Current ASD treatments focus on targeting symptom domains
TORONTO — Innovations in the treatment of autism spectrum disorder will seek to address this heterogeneous condition by taking into account genetic mechanisms, psychiatric and medical comorbidities and behavioral problems, according to a presentation by Jeremy Veenstra-VanderWeele, MD, at the 2015 American Psychiatric Association Meeting.
“I never see a child who only has autism spectrum disorder. The challenge of heterogeneity really presents itself every time I see a patient in a clinic,” said Veenstra-VanderWeele, medical director of the Treatment and Research Institute for Autism Spectrum Disorders at Vanderbilt University School of Medicine. “But our treatment studies, we have to acknowledge, take a child who may fit the pattern of ASD, take 150 other children, put them together, and say we have a treatment for ASD. You can imagine the challenge of drawing conclusions about the child who’s sitting in front of you, who may have quite a different pattern than the other 150 children in those studies.”
In his presentation, Veenstra-VanderWeele discussed the latest in genetics, emerging treatments and behavioral characteristics of this diverse population.
Veenstra-VanderWeele said at the genetic level, autism appears to be expressed as multiple common risk factors which, in combination, lead to convergent risk for ASD in an individual.
“This model is now supported in schizophrenia, where there are more than 100 genes that you can point to as having relatively small effect sizes, and likely summing up within individuals,” he said. “In autism, unfortunately, we don’t yet understand what those risk factors are. We probably will in the next couple of years.”
Instead, what have been identified are a number of rare, “almost causal” variants, Veenstra-VanderWeele said, which appear to lead to an increased risk for ASD. He cited Fragile X syndrome, which is among the most common of these variants, but affects only approximately 1% of the population.
“A number of others that have emerged occur in less than 1%,” he said. “But just in the past few years, we’ve gone from having only syndromes that we can identify to having a couple of genes, to now having about 30 genes that can be identified as contributing to risk.”
While some mouse studies have partly revealed the genetic pathway of Fragile X syndrome, Veenstra-VanderWeele said there is still limited understanding on how the variant affects behavior.
“By and large, this is where we’ve been stuck,” he said. “We’re at the point where we understand the genes, and we understand something about the corresponding proteins, but we don’t yet understand how this feeds forward at the level of behavior.”
He said part of the goal, in terms of genetics, is to determine a common pathway that may be involved in ASD behavior.
“What we hope is that we’re able to identify core circuits that are implicated across multiple of these rare genetic contributors that might lead us to a better understanding of what underlies behavior,” he said.
Veenstra-VanderWeele discussed some of the latest behavioral interventions and pharmaceutical treatments developed by Vanderbilt’s Evidence-Based Practice Center. He said in terms of behavioral approaches, early intensive interventions for preschoolers have emerged as being particularly promising.
“These involve 30-plus hours a week of intervention, and they have significant evidence for benefiting things like IQ, language function and adaptive behavior, but not necessarily treating the diagnosis or core symptoms themselves,” he said. “There are other behavioral interventions that have some evidence, but these are more niches, like social skills, or interventions for really high-functioning kids or kids with anxiety disorders.”
He said behavioral interventions are very important for children with autism.
“This is really where kids with autism should be spending most of their time,” he said.
In terms of medications, Veenstra-VanderWeele said there is little progress to report. He discussed the role of antipsychotic medications, such as risperidone and aripiprazole, which have some benefit in relieving symptoms of aggression, self-injury and other disruptive behaviors that interfere with classroom integration.
“These medicines, unfortunately, also lead to significant side effects, as we’re all aware, and so we try to avoid these medicines as much as possible,” he said.
Under the DSM-5, Veenstra-VanderWeele said, attention-deficit/hyperactivity disorder can now be diagnosed within the context of ASD, a change that may not ultimately benefit ASD children.
“It turns out medicines that treat ADHD do so whether or not you have ASD,” he said, “but unfortunately, in the ASD population, you see more side effects and less benefit than in the general population.”
Evidence is also accruing in support of the use of selective serotonin reuptake inhibitors for ASD, although children and adolescents with ASD seem to be disproportionately affected more by activation syndrome when starting SSRIs.
“This is a problem in children generally, but in ASD, it’s a bigger problem,” he said. “They stop sleeping and they’re more impulsive, and these medicines become very difficult to use for that reason. In contrast, in adults, these medicines clearly help with OCD-like behaviors, as we might expect them to.”
Social neuroscience and oxytocin
Veenstra-VanderWeele said some studies have suggested that oxytocin may have an effect on social behavior and may be beneficial in ASD.
He said in a laboratory setting, single-dose intranasal oxytocin was able prompt a patient with ASD to want to play a virtual ball game in an interactive manner, with a person who throws the ball back to them. He said the drug was also found to activate the nucleus accumbens center of the brain in response to social stimuli.
“These are things based on a single-dose administration in a laboratory setting, placebo-controlled,” he said. “This is important, but it isn’t real-world.”
Veenstra-VanderWeele said Vanderbilt is currently involved in a large treatment trial investigating the safety and efficacy of oxytocin in 300 children.
“We’re making sure there isn’t some negative effect of chronic administration of what is essentially an agonist drug that could lead to tachyphylaxis,” he said. “This could lead to a lack of benefit from those regular interactions that trigger oxytocin release.”
He said the future of treatments for ASD will most likely be as heterogeneous as the patient population itself, targeted to specific subgroups and symptoms.
“I would say that treatments that benefit the majority of children are likely to be symptomatic, and probably aren’t going to address the core pathophysiology in every child,” he said. “These treatments are unlikely to be experienced as cures. They may benefit only one symptom domain.” – by Jennifer Byrne
Veenstra-VanderWeele J. Pathways to new treatments in Autism Spectrum Disorders. Presented at: the American Psychiatric Association Annual Meeting; May 16-20, 2015; Toronto.
Disclosure: Veenstra-VanderWeele reports serving as a consultant/on the advisory board for SynapDx. He also reports receiving grant/research support from Forest, Novartis, Roche, Seaside Therapeutics, Sunovion and SynapDx.