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Study and re-study
DETROIT, Mich.—Seeking to find a way to stem the repetitive actions, tics and "stimming" behavior of children suffering from obsessive-compulsive disorder (OCD), researchers from Wayne State University (WSU), the University of Michigan and the Hospital for Sick Children/University of Toronto will examine the role of glutamate in a study involving 400 children.
The National Institute of Mental Health (NIMH) paved the way for the initial research with a grant of nearly $2.7 million, bringing the total award for OCD research to more than $6.1 million.
This is the first-ever study in child psychiatry to combine imaging and genetics research on obsessive-compulsive disorder (OCD), a severe, prevalent and chronically disabling disease, said David Rosenberg, professor of psychiatry in the School of Medicine at WSU, and principal investigator.
OCD affects approximately 1 to 3 percent of the population nationwide, with about 50 percent of all OCD cases beginning in childhood and adolescence, said Rosenberg, considered an international expert in childhood OCD. The key to understanding the syndrome is glutamate, he says.
"Glutamate is the brain's light switch which helps turn serotonin and other chemicals off and on," Rosenberg says. "Our research has shown that glutamate abnormalities in OCD have significant treatment implications. This new study will further our research by combining imaging and genetics, something never assessed in OCD patients."
The expertise at WSU is brain imaging, Rosenberg said. WSU has the only pediatric center in the country with both positron emission tomograpy (PET) and magnetic resonance imaging (MRI) in a pediatric center, so it's ideally positioned to do these studies in children.
In the pediatric center at the Children's Hospital of Michigan, there is also a very powerful high-field MRI scanner that can look at the brain's chemistry, structure and physiology with great precision, without the need of shots, needles or radiation.
The current research is a follow-up to the initial study showing glutamate plays a key role in OCD in children.
This time investigators will combine brain imaging and genetic with a more powerful MRI machine that can better discriminate brain chemicals—including glutamate and other related and relevant chemicals—along with more sophisticated genetics studies in glutamate genes, Rosenberg says.
"We are beginning to elevate child psychiatry to traditional pediatric medicine and neurology, which will help defeat some of the stigma about mental illness, and ultimately lead to enhanced diagnosis and better treatment," he says. "Glutamate-modulating drugs are already being tested in childhood and adult OCD based on these prior genetic and imaging findings of glutamate involvement in OCD. Therefore, specific brain patterns and genetic findings may help predict who is more or less likely to respond to a particular treatment."
Dr. Gregory Hanna, associate professor of psychiatry and director of the Pediatric Anxiety and Tic Disorder Program at the University of Michigan, will lead recruiting efforts for patients. Dr. Paul Arnold, assistant professor of psychiatry at the University of Toronto and SickKids, will lead the genetic studies.
"The principal investigators in this study have a long history of collaboration with one another," Arnold says. "Drs. Rosenberg and Hanna co-wrote a prescient review on the possibility of imaging genetic studies in OCD almost a decade ago (published in 2000), and Drs. Hanna and Arnold have collaborated for some time in genetic studies of OCD. We conducted a small pilot study in which children with OCD who had previously received magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) scans at Wayne State were genotyped for the same variants in GRIN2B and SLC1A1 that had previously been associated with OCD. This work led to some exciting early results, recently published in Brain Imaging and Behavior and Psychiatry Research: Neuroimaging. The current, more ambitious project builds on this earlier work by taking advantage of cutting edge imaging and genomic technology."
Specifically, investigators will collect a larger population of 400 children (50 percent with OCD) and their parents, then compare the 200 children with OCD and their 200 age-matched controls with regard to a much wider array of glutamate system variants than studied previously.
"As with all genetic association studies, the first step would be to ensure that our findings are replicated in other independent samples," Arnold says. "If the results consistently identify associations with specific genes or biological pathways, then targeted re-sequencing of the implicated genetic loci will be needed to provide a complete picture of the common and uncommon variants that may be influencing genetic susceptibility to OCD and related disorders. We expect that one of the eventual outcomes of our collaborative study will be the identification of biological pathways that lead to OCD and related disorders. Identification of specific genes and pathways will provide important clues regarding potential pharmacological agents not yet developed or tested for this disorder. Collectively, our previous work has already led to a re-thinking of OCD as being related to abnormalities in glutamate neurotransmission, and glutamatergic drugs are consequently being tested in OCD."
It is unlikely that this research will ultimately lead to a "cure" for OCD, he says. That's because OCD comprises a highly complex set of behaviors, many of which represents extremes on a continuum of behavior that we all exhibit from time to time.
"Therefore, it would be impractical and unwise to attempt to 'cure' such behavior," Arnold says. "Instead, we hope that our research will ultimately lead to more effective, safer and selective treatments that help alleviate suffering in individuals with OCD symptoms that interfere with their ability to function and enjoy a good quality of life."
OCD still holds its secrets, he adds.
"As a scientist, I believe that obsessive-compulsive symptoms represent something fundamental about the functioning of the human mind, " Arnold says. "Therefore, a more refined understanding of the pathogenesis of this condition will teach us important lessons about normal brain functioning and what can go wrong with this functioning. As a child psychiatrist treating children with OCD, I am hopeful that our collaborative research will ultimately lead to more effective treatments and improved diagnostic methods that will help alleviate the considerable suffering experienced by children and adults with OCD. Because OCD overlaps to some extent with other neurodevelopmental disorders, it is possible that our research will also provide a better understanding and better treatments for Tourette's disorder, autistic disorder, separation anxiety disorder and trichotillomania."