In another small-scale intramural study, Treatment of Childhood Regressive Autism With Minocycline(Drug information on minocycline): An Anti-Inflammatory Agent Active Within the CNS, NIMH researchers are examining the use of the antibiotic minocycline (Dynacin, Minocin, Myrac) in children aged 3 to 12 years with regressive autism.
“We are using minocycline, a tetracycline(Drug information on tetracycline) derivative, not for its effectiveness as an antibiotic but rather for its ability to modulate the immune system,” Swedo said. “It has fairly specific effects on NF-kappa B and therefore inhibits the initiation of the cascade that leads to inflammation. Published data from the Johns Hopkins group [2,3] demonstrate that brains of individuals with autism have evidence of chronic neuroinflammation. We hope that by stopping that process, the children will be able to recover some of their skills. We are conducting an open-label trial in 10 children and are accepting referrals. If the results are encouraging, we will do a placebo-controlled trial in a larger cohort of subjects.”
Asked about other pharmacologic approaches being investigated at NIMH, Swedo responded, “We have a few in [the] pipeline, but it is premature to talk about them. Eric Hollander, MD, has been doing some work with oxytocin(Drug information on oxytocin), reported at the American College of Neuropsychopharmacology's annual meeting.”
Hollander, chairman of psychiatry at the Mt Sinai School of Medicine in New York and director of the Seaver and New York Autism Center of Exellence, and Jennifer Bartz, PhD, found that pitocin (synthetic oxytocin), administered intravenously or nasally, may have significant positive effects in adults with autism. Oxytocin, a hormone that is best known for activity during birth and lactation, is also a brain neurotransmitter involved in social recognition and bonding.
The third NIMH study, “Mercury Chelation to Treat Autism,” seeks to address whether chelation therapy can be helpful for autism. The chelation study is a placebo-controlled trial that involves use of meso-2,3-dimercaptosuccinic acid (DMSA, succimer), an orally adminstered chelating agent that binds to all metals including mercury and lead but also to some beneficial metals, such as zinc and iron, according to Swedo. DMSA is commonly used to treat autism, with some surveys estimating that 1 in 12 children with autism has undergone chelation, although it has never been tested in a controlled study and there is no proof that it helps children with the disorder. Support for its use is based on single-case reports of benefits of chelation with DMSA.
Children aged 4 to 10 years in whom autism, Asperger disorder, or pervasive child developmental disorders have been diagnosed; who weigh at least 33 lb; who have detectable, but not toxic, levels of mercury or lead in the blood; and who have not previously received chelation therapy may be eligible for this study.
“The chelation study is based on the hypothesis that mercury toxicity is responsible for at least some cases of autism,” Swedo said. She explained that extensive controversy surrounds the issue of mercury toxicity in autism. The Institute of Medicine (IOM) conducted a comprehensive study of the question of whether thimerosal, an ethylmercury-based compound used previously in the United States as a vaccine preservative for routine childhood immunizations, contributed to the apparent increase in the prevalence of ASDs. 4 The IOM panel concluded that there was no evidence for an association, but the report has been dismissed by some parents who report “toxic mercury levels” among their affected children and who have observed benefits of open-label DMSA administration.
To answer the question in a controlled fashion, the NIMH will enroll about 120 children in the chelation study, with half randomized to placebo and half to DMSA. The trial will last for 6 months, and researchers are enrolling participants now. “We would love to receive referrals,” Swedo said, adding that psychiatrists can find out more by going to www.clinicaltrials.gov or by contacting Lorraine Lougee, LCSW, research coordinator. Lougee's e-mail address is LougeeL@intra.nimh.nih.gov.
Incidence and prevalence
Because of recurrent questions about whether autism is increasing, Swedo was asked about incidence and prevalence. “We have absolutely no data on incidence,” she said. “We can say the disorder appears to be more prevalent now than it has been reported in the past. However, there was a major change in diagnostic criteria and case-finding methods, so it is unclear [whether] it represents a true change in rates of affected individuals. . . . The CDC is conducting several studies currently to address that question.”
There is increasing agreement on what true autism is, using the Autism Diagnostic Observational Schedule, a semistructured observational scale developed to assess social interaction, communication, and play in persons suspected of having autism, and the Autism Diagnostic Interview, Swedo said.
“Those 2 give you nice, reliable cutoffs where you can say a child has autism, is on the autism spectrum, or is developing typically. Including children on the autism spectrum will increase apparent prevalence rates,” Swedo said. “The figure of 1 in 166 children having autism was recently confirmed in a CDC study that reviewed school records and confirmed the diagnosis from medical records. But the study included all children with an ASD as having ‘autism'—this included not only severely affected individuals with full-blown autism but also those with a pervasive developmental disorder not otherwise specified and those with Asperger disorder, a condition [that] is not as impairing.”
“In order to determine the true prevalence of autism and to know whether there is an ‘epidemic' as some have asserted,” Swedo continued, “we need to have better data about the current prevalence of autism and related disorders and then compare those data with comparable data from previous studies. The CDC is conducting surveillance studies at a number of US sites, and the NIH is sponsoring longitudinal investigations here and abroad to address those questions.”
1. Centers for Disease Control and Prevention. How common are autism spectrum disorders (ASD)? Available at: http://www.cdc.gov/ncbddd/autism/asd_common.htm. Accessed January 5, 2007.
2. Pardo CA, Vargas DL, Zimmerman AW. Immunity, neuroglia and neuroinflammation in autism. Int Rev Psychiatry. 2005;17:485-495.
3. Vargas DL, Nascimbene C, Krishnan C, et al. Neuroglial activation and neuroinflammation in the brain of patients with autism [published correction appears in Ann Neurol. 2005;57:304]. Ann Neurol. 2005;57:67-81.
4. Board on Health Promotion and Disease Prevention, Institute of Medicine. Immunization Safety Review: Vaccines and Autism (2004). Available at: http://www.nap.edu/books/030909237X/html/1.html. Accessed January 5, 2007.