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.
“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, N.C., told this news organization. “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 in The New England Journal of Medicine. To say that they are disappointing, Dr. Sikich said, is an understatement.
Increase in off-label use
Most studies in mouse models of ASD and small trials in children produced conflicting results, although there were modest improvements in social functioning associated with the use of intranasal oxytocin. Some clinicians were already prescribing it off label.
On the basis of this research and early feedback from parents of children, Dr. Sikich and colleagues were hopeful.
However, results from a rigorous, 5-year, $11.4 million randomized trial were negative. Yet, parents were convinced their child improved during the study, and there was a significant increase in off-label prescribing of a treatment her research says doesn’t work. What’s next for oxytocin?
Known as the “love hormone,” oxytocin is 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. Some findings link its use to improvements in core deficits associated with ASD, including repetitive behaviors, fixated or restricted interest, and social communication. A study published in 2020 showed that the treatment improved symptoms in high-functioning adults with ASD.
These were mostly small studies and were underpowered to reliably detect an effect of the therapy on social functioning. They often involved only a single dose of oxytocin. Some studies showed improvements, but 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, Dr. 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 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, which is expensive and is challenging to use in this study population. Then there was the acquisition of the drug itself.
The Food and Drug Administration has approved intravenous oxytocin for inducing labor. Intranasal oxytocin is not approved for any indication and isn’t available commercially in the United States. Patients or researchers must secure the drug from a manufacturer in a country where it is approved or order it from a U.S. pharmacy that is capable of compounding IV oxytocin into an intranasal formulation.
The pharmacy in Switzerland Dr. Sikich planned to use couldn’t make enough for the study. Contracting with a compounding pharmacy in the United States 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 Dr. 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. After that, the dosage could be titrated to a maximum of 80 IU/d. The mean maximal total daily dose of oxytocin throughout the study was 67.6 ± 16.9 IU.