抗憂鬱藥物與神經退化性疾病之關聯

The Study of Antidepressants and Neurodegenerative Diseases

鄧志堅(Chee-Kin Then)

指導教授 ： 沈芯伃

共同指導教授 ： 林彥光(Yen-Kuang Lin)

臺北醫學大學/醫學院/醫學科學研究所/博士(2018年)

摘要

憂鬱症及失智症皆是重要的公共衛生議題，彼此之間關係密切。先前研究提出兩種假說，(1)早發性的憂鬱症會增加晚發性失智症的風險，以及(2)憂鬱症只是失智症的疾病結果或所表現的其中一種症狀。不過，抗憂鬱藥物在失智症中扮演的角色至今仍不清楚。我們利用健保資料庫執行長達九年的回溯性世代研究。從2003年到2006年的百萬歸人檔中，我們選取5819名個案納入服藥組，並且依據年齡、性別、index-date配對，以1：4的比例選取了23276名個案納入對照組。相較於對照組，有憂鬱症的服藥組發生失智症的風險比為2.42 (95% CI: 1.15-5.10),沒憂鬱症的服藥組則為 4.05 (95% CI: 3.19-5.15)。針對6大類在台灣常用的抗憂鬱藥物，經過危險因子（包括憂鬱症）的校正後，這些藥物對於發生失智症的風險比個別為SSRIs 3.66 (95% CI: 2.62-5.09), SNRI 4.73 (95% CI: 2.54-8.80), TCAs 3.26 (95% CI: 2.30-4.63), TeCA 6.62 (95% CI: 3.34-13.13), MAOI 4.94 (95% CI: 2.17-11.24), 及SARI 4.48 (95% CI: 3.13-6.40)。我們進一步以細胞實驗探討抗憂鬱藥物對失智症發生的潛在影響。基於以神經膠質細胞為中心所引起神經退化性疾病的觀點，我們分析了12種常用抗憂鬱藥物對星狀膠質細胞株、初代培養神經細胞及神經膠質細胞的存活影響。我們發現10 ?M sertraline及20 ?M paroxetine會顯著降低細胞存活率。觀察發現10uM sertraline及20uM paroxetine會誘導鈣離子濃度上升，破壞粒腺體，增加ROS形成及活化caspase 3，進一步誘導細胞凋亡。綜合以上結果，不管在有或無憂鬱症的族群中，服用抗憂鬱藥物被證實是失智症的潛在風險因子，以及sertraline和paroxetine所造成的神經膠質細胞的凋亡可能進一步造成神經退化性疾病的重要機轉。

關鍵字

抗憂鬱藥物；失智症；健保資料庫；粒線體損壞；星狀膠質細胞凋亡

並列摘要

Depression and dementia are common clinical entities and are associated with each other in several ways. Early-life depression is associated with increased risk of later life dementia, and depression can present as a preclinical symptom or consequence of dementia. The impacts of antidepressants on the pathogenesis of dementia remain unclear despite depression and dementia are closely related. We conducted a 9-year retrospective analysis of Taiwan’s National Health Insurance Research Database (NHIRD), enrolling 5819 cases who had received prescriptions of antidepressants between 2003 and 2006, and 23,276 (with ratio of 1:4) age-, sex-, and index date-matched controls. The hazard ratio (HR) of dementia among antidepressant users with depression was 2.42 (95% confidence interval (CI): 1.15-5.10), for those without depression was 4.05 (95% CI: 3.19-5.15), compared to antidepressant non-users with or without depression respectively. Among the 6 classes of common antidepressants used in Taiwan, the adjusted HRs were 3.66 (95% CI: 2.62-5.09) for SSRIs, 4.73 (95% CI: 2.54-8.80) for SNRI, 3.26 (95% CI: 2.30-4.63) for TCAs, 6.62 (95% CI: 3.34-13.13) for TeCA, 4.94 (95% CI: 2.17-11.24) for MAOI, and 4.48 (95% CI: 3.13-6.40) for SARI. We further explored the underlying mechanisms of antidepressants in dementia, the general symptom of neurodegenerative disease such as Alzheimer’s disease. Based on the ‘astroglio-centric’ perspective of neurodegenerative diseases, we used an astrocyte cell line, primary cultured astrocytes and neuron cells, to identify the effects of the aforementioned antidepressants on nervous system. We found that treatment with 10 uM sertraline and 20 uM paroxetine significantly reduced cell viability. We also revealed that sertraline and paroxetine induced the elevation of [Ca2+]i level, mitochondrial damage, ROS generation, and caspase 3-mediated astrocyte apoptosis. Thus, we concluded that antidepressant is a potential risk factor for dementia, independent from any effect of depression itself, while sertraline- and paroxetine-induced astrocyte dysfunction may be involved in the pathogenesis of neurodegenerative diseases.

並列關鍵字

Antidepressant ； dementia ； National Health Insurance Database ； calcium overload ； mitochondrial damage ； astrocyte apoptosis

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