DNA Diagnostics for Minimizing Metabolic Side-Effects of Antipsychotics

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DESCRIPTION (provided by applicant): Atypical antipsychotic drugs (AAPs) are indicated in the treatment for schizophrenia, bipolar disorder, psychotic depression and other psychiatric disorders. Their drawback is drug-induced metabolic derangements including weight gain, hyperlipidemia, and diabetic risks. These diabetic metabolic symptoms (DiMS) vary widely between drugs and from patient to patient. We propose to develop a novel product termed "Physiotype" to deliver personalized information for each patient on the drug- specific risks among aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone. The Physiotype consists of a multi-gene ensemble of single nucleotide polymorphisms (SNPs) that, interpreted with a biomathematical algorithm, may explain most of the inter-individual differences in DiMS among the 5 AAPs The proprietary physiogenomics technology and state-of-the-art genotyping laboratories of Genomas will be integrated with the clinical resources of the Institute of Living (Hartford CT) and of the University of Kentucky (Lexington KY), through subcontracts, respectively, to Dr. John Goethe and Dr. Jose de Leon. Our goal in Phase II is to discover SNPs predictive of differences in DiMS side effects between these 5 AAPs and to develop them into predictive diagnostic products for psychiatrists in their practice. We will recruit 200 patients treated by each of the 5 AAPs, characterize their weight and lipid profiles, and obtain their DNA for creation of a clinical registry and DNA repository. We will determine each patient's genotype at 100,000 SNPs covering all ~30,000 genes and also evolutionary conserved regions for a comprehensive, hypothesis-free search for genetic markers of DiMS. In Phase I, the collaborators have already accumulated a registry and DNA repository of 374 AAP-treated patients and their DNA. We have genotyped DNA from olanzapine- and risperidone-treated patients in the repository for an array of 384 SNPs in 222 cardiovascular, metabolic and psychiatric candidate genes and performed physiogenomic predictive modeling. We have discovered novel drug-specific DiMS markers for olanzapine and risperidone including the apolipoprotein E and leptin receptor genes, respectively. We have developed a prototype Physiotype and tested it in an independent psychiatric population. The Physiotype predicted that ~20% of patients have the most weight associated with risperidone and ~80% with olanzapine, which is consistent with known olanzapine average effects, and also pinpoints the greater risperidone-specific risk for many individuals. In Phase III, a prospective randomized trial of all 5 AAPs is planned as part of FDA review of a Physiotype device. The Physiotype will assist psychiatrists to avoid side effects by guiding drug selection for each patient according to innate characteristics unraveled and interpreted directly from the person's own DNA. The proposed program will develop DNA diagnostic products to enhance safety of atypical antipsychotic drugs (AAPs) and improve the medical management of schizophrenia and related disorders leading to better outcomes. As of now, the development of AAP side effects is unpredictable, potentially disabling to the patient, and discourages patient compliance. The products will enable DNA- guided medicine: the determination of which AAP is most suitable and the implementation of clinical safeguards, individualized to each patient, using his/her personal genome.