Intranasal Oxytocin for Autism Promising ― Then Came the Data

When parents of children with autism spectrum disorder (ASD) participating in the largest clinical trial of intranasal oxytocin to date came in for follow-up visits with investigators, they reported marked improvement in the children's social functioning.

Kids who rarely communicated with their families began to interact more. Those who usually preferred to isolate themselves started joining their parents for meals. It all seemed so promising ― until the data came in.

Dr Linmarie Sikich

"Those sounded like real improvements to me, and it seemed like they increased over the period of the study," lead investigator Linmarie Sikich, MD, an associate clinical professor of psychiatry with Duke University School of Medicine and the Duke Center for Autism and Brain Development, Durham, North Carolina, told Medscape Medical News. "Turns out it wasn't oxytocin that was making that difference."

Researchers found that after 24 weeks of daily treatment with intranasal oxytocin, there were no significant differences in social functioning between children who received active treatment and those in the placebo group.

The much-anticipated results were published online last month in The New England Journal of Medicine. To say that they are disappointing, Sikich said, is an understatement.

Increase in Off-Label Use

While most studies in mouse models of ASD and small trials in children produced conflicting results, there were modest improvements in social functioning associated with the use of intranasal oxytocin. Some clinicians were already prescribing it off label, since it has not been approved by the US Food and Drug Administration (FDA).

Based on this research and early feedback from parents of children, Sikich and colleagues were hopeful.

Instead, Sikich is left with negative results from a rigorous, five-year, $11.4 million randomized trial, parents who are convinced their child improved during the study, a significant increase in off-label prescribing of a treatment her research says doesn’t work, and a big question: What’s next for oxytocin?

Known as the "love hormone," oxytocin is also a neurotransmitter that is primarily synthesized in the hypothalamus. It plays a role in childbirth and lactation and is also involved in the regulation of social functioning and emotions. Research suggests low oxytocin levels are associated with diminished social functioning, regardless of ASD status.

Its potential as an autism therapy for children has been under study for a decade, with some findings linking its use to improvements in core deficits associated with ASD, including repetitive behaviors, fixated or restricted interest, and social communication. A study published last year showed that the treatment improved symptoms in high-functioning adults with ASD.

These were mostly small studies, underpowered to reliably detect an effect of the therapy on social functioning and often involving only a single dose of oxytocin. While some studies showed improvements, others did not.

Still, interest in the treatment grew. Physicians began prescribing it for children with ASD, and parents began buying products containing oxytocin on the internet. Researchers feared this off-label use was becoming widespread, despite inconclusive evidence of efficacy.

High Hopes

With support from a National Institutes of Health grant, Sikich and her team designed a phase 2, multicenter, randomized, double-blind, placebo-controlled study to determine whether the use of oxytocin in children with ASD actually works and is safe.

The challenges began before they even enrolled a single child. A number of behavioral assessment tools are used to measure social function in ASD, but there is no consensus on which one is best.

A simple blood test could determine how much oxytocin from the nasal spray was absorbed in the blood, but identifying how much made it to the brain would require fMRI, an expensive test that’s challenging to use in this study population. Then there was the acquisition of the drug itself.

The FDA has approved intravenous oxytocin to induce labor. Intranasal oxytocin is not approved for any indication and isn't available commercially in the US. Patients or researchers must secure the drug from a manufacturer in a country where it is approved or order it from a pharmacy in the US that is capable of compounding IV oxytocin into an intranasal formulation.

The pharmacy in Switzerland Sikich planned to use couldn't make enough for the study. So researchers worked with a pharmaceutical company in the US that could compound the oxytocin and transport it across state lines. It was significantly more expensive and time consuming, but it was the researchers' only option.

"If it hadn't been something we expected to have a major benefit, I think we would have given up the project at multiple points along the line due to all of these challenges," said Sikich.

In August 2014, with all the pieces finally in place, researchers began enrolling children aged 3–17 years. The final cohort included 290 participants with ASD, 146 in the oxytocin group and 144 in the placebo group. Of these, 48% had minimal verbal fluency, and 52% had fluent verbal speech.

Participants received daily synthetic oxytocin or placebo via a nasal spray for 24 weeks. The daily oxytocin dose was 48 IU for the first 7 weeks, with leeway to titrate the dose to a maximum of 80 IU/d. The mean maximal total daily dose of oxytocin throughout the study was 67.6 ± 16.9 IU.

"It Just Didn't Work"

Both study groups showed improvement in social withdrawal beginning at 4 weeks and continuing throughout the trial, based on caretakers' responses on the Aberrant Behavior Checklist Modified Social Withdrawal Subscale, the study's primary outcome measure.

Sociability and social motivation also improved in both groups, as measured by the Pervasive Developmental Disorders Behavior Inventory and the Social Responsiveness Scale.

But by the end of the trial, the difference between the groups in improvement of social function wasn't significant (difference, -0.2 points; P = .61), even after adjusting for age, verbal fluency, and baseline oxytocin level.

"We were so convinced that it would work," Sikich said, "but it just didn't."

Based on the observations they offered, parents were also convinced the therapy was working. In fact, at the trial's conclusion, fewer than half of caregivers correctly guessed whether their child was in the treatment group or if they were in the placebo group.

A lot of developmental changes can happen in a child over 6 months. It's possible the improvements would have occurred regardless of the trial, Sikich said. Parents' perceptions could also be a “placebo effect.” Their child was in a clinical trial of a drug they believed could improve social functioning, so in their mind, it did.

Caregivers also received training in how to identify certain behavioral changes, which may have helped them spot an existing positive change they had previously overlooked. Or they may have worked with their child more intently as a result of their participation in the trial.

"People may start doing more things or doing them more intensively or purposefully, consciously or subconsciously, to try to help their child improve the skills or behaviors targeted by the active therapy in the study," Sikich said. "These are things that might really help the child move forward which are completely separate from the medication being studied."

The safety analysis offered more hopeful results. Only one serious adverse event from the treatment was reported: A 17-year-old participant taking a daily dose of 48 IU experienced a sedating effect while driving and had an accident.

Too Soon to Walk Away?

Perhaps the most important take-away from the study is that even if it's safe, intranasal oxytocin as it is currently used doesn't work and clinicians shouldn't prescribe it, said Daniel Geschwind, MD, PhD, director of the University of California, Los Angeles (UCLA) Center for Autism Research, who penned a commentary on the study and discussed the findings with Medscape Medical News.

"This study shows that using oxytocin the way it's used in the community right now is not helping anybody, so why put a child through that?" added Geschwind, who also is a professor of genetics, neurology, and psychiatry at UCLA.

Dr Daniel Geschwind

The trial highlights areas that need to be addressed in order to improve research in the field, he said. Establishing a consensus process to measure social functioning and figuring out a better way to access intranasal oxytocin would lead to studies that are more conclusive, comparable, and less expensive. Sikich agrees.

Despite the findings, Geschwind and other autism researchers say it's too soon to walk away from oxytocin altogether, although it may be time to change the approach to autism research.

"We have to take a page from the playbook of modern medicine in other areas and begin to recognize that these syndromes are incredibly heterogeneous," Geschwind says. "We can surmise, although we don't know, that there might be different biological forms of autism that have different pathways involved that are going to respond differently to different medications."

Calling the researchers' efforts "heroic," Karen Parker, PhD, an associate professor and associate chair of psychiatry and behavioral sciences at Stanford University, Stanford, California, says efficacy trials such as this one are critical. However, Parker told Medscape Medical News, there are a number of questions that the findings didn't address.

The majority of medication dispensed in a standard intranasal device drains down the nose into the back of the throat. Regular blood tests confirmed that oxytocin was getting into a participant's system, but given how quickly oxytocin degrades in the blood, and the fact that brain-relevant fluid measurements were not made in the study, Parker said it's hard to know just how much oxytocin reached the brain.

It's also unclear whether the results would have been different had the treatment been paired with behavioral therapy, an approach Parker suggests might benefit a subset of children with ASD.

A 2017 study from Parker's lab showed that children with ASD and low blood oxytocin levels at baseline had greater benefit from synthetic oxytocin, something the new study failed to show. Still, Parker said, it's possible that children with certain genetic syndromes with high penetrance for autism and uniformly low blood oxytocin levels may benefit from oxytocin treatment.

"When you see a negative trial like this, it decreases enthusiasm for the medication for autism in this context," Parker said. "I hope people who are studying these genetic syndromes will continue to explore oxytocin as a treatment."

The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development through the Autism Centers of Excellence Program and the Department of Psychiatry and Behavioral Sciences at Duke University. Full disclosures of possible conflicts of interest are available online.

N Engl J Med. Published online October 13, 2021. Abstract

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