精神医学53巻4号

2011年04月発行

シンポジウム 気分障害の生物学的研究の最新動向─DSM，ICD改訂に向けて

気分障害の分子神経生物学

著者： 加藤忠史¹

所属機関： ¹理化学研究所脳科学総合研究センター精神疾患動態研究チーム

ページ範囲：P.373 - P.381

文献概要

はじめに

　国民の社会生活障害の大きな要因となっているうつ病の患者数は，近年急速に増加し，社会問題となっている。抗うつ薬によく反応するメランコリー型に加え，抗うつ薬により悪化する双極スペクトラム，抗うつ薬が奏効しにくく心理療法も重要となる非定型うつ病，難治化しやすい血管性うつ病など，治療抵抗性のうつ病が増加し，うつ病診療は混沌とした状況にある。一方，抗うつ薬により，攻撃性，衝動性が高まる，「賦活症候群」が引き起こされるのではないか，との懸念が繰り返し報道され，一部には精神医療バッシング的な動きさえ見受けられる。抗うつ薬による悪化を防ぐためには，双極性障害における初発の大うつ病エピソードを，その生物学的基盤に基づいて診断できるようにすることが必要であるが，面接による現在の診断法には限界があり，今後，分子神経生物学的な病態に基づいて，気分障害の疾患概念と亜型分類を確立し，生物学的な診断分類に基づいて治療を最適化する必要がある。

参考文献

1) Alexopoulos GS, Meyers BS, Young RC, et al：Clinically defined vascular depression. Am J Psychiatry 154：562-565, 1997

2) Benes FM, Lim B, Matzilevich D, et al：Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars. Proc Natl Acad Sci U S A 104：10164-10169, 2007

3) Berk M, Dodd S, Kauer-Sant'anna M, et al：Dopamine dysregulation syndrome：Implications for a dopamine hypothesis of bipolar disorder. Acta Psychiatr Scand Suppl：41-49, 2007

4) Carroll BJ, Martin FI, Davies B：Resistance to suppression by dexamethasone of plasma 11-O.H.C.S. levels in severe depressive illness. Br Med J 3：285-287, 1968

5) Daniels WM, Fairbairn LR, van Tilburg G, et al：Maternal separation alters nerve growth factor and corticosterone levels but not the DNA methylation status of the exon 1(7)glucocorticoid receptor promoter region. Metab Brain Dis 24：615-627, 2009

6) Ebmeier K, Rose E, Steele D：Cognitive impairment and fMRI in major depression. Neurotox Res 10：87-92, 2006

7) Elashoff M, Higgs BW, Yolken RH, et al：Meta-analysis of 12 genomic studies in bipolar disorder. J Mol Neurosci 31：221-243, 2007

8) Ellison-Wright I, Bullmore E：Anatomy of bipolar disorder and schizophrenia：A meta-analysis. Schizophr Res 117：1-12, 2010

9) Eriksson PS, Perfilieva E, Bjork-Eriksson T, et al：Neurogenesis in the adult human hippocampus. Nat Med 4：1313-1317, 1998

10) Ferreira MA, O'Donovan MC, Meng YA, et al：Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 40：1056-1058, 2008

11) Frausto da Silva JJ, Williams RJ：Possible mechanism for the biological action of lithium. Nature 263：237-239, 1976

12) Fujikawa T, Yamawaki S, Touhouda Y：Incidence of silent cerebral infarction in patients with major depression. Stroke 24：1631-1634, 1993

13) Gould E, McEwen BS, Tanapat, P et al：Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J Neurosci 17：2492-2498, 1997

14) Hahn CG, Gomez G, Restrepo D, et al：Aberrant intracellular calcium signaling in olfactory neurons from patients with bipolar disorder. Am J Psychiatry 162：616-618, 2005

15) Hamilton JP, Siemer M, Gotlib IH：Amygdala volume in major depressive disorder：A meta-analysis of magnetic resonance imaging studies. Mol Psychiatry 13：993-1000, 2008

16) Hayashi A, Kasahara T, Iwamoto K, et al：The role of brain-derived neurotrophic factor(BDNF)-induced XBP1 splicing during brain development. J Biol Chem 282：34525-34534, 2007

17) Hayashi A, Kasahara T, Kametani M, et al：Aberrant endoplasmic reticulum stress response in lymphoblastoid cells from patients with bipolar disorder. Int J Neuropsychopharmacol 12：33-43, 2009

18) Heine VM, Maslam S, Zareno J, et al：Suppressed proliferation and apoptotic changes in the rat dentate gyrus after acute and chronic stress are reversible. Eur J Neurosci 19：131-144, 2004

19) Heuser I, Yassouridis A, Holsboer F：The combined dexamethasone/CRH test：A refined laboratory test for psychiatric disorders. J Psychiatr Res 28：341-356, 1994

20) Iwamoto K, Bundo M, Kato T：Altered expression of mitochondria-related genes in postmortem brains of patients with bipolar disorder or schizophrenia, as revealed by large-scale DNA microarray analysis. Hum Mol Genet 14：241-253, 2005

21) Kakiuchi C, Iwamoto K, Ishiwata M, et al：Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder. Nat Genet 35：171-175, 2003

22) Kato T：Molecular neurobiology of bipolar disorder：A disease of ‘mood-stabilizing neurons'? Trends Neurosci 31：495-503, 2008

23) 加藤忠史：脳と精神疾患．朝倉書店，2009

24) Kato T, Kapczinski F, Berk M：Bipolar Disorder：Clinical and Neurobiological Foundations. In：Yathan LN, Maj M, ed. Wiley-Blackwell, Chichester, 2010

25) Kempton MJ, Geddes JR, Ettinger U, et al：Meta-analysis, database, and meta-regression of 98 structural imaging studies in bipolar disorder. Arch Gen Psychiatry 65：1017-1032, 2008

26) Kitamura T, Saitoh Y, Takashima N, et al：Adult neurogenesis modulates the hippocampus-dependent period of associative fear memory. Cell 139：814-827, 2009

27) Konradi C, Eaton M, MacDonald ML, et al：Molecular evidence for mitochondrial dysfunction in bipolar disorder. Arch Gen Psychiatry 61：300-308, 2004

28) Krishnan KR, Hays JC, Blazer DG：MRI-defined vascular depression. Am J Psychiatry 154：497-501, 1997

29) 久保千春：うつ病は身体疾患の発症や予後を左右する．医学のあゆみ 219：1125-1128, 2006

30) Lucassen PJ, Muller MB, Holsboer F, et al：Hippocampal apoptosis in major depression is a minor event and absent from subareas at risk for glucocorticoid overexposure. Am J Pathol 158：453-468, 2001

31) Manji HK, Duman RS：Impairments of neuroplasticity and cellular resilience in severe mood disorders：Implications for the development of novel therapeutics. Psychopharmacol Bull 35：5-49, 2001

32) McCurdy RD, Feron F, Perry C, et al：Cell cycle alterations in biopsied olfactory neuroepithelium in schizophrenia and bipolar I disorder using cell culture and gene expression analyses. Schizophr Res 82：163-173, 2006

33) McGowan PO, Sasaki A, D'Alessio AC, et al：Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci 12：342-348, 2009

34) Meaney MJ：Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations. Annu Rev Neurosci 24：1161-1192, 2001

35) Mirescu C, Peters JD, Gould E：Early life experience alters response of adult neurogenesis to stress. Nat Neurosci 7：841-846, 2004

36) Mitra R, Jadhav S, McEwen BS, et al：Stress duration modulates the spatiotemporal patterns of spine formation in the basolateral amygdala. Proc Natl Acad Sci U S A 102：9371-9376, 2005

37) Muller MB, Lucassen PJ, Yassouridis A, et al：Neither major depression nor glucocorticoid treatment affects the cellular integrity of the human hippocampus. Eur J Neurosci 14：1603-1612, 2001

38) Nibuya M, Morinobu S, Duman RS：Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 15：7539-7547, 1995

39) Nys GM, van Zandvoort MJ, van der Worp HB, et al：Early depressive symptoms after stroke：Neuropsychological correlates and lesion characteristics. J Neurol Sci 228：27-33, 2005

40) 奥村正紀，須原哲也：うつ病の画像研究．医学のあゆみ 219：1051-1055, 2006

41) Radley JJ, Rocher AB, Miller M, et al：Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex. Cereb Cortex 16：313-320, 2006

42) Reif A, Fritzen S, Finger M, et al：Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol Psychiatry 11：514-522, 2006

43) Risch N, Herrell R, Lehner T, et al：Interaction between the serotonin transporter gene(5-HTTLPR), stressful life events, and risk of depression：A meta-analysis. JAMA 301：2462-2471, 2009

44) Rush AJ, Giles DE, Schlesser MA, et al：The dexamethasone suppression test in patients with mood disorders. J Clin Psychiatry 57：470-484, 1996

45) Salaycik KJ, Kelly-Hayes M, Beiser A, et al：Depressive symptoms and risk of stroke：The Framingham Study. Stroke 38：16-21, 2007

46) Santarelli L, Saxe M, Gross C, et al：Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301：805-809, 2003

47) Sheline YI, Barch DM, Donnelly JM, et al：Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment：An fMRI study. Biol Psychiatry 50：651-658, 2001

48) Shyn SI, Shi J, Kraft JB, et al：Novel loci for major depression identified by genome-wide association study of Sequenced Treatment Alternatives to Relieve Depression and meta-analysis of three studies. Mol Psychiatry 16：202-215, 2011

49) So J, Warsh JJ, Li PP：Impaired endoplasmic reticulum stress response in B-lymphoblasts from patients with bipolar-I disorder. Biol Psychiatry 62：141-147, 2007

50) Starkstein SE, Robinson RG：Affective disorders and cerebral vascular disease. Br J Psychiatry 154：170-182, 1989

51) Tomita H, Vawter MP, Walsh DM, et al：Effect of agonal and postmortem factors on gene expression profile：Quality control in microarray analyses of postmortem human brain. Biol Psychiatry 55：346-352, 2004

52) Warsh JJ, Andreopoulos S, Li PP：Role of intracellular calcium signaling in the pathophysiology and pharmacotherapy of bipolar disorder：Current status. Clinical Neuroscience Research 4：201-213, 2004

53) Watanabe Y, Gould E, McEwen BS：Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons. Brain Res 588：341-345, 1992

54) Weaver IC, Cervoni N, Champagne FA, et al：Epigenetic programming by maternal behavior. Nat Neurosci 7：847-854, 2004

55) Widom CS, DuMont K, Czaja SJ：A prospective investigation of major depressive disorder and comorbidity in abused and neglected children grown up. Arch Gen Psychiatry 64：49-56, 2007

56) Yildiz A, Sachs GS, Dorer DJ, et al：31P Nuclear magnetic resonance spectroscopy findings in bipolar illness：A meta-analysis. Psychiatry Res 106：181-191, 2001