臺灣博碩士論文加值系統

背景：許多證據暗示血清素轉運體經由再回收血清素可能在憂鬱症的致病機轉與抗鬱藥物療效上扮演重要的角色。本研究目的在檢驗治療前的血清素轉運體密度或在神經投射末梢區域與中腦縫核區的血清素轉運體比率是否與自殺行為相關，與檢驗是否會影響以血清素轉運體為標的抗鬱藥物療效。另外基因變異可能調節血清素與正腎上腺功能以至於影響venlafaxine抗鬱藥物療效，因此我們也利用正腎上腺素轉運體基因變異來探討對Venlafaxine，一種血清素與正腎上腺素再回收抑制劑，的治療效果是否相關。
方法：我們招募了39位未使用過藥物的嚴重型憂鬱症患者及39位正常人作為對照組。利用正子照影與血清素轉運體的追蹤劑N,N-dimethyl-2- (2-amino-4-[18F] fluorophenylthio) benzylamine (4-[18F]-ADAM)來測量治療前血清素轉運體的可獲至率(availability)。用21項次的漢式憂鬱症量表來評估每周的憂鬱症嚴重程度直到完成第六週治療，也利用貝氏自殺意念量表來療前自殺意念強度。所有招募的嚴重型憂鬱症患者的漢式憂鬱症量表分數至少達18分以上。另外我們招募243位使用抗鬱藥物Venlafaxine治療的嚴重型憂鬱症患者，並挑選正腎上腺素轉運體基因(SLC6A2)中7個單一核甘酸變異(SNPs)運用回歸分析來探討對於療效的預測效果。
結果：首先，自殺企圖組相較於沒有自殺企圖組與對照組，有較高的前額葉/中腦縫核區的血清素結合比值，且與自殺前意念強度呈現正相關。其次，憂鬱症患者治療前的血清素轉運體在丘腦及紋狀體的含量與第三週的漢式憂鬱症量表下降分數呈正相關。治療療效不佳者與中斷治療者其血清素轉運體在神經投射末梢區域與中腦縫核區相較於正常對照組呈現等比例的降低。相反的，治療有療效者則是被觀察到其血清素轉運體在神經投射末梢區域與中腦縫核區呈現不等比例的降低。正腎上腺素轉運體基因(SLC6A2)變異(rs28386840, rs40434, and rs187714)則能預測抗鬱藥物Venlafaxine的療效。
結論：本研究結果暗示著血清素轉運體在神經投射末梢區域與中腦縫核區不等比例的降低可能預測自殺行為的發生與嚴重型憂鬱症患者對抗鬱藥物的治療結果。此外，正腎上腺素轉運體基因(SLC6A2)變異可能與抗鬱藥物Venlafaxine的療效有關。

Background: Many lines of evidence suggest the role of serotonin transporter (SERT)-mediated reuptake of serotonin in the pathophysiology and treatment of major depressive disorder (MDD). The study aimed to examine whether the pretreatment SERT binding potential or SERT binding ratio between terminal projection regions relative to the midbrain raphe nuclei was associated with suicide attempts and treatment outcome to SERT-targeted antidepressants. Moreover, genetic polymorphisms may modulate serotonergic and noradrenergic function, thereby affecting the treatment efficacy of venlafaxine, a serotonin-norepinephrine reuptake inhibitor. The aim of this study was to examine whether polymorphisms in the norepinephrine transporter gene (SLC6A2) associate with remission after venlafaxine treatment, a serotonin-norepinephrine reuptake inhibitor.
Methods: We recruited 39 antidepressant-naïve patients with MDD and 39 heathy controls. Positron emission tomography with N,N-dimethyl-2- (2-amino-4-[18F]fluorophenylthio)benzylamine (4-[18F]-ADAM) was used to measure in vivo SERT availability prior to antidepressant treatment. The 21-item Hamilton Depression Rating Scale (HDRS) was use to assess the severity of depression from baseline to week 6. The Beck Scale for Suicide Ideation (BSS) was used to assess intensity of suicide ideation before treatment. All the patients with MDD had HDRS scores of 18 or more at baseline. In addition, we recruited 243 patients with MDD who were under treatment with venlafaxine. We screened seven single-nucleotide polymorphisms of the SLC6A2 gene in these patients and explored the association between SLC6A2 variants and treatment response by regression model.
Results: First, higher SERT binding ratio in the prefrontal cortex (PFC) relative to midbrain was found in suicide attempters compared to non-attempters and healthy controls. Further, the PFC/midbrain binding ratio positively correlated with BSS scores. Second, pretreatment SERT binding in the thalamus and striatum positively correlated with an early reduction in HDRS scores at week 3. Non-responders and dropout patients showed a proportionate reduction in SERT binding in the terminal projection regions and midbrain compared to healthy controls. In contrast, a disproportionate reduction in SERT binding in the terminal projection regions relative to midbrain was observed in responders. SLC6A2 variants (rs28386840, rs40434, and rs187714) may predict remission after treatment with venlafaxine.
Conclusions: The results of this study suggested that a disproportionate reduction in SERT binding between terminal projection regions and midbrain may predict suicide attempts and treatment outcome in patients with MDD. In addition, variation of the SLC6A2 gene is associated with treatment remission after venlafaxine in patients with MDD.

Index of Contents I
List of Tables III
List of Figures IV
Chinese Abstract VI
English Abstract VIII
List of Abbreviations XI
Introduction 1
Association between neuroimaging and major depression, suicide behaviors and treatment response to antidepressants. 1
Association between genetic variants and treatment response to antidepressants. 8
Materials and Methods 12
Part I: Patient selection in exploring the biomarker for suicide attempts 12
Part II: Patient selection for exploring the biomarker for response to antidepressants 14
Part III: Patient selection for genetic study 15
Interview Screening Tool 16
The Psychometric Assessments 17
PET Procedure 18
Image Acquisition 19
Selection of SLC6A2 gene variants 20
Genotyping methods for the SLC6A2 gene 21
Statistical Analyses 22
Results 26
Part I. Demographic data and effect on SERT BPND 26
Part I. Effect of MDD diagnosis and severity on SERT BPND 27
Part I. Effect of recent suicide attempt and suicide intensity on SERT BPND 28
Part I. Association between projection area/midbrain SERT BP ratios and suicide attempt and intensity 29
Part II. Demographic characteristics for treatment response study 30
Part II. Possible effects of demographic data on regional SERT binding 30
Part II. The association of regional SERT BPND or projection area/midbrain SERT BPND ratios with early response to antidepressants 32
Part II. The association of regional SERT BPND or projection area/midbrain SERT BPND ratios with outcome to antidepressants at week 6 33
Part II. The prediction of responders based on projection area/midbrain SERT BPND ratios 34
Part III. Association between SLC6A2 variants and venlafaxine treatment response. 35
Discussion 38
Part I. The association of SERT BPND or SERT BPND ratios with suicide attempts 38
Part II. The association of SERT BPND or SERT BPND ratios with treatment response to antidepressants 45
Part III. SLC6A2 variants may predict remission from major depression after venlafaxine treatment 55
Conclusion 62
References 64
Tables 79
Figures 89
Appendix 100

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