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Symposium 35 WFSBP/JSBP Joint SymposiumFrontier symposium on schizophrenia and mood disorders シンポジウム35 日本生物学的精神医学会/WFSBP合同セッション SY35-1 Application of Panels of Brain-Expressed Genes to Predict Side Effects in Antipsychotic Use Kennedy James L.1,2,6，Tanner Julie-Anne1,2,3，Davies Paige E.3，Brown Lisa C.4，Herbert Deanna1，Shahmirian Anashe1，King Nicole1，Tiwari Arun K.1,2，Zai Clement C.1,2,5，Müller Daniel J.1,2,6,7，Dechairo Bryan M.4 1Tanenbaum Pharmacogenetics Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health 2Department of Psychiatry, University of Toronto, Toronto, ON, Canada 3Assurex Health Ltd., Toronto, ON, Canada. 4Assurex Health, Mason, OH, USA. 5Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada. 6Institute of Medical Science, University of Toronto, Toronto, ON, Canada 7Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada. Mental illness is a significant global burden of health. Given that pharmacotherapy is a primary form of treatment for mental illness, and the wide variation in individual response, there is a need to optimize medication selection. The IMPACT study was designed to assess the utility of pharmacogenomics (PGx) in the treatment of mental illness in a real-world setting. The Individualized Medicine: Pharmacogenetic Assessment and Clinical Treatment (IMPACT) project is a seven-year, naturalistic, open-label, prospective study examining PGx guidance in 11,000 patient medication decisions (impact.camhx.ca/en/home.php). IMPACT participants were administered the GeneSight combinatorial PGx test, for eight pharmacokinetic and two pharmacodynamics genes, stratifying 33 drugs into three risk groups. In addition, based on the literature and our own discovery work, we have developed panels of genetic markers to predict response to antipsychotics, and side effects including antipsychotic-induced weight gain and tardive dyskinesia (TD). The weight gain is predicted by appetite-related genes in the hypothalamus, and TD by the VMAT2 and other dopamine system genes. We have demonstrated that PGx testing improves outcomes in psychiatric patients, and we are making new discoveries of pharmacogenetic effects that predict patients’ susceptibility to treatment resistance as well the as side effects of Antipsychotic Induced Weight Gain, and Tardive Dyskinesia. SY35-2 Schizophrenia paradox - A material or an event 統合失調症パラドックスーモノとコトー Itokawa Masanori（糸川 昌成） Tokyo Metropolitan Institute of Medical Science Levodopa improves tremor derived from cell death of dopamine neuron at substantia nigra in patient with Parkinson disease. Chlorpromazine reduces auditory hallucination of schizophrenia by antagonizing dopamine D2 receptor. They have identical construct as treating patient with diagnosed illness. But former is causal therapy of disease and latter is symptomatic therapy of syndrome. 1,717 studies of 8,788 polymorphisms in 1.008 genes had been published until 2011 and most of the odds ratio of 287 meta analyses are under 1. 5. Why couldn’t we identify the nucleotide change with large odds ratio detected in neurodegenerative disease ? The reason was that schizophrenia is not a disease but syndrome.There was a case in which disease was extracted from the syndrome of mental disorders in history of psychiatry. Progressive paralysis, so called neurosyphilis, was considered a representative mental disease occupying majority of psychiatric beds in Europe in the 19th century. Neurosyphilis exchanged a disease from syndrome after Wassermann reaction was discovered in 1906, Fritz Schaudinn and Erich Hoffmann identified Spirochaeta pallida from patients in 1905 and Mahoney and colleagues reported the effectiveness of penicillin in 1943. In order to detect a mutation with large effect sizes, we investigated families having multiple affected members. We found a frame shift mutation that inactivates enzyme activity in glyoxalase 1 gene. Enhanced carbonyl stress was observed in this case because glyoxalase 1 was a detoxifying enzyme of carbonyl stress. Carbonyl stress was detected from 40% of 300 schizophrenia (odds ratio 25). We conducted clinical trial using vitamin B 6 eliminating carbonyl stress 5 of 10 cases reduced more than 10% of total PANSS score. SY35-3 New targets for treating depression: inflammation, oxidative stress and neurotrophic factors Berk Michael Deakin University, Australia There is abundant evidence that inflammatory and oxidative processes, altered neurogenesis and mitochondrial dysfunction play a role in the genesis and neuroprogression of bipolar disorder. There is evidence of increased inflammatory activity, oxidative stress, mitochondrial dysfunction as well as altered neurogenesis in most major neuropsychiatric disorders. The consequences of inflammatory and oxidative stress include lipid peroxidation, DNA fragmentation, telomere shortening, protein carbonylation, reduced neurogenesis and an increased vulnerability to apoptosis. Inflammatory and oxidative stress can lead to decreased BDNF and other trophic factors. In sum, these processes can further damage neurocircuitry and may lead to progression of the disorder. The role of the above pathways suggests a new range of therapeutic possibilities. Many of these are repurposed, and hence have established tolerability and safety profiles. The agent for which the largest amount of data is currently available is N-acetylcysteine. Positive placebo controlled data is currently available in bipolar disorder, depression and other disorders. Agents targeting inflammatory pathways additionally show promise. These include aspirin, minocycline, infliximab, celecoxib and statins, with largest current database for the latter two. Mitochondrial dysfunction also offers druggable targets, with the first trial in bipolar disorder completed. Lastly, some agents such as aspirin may have as preventive potential as part of integrated preventive programs targeting non-communicable disorders. These findings not only offer the promise of novel treatments, but serve as proof of principle of the role of inflammation and oxidative stress in the pathophysiology of bipolar disorder.