Evaluation and Treatment of Obsessive Compulsive and Related Disorders

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There are two projects within this research portfolio. The first includes a series of studies of children in the PANDAS subgroup (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections) and the second is a clinical trial of riluzole - a glutamate antagonist with some preliminary evidence of benefit for children and adolescents with obsessive-compulsive disorder (OCD). A double-blind, placebo-controlled trial of riluzole is currently underway for children ages 7 - 17 years. During the previous reporting period, the mid-point of the study was reached and an interim data analysis revealed encouraging, but not yet significant, results. Further analyses revealed that the full cohort of 60 children will be required to reach statistical significance. Therefore, enrollment is ongoing and interested individuals are invited to learn more about the study at: http://clinicalstudies.info.nih.gov/detail/A_2005-M-0225.html In some cases, childhood-onset OCD and tic disorders appear to arise as sequelae of common childhood infections, including Group A beta-hemolytic streptococcal (GABHS) infections. Children whose symptoms begin or exacerbate following GABHS infections may belong to a subgroup of neuropsychiatric disorders identified by the acronym PANDAS (for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections). The PANDAS subgroup shares several common clinical characteristics and may share a common pathophysiology for their symptoms. The postulated etiology for the PANDAS subgroup is that specific strains of GABHS, in genetically susceptible individuals, elicit the production of cross-reactive antibodies which recognize antigens not only on the strep. cell wall, but also in the host brain tissue, eliciting obsessions, compulsions, tics and other neuropsychiatric symptoms. The cross-reactive antibodies have been shown to correlate with other anti-streptococcal antibodies and also with neuropsychiatric symptom severity, with highest titers seen in children acutely ill with Sydenham chorea or PANDAS symptomatology. A recent report by Yaddanapudi et al (Mol Psychiatry advance on-line publication, 11 Aug 2009; doi10.1038/mp.2009.77)demonstrated that passive transfer of these cross-reactive antibodies resulted in stereotypies and other neurologic symptoms in the recipient mice. This paper adds to the results of more than 15 years of research at the NIMH intramural program and elsewhere, demonstrating that: the PANDAS subgroup has a specific and identifiable symptom course (marked most notably by the acute, abrupt, overnight onset of symptoms ("zero to sixty in less than 24 hours"); the cross-reactive antibodies correlate with both GABHS infection status and neuropsychiatric symptom severity; prevention of GABHS infections through antibiotic prophylaxis results in prevention of neuropsychiatric symptom exacerbations; and, treatment of acutely ill children with immunomodulatory therapies (specifically, intravenous immunoglobulin (IVIG)or plasmapheresis) results in dramatic reductions in symptom severity. This line of research is unusual, in that it reversed the typical "bench to bedside" progression and took clinical observations and experiences into the laboratory in search of information about etiopathogenic mechanisms. The results proved exciting, as the cross-reactive antibodies identified antigenic targets in the CNS which might provide new targets for therapeutic interventions. During the current reporting period, Dr. Swedo entered a collaborative relationship with Dr. James Leckman and colleagues at the Yale University Child Study Center and Dr. Madeleine Cunningham of the University of Oklahoma Health Sciences Center. Drs. Swedo, Leckman and Cunningham were the joint recipients of an NIH "Bench to Bedside" award which will help fund a new multi-site placebo-controlled trial of intravenous immunoglobulin (IVIG) for severely ill children with PANDAS. Up to 50 children (3-12 yrs old) willl be enrolled in the trial and randomly assigned to receive an infusion of IVIG or placebo. In addition to the information provided about the utility of IVIG treatment for PANDAS, the trial will generate additional biological samples to be analyzed by Dr. Cunningham and others, with the goal of further delineating the pathologic role of the cross-reactive antibodies, as well as potentially developing biomarkers for disease activity and treatment response. The trial is in the final stages of review and enrollment is expected to begin early in the next reporting period (October or November 2010).