探討重鬱症病人接受抗憂鬱劑治療在腦部白質與抗氧化活性的影響

Effects of Antidepressants Therapy to Brain White Matter and Antioxidative Activity in Patients with Major Depressive Disorder

李俊德(Chun-Te Lee)

指導教授 ： 賴德仁

中山醫學大學/醫學院/醫學研究所/博士(2012年)

https://doi.org/10.6834/CSMU.2012.00012

摘要

目的： 重度憂鬱症 (重鬱症，major depressive disorder ) 是破壞力極大的一種疾病，而且讓很多病人遭受折磨中。本研究目的為探討重鬱症病人接受抗憂鬱劑治療在腦部白質 (white matter)、抗氧化活性 (antioxidtive activity) 與細胞激素 (cytokine) 的影響。

方法： 本研究的重鬱症病人組，來自於中山醫學大學附設醫院精神科門診病人，診斷符合DSM-IV重鬱症且年紀介於18歲到55歲之患者，給予抗憂鬱劑治療持續12週。憂鬱症病人組在抗憂鬱劑治療前與抗憂鬱劑治療滿12週時，兩次的檢查皆相同，包括：漢氏憂鬱量表 (Hamilton Depression Rating Scale, HDRS)、腦部擴散張量影像檢查 (brain diffusion tensor imaging, brain DTI)、總抗氧化能力 (total radical-trapping antioxidant parameter，TRAP)、超氧自由基 (superoxide radicals), 氫氧自由基 (hydroxyl radicals) 與介白質-6 (Interleukin-6，IL-6)。本研究的健康對照組來自於健檢與社區健康志願者，其年紀介於18歲到55歲而且無精神疾病與身體健康者，與憂鬱症病人組做性別與年齡的配對後，和憂鬱症病人組一樣接受一次的腦部擴散張量影像檢查、總抗氧化能力、超氧自由基、氫氧自由基與介白質6 (Interleukin-6，IL-6) 檢查。

結果： (1) 有35名重鬱症病人組 (憂鬱症組) (平均年齡39.14歲，女性22名（62.86%）) 與35名健康對照組 (對照組) (平均年齡39.37歲，女性24名（68.57%）)接受評估。憂鬱症組在抗憂鬱劑治療滿12週時有19名，這19名於抗憂鬱劑治療滿12週的憂鬱症狀全部達到緩解 (remission)且自殺症狀顯著下降。(2) 腦部擴散張量影像檢查：憂鬱症組與對照組比較，憂鬱症組在治療前12個部位的各向異性分數 (fractional anisotropy, FA) 皆較對照組為低，憂鬱症組在右側與左側之上額葉白質 (superior frontal white matter) 的FA值 (p = 0.037, p = 0.006) 皆比對照組顯著降低。比較憂鬱症組治療前與治療後（抗憂鬱劑治療滿12週時），治療後各部位的FA值都增加，治療後的右側與左側上額葉白質的FA值 (p = 0.001, p = 0.016) 皆比對照組顯著增加。(3) 氧化抗氧化系統 (Oxidative-antioxidative systems) 檢查：比較憂鬱症治療前與對照組，憂鬱症治療前的總抗氧化能力顯著低於對照組 (p = 0.011)。比較憂鬱症病人組治療前與治療後，結果顯示治療後的總抗氧化能力顯著高於治療前 (p = 0.000)，而治療後的超氧自由基顯著低於治療前 (p = 0.013)。(4) IL-6檢查：憂鬱症組與對照組比較，兩組的IL-6無顯著差異。然而憂鬱症治療後的IL-6顯著低於治療前組 (p = 0.032)。

結論： 本研究接受抗憂鬱劑治療滿12週的完成率有54% (19/35)。在接受抗憂鬱劑治療滿12週時，其憂鬱症狀全部達到緩解 (remission) 的比率100% (19/19)，其自殺危機也明顯的消失。關於腦部擴散張量影像檢查研究，憂鬱症病人急性發病期時，在兩側上額葉白質合併出現白質微細結構的異常 (microstructural abnormalities of white matter)，此發現支持以下的觀點：額葉白質異常傷害到調控情緒的皮質皮質下迴路 (cortico-subcortical circuits) 而造成切斷症候群 (disconnection syndrome)，而與重鬱症的臨床與神經病理的變化產生關聯；重鬱症病人接受抗憂鬱劑治療達緩解後，其兩側上額葉白質受損的白質之微細結構又會可逆性的復原。對於氧化抗氧化系統的研究，重鬱症病人急性期時合併出現氧化壓力；重鬱症病人接受抗憂鬱劑治療達緩解後，氧化壓力明顯減除。對於IL-6研究，重鬱症病人接受抗憂鬱劑治療達緩解後，能顯著降低免疫活化反應。總之，本研究關於重鬱症合併出現上額葉白質微細結構的異常與氧化壓力，就像很多證據顯示憂鬱病人會合併出現腦部結構與功能的改變。然而，這些觀察到的改變到底是導致產生憂鬱症的病因，或是憂鬱症結果的一部分，目前仍然不清楚，未來還需要更多的研究與臨床觀察來證實。

關鍵字

重鬱症 ； 抗憂鬱劑 ； 擴散張量影像 ； 總抗氧化活性 ； 自由基 ； 細胞激素

並列摘要

Aims: Major depressive disorder (MDD) is a devastating disease that afflicts large populations. The study investigated effects of antidepressants therapy to brain white matter, antioxidative activity and cytokine in patients with MDD.

Methods: In this prospective study, the depressed patients, with MDD and aging 20 to 55 years, were enrolled from psychiatric clinics in Chung Shan Medical University Hospital. The depressed patients were surveyed at baseline and at follow-up after receiving antidepressant treatment 12 weeks later. They received the examinations of Hamilton Depression Rating Scale (HDRS), brain diffusion tensor imaging (DTI), total radical-trapping antioxidant parameter (TRAP), superoxide radicals, hydroxyl radicals, and Interleukin-6 (IL-6), respectively. Besides, the healthy controls, aging 20 to 55 years, were matched by age and sex with depressed patiens. The healthy controls obtained the same examinations once as the depressed group.

Results: (1) Thirty five depressed patients were recruited. Their mean age was 39.14 years, 62.86% (n = 22) were female .At the end of antidepressant treatment for 12 weeks, there were 19 patients (19/35, 54.29%) completing the antidepressant treatment and reaching remission of depression. (2) In the DTI study, compared with healthy controls, all fractional anisotropy (FA) values of 12 regions of interest (ROI) in DTI among depressed patients were lower. Besides, the depressed patiens displayed significantly decrease FA in right superior frontal white matter (p = 0.037) and left superior frontal white matter (p = 0.006), respectively. Compared with pretreatment group, the posttreatment group demonstrated increased FA value in 12 ROI in DTI, and significantly increased FA in right superior frontal white matter (p = 0.001) and left superior frontal white matter (p = 0.016), respectively. (3) In the oxidative-antioxidative systems study, compared with healthy controls, the depressed group displayed significantly decreased TRAP (p = 0.011). Compared with pretreatment group, the posttreatment group demonstrated significantly increased TRAP (p = 0.000) and decreased superoxide radicals level (p = 0.013), respectively. (4) In the IL-6 study, compared with healthy controls, the depressed patients displayed increased IL-6 level but did not reach significance. Compared with pretreatment group, the posttreatment group demonstrated significantly decreased IL-6 (p = 0.032).

Conclusions: Fifty-four percent patients with MDD obtained antidepressant treatment for 12 weeks, they all reached remission of depression. In the DTI study, patients with MDD under acute phase were accompanied with microstructural abnormalities of bilaterally superior frontal white matter, which support the idea that white matter lesions may disrupt the cortico-subcortical neural circuits involved in mood regulation and thus result in disconnection syndrome in MDD, which may be associated with neuropathology and clinical manifestation of MDD. MDD under remission phase demonstrated restoring frontal white matter integrity. In the oxidative-antioxidative systems study, MDD under acute phase was associated with oxidative stress. MDD under remission phase demonstrated no significantly oxidative stress.In the IL-6 study, remission of MDD under antidepressant treatment demonstrated significantly decreased activation of immunological reaction. In brief, these findings in our study showed frontal white matter microstructural abnormalities and oxidative stress associated with MDD. However, we could not confirm whether observed changes are etiology of depression or the consequences of depression, which need more study and clinical survey to confirm the cause-effect .

並列關鍵字

major depressive disorder ； antidepressant ； diffusion tensor imaging ； antioxidative activity ； radical ； cytokine

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