精神医学65巻8号

2023年08月発行

特集 複雑性PTSDの臨床

複雑性PTSDの神経生物学—逆境的小児期体験（ACEs）と心的外傷後ストレス症（PTSD）の研究からの考察

著者： 堀弘明¹

所属機関： ¹国立精神・神経医療研究センター精神保健研究所行動医学研究部

ページ範囲：P.1172 - P.1182

抄録
　複雑性心的外傷後ストレス症（PTSD）は，幼少期の虐待などの長期にわたり持続・反復するトラウマとの関連が強い精神疾患である。ICD-11において初めて公式診断に採用されたという経緯もあり，公式診断基準での複雑性PTSDを対象とした神経生物学的研究の報告は現在のところほとんど存在しない。一方，逆境的小児期体験（ACEs）による神経生物学的変化についての知見や，PTSD患者における神経生物学的異常についての知見が蓄積されてきている。そのうちACEsを有する者とPTSD患者に共通に認められる重要な所見として，視床下部-下垂体-副腎系の機能異常，炎症の亢進，扁桃体の過活動，海馬の体積減少が挙げられる。これらの知見はACEsからPTSDへと至る生物学的経路を示唆していると考えられ，複雑性PTSDの病因・病態を理解する上でも手がかりになる可能性がある。今後，複雑性PTSDを対象とした神経生物学的研究が進展することにより，病態に基づいたよりよい治療法の開発へとつながっていくことが期待される。

参考文献

1）Felitti VJ, Anda RF, Nordenberg D, et al：Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The Adverse Childhood Experiences（ACE）Study. Am J Prev Med 14：245-258, 1998

2）Morris MC, Compas BE, Garber J：Relations among posttraumatic stress disorder, comorbid major depression, and HPA function：A systematic review and meta-analysis. Clin Psychol Rev 32：301-315, 2012

3）Hakamata Y, Suzuki Y, Kobashikawa H, et al：Neurobiology of early life adversity：a systematic review of meta-analyses towards an integrative account of its neurobiological trajectories to mental disorders. Front Neuroendocrinol 65：100994, 2022

4）Yehuda R, McFarlane AC, Shalev AY：Predicting the development of posttraumatic stress disorder from the acute response to a traumatic event. Biol Psychiatry 44：1305-1313, 1998

5）Yehuda R, Golier JA, Yang RK, et al：Enhanced sensitivity to glucocorticoids in peripheral mononuclear leukocytes in posttraumatic stress disorder. Biol Psychiatry 55：1110-1116, 2004

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

7）Perroud N, Paoloni-Giacobino A, Prada P, et al：Increased methylation of glucocorticoid receptor gene（NR3C1）in adults with a history of childhood maltreatment：A link with the severity and type of trauma. Transl Psychiatry 1：e59, 2011

8）Watkeys OJ, Kremerskothen K, Quidé Y, et al：Glucocorticoid receptor gene（NR3C1）DNA methylation in association with trauma, psychopathology, transcript expression, or genotypic variation：A systematic review. Neurosci Biobehav Rev 95：85-122, 2018

9）Bartels M, Van den Berg M, Sluyter F, et al：Heritability of cortisol levels：Review and simultaneous analysis of twin studies. Psychoneuroendocrinology 28：121-137, 2003

10）Binder EB, Bradley RG, Liu W, et al：Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA 299：1291-1305, 2008

11）Hori H, Kim Y：Inflammation and post-traumatic stress disorder. Psychiatry Clin Neurosci 73：143-153, 2019

12）Hori H, Izawa S, Yoshida F, et al：Association of childhood maltreatment history with salivary interleukin-6 diurnal patterns and C-reactive protein in healthy adults. Brain Behav Immun 101：377-382, 2022

13）Imai R, Hori H, Itoh M, et al：Inflammatory markers and their possible effects on cognitive function in women with posttraumatic stress disorder. J Psychiatr Res 102：192-200, 2018

14）Baumeister D, Akhtar R, Ciufolini S, et al：Childhood trauma and adulthood inflammation：A meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-alpha. Mol Psychiatry 21：642-649, 2016

15）Stein MB, Chen CY, Ursano RJ, et al：Genome-wide association studies of posttraumatic stress disorder in 2 cohorts of US Army soldiers. JAMA Psychiatry 73：695-704, 2016

16）Breen MS, Tylee DS, Maihofer AX, et al：PTSD blood transcriptome mega-analysis：Shared inflammatory pathways across biological sex and modes of trauma. Neuropsychopharmacology 43：469-481, 2018

17）Eraly SA, Nievergelt CM, Maihofer AX, et al：Assessment of plasma C-reactive protein as a biomarker of posttraumatic stress disorder risk. JAMA Psychiatry 71：423-431, 2014

18）Pankow JS, Folsom AR, Cushman M, et al：Familial and genetic determinants of systemic markers of inflammation：The NHLBI family heart study. Atherosclerosis 154：681-689, 2001

19）Otsuka T, Hori H, Yoshida F, et al：Association of CRP genetic variation with symptomatology, cognitive function, and circulating proinflammatory markers in civilian women with PTSD. J Affect Disord 279：640-649, 2021

20）Murthy S, Gould E：How early life adversity influences defensive circuitry. Trends Neurosci 43：200-212, 2020

21）Yehuda R, Hoge CW, McFarlane AC, et al：Post-traumatic stress disorder. Nat Rev Dis Primers 1：15057, 2015

22）Bromis K, Calem M, Reinders AATS, et al：Meta-analysis of 89 structural MRI studies in posttraumatic stress disorder and comparison with major depressive disorder. Am J Psychiatry 175：989-998, 2018

23）Bryant RA, Felmingham KL, Malhi G, et al：The distinctive neural circuitry of complex posttraumatic stress disorder during threat processing. Psychol Med 51：1121-1128, 2021

24）Naim R, Abend R, Wald I, et al：Threat-related attention bias variability and posttraumatic stress. Am J Psychiatry 172：1242-1250, 2015

25）Hori H, Itoh M, Lin M, et al：Childhood maltreatment history and attention bias variability in healthy adult women：Role of inflammation and the BDNF Val66Met genotype. Transl Psychiatry 11：122, 2021

26）Scott JC, Matt GE, Wrocklage KM, et al：a quantitative meta-analysis of neurocognitive functioning in posttraumatic stress disorder. Psychol Bull 141：105-140, 2015

27）Narita-Ohtaki R, Hori H, Itoh M, et al：Cognitive function in Japanese women with posttraumatic stress disorder：Association with exercise habits. J Affect Disord 236：306-312, 2018

28）Su Y, D'Arcy C, Yuan S, et al：How does childhood maltreatment influence ensuing cognitive functioning among people with the exposure of childhood maltreatment? A systematic review of prospective cohort studies. J Affect Disord 252：278-293, 2019

29）Gale CR, Deary IJ, Boyle SH, et al：Cognitive ability in early adulthood and risk of five specific psychiatric disorders in mid-life：The Vietnam experience study. Arch Gen Psychiatry 65：1410-1418, 2008

30）Maercker A, Cloitre M, Bachem R, et al：Complex post-traumatic stress disorder. Lancet 400：60-72, 2022

31）Ishikawa R, Fukushima H, Frankland PW, et al：Hippocampal neurogenesis enhancers promote forgetting of remote fear memory after hippocampal reactivation by retrieval. Elife 5：e17464, 2016

32）Ishikawa R, Uchida C, Kitaoka S, et al：Improvement of PTSD-like behavior by the forgetting effect of hippocampal neurogenesis enhancer memantine in a social defeat stress paradigm. Mol Brain 12：68, 2019

33）Hori H, Itoh M, Matsui M, et al：The efficacy of memantine in the treatment of civilian posttraumatic stress disorder：An open-label trial. Eur J Psychotraumatol 12：1859821, 2021