This revised submission of the Clinical Trials Section of the Silvio O. Conte Neuroscience Center for thestudy of Glutamate Dysregulation in Schizophrenia has been enhanced by a new collaboration with Dr.Daniel Javitt. We will extend findings produced during the first five years and will examinepossible explanations for the negative findings of our six month trial with D-cycloserine and the 'CONSIST'trial, a 4 month comparison of glycine and D-cycloserine-- neither found effects on negative symptoms orcognition. Because neither D-cycloserine nor glycine may adequing Dr. Javitt's IND, we will conduct aplacebo-controlled trial of D-serine a glycine site partial agonist, did not produce siginificant improvement innegative or cognitive symptoms will be followed-up by a new approach in which D-cycloserine isadministered once-weekly. This design is intended to avoid tolerance to repeated dosing with D-cycloserine;animal studies and recent studies in patients with phobia indicate that single doses substantially improvecognitive function, but that tolerance develops after approximately two weeks of daily dosing. Wewill conduct a trial of D-serine co-treatment. This study follows from a previous finding by Tsai andcolleagues that the more potent, full agonist D-serine may be effective for positive, negative and cognitivesymptoms without evidence for tolerance with repeated dosing. The recent completion of toxicology studieswill allow us to obtain an IND for study of D-serine within the next year. In collaboration with Dr. Yurgelun-Todd, we will perform fMRI at baseline and week 8 of the D-serine trial to extend our previousfinding of enhanced temporal lobe activation with D-cycloserine which correlated with improvement ofnegative symptoms. We will expand our collection of DNA samples and our extensive databaseof phenotypic information from 200 to 500 patients to allow examination of alleles relevant to glutamatergicregulation in relation to clinical characteristics and response to glutamatergic agents. Study ofpolymorphisms of G72 and D-amino acid oxidase as predictors of D-serine response is one example. Wewill also further pursue our studies of GCPII by examining two additional polymorphisms in a larger sample.In collaboration with Dr. Yurgelun-Todd, we will also examine NAA/NAAG concentrations inprefrental cortex as a potential biological marker of GCPII activity.
Showing the most recent 10 out of 128 publications
