‘It just didn’t work’
Both study groups showed improvement in social withdrawal beginning at 4 weeks and continuing throughout the trial, as determined on the basis of 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) after adjusting for age, verbal fluency, and baseline oxytocin level.
“We were so convinced that it would work,” Dr. Sikich said, “but it just didn’t.”
From observation, parents were also convinced the therapy was working. At the trial’s conclusion, fewer than half of caregivers correctly guessed whether their child was in the treatment group or the placebo group.
A lot of development changes can happen in a child over 6 months. It’s possible the improvements would have occurred regardless of the trial, Dr. 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 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,” Dr. 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 this news organization.
“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 Dr. Geschwind, who also is a professor of genetics, neurology, and psychiatry at UCLA.
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. Dr. Sikich agrees.
Despite the findings, Dr. 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,” Dr. 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 (Calif.) University, says efficacy trials such as this one are critical. However, Dr. Parker said in an interview, there are a number of questions that the study didn’t address.
The majority of medication dispensed in a standard intranasal device is sprayed into the back of the throat. Regular blood tests confirmed that oxytocin was getting into participants’ system, but, given how quickly oxytocin degrades in the blood, Dr. Parker said it’s hard to know just how much reached the brain.
It’s also unclear whether the results would have been different had the treatment been paired with behavioral therapy, an approach Dr. Parker suggests might benefit a subset of children with ASD.
A 2017 study from Dr. Parker’s lab found that children with ASD whose use of oxytocin at baseline was low derived greater benefit from synthetic oxytocin, something the new study failed to find. Still, Dr. Parker said, it’s possible oxytocin might increase social motivation and increase a child’s receptiveness to behavioral therapy.
“When you see a negative trial like this, it decreases enthusiasm for the therapy for autism in this context,” Dr. Parker said. “I hope people who are studying these syndromes will continue to explore oxytocin as a therapy.”
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 the authors’ possible conflicts of interest are available online.
A version of this article first appeared on Medscape.com.