Two clinical trials show promise for autism treatment

Many people with autism struggle to understand social cues and facial expressions, leading to difficulty with social interactions, which impacts their quality of life.

Current treatments for autism focus on improving mood because trouble with social interactions can lead to irritability and depression, says neuroscientist Karen Parker of Stanford University. Currently, there aren’t many pharmacological solutions to address autism’s core feature, the social deficits, she says.

That may be changing.

The results of two recent clinical trials suggest that a hormone called arginine vasopressin (or simply vasopressin) and a small molecule that targets one of its brain receptors might mitigate some social deficits in people with autism. The results, says Karen Bales, a behavioral neuroscientist at the University of California, Davis, who was not involved in the studies, mimic what she and others have seen when studying vasopressin-related behavioral changes in lab animals.

“We have so few approved treatments for autism, and the ones we have are really just for sort of secondary things, like irritability, that come along with not being able to communicate effectively,” Bales says. “So it’s very exciting to see a potential treatment for one of the core symptoms”.

Vasopressin is a nine-amino-acid hormone that is made in the brain and has many functions in the human body. It acts on the kidneys and reduces urination, but in parallel with another hormone, oxytocin, it regulates emotion in the brains. In previous studies of healthy people, a spritz of vasopressin up the nose seemed to enhance memory, especially of faces expressing some sort of emotion. Parker wondered whether the hormone might help people with autism discern emotion and facial expressions. After discovering that people with autism tended to have low levels of vasopressin in their cerebrospinal fluid, she and her team decided to test it on children with the disease.

In their pilot study, they treated 30 children, mostly boys age 6 to 12, for 4 weeks with nasal spritzes of vasopressin, which improve the chances of the hormone getting into the brain. After an initial large dose, the children’s parents treated them twice per day with a smaller dose that increased each week. The trial was randomized and double-blinded, so neither parents nor doctors nor researchers knew which child was getting the drug and which was getting the placebo (Sci. Transl. Med. 2019 DOI: 10.1126/scitranslmed.aau7356).

After the 4-week trial, the children took several tests, including one that asked them to interpret emotion from facial features. Their parents filled out a survey designed to measure their child’s communication and social deficits, and their doctors completed a report on whether the kids showed any improvement in communication or social cues. In all tests, Parker says, the children who got vasopressin did somewhat better than the children who got the placebo.

In the parent report, called the Social Responsiveness Scale-2 (SRS2), children treated with vasopressin improved by seven points more than children who got the placebo. Parker says an improvement of 10 or more points is considered clinically significant. In the facial features test, the children given vasopressin got scores five points higher than children on the placebo. Children receiving the placebo had an average score of –1, while children on vasopressin had an average score of 4. The highest possible score is 28, Parker says. The evidence from the three tests and reports converged on a similar conclusion, Parker says: vasopressin improved the children’s social behavior.

Parker says that one thing they noticed was that children with lower levels of natural circulating vasopressin saw less improvement from the nasal spritzes than children with higher circulating levels. She wonders if this might be related to the dose the researchers used—perhaps children will less vasopressin to begin with might need a higher dose to see a larger effect. Parker’s team is continuing with a larger trial, and to overcome any possible subjectivity in results, they are adding brain activity and eye-tracking measurements.

In the other trial, Roche Innovation Center researchers tested a small molecule called balovaptan for its effect on social behavior in adult men with autism. Balovaptan acts opposite to vasopressin—it inhibits the arginine vasopressin receptor 1A in the brain (Sci Transl. Med. 2019, DOI: 10.1126/scitranslmed.aat7838).

“Being able to really find a molecule that was specific to V1A was really a feat of chemistry,” says Paulo Fontoura, the Roche scientist who led the trial. Fontoura says that when developing the molecule, they wanted to avoid side effects by making sure that it didn’t interact with the vasopressin receptor in the kidneys.

In the Phase II trial, 223 men got either a placebo or a dose of balovaptan ranging from 1.5 to 10 mg once per day for 12 weeks. The results were not as clear as the vasopressin trial in children. For example, the researchers saw no change in SRS-2 test scores in the adults. But in a different test, the Vineland-II test, which measures communication and daily living skills, they did see a change.

“We got a five point increase in three months,” Fontoura says, pointing out that this test is often used as a measure of improvement in people with autism undergoing behavioral therapy, and that it can take up to two years to get a three-point improvement.

The Food and Drug Administration has given balovaptan a breakthrough designation, so its progress through the clinical trials and review system will be expedited. Fontoura says they are now recruiting children for their next trial.

One thing that remains to be explained is how a treatment that activates the vasopressin receptor and one that inhibits it can have similar effects in people. UC Davis’s Bales points out that vasopressin can also bind the oxytocin receptor, which is also involved in social interaction. This nonspecific binding by vasopressin may explain some of the results in the children study.

Researchers will also need to determine when to deliver such treatments, Bales says. For example, will people take them daily or in specific situations? Bales has studied the chronic use of vasopressin in animals and says that after a while, there may be some unintended secondary effects in the brain. “The cautious way to proceed would be to use it for some period of time, and see what results you get, and then maybe use it as an adjunct for social skills training,” she says.

Fontoura agrees, adding that people might not take such drugs daily, instead taking them at specific times and at a tailored dose in anticipation of a social event. “There’s an aspect here that is very individual,” he says. A child at home may not need it, while a child in school or a young adult going for a job interview might want to take something. “These are all different behavioral challenges, so you might dose more often.”