研究背景: 重度憂鬱症患者的調控壓力系統失衡而產生憂鬱情緒，雖然使用抗憂鬱劑可以調整情緒，卻有部分人出現代謝異常。最近研究指出催產素-催產素受體系統可以降低壓力反應、調節能量、情緒及社交行為。此外，基因多型性可能牽涉到病患個體間是否產生代謝異常的現象，催產素受體基因多型性與重度憂鬱症及壓力反應有關。然而，目前尚未有研究針對催產素濃度及催產素受體基因多型性作為預測重度憂鬱症患者服用抗憂鬱劑後治療反應的指標。

目標:本研究探討(1)催產素濃度與臨床指標在健康人或重度憂鬱症病患的關聯，(2)催產素受體基因多型性對臨床指標在健康人或重度憂鬱症病患的關聯，(3)利用催產素濃度或催產素受體基因多型性預測重度憂鬱症病患使用抗憂鬱劑的治療反應。

材料與方法: 招募18到65歲符合精神疾病診斷與統計手冊第四版(DSM-IV)診斷為重度憂鬱症且漢氏憂鬱量表大於15分的病患。在簽署受試者同意書後，會被有受過訓練的精神科醫師收錄進本研究中。所有被收錄進來的病人都會隨機被分配到氟西汀組(Fluoxetine)或是文拉法辛組(Venlafaxine)。重鬱症患者在治療前及治療後第2、4、6週紀錄漢氏憂鬱量表。而治療前及治療後第6週測驗認知功能及抽取空腹靜脈血來檢測代謝指標及催產素濃度。除此之外，還會蒐集問卷，包括社會支持量表、生活事件量表及生活品質量表。而本研究也透過社區廣告招收健康受試者，對於以上測驗健康受試者皆會測量一次。

結果: 本研究收錄了111位重度憂鬱症病患及96位健康受試者。病人的平均年紀為39.4±12.6歲，健康受試者的平均年紀為33.3±12.1歲。病人有26.1%為男性，健康受試者則有42.7%為男性。在基本資料的分析，重度憂鬱症病患比健康受試者有較高的漢式憂鬱量表分數、空腹血糖、催產素濃度及C反應蛋白濃度。另外，重度憂鬱症病患比健康受試者有較低的體重、瘦素濃度、認知功能、社會支持量表分數及生活品質量表分數。在治療過後，重度憂鬱症病患的漢氏憂鬱量表分數顯著下降，且認知功能得到改善。然而，三酸甘油脂濃度及C反應蛋白濃度在治療後有上升的情形。結果1: 在健康受試者當中，催產素濃度顯著的與胰島素及穩態模型胰島素阻抗指數(The homeostasis model of assessment for insulin resistance, HOMA-IR)呈負相關。在病人當中則是治療後催產素濃度的改變量與穩態模型貝塔細胞功能指數(The homeostasis model of assessment for pancreatic β-cell secretory function, HOMA-β)的改變量呈正相關。結果2:健康受試者帶有GG基因型比帶有A對偶基因的人有較高的漢氏憂鬱量表分數及皮質固醇濃度。此外，病人帶有GG基因型的比帶有A對偶基因的人有較高的空腹血糖、醣化血色素及低密度蛋白質膽固醇濃度。治療後，病人帶有GG基因型的比帶有A對偶基因的人有較高的醣化血色素，但較低的催產素濃度。結果3:重度憂鬱症病人治療前的催產素濃度顯著的與治療後催產素濃度改變量呈負相關。另一方面，病人帶有GG基因型比帶有A對偶基因在治療後降低較多的膽固醇濃度及低密度蛋白質膽固醇濃度。帶有GG基因型的病人在藥物介入後會改善慣用手手指輕敲測驗的能力。帶有GG基因型的病人若是社會支持量表的分數越高，其醣化血色素在治療後下降的越多。

結論:健康受試者的催產素濃度越高會有越低的胰島素阻抗，但在重度憂鬱症病患身上卻沒有這個現象。除此之外，重度憂鬱症病患帶有GG基因型有較低的催產素濃度，但在治療後對代謝反應的調節更為敏感。因此，催產素濃度與催產素受體基因多型性對於調節能量是相當重要的。

Background: Major depressive disorder (MDD) patients have depressive mood caused by dysfunction of stress system. Patients regulate depressive mood through antidepressants, but some of them cause energy metabolic disturbance. Recent studies indicated that oxytocin - oxytocin receptors system has effect on reducing stress response as well as regulating energy, emotion and social process. Genetic factors may involve in individual difference. Oxytocin receptor polymorphism (OXTR) was associated with MDD and with stress response. However, there was no study focusing on oxytocin level and OXTR as predicting factors for antidepressant treatment outcome in MDD patients.

Aims: In this study, we aimed to investigate (1) the correlation between plasma oxytocin and clinical features in healthy controls and in MDD patients, (2) the association between OXTR and clinical features in healthy controls and in MDD patients, and (3) the prediction of treatment outcome by plasma oxytocin or OXTR after antidepressant treatment in patients with MDD.

Materials and Methods: Patients (aged 18–65 years) who met the Diagnostic and Statistical Manual of Mental Disorders, 4th version (DSM-IV) for major depressive disorder, and Hamilton depression rating scale (HAMD) greater than 15 scores were enrolled consecutively by trained psychiatrists. MDD patients were randomly treated with fluoxetine or venlafaxine. MDD patients were assessed HAMD at baseline and week 2, 4, and 6. Cognitive function tests and fasting blood sample, detected metabolic indices and oxytocin level, were collected at baseline and after 6 weeks of treatment. In addition, we also collected questionnaire, including social support, life event scales and WHO quality of life. In addition, healthy controls were enrolled from community through advertisement.

Result: We recruited 131 MDD patients and 96 healthy controls in this study. The mean age of MDD patients and healthy controls were 39.4±12.6 and 33.3±12.1 years old, respectively. There were 26.9% male in MDD patients and 42.7% male in healthy controls. MDD patients had higher HAMD scores, fasting blood glucose, oxytocin level and CRP compared to controls. Moreover, MDD patients had lower weight, leptin, cognitive function test, social support scale and WHO quality of life than controls. After treatment, the HAMD scores and cognitive function were significant improved in MDD patients. However, TG and CRP were elevated. Result 1: Plasma oxytocin was negatively correlated with insulin and the homeostasis model of assessment for insulin resistance (HOMA-IR) in healthy controls. The change of oxytocin was positively correlated with the change of the homeostasis model of assessment for pancreatic β-cell secretory function (HOMA-β) in patients with MDD after treatment. Result 2: Controls with GG genotype had higher HAMD and cortisol than those with A allele. Moreover, patients with GG genotype had higher fasting blood sugar, HbA1c and LDL than those with A allele. After treatment, patients with GG genotype also had higher HbA1c and oxytocin. Result 3: Baseline oxytocin was negatively correlated with the change of oxytocin in MDD patients. On the other hand, patients with GG genotype decreased more cholesterol and LDL after treatment. Patients with GG genotype improved more dominant finger with FTT test by antidepressant intervention. Patients with GG genotype decreased more HbA1c by higher social support effect after treatment.

Conclusion: Our findings suggest that higher oxytocin level would have lower insulin resistance in healthy controls, but not in patients with MDD. In addition, patients with the GG genotype, whom have lower oxytocin level, were more sensitive to metabolic regulation from treatment. These findings also indicate that oxytocin level and OXTR are important moderators that shape metabolic features.

中文摘要 I
Abstract III
致謝 V
Contents VI
Table of contents VII
Figure of contents X
Abbreviations XIII
1. Introduction 1
1.1 Major depressive disorder 1
1.2 Current pharmacological treatment of major depressive disorder 1
1.3 Antidepressant-related energy metabolism disturbance 2
1.4 Possible risk factors of disturbance energy metabolism in patient with MDD 2
1.5 Oxytocin – oxytocin receptor system 2
1.6 Oxytocin receptor gene (OXTR) 4
1.7 Pharmacogenomics 4
2. Objectives of current study 5
3. Materials and methods 6
3.1 Study design 6
3.2 Subjects and method 6
3.3 Measurements 6
3.4 Statistics 10
4. Results 11
4.1 Demographic features of patients and healthy controls 11
4.2 The correlation between plasma oxytocin level and clinical features 14
4.3 Association between the rs53576 of oxytocin receptor polymorphism (OXTR) and treatment outcome 16
4.4 Effect of antidepressants on treatment outcome 24
5. Discussion 128
5.1 The role of oxytocin system on major depressive disorder and energy homeostasis 128
5.2 The role of OXTR on major depressive disorder and energy homeostasis 132
5.3 Limitation 134
6. Conclusion 135
7. Reference 136
8. Appendix 142

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