ATLANTA—Targeted toward stepping up its pace toward treating the growing rate of children diagnosed with autism, a multidisciplinary team of researchers has been awarded a contract from the National Institute of Mental Health (NIMH) to conduct ambitious, fast-paced studies of new drugs to treat the neurological disorder affecting one in 88 U.S. births. The program is part of the NIMH's new experimental medicine program: Fast-Fail Trials in Autism Spectrum Disorder (FAST-AS).
The team includes investigators at the Marcus Autism Center of Children's Healthcare of Atlanta, the Emory Autism Center, the Emory University School of Medicine Department of Pediatrics and Department of Psychiatry and the Georgia State University Department of Psychology. The group is joining a network of other leading medical centers, including the University of California at Los Angeles (UCLA), Harvard University and the University of Washington.
Autism spectrum disorder (ASD) is usually diagnosed when children are toddlers, after parents notice a decrease in social inter-action, especially in language, eye contact and play. Other signs include repetitive behavior or “stimming” and restricted patterns of interest.
While all individuals with ASD require supportive services, some are more severely affected and need a full range of medical, behavioral and educational services, according to the NIMH. This has opened the door to debate among medical professionals and parents as to whether ASD has been overdiagnosed. Years ago, the same kind of symptoms in children would, more often than not, yield a diagnosis of attention deficit hyperactivity disorder.
The question of how ASD is formed, or how it begins makes treating the disorder difficult.
Many medical researchers today believe there is a genetic component to ASD, possibly present at birth, and even in utero. Although it is unlikely that ASD has a single cause, several genes have been identified in the last decade which dramatically increase the risk of ASD, researchers have reported. These recent advances in genetics and neurobiology offer clues on possible drug treatments focused on core aspects of the disorder.
“Currently, there are no medications approved by the Food and Drug Administration for treating the social disability and repetitive behavior that define ASD,” Dr. Lawrence Scahill, director of clinical trials at Marcus Autism Center and professor of pediatrics at Emory School of Medicine, stated in a news release. “The two FDA-approved medications that are used to treat serious behavioral problems in children with ASD may not address the core problems of the disorder.”
The Atlanta FAST-AS team led by Scahill also includes Dr. Joseph Cubells, medical director of the Emory Autism Center, and Dr. Gwen Frishkoff, assistant professor in the Department of Psychology at Georgia State University.
Cubells has extensive experience treating adults with ASD, while Frishkoff brings specific expertise in measuring brain physiology using electroencephalography, which is a primary outcome of interest in the first clinical trial, according to a news release.
The first FAST-AS study conducted by the key Atlanta institutions will examine a compound that boosts the function of a brain chemical called gamma-aminobutyric acid (GABA), according to the NIMH. Previous evidence shows that GABA signaling is decreased in individuals with ASD. The study aims to confirm the mechanism and tolerability of the drug in adults with ASD.
If this pilot study is successful, the drug may be ready for larger clinical trials designed to evaluate its effectiveness for social disability, according to the researchers.
The NIMH and National Institutes of Health have stated, “There is an urgent need for new medications to treat mental disorders. Existing medications can be helpful but have significant limitations.”
“For example, antidepressants now available require weeks to take effect and they fail to relieve symptoms in about a third of people who try them,” the NIMH states on its website. “Currently approved medications also do not target some of the core symptoms of CNS disorders; for example, cognitive difficulties in schizophrenia and the repetitive behaviors, social function and communication deficits associated with autism. Side effects of the marketed drugs can also be a significant issue for patients.”
Another major reason for speeding up the process is that developing new medications is a lengthy and expensive process, the NIMH acknowledges. Many promising compounds fail to prove effective in clinical testing after years of preliminary research. Many of the psychiatric medications available now are variations on a theme, interacting in similar ways on the same targets in the brain. Yet the exact mechanisms by which these medications have their beneficial effects are incompletely understood.
“A necessary first step towards developing a wider array of medications that offer alternatives to those available now is to identify targets in the brain at which intervention, like a pharmaceutical, could be directed to correct a dysfunction contributing to illness,” the NIMH states. “The lack of such targets is one of the most important factors underlying the slow pace of medication development for mental illnesses and autism.”
The aim is not only to quickly identify compounds that merit more extensive testing, but to identify targets in the brain for the development of additional candidate compounds, the NIMH indicates.
Besides funding the FAST-AS in ASD disorders, which also includes Dr. James McCracken of UCLA, the NIMH is backing studies in Mood and Anxiety Spectrum Disorders (FAST-MAS) and Psychotic Spectrum Disorders (FAST-PS).
According to the NIMH, FAST studies will aim at answering the following questions: Does the compound engage a target in the brain? For example, does it interact with a specific receptor in brain cells or alter signaling in the brain by a specific neurotransmitter? Does it measurably alter a feature of brain function? For example, does it change the results of a test of memory, cognition or attention?
Unlike standard clinical drug-testing trials, clinical trials in FAST will be small (about 10 to 30 subjects), and will be in human patients, the NIMH states. Years of experience in drug testing suggests that positive results in animals do not necessarily translate to humans. With this type of testing, compounds that are found to engage a target in the brain and alter an indicator (or biomarker) of brain function can quickly go forward to further testing.
Even negative results will avoid costly and time-consuming testing, and also provide information that will be helpful in designing future trials, according to the NIMH. The identification of new targets in the brain identified through this approach will broaden the avenues available for development and screening of new candidate compounds.
And finally, the fast-fail approach aims to tie prospective therapies to underlying disease mechanisms from the very start, the NIMH states. The idea is to fund small, early-stage clinical studies that include a clearly defined biological readout of whether a compound has hit its intended target. Molecules that miss their mark would be discarded without expending any further resources, saving the resources to test other promising candidates.
The NIMH is supporting the Fast-Fail Trials (FAST) initiative through three NIMH contracts awarded in September 2012 (period of performance from Sept. 24, 2012 through Sept. 23, 2015), to provide a rapid way to test new or repurposed compounds for their potential as psychiatric medications.
The Marcus Autism Center is a not-for-profit organization and an affiliate of Children’s Healthcare of Atlanta that treats more than 5,500 children with autism and related disorders a year. As one of the largest autism centers in the U.S. and one of only three National Institutes of Health Autism Centers of Excellence, Marcus Autism Center offers families access to the latest research, comprehensive evaluations and intensive behavior treatments. With the help of research grants, community support and government funding, Marcus Autism Center aims to maximize the potential of children with autism today and transform the very nature of autism for future generations.
The Emory Autism Center is a component of the Department of Psychiatry and Behavioral Sciences at Emory University School of Medicine. The program was opened in 1991 as a public, private and university collaboration. Since opening, the Emory Autism Center has become a national model for diagnosis, family support and innovative treatment, as well as a vital source of professional training.