Symposium

Symposium 5 Metabolome analyses of psychiatric disordes シンポジウム5 精神疾患のメタボローム解析

SY5-1 Plasma metabolomics of major depressive disorder うつ病の血漿を用いたメタボローム解析 Numata Shusuke（沼田周助） Department of Psychiatry, Graduate School of Biomedical Sciences, Tokushima University [Purpose] To gain insight into the molecular mechanisms underlying major depressive disorder (MDD), a comprehensive metabolic profiling was conducted in a Japanese cohort of well characterized plasma specimens from individuals with MDD and non-psychiatric controls. [Methods] Thirty-three medication-free patients with MDD and thirty-three age- and sex-matched non-psychiatric healthy control subjects were recruited. We followed up 10 patients who received treatment with an antidepressant. The levels of metabolites in the plasma samples were measured using Capillary electrophoresis-time-of-flight mass spectrometry (CE-TOFMS). This study protocol was approved by the institutional ethics committee of Tokushima University, and all enrolled subjects provided their signed written informed consent for participation. [Results] We identified novel differential metabolites as well as imbalances of specific metabolite in the plasma of medication-free MDD patients. We also identified metabolic changes after treatment with antidepressants. [Conclusion] Our results suggest that imbalances of specific metabolites may be involved in the pathology of MDD, and provide insight into the mechanisms by which antidepressants affect MDD.		SY5-2 Metabolomics analysis on schizophrenia 統合失調症のメタボローム解析 Kunugi Hiroshi（功刀浩），服部功太郎 Dep. Mental Disorder Res. NCNP We aimed to find the alterations in the profiles of low-molecular-weight metabolites in the brains of schizophrenia patients that may reflect the pathophysiology of the disorder. Human postmortem brain tissues from the frontal cortex (15 schizophrenia patients and 15 controls) and the hippocampus (14 schizophrenia patients and 15 controls) were obtained from the Stanley Foundation Neuropathology Consortium. We analyzed ~300 metabolites, using capillary electrophoresis with time-of-flight mass spectrometry. In the frontal cortex, the mean levels of 29 metabolites were significantly different between the schizophrenia and control groups. In the hippocampus, only a dipeptide, glycylglycine was significantly (nominal p <0.001) increased in schizophrenia. Glycylglycine was also significantly (p = 0.007) increased in the frontal cortex of schizophrenia. Lactic acid was also elevated in both frontal cortex and hippocampus in the patients. The pathway analyses revealed that several metabolic pathways including KEGG “Central carbon metabolism in cancer” and “Protein digestion and absorption” were commonly affected in the frontal cortex and the hippocampus of schizophrenia patients. These findings may point out alterations in glucose metabolism and proteolysis in the brains of schizophrenia.

SY5-3 Metabolomics of cerebrospinal fluid o mood disorders 気分障害の脳脊髄液を用いたメタボローム解析 Hashimoto Kenji（橋本謙二） Div. Clinical Neuroscience, Chiba Univ. Ctr Forensic Mental Health Major depressive disorder (MDD) and bipolar disorder (BD) are the most common mood disorders. They are etiologically related but clinically distinct psychiatric illnesses. Their shared clinical features result in high rates of misdiagnosis due to a lack of biomarkers that allow differentiation between them. BD is more frequently misdiagnosed as MDD because of their overlapping symptomology, often later onset of mania, and frequent occurrence of depressive episodes in patients with BD. Metabolomics involves the profiling of small-molecule metabolites and provides the potential to characterize specific metabolic phenotypes associated with a disease. Metabolomics has an advantage over other “omics” techniques because it involves direct sampling of the metabolic changes in an organism and the integration of information from changes at the gene, transcript, and protein levels, as well as post-translational modifications. Cerebrospinal fluid (CSF) is arguably the most relevant sampling substrate for the in vivo study of brain disorders as it reflects the metabolic status and the biochemistry of the brain. Metabolomic analyses of CSF in patients and controls thus have the potential to reveal differences in the levels of proteins linked to the pathogenesis of neuropsychiatric disorders that may have value as biomarkers and might be targets for novel treatments. In this symposium, the author presents an overview and future perspective of the identification of biomarkers for mood disorders using metabolomics.		SY5-4 Biomarker for mood disorder using plasma metabolites 血漿代謝産物を利用した気分障害のバイオマーカー Kageyama Yuki（影山祐紀）¹，笠原和起²，中村健道⁴，服部功太郎⁵，出口裕彦³，谷宗英⁶，黒田健治⁷，吉田寿美子^5,8，後藤雄一⁵，井上幸紀³，加藤忠史² ¹Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, USA ²Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science, Saitama, Japan ³Department of Neuropsychiatry, Osaka City University, Graduate School of Medicine, Osaka, Japan ⁴Molecular Structure Characterization Unit, RIKEN Center for Sustainable Resource Science, Saitama, Japan ⁵Medical Genome Center, National Center of Neurology and Psychiatry, Tokyo, Japan ⁶Tani Mental clinic, Osaka, Japan ⁷Department of Psychiatry, Hannan Hospital, Osaka, Japan ⁸Department of Psychiatry, National Center of Neurology and Psychiatry Hospital, Tokyo, Japan There is an urgent need for diagnostic biomarkers of major depressive disorder (MDD) and bipolar disorder (BD) because there is no currently available biomarker. We performed comprehensive metabolome analysis of plasma samples from drug-free patients with MDD (n = 9), BD (n = 6), and schizophrenia (n = 17), and matched healthy controls (n = 19), using liquid chromatography time-of-flight mass spectrometry. A significant effect of diagnosis was found for two metabolites; nervonic acid and cortisone. Reproducibility and the effects of psychotropic medication on nervonic acid, the most significantly altered metabolite, were verified in an independent sample set with medicated patients (MDD (n = 45), BD (n = 71), SZ (n = 115), and controls (n = 90)) using gas chromatography time-of-flight mass spectrometry. Higher nervonic acid levels in MDD compared with controls or BD were replicated in the independent sample set. Plasma nervonic acid levels were higher in MDD compared to SZ in the cohort 2. As for state-dependent alteration, nervonic acid levels were higher in the depressive state of MDD than in the remission state of MDD or depressive state of BD in the cohort 2. These results shows that plasma nervonic acid is a good candidate of diagnostic biomarker for MDD.