very little response among those with AVP-D, suggesting that the latter patients were deficient in oxytocin.
"These findings are suggestive of a new hypothalamic–pituitary disease entity and contribute to deepening our understanding of oxytocin as a key hormone in centrally generated socioemotional effects, as reflected by reduced prosocial, empathic, and anxiolytic effects in patients with an oxytocin deficiency," write Cihan Atila, MD, of the University of Basel, Switzerland, and colleagues.
"Future studies should evaluate whether oxytocin replacement therapy can alleviate residual symptoms related to oxytocin deficiency in patients with [AVP-D]," they add.
The findings, from a single-center study of 15 patients with AVP-D and 15 healthy control persons, were published online in The Lancet Diabetes and Endocrinology.
"Atila and colleagues provide compelling evidence for a clinically relevant oxytocin deficiency in this population of patients, which appears to be at least partly responsible for the associated increase in psychopathological findings," say Mirela Diana Ilie, MD, an endocrinologist in training at the National Institute of Endocrinology, Bucharest, Romania, and Gérald Raverot, MD, professor of endocrinology at Lyon University Hospital, France, in an accompanying editorial.
"From a therapeutic viewpoint, the findings...pave the way to intervention studies assessing the effect of intranasal oxytocin in patients with [AVP-D] and better clinical care for these patients," they add.
However, Ilie and Raverot urge caution for a variety of reasons, including the fact that, thus far, only one patient with arginine vasopressin deficiency has been administered oxytocin on a long-term basis. They urge further studies to answer many pertinent questions, such aswhat the appropriate doses and frequency of oxytocin administration are; whether the dose should remain constant or be increased during stress or particular acute situations; whether long-term administration is suitable for all patients regardless of the extent of oxytocin deficiency; and how follow-up should be conducted.
"Answering these questions seems all the more important considering that oxytocin therapy has shown conflicting results when administered for psychiatric disorders," say Ilie and Raverot.
In the meantime, "independent of the potential use of oxytocin, given the frequent and important psychological burden of [AVP-D], clinicians should screen patients for psychological comorbidities and should not hesitate to refer them to appropriate psychological and psychiatric care," the editorialists urge.
Eightfold Increase in Plasma Oxytocin Levels in Patients vs Control Persons
The 15 AVP-D patients and 15 matched healthy control persons were recruited between February 1, 2021, and May 1, 2022. Of those with AVP-D, eight had an isolated posterior pituitary dysfunction, and seven had a combined pituitary dysfunction. The patients had significantly higher scores on measures of anxiety, alexithymia, and depression, and self-reported mental health was lower compared with control persons.
All participants were randomly assigned to receive either a single oral dose of MDMA 100 mg or placebo in the first experimental session and the opposite treatment in a second session. There was a 2-week washout period in between.
Median oxytocin concentrations at baseline were 77 pg/mL in the healthy control persons and peaked after MDMA stimulation to 624 pg/mL after 180 minutes, with a maximum of 659 pg/mL. In contrast, among the patients with AVP-D, baseline oxytocin levels were 60 pg/mL and peaked to just 92 pg/mL after 150 minutes, with a maximum change in concentration of 66 pg/mL.
In response to MDMA, there was an eightfold increase in plasma oxytocin area under the curve among the control persons, vs no notable increase in the patients with AVP-D.
The net incremental oxytocin area under the curve after MDMA administration was 82% higher among control persons than patients (P < .0001).
The MDMA-induced increase in oxytocin was associated with reduced anxiety scores among the control persons but not the AVP-D patients. Similar results were seen for subjective prosocial and empathic effects.
The most frequently reported adverse effects of the MDMA provocation in both groups were fatigue, lack of appetite, and dry mouth, all of which occurred in more than half of participants.
"These findings contradict the previous theory that oxytocin stimulation has only a secondary role in the effects of MDMA. Our results, by contrast, suggest a paradigm shift and underline the importance of oxytocin as a key feature of the effects of MDMA," Atila and colleagues conclude.
Atila, Ilie, and Raverot have disclosed no relevant financial relationships. One study author owns stock in MiniMed.
Lancet Diabetes Endocrinol. Published online May 13, 2023. Abstract, Editorial
Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape. Other work of hers has appeared in the Washington Post, NPR's Shots blog, and Diabetes Forecast magazine. She can be found on Twitter @MiriamETucker.
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