Dr. Mercedes Alfonso-Prieto from the Institute for Computational Biomedicine at Forschungszentrum Jülich CREDIT Forschungszentrum Jülich / Ralf-Uwe Limbach

Oxytocin is known as the “love hormone”. It strengthens social bonding and promotes trust and empathy. These behavioral traits are caused by the binding of the hormone to the oxytocin receptor in the brain. Researchers at the University of Regensburg and Forschungszentrum Jülich have now demonstrated, with the help of cell culture experiments and computer simulations, how genetic variations of the receptor affect the hormone signaling inside brain cells. Their findings provide a better understanding why nasal sprays with oxytocin are not always helpful to treat autistic patients and they point to alternative strategies that could lead to new therapies in the long term.

Changes in the finely tuned mechanism of oxytocin interacting with its receptor might trigger psychosocial disorders. Researchers have been assuming this for a long time. In fact, genetic variants of the oxytocin receptor have already been associated with autism spectrum disorder. However, the causal mechanisms linking these mutations to the onset of autism are still unknown.

Structure of the oxytocin receptor (left) and the mutant receptor variant A218T (right) CREDIT Forschungszentrum Jülich / Mercedes Alfonso-Prieto

There are some indications that there is more than one single cause. As a consequence, the simple use of nasal sprays with oxytocin helps only in certain cases to improve social interaction in children and adolescents with autism spectrum disorder. Various studies on therapeutic effects, conducted for example by researchers at Forschungszentrum Jülich ( DOI: 10.1038/s41386-018-0258-7) or recently published by US researchers in the New England Journal of Medicine in October (DOI: 10.1056/NEJMoa2103583), obtained quite different results, with the treatment efficacy being highly variable among patients. But without the knowledge of the molecular mechanism that causes oxytocin nasal sprays to work only in some patients, an effective, standardized treatment is unattainable.

In a recent work, together with partners from the University of Regensburg, researchers at the Jülich Institute for Neuroscience and Medicine (INM-9/IAS-5) have now described in detail how a specific variant in the DNA sequence of the oxytocin receptor affect the hormone-triggered response of the neurons.

“The devil really is in the detail here,” explains Dr. Mercedes Alfonso-Prieto. “The oxytocin receptor consists of 389 amino acids. The variant we studied deviates from the normal type in only one – a rather subtle change, but one that is amplified inside the cell as if by a kind of domino effect.”

Together with colleagues at her institute, led by Prof. Paolo Carloni, she modelled and simulated the effect of the mutation. “We focused on understanding the mechanism of how the structure of the oxytocin receptor is changed and how this affects the subsequent cellular response,” explains Mercedes Alfonso-Prieto.

The surprising result: the mutated variant is more active and stable than the normal receptor, contrary to what might intuitively be expected.

„Despite its connection to autism, we were puzzled that the receptor variant had been previously classified as non-pathogenic“, say Dr. Magdalena Meyer and Dr. Benjamin Jurek from the University of Regensburg, who studied the cell response to oxytocin experimentally in the laboratory. The Regensburg working group, led by Prof. Inga Neumann, has been researching the neurobiological effects of oxytocin for many years. The current work in the prestigious journal Molecular Psychiatry now provides new starting points for developing new therapies in the long term.

“Since the mutant variant reacts excessively to oxytocin, increasing the oxytocin level by means of a nasal spray is probably not the best therapeutic strategy for treating autistic patients with this mutation,” explains Magdalena Meyer. More success is promised by drug development approaches that aim to find molecules that can restore the normal response levels of the receptor.

Oxytocin, a naturally occurring hormone that acts as a chemical messenger in the brain, showed no evidence of helping children with autism gain social skills, according to a large national study appearing Oct. 13 in the New England Journal of Medicine.

While disappointing for those holding hope that oxytocin could benefit children with autism, the long-awaited finding provides clarity for a drug that has shown mixed outcomes in smaller, less robust studies.

“There was a great deal of hope this drug would be effective,” said the study’s principal investigator and lead author, Linmarie Sikich, M.D., associate consulting professor in the Department of Psychiatry & Behavioral Sciences at Duke University School of Medicine. “All of us on the study team were hugely disappointed, but oxytocin does not appear to change social function of people with autism.”

Oxytocin is typically used to induce labor, but because of its activity in the brain, it has been investigated as a treatment for autism. Evidence has been conflicting, with several smaller studies suggesting it improved social and cognitive function among some children with autism, while other studies showed no benefit.

Sikich and colleagues, including senior author Jeremy Veenstra-VanderWeele, M.D., of New York State Psychiatric Institute and Columbia University, designed the multi-site trial to provide the best evidence yet about whether oxytocin was a safe and effective treatment for children with Autism.

The research team enrolled 290 children ages 3-17, stratified by age and the severity of their autism symptoms. The children were randomized in similar, equal-sized groups to receive oxytocin or a placebo via a daily nasal spray over 24 weeks.

The study aimed to see if the regimen of oxytocin would have a measurable impact on the children’s social abilities based on screenings and assessments at the start of the trial, midway through and at the end. Both researchers and the children’s parents provided assessments using standard analytic tools for autism.

While the oxytocin was well tolerated and had few side effects, it showed no significant benefit among the group of children who received it compared to those who received the placebo.

“Thousands of children with autism spectrum disorder were prescribed intranasal oxytocin before it was adequately tested,” Veenstra-VanderWeele said. “Thankfully, our data show that it is safe. Unfortunately, it is no better than placebo when used daily for months. These results indicate that clinicians and families should insist that there is strong evidence for the safety and benefit of new treatments before they are provided to patients in the clinic.”

Sikich said no further study is likely of oxytocin, given the negative findings: “Our consensus as investigators is that there is no evidence in this large study that is strong enough to justify more investigation of oxytocin as a treatment for autism spectrum disorders.”