Memantine Study to Target Motor Dysfunction in Autism

Date: 
April 15, 2008
Cure Autism Now Kicks Off Recruitment for its First Clinical Trials Network Study



Most parents can describe differences in their children with autism that are not revealed in standard diagnostic measures. These may include some of their earliest concerns--a baby who does


not like to be held, or needs to be held continuously; a toddler who cannot seem to sit still but runs with an irregular gait. And they persist as the children age, to a kindergartner who reads but is stymied at the prospect of tying his shoes, or a school-age child whose handwriting makes academics a chore and whose social experiences are limited by the overwhelming challenges of kicking a soccer ball or riding a bicycle.

Motor deficits have been described in children with autism spectrum disorders (ASD) in multiple studies, and are often viewed as one sign of the syndrome. As early as 1996 researchers revealed that difficulty in motor planning and coordination are often co-occurring conditions and perhaps “soft neurological signs” of the disorder. While not a diagnostic criterion, clumsiness was originally proposed as an essential feature of Asperger syndrome. Coordination, motor dysregulation and fine motor difficulties have been identified in all ASD groups, and the scope of motor deficits suggests that this may be a characteristic of the pervasive neurological nature of autism. The possibility of motor deficits as an early marker was revealed by a retrospective study of infant videos, where children showed movement disturbances at four to six months of age, long before an autism diagnosis was made. These early signs included an abnormally shaped mouth and disturbances in lying down, righting, sitting, crawling and walking.

The exact pattern of motor deficits in autism has not been clearly described in scientific literature. Current studies report deficits in motor planning, but also atypical movement that may be characteristic of abnormalities in brain areas such as the basal ganglia (as in Parkinson's disease) or the cerebellum. One elegant study demonstrated reduced postural stability in subjects with autism, while others suggest abnormalities in sensory integration.

It has been hypothesized that movement disturbances may be related to, or perhaps contribute to, the core features of autism. From a social deficits perspective, “failure to cuddle” may be related to postural and tone abnormalities, “indifference to affection” may be related to marked under-activity, and motor deficits in infancy and early childhood might contribute to joint attention and imitation challenges. Similarly, from a language perspective, the impact of oral-motor abnormalities (e.g. dyspraxia and apraxia) on language development and expressive output are of significant consideration. As such, it is possible that improvements in motor skills may influence not only motor ability and activities of daily living, but also some of the core social and language symptoms of autism.

The idea of treating motor deficits with the possibility of reducing autistic symptoms will need to be tested in a controlled fashion. While the neuro-circuitry of motor deficits observed in autism is an area of active research, interventions are concentrated in traditional occupational and speech therapy techniques and no new interventions are available for more targeted treatment of deficits.

From a pharmacological standpoint, there have been few well controlled studies in autism. Just recently, risperidone (marketed as Risperdal), targeting the irritability associated with autism (e.g. aggression, self-injurious behavior, temper tantrums) became the first medication with specific labeling for use in autism approved by the Food and Drug Administration (FDA).

In an effort to explore the possible role of pharmacological treatment of motor deficits in individuals with autism, Cure Autism Now has recently awarded a pilot grant to Evdokia Anagnostou, M.D. from the Seaver and New York Autism Center of Excellence at Mount Sinai School of Medicine. The Mount Sinai team will lead a collaboration of treatment sites in conducting research into the effectiveness of memantine (marketed as Namenda). This medication modulates the glutamate neurotransmitter system in the brain by blocking the activity of one particular type of glutamate receptor, the NMDA receptor, which plays an integral role in cell-cell communication in the brain. Glutamate is the most prevalent neurotransmitter in the brain, and in individuals with autism there is scientific evidence from blood, post-mortem tissue, and genetic studies suggesting abnormalities in the glutamate neurotransmitter system. Early data from open label treatment with memantine, carried out by Michael Chez, M.D. (see reference below) has suggested that it may be helpful in targeting symptoms of motor planning, language, and cognitive function challenges in autism. Based on the available science and the promising but preliminary clinical data, a randomized multi-center clinical trial of memantine is warranted.

The CAN-funded study will recruit children with ASD, who are ages 6-12 and verbal. Initial screening will include state of the art diagnostic evaluation, as well as evaluation of motor abilities, motor planning, language, and adaptive skills. Children will be randomly assigned to either memantine or placebo (a medically inactive substance) and will be followed closely for 6 months. They will be expected to come to clinic every 2 weeks for the first 3 months and monthly for the second 3 months. Children who are revealed to have been on placebo at the end of 6 months will be given the opportunity to receive memantine thereafter. Gold standard diagnostic and functional evaluations will be of direct benefit to all participants.

This is the first study to be undertaken by the Clinical Trials Network (CTN) created by Cure Autism Now. While Dr. Anagnostou has designed the study parameters and is the lead investigator, each site participating in the study will benefit from participation in the CTN. The CTN enables the study to enroll children across the country, and thereby reach a sufficient sample size and be completed in a much shorter amount of time than any single site could complete on its own. Recruitment for the study is initially being launched at the Mount Sinai School of Medicine in New York, and as recruitment begins at each of the additional clinical trial sites, information will be placed on our Clinical Trials/Research Project listing service. Each site has its own recruitment contact and will post information when the site is ready to recruit. This study was made possible by a generous donation from Sallie and Tom Bernard.

Participating sites include:

Mount Sinai School of Medicine, NY (lead site)

University of North Carolina, NC

(Sites to seek participants in the near future)

Long Island Jewish Hospital, NY
Contact: Linda Spritzer

Yale University, CT
Contact: Erin Kustan

University of Medicine and Dentistry, New Jersey (UMDNJ Newark), NJ
Contact: Gerard Joe

Ohio State University, OH
Contact: Ashley Jones

Southwest Autism Research and Resource Center (SARRC), AZ
Contact: Sharman Ober-Reynolds

University of Washington/Seattle Children's Hospital WA
Contact: Leslie Pierson

References

Chez M, Hing P, Chin K, Memon S, Kirschner S. (2004). Memantine experience in children and adolescents with autism spectrum Disorders. Annals of Neurology, 56, (S8).

Ehlers S and Gillberg C. (1993). The epidemiology of Asperger syndrome. A total population study. Journal of Child Psychological Psychiatry, 34, 1327-50.

Ghaziuddin M and Butler E. (1998). Clumsiness in autism and Asperger syndrome: a further report. Journal of Intellectual Disability Research, 42, 43-8.

Hollander E, Phillips A, Chaplin W, Zagursky K, Novotny S, Wasserman S, et al. (2005). Placebo Controlled Crossover Trial of Liquid Fluoxetine on Repetitive Behaviors in Childhood and Adolescent Autism. Neuropsychopharmacology, 30, 582-9.

Leary MR and Hill DA. (1996). Moving on: autism and movement disturbance. Mental Retardation, 34, 39-53.

Manjiviona J and Prior M. (1995). Comparison of Asperger syndrome and high-functioning autistic children on a test of motor impairment. Journal of Autism and Developmental Disorders, 25, 23-39.

McCracken JT, McGough J, Shah B, Cronin P, Hong D, Aman MG, et al; Research Units on Pediatric Psychopharmacology Autism Network. (2002). Risperidone in children with autism and serious behavioral problems. New England Journal of Medicine, 347, 314-21.

McDougle CJ, Scahill L, Aman MG, McCracken JT, Tierney E, Davies M et al. (2005). Risperidone for the core symptom domains of autism: results from the study by the autism network of the research units on pediatric psychopharmacology. American Journal of Psychiatry, 162, 1142-8.

Minshew NJ, Sung K, Jones BL, and Furman JM. (2004). Underdevelopment of the postural control system in autism. Neurology, 63, 2056-2061.

Miyahara M, Tsujii M, Hori M, Nakanishi K, Kageyama H, Sugiyama T. (1997). Brief report: motor incoordination in children with Asperger syndrome and learning disabilities. Journal of Autism and Developmental Disorders, 27, 595-603.

Naas R and Gutman R. (1997). Boys with Asperger's disorder, exceptional verbal intelligence,
tics, and clumsiness. Developmental Medicine and Child Neurology, 39, 691-5.

Noterdaeme M, Mildenberger K, Minow F, and Amorosa H. (2002). Evaluation of neuromotor deficits in children with autism and children with a specific speech and language disorder. European Child & Adolescent Psychiatry, 11, 219-225.

Tuchman RF. (1996). Pervasive developmental disorders: neurological perspectives. Revista de Neurologia, 24, 1446-50.


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