SBIR-STTR Award

Schizophrenia is a major mental disorder with estimated prevalence of 1 percent of the population. Current treatment approaches for schizophrenia rely on the use of dopamine antagonists (antipsychotics). These drugs have only partial effectiveness in a large percentage of patients, especially in the treatment of negative and cognitive symptoms. This project will explore alternative treatment strategies for schizophrenia based upon the PCP model of the disorder. PCP (phencyclidine, "angel dust") induces symptoms that closely resemble those of schizophrenia, by blocking neurotransmission mediated at N-methyl-D-aspartate (NMDA) type glutamate receptors. Several dietary amion acids, including glycine and D-serine, potentiate activation of NMDA receptors in vitro and reverse behavioral effects of PCP in vivo. In small scale clinical trials, glycine and D-serine have been shown to be effective in the treatment of persistent symptoms of schizophrenia. This project will focus on development of commercializable formulations of glycine and D-serine. Both products fall within the scope of Federal medical foods legislation. The specific aims are to explore feasibility of glycine and D-serine development as medical foods for dietary management of schizophrenia. In the case of D-serine, preclinical toxicology would be required. In successful, this project will lead to development of new treatment approaches for schizophrenia. PROPOSED COMMERCIAL APPLICATIONS: This project will permit commercialization of a diet-based treatment approach for schizophrenia

Thesaurus Terms:
NMDA receptor, antipsychotic agent, dietary supplement, drug design /synthesis /production, glycine, psychopharmacology, schizophrenia, serine food science /technology, mental disorder chemotherapy alternative medicine, clinical research, human subject, patient oriented research, placebo

Schizophrenia is a major mental disorder that affects approximately 1% of the population worldwide. Although many patients respond well to currently available medications, including both typical and atypical antipsychotics, the majority of patient shows significant residual symptoms despite best available treatment. Persistent negative and cognitive symptoms are particularly associated with poor outcome in schizophrenia. All current medications for schizophrenia, including both typical and atypical antipsychotics, bind primarily to dopamine (D2) receptors. The goal of the present study is to develop an adjunctive treatment strategy for schizophrenia based upon the PCP/NMDA model. Phencyclidine (PCP) induces psychotic symptoms in schizophrenia by blocking neurotransmission at N-methyI-D-aspartate (NMDA)-type glutamate receptors. Behavioral effects of PCP in rodents are reversed by the amino acids glycine and D-serine, which bind to the glycine modulatory site of the NMDA receptor complex. In schizophrenia, both glycine and D-serine have been shown to ameliorate persistent negative and cognitive symptoms of the disorder. The goal of the present study is to develop glycine and D-serine as commercializable treatments for schizophrenia. Glycine must be administered at relatively high dose (60 g/d) to significantly elevate brain glycine levels. In the case of glycine, therefore, the goal of the present project is to develop a palatable, unit dose formulation that can be administered in routine clinical practice. D-serine is effective at doses of approximately 2 g/d. However, D-serine has been shown to be nephrotoxic in rats (but not other species). In order for D-serine to be approved for use in the US, therefore, formal preclinical toxicity studies must be performed. Funds are therefore requested to conduct preclinical toxicology studies, followed by a double blind, placebo-controlled study. The overall goal of these projects is to develop new treatments for persistent negative and cognitive symptoms of schizophrenia. Development of D-serine and/or glycine will be conducted under FDA supervision, and will conform to all required FDA policies and procedures