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研究生：	李俊頡 Lee, Chun-Chieh
論文名稱：	於第二型雙極性疾患中，建立丙戊酸治療反應之預測因子：針對GNB3基因型及C反應蛋白 Predicting factors for valproate treatment outcome among bipolar II patients – focused on GNB3 and CRP level
指導教授：	張惠華 Chang, Hui-Hua
共同指導教授:	陳柏熹 Chen, Po-See
學位類別：	碩士 Master
系所名稱：	醫學院 - 臨床藥學與藥物科技研究所 Institute of Clinical Pharmacy and Pharmaceutical sciences
論文出版年：	2015
畢業學年度：	103
語文別：	英文
論文頁數：	255
中文關鍵詞：	丙戊酸、第二型雙極性疾患、GNB3基因、C-反應蛋白
外文關鍵詞：	Valproate, Bipolar II disorder, GNB3, C-reactive protein
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研究背景：丙戊酸(valproate)是種用來治療第二型雙極性疾患的情緒穩定劑，然而某些病患使用丙戊酸之後會出現代謝異常的副作用。基因與環境因子可能牽涉到病患個體間是否產生代謝異常的現象。造成代謝異常的基因因子包含了：PPAR-γ基因、瘦素受體基因、G蛋白相關的基因…等；其中，GNB3基因位於異三元體G蛋白中的β3次單元之中，而這個次單元是個與代謝調節有關的胞內訊息傳遞重要因子。除此之外，在環境因子的部分，C反應蛋白，一個用來偵測發炎反應的敏感因子，在過去的研究中，跟雙極性疾患的致病與代謝異常相關。於雙極性疾患的用藥中添加美金剛 (memantine)，一種抗發炎藥物，或許能改善代謝異常的狀況。然而，目前尚未有研究針對GNB3基因多型性及C反應蛋白濃度作為預測第二型雙極性疾患服用丙戊酸後治療反應的因子。

研究材料與方法：18到65歲的病人只要符合精神疾病診斷與統計手冊第四版(DSM-IV)、及中文版的終生精神疾病診斷晤談手冊(SADS-L) 的第二型雙極性疾患診斷，於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。此外，這些病患在尚未用藥前的漢氏憂鬱量表分數必須要大於18分，在臨床上代表著這些病患是處於憂鬱階段的雙極性疾患。所有被收錄進來的病人都會隨機被分配到丙戊酸加上安慰劑組或是丙戊酸加上美金剛組。另一方面，本篇研究會於早上8到10點抽病人的靜脈血，這些血液樣本會用來檢測代謝指標、C反應蛋白及GNB3 C825T的基因型。此外，病人的身體質量指數(BMI)、腰圍、疾病嚴重程度及認知功能也會進行檢測。

結果：本研究收錄了211位第二型雙極性疾患，其中95位病人在研究過程中退出。這群病人的平均年紀為31.89±11.44歲，其中54.5%是女性。結果1：在尚未服用藥物前，帶有GNB3 C825T之CC基因型的病人其三酸甘油脂濃度為三組中最高且具有統計差異；在接受治療的期間內，GNB3 C825T基因多型性與身體質量指數、總膽固醇、三酸甘油脂、低密度脂蛋白及瘦素的濃度顯著相關。此外，帶有CT及CC基因型的病人在經過12周的藥物治療後，認知功能有顯著改善。結果2：服藥前，不論C反應蛋白濃度，使用丙戊酸加上安慰劑組及丙戊酸加上美金剛組都沒有任何指標有顯著差異。本研究接著把病人依照未用藥前的C反應蛋白濃度分群，分界點為C反應蛋白濃度等於2322 ng/mL。在C反應蛋白濃度大於分界點的病患之中，身體質量指數、腰圍、總膽固醇、低密度脂蛋白、低密度/高密度脂蛋白比值及C反應蛋白在接受治療的期間內於丙戊酸加上安慰劑組和丙戊酸加上美金剛組之間有顯著差異。然而，這群病人的認知功能，不論是丙戊酸加上安慰劑組或丙戊酸加上美金剛組，在用藥12週後並沒有顯著改善。在C反應蛋白濃度小於等於分界點的病患之中，漢氏憂鬱量表及三酸甘油脂在接受治療的期間內於兩組之間有顯著差異。此外，在這群病人之中，服用丙戊酸加上安慰劑組其認知功能在用藥12週後有獲得顯著改善。結果3：未用藥前的身體質量指數、腰圍、三酸甘油脂、空腹血糖、胰島素、HOMA穩態模型(胰島素抗性及β細胞功能)、瘦素及C反應蛋白濃度於TT+CT基因型與C反應蛋白≤2322 ng/mL組、TT+CT基因型與C反應蛋白>2322 ng/mL組、CC基因型與C反應蛋白≤2322 ng/mL組及CC基因型與C反應蛋白>2322 ng/mL組之間有顯著差異；在接受治療的期間內，胰島素濃度及HOMA穩態模型-胰島素抗性於四組之間有顯著差異。

結論：根據以上的結果，本研究推論帶有GNB3 C825T之CC基因型的第二型雙極性疾患有較高的風險服用丙戊酸之後產生代謝異常。此外，本研究也推論C反應蛋白濃度可以當作預測雙極性疾患服用丙戊酸之後產生代謝異常的生物指標。至於未來的研究方向，可以試著利用較複雜的統計模型，像是多功能線性回歸模型或是類神經網路對於丙戊酸治療反應的影響。

Background: Valproate (VPA) is a mood stabilizer for the treatment of bipolar II disorder (BD II) patients, but it may cause metabolic disturbances in certain patients. Genetic and environmental factors may involve in individual difference of metabolic disturbances. Genetic factors include PPAR-γ gene, leptin receptor gene (LEPR), guanosine nucleotide-binding proteins (G protein) associated gene, etc. Guanine nucleotide-binding protein beta 3 (GNB3) gene encodes the β3 subunit of heterotrimeric G proteins, which is the key component of intracellular signal transduction of metabolic regulation. In addition, increased level of C-reactive protein (CRP), a sensitive marker of inflammation, was associated with disease progress of BD, and the association between plasma CRP level and metabolic indices had been found in previous study. Add-on memantine, a kind of anti-inflammation drug, may improve metabolic disturbances in BD patients. However, there were no studies focusing on GNB3 polymorphism and CRP level as predicting factors for VPA treatment outcome among BD II patients.

Materials and Methods: Patients (aged 18–65 years) who met the DSM-IV and the Chinese Version of SADS-L diagnostic criteria for BD II were enrolled consecutively by trained psychiatrists. In addition, baseline HDRS score of all patients were > 18, which considered as bipolar depression state. All patients were randomized to VPA + placebo or VPA + memantine group. We also collected fasting blood samples between 8–10 am to measure metabolic indices, CRP level and the genotype of GNB3 C825T (rs5443). In addition, body mass index (BMI), waist circumference, disease severity and cognitive function were also measured.

Results: We recruited 211 bipolar II disorder patients, among of whom 95 patients dropped out during the study period. The mean age of recruited patients was 31.89 ± 11.44 years, and a total of 54.5% of the patients was female. Result 1: At baseline, BD II patients with CC genotype of GNB3 C825T polymorphism had the highest triglyceride (TG) level. During the treatment period, body mass index (BMI), cholesterol, TG, low density lipoprotein (LDL) and leptin level were significantly associated with this polymorphism. In addition, after 12-week treatment, cognitive function in the CT and CC groups were significantly improved. Result 2: At baseline, no significant difference were found between VPA + placebo and VPA + memantine groups no matter the baseline CRP level. We sub-grouped our patients based on baseline level of CRP at 2322 ng/mL. In CRP level >2322 ng/mL group, there were significant differences in BMI, waist circumference, cholesterol, LDL, LDL/HDL ratio and CRP between VPA + placebo and VPA + memantine groups during the treatment period. However, cognitive function was not significantly improved after 12-week treatment in two groups. In CRP level ≤2322 ng/mL group, there were significant differences in HDRS score and TG between two groups during the treatment period. In addition, cognitive function in the VPA + placebo group was significantly improved after 12-week treatment. Result 3: The basal level of BMI, waist circumference, TG, AC glucose, insulin, homeostasis model assessment-insulin resistance (HOMA-IR), homeostasis model assessment-insulin resistance-β cell function (HOMA-β), leptin and CRP level were significantly different among TT+CT & CRP≤2322 ng/mL group, TT+CT & CRP>2322 ng/mL group, CC & CRP≤2322 ng/mL group and CC & CRP>2322 ng/mL group. During the treatment period, there were significant differences in insulin and HOMA-IR among four groups.

Conclusions: This study indicated that BD II patients with CC genotype of GNB3 C825T and the baseline level of CRP>2322 ng/mL have worse VPA-induced metabolic disturbances. Both the genotype of GNB3 C825T and the level of CRP could be biomarkers to predict VPA treatment outcome. In the future study, we may use complicated models, such as functional linear model or artificial neural networks to predict VPA treatment outcome.

Contents
中文摘要.................................................I
Abstract..............................................III
誌謝..............................................V
Contents..............................................VI
Table of contents.....................................XIV
Figure of contents...................................XVII
Abbreviations...................................XIX
Chapter 1 Introduction..................................1
1.1 Bipolar disorder..................................1
1.2 Current pharmacological treatment of bipolar disorder	..................................1
1.2.1 Pharmacological treatment of manic phase..........2
1.2.2 Pharmacological treatment of depressive phase.....2
1.2.3 Pharmacological treatment of maintenance phase....2
1.3 Valproate..................................12
1.3.1 Valproate’s pharmacokinetics and pharmacodynamics	..................................12
1.3.2 The importance of valproate......................12
1.4 Valproate and metabolic disturbances...............18
1.4.1 Valproate may increase the risk of metabolic disturbances...............18
1.4.2 The influence of metabolic disturbances..........18
1.4.3 Mechanisms of valproate-induced metabolic disturbances...............18
1.5 Risk factors of metabolic disturbances.............23
1.6 G protein associated gene background review........23
1.6.1 G protein...............23
1.6.2 Association between G protein and valproate	...............24
1.6.3 Guanine nucleotide-binding protein beta 3 (GNB3) gene...............24
1.7 Inflammatory status and bipolar disorder..........26
1.7.1 Bipolar disorder and inflammation...............26
1.7.2 CRP and cardio-vascular events, metabolic disturbances, psychiatric disease.....................26
1.7.3 Memantine and anti-inflammatory effect..........27
1.8 G protein and inflammation........................29
1.9 Pharmacogenomics..................................29
Chapter 2 Objectives of current study.................30
Chapter 3 Materials and methods.......................31
3.1 Study design...............31
3.2 Subjects and method...............31
3.3 Measurements...............31
3.3.1 Disease severity...............31
3.3.2 Blood...............32
3.3.3 Blood lipid profile...............32
3.3.4 Blood sugar profile...............32
3.3.5 Leptin...............32
3.3.6 CRP...............33
3.3.7 Drug concentration...............33
3.3.8 Adiposity and body fat distribution..............33
3.3.9 Neuropsychological assessment....................33
3.3.10 DNA extraction...............34
3.3.11 SNP determination and genotyping...............35
3.4 Statistics...............35
Chapter 4 Results...............36
4.1 Demographic characteristics and clinical features of all patients at baseline...............36
4.1.1 Disease severity...............36
4.1.2 Metabolic indices...............36
4.1.3 Inflammatory biomarker...............38
4.2 Result 1: Association between GNB3 C825T polymorphism and treatment outcome...............41
4.2.1 Demographic characteristics and clinical features at baseline: VPA + placebo group...............41
4.2.1.1 Disease severity...............41
4.2.1.2 Metabolic indices...............41
4.2.1.3 Inflammatory biomarker...............43
4.2.2 Treatment outcome after 2-week VPA treatment: VPA + placebo group...............43
4.2.2.1 Drug concentration...............43
4.2.2.2 Disease severity...............43
4.2.2.3 Metabolic indices...............43
4.2.2.4 Inflammatory biomarker...............45
4.2.3 Treatment outcome after 8-week VPA treatment: VPA + placebo group...............45
4.2.3.1 Drug concentration...............45
4.2.3.2 Disease severity...............45
4.2.3.3 Metabolic indices...............45
4.2.3.4 Inflammatory biomarker...............47
4.2.4 Treatment outcome after 12-week VPA treatment: VPA + placebo group...............47
4.2.4.1 Drug concentration...............47
4.2.4.2 Disease severity...............47
4.2.4.3 Metabolic indices...............47
4.2.4.4 Inflammatory biomarker...............49
4.2.5 Time, GNB3 and time×GNB3 effect on treatment outcome: VPA + placebo group...............49
4.2.5.1 Drug concentration...............49
4.2.5.2 Disease severity...............49
4.2.5.3 Metabolic indices...............50
4.2.5.4 Inflammatory biomarker...............51
4.2.6 The change in treatment outcome after 2-week VPA treatment: VPA + placebo group...............51
4.2.6.1 Disease severity...............51
4.2.6.2 Metabolic indices...............52
4.2.6.3 Inflammatory biomarker...............53
4.2.7 The change in treatment outcome after 8-week VPA treatment: VPA + placebo group...............53
4.2.7.1 Disease severity...............53
4.2.7.2 Metabolic indices...............53
4.2.7.3 Inflammatory biomarker...............55
4.2.8 The change in treatment outcome after 12-week VPA treatment: VPA + placebo group...............55
4.2.8.1 Disease severity...............55
4.2.8.2 Metabolic indices...............55
4.2.8.3 Inflammatory biomarker after 12-week VPA treatment...............56
4.2.9 Time, GNB3 and Time×GNB3 effect on the change of treatment outcome: VPA + placebo group...............57
4.2.9.1 Disease severity...............57
4.2.9.2 Metabolic indices...............57
4.2.9.3 Inflammatory biomarker...............59
4.2.10 Cognitive function before and after 12-week VPA treatment: VPA + placebo group...............59
4.2.11 Time, GNB3 and Time×GNB3 effect on cognitive function: VPA + placebo group...............60
4.3 Result 2: Association between CRP level and treatment outcome...............85
4.3.1 ROC analysis of CRP cut-off point in VPA + placebo group...............85
4.3.2 Demographic characteristics and clinical features at baseline: VPA + placebo group...............85
4.3.2.1 Disease severity...............85
4.3.2.2 Metabolic indices...............86
4.3.2.3 Inflammatory biomarker...............87
4.3.3 Treatment outcome after 2-week VPA treatment: VPA + placebo group...............87
4.3.3.1 Drug concentration...............87
4.3.3.2 Disease severity...............87
4.3.3.3 Metabolic indices...............88
4.3.3.4 Inflammatory biomarker...............89
4.3.4 Treatment outcome after 8-week VPA treatment: VPA + placebo group...............89
4.3.4.1 Drug concentration...............89
4.3.4.2 Disease severity...............89
4.3.4.3 Metabolic indices...............90
4.3.4.4 Inflammatory biomarker...............91
4.3.5 Treatment outcome after 12-week VPA treatment: VPA + placebo group...............91
4.3.5.1 Drug concentration...............91
4.3.5.2 Disease severity...............91
4.3.5.3 Metabolic indices...............92
4.3.5.4 Inflammatory biomarker...............93
4.3.6 Cognitive function before and after 12-week VPA treatment: VPA + placebo group...............93
4.3.7 Demographic characteristics and clinical features at baseline: VPA + memantine group...............94
4.3.7.1 Disease severity...............95
4.3.7.2 Metabolic indices...............95
4.3.7.3 Inflammatory biomarker...............96
4.3.8 Treatment outcome after 2-week VPA treatment: VPA + memantine group...............97
4.3.8.1 Drug concentration...............97
4.3.8.2 Disease severity...............97
4.3.8.3 Metabolic indices...............97
4.3.8.4 Inflammatory biomarker...............98
4.3.9 Treatment outcome after 8-week VPA treatment: VPA + memantine group...............99
4.3.9.1 Drug concentration...............99
4.3.9.2 Disease severity...............99
4.3.9.3 Metabolic indices...............99
4.3.9.4 Inflammatory biomarker...............100
4.3.10 Treatment outcome after 12-week VPA treatment: VPA + memantine group...............101
4.3.10.1 Drug concentration...............101
4.3.10.2 Disease severity...............101
4.3.10.3 Metabolic indices...............101
4.3.10.4 Inflammatory biomarker...............103
4.3.11 Cognitive function before and after 12-week VPA + memantine treatment: VPA + memantine group............103
4.3.12 Sub-grouped by CRP cut-off point...............104
4.3.13 Demographic characteristics and clinical features at baseline: CRP level >2322 ng/mL group..............105
4.3.13.1 Disease severity...............105
4.3.13.2 Metabolic indices at baseline...............105
4.3.13.3 Inflammatory biomarker...............106
4.3.14 Treatment outcome after 2-week VPA + placebo or VPA + memantine treatment: CRP level >2322 ng/mL group...............107
4.3.14.1 Drug concentration...............107
4.3.14.2 Disease severity...............107
4.3.14.3 Metabolic indices...............107
4.3.14.4 Inflammatory biomarker...............108
4.3.15 Treatment outcome after 8-week VPA + placebo or VPA + memantine treatment: CRP level >2322 ng/mL group...............109
4.3.15.1 Drug concentration...............109
4.3.15.2 Disease severity...............109
4.3.15.3 Metabolic indices...............109
4.3.15.4 Inflammatory biomarker...............110
4.3.16 Treatment outcome after 12-week VPA + placebo or VPA + memantine treatment: CRP level >2322 ng/mL group...............111
4.3.16.1 Drug concentration...............111
4.3.16.2 Disease severity...............111
4.3.16.3 Metabolic indices...............111
4.3.16.4 Inflammatory biomarker...............112
4.3.17 Time, memantine and time×memantine effect on treatment outcome: CRP level >2322 ng/mL group........113
4.3.17.1 Disease severity...............113
4.3.17.2 Metabolic indices...............113
4.3.17.3 Inflammatory biomarker...............115
4.3.18 Cognitive function before and after 12-week VPA + placebo or VPA + memantine treatment: CRP level >2322 ng/mL group...............115
4.3.19 Time, memantine, and time × memantine effect on cognitive function: CRP level >2322 ng/mL group.......116
4.3.20 Demographic characteristics and clinical features at baseline: CRP level ≤2322 ng/mL group..............117
4.3.20.1 Disease severity...............117
4.3.20.2 Metabolic indices...............117
4.3.20.3 Inflammatory biomarker...............118
4.3.21 Treatment outcome after 2-week VPA + placebo or VPA + memantine treatment: CRP level ≤2322 ng/mL group...............119
4.3.21.1 Drug concentration...............119
4.3.21.2 Disease severity...............119
4.3.21.3 Metabolic indices...............119
4.3.21.4 Inflammatory biomarker...............120
4.3.22 Treatment outcome after 8-week VPA + placebo or VPA + memantine treatment: CRP level ≤2322 ng/mL group...............121
4.3.22.1 Drug concentration...............121
4.3.22.2 Disease severity...............121
4.3.22.3 Metabolic indices...............121
4.3.22.4 Inflammatory biomarker...............122
4.3.23 Treatment outcome after 12-week VPA + placebo or VPA + memantine treatment: CRP level ≤2322 ng/mL group...............123
4.3.23.1 Drug concentration...............123
4.3.23.2 Disease severity...............123
4.3.23.3 Metabolic indices...............123
4.3.23.4 Inflammatory biomarker...............124
4.3.24 Time, memantine and time×memantine effect on treatment outcome: CRP level ≤2322 ng/mL group........125
4.3.24.1 Disease severity...............125
4.3.24.2 Metabolic indices...............125
4.3.24.3 Inflammatory biomarker...............127
4.3.25 Cognitive function before and after 12-week VPA + placebo or VPA + memantine treatment: CRP level ≤2322 ng/mL group...............127
4.3.26 Time, memantine, and time × memantine effect on cognitive function: CRP level ≤2322 ng/mL group.......128
4.4 Result 3: Association between GNB3 C825T & CRP level and treatment outcome...............162
4.4.1 Demographic characteristics and clinical features at baseline: VPA + placebo group...............162
4.4.1.1 Disease severity...............162
4.4.1.2 Metabolic indices...............163
4.4.1.3 Inflammatory biomarker...............164
4.4.2 Treatment outcome after 2-week VPA treatment: VPA + placebo group...............164
4.4.2.1 Drug concentration...............164
4.4.2.2 Disease severity...............164
4.4.2.3 Metabolic indices...............165
4.4.2.4 Inflammatory biomarker...............166
4.4.3 Treatment outcome after 8-week VPA treatment: VPA + placebo group...............166
4.4.3.1 Drug concentration...............166
4.4.3.2 Disease severity...............166
4.4.3.3 Metabolic indices...............167
4.4.3.4 Inflammatory biomarker...............168
4.4.4 Treatment outcome after 12-week VPA treatment: VPA + placebo group...............168
4.4.4.1 Drug concentration...............168
4.4.4.2 Disease severity...............168
4.4.4.3 Metabolic indices...............169
4.4.4.4 Inflammatory biomarker...............170
4.4.5 Time and GNB3 C825T & CRP level effect on treatment outcome: VPA + placebo group...............170
4.4.5.1 Drug concentration...............170
4.4.5.2 Disease severity...............170
4.4.5.3 Metabolic indices...............171
4.4.5.4 Inflammatory biomarker...............172
4.4.6 The change in treatment outcome after 2-week VPA treatment: VPA + placebo group...............172
4.4.6.1 Disease severity...............172
4.4.6.2 Metabolic indices...............172
4.4.6.3 Inflammatory biomarker...............173
4.4.7 The change in treatment outcome after 8-week VPA treatment: VPA + placebo group...............174
4.4.7.1 Disease severity...............174
4.4.7.2 Metabolic indices...............174
4.4.7.3 Inflammatory biomarker...............175
4.4.8 The change in treatment outcome after 12-week VPA treatment: VPA + placebo group...............176
4.4.8.1 Disease severity...............176
4.4.8.2 Metabolic indices...............176
4.4.8.3 Inflammatory biomarker...............177
4.4.9 Time and GNB3 C825T & CRP level effect on the change of treatment outcome: VPA + placebo group...............178
4.4.9.1 Disease severity...............178
4.4.9.2 Metabolic indices...............178
4.4.9.3 Inflammatory biomarker...............179
Chapter 5 Discussion...............220
5.1 Discussion 1: GNB3 polymorphism and treatment outcome	...............220
5.1.1 Genotype frequency...............220
5.1.2 Association between disease severity and GNB3 polymorphism...............220
5.1.3 Association between metabolic indices and GNB3 polymorphism...............221
5.1.4 Association between cognitive function and GNB3 polymorphism...............222
5.2 Discussion 2: CRP level and treatment outcome...............224
5.2.1 Why set a CRP cut-off point?...............224
5.2.2 CRP level as a biomarker for improvement of disease severity...............224
5.2.3 Memantine may reduce metabolic disturbances.....225
5.2.4 The effect of memantine on cognitive function...226
5.3 Discussion 3: Integration effect of GNB3 and CRP level on treatment outcome...............227
5.3.1 Integration effect of GNB3 and CRP level on disease severity...............227
5.3.2 Integration effect of GNB3 and CRP level on metabolic indices...............228
5.3.3 Methods for investigate the integration effect of gene and environmental factors...............229
5.4 Clinical implications-- focus on metabolic disturbances.................231
5.4.1 Validation two predictive factors on metabolic disturbances and apply to clinical...............231
5.4.2 Strategies against VPA-induced metabolic disturbances in BD II patients...............232
5.5 Limitations...............233
Chapter 6 Conclusion...............234
Chapter 7 Reference...............236
Chapter 8 Appendix...............250

Table of contents
Table 1. Diagnostic criteria for mania...............3
Table 2. Diagnostic criteria for hypomania.............4
Table 3. Diagnostic criteria for major depression......5
Table 4. Recommendations for pharmacological treatment of acute mania...............7
Table 5. Recommendations for pharmacological treatment of bipolar depression...............8
Table 6. Recommendations for maintenance pharmacotherapy of bipolar disorder...............9
Table 7. Psychotropic Medications Taken by Subjects who were in Recovered Status at Baseline or who Reached Recovered Status during Follow-up, by Age..............14
Table 8. First-line treatment of drugs in different phase of bipolar disorder...............15
Table 9. Weight gain in valproate-treated patients.....20
Table 10. Metabolic index in bipolar patients who received VPA treatment...............21
Table 11. Definition of metabolic disturbances.........22
Table 12. Cross-sectional associations between inflammation and psychopathology at baseline...........28
Table 13. Overview of major clinical studies of hs-CRP in ACS...............28
Table 14. Demographic characteristics and measurements of bipolar II patients-- VPA + placebo and VPA + memantine groups...............40
Table 15. Demographic characteristics and clinical features at baseline-- GNB3 genotype...............61
Table 16. Treatment outcome after 2-week VPA treatment-- GNB3 genotype...............62
Table 17. Treatment outcome after 8-week VPA treatment-- GNB3 genotype...............63
Table 18. Treatment outcome after 12-week VPA treatment-- GNB3 genotype...............64
Table 19. The change of treatment outcome after 2-week VPA treatment-- GNB3 genotype...............65
Table 20. The change of treatment outcome after 8-week VPA treatment-- GNB3 genotype...............66
Table 21. The change of treatment outcome after 12-week VPA treatment-- GNB3 genotype...............67
Table 22. Performance of the neuropsychological functional test before and after 12-week VPA treatment-- GNB3 genotype...............68
Table 23. Demographic characteristics and clinical features at baseline-- CRP cut-off point, VPA + placebo group...............130
Table 24. Treatment outcome after 2-week VPA treatment-- CRP cut-off point...............131
Table 25. Treatment outcome after 8-week VPA treatment-- CRP cut-off point...............132
Table 26. Treatment outcome after 12-week VPA treatment-- CRP cut-off point...............133
Table 27. Performance of the neuropsychological functional test before and after 12-week VPA treatment-- CRP cut-off point...............134
Table 28. Demographic characteristics and clinical features at baseline-- CRP cut-off point, VPA + memantine group...............135
Table 29. Treatment outcome after 2-week VPA + memantine treatment-- CRP cut-off point...............136
Table 30. Treatment outcome after 8-week VPA + memantine treatment-- CRP cut-off point...............137
Table 31. Treatment outcome after 12-week VPA + memantine treatment-- CRP cut-off point...............138
Table 32. Performance of the neuropsychological functional test before and after 12-week VPA + memantine treatment-- CRP cut-off point...............139
Table 33. Demographic characteristics and clinical features at baseline-- CRP level >2322 ng/mL group....140
Table 34. Treatment outcome after 2-week VPA + placebo or VPA + memantine treatment-- CRP level >2322 ng/mL group...............141
Table 35. Treatment outcome after 8-week VPA + placebo or VPA + memantine treatment-- CRP level >2322 ng/mL group	...............142
Table 36. Treatment outcome after 12-week VPA + placebo or VPA + memantine treatment-- CRP level >2322 ng/mL group...............143
Table 37. Performance of the neuropsychological functional test before and after 12-week VPA + placebo or VPA + memantine treatment-- CRP level >2322 ng/mL group	...............144
Table 38. Demographic characteristics and clinical features at baseline-- CRP level ≤2322 ng/mL group	...............145
Table 39. Treatment outcome after 2-week VPA + placebo or VPA + memantine treatment-- CRP level ≤2322 ng/mL group	...............146
Table 40. Treatment outcome after 8-week VPA + placebo or VPA + memantine treatment-- CRP level ≤2322 ng/mL group	...............147
Table 41. Treatment outcome after 12-week VPA + placebo or VPA + memantine treatment-- CRP level ≤2322 ng/mL group...............148
Table 42. Performance of the neuropsychological functional test before and after 12-week VPA + placebo or VPA + memantine treatment-- CRP level ≤2322 ng/mL group	...............149
Table 43. Demographic characteristics and clinical features at baseline-- GNB3 genotype & CRP level	...............180
Table 44. Treatment outcome after 2-week VPA treatment-- GNB3 genotype & CRP level...............181
Table 45. Treatment outcome after 8-week VPA treatment-- GNB3 genotype & CRP level...............182
Table 46. Treatment outcome after 12-week VPA treatment-- GNB3 genotype & CRP level...............183
Table 47. The change of treatment outcome after 2-week VPA treatment-- GNB3 genotype & CRP level.............184
Table 48. The change of treatment outcome after 8-week VPA treatment-- GNB3 genotype & CRP level.............185
Table 49. The change of treatment outcome after 12-week VPA treatment-- GNB3 genotype & CRP level.............186
Table 50. GNB3 genotype frequencies for BD II patients and healthy control.............223
Table 51. Gene (GNB3) x environment (CRP) effect on treatment outcome after 12-week VPA treatment.........230

Figure of contents
Figure 1. Treatment algorithm for acute mania..........10
Figure 2. Treatment algorithm for bipolar depression...11
Figure 3. Metabolic pathway of valproate.............16
Figure 4. Mechanisms of valproate.............17
Figure 5. Polymorphisms in GNB3 gene.............25
Figure 6. Gβ protein content as measured by Western blot in GNB3 gene of fat cell.............25
Figure 7. Flow chart of bipolar II patients............39
Figure 8. As time progress, time, GNB3 genotype, and time×GNB3 genotype effect on valproate level...........69
Figure 9. As time progress, time, GNB3 genotype, and time×GNB3 genotype effect on disease severity..........70
Figure 10. As time progress, time, GNB3 genotype, and time×GNB3 genotype effect on BMI and waist circumference	.............71
Figure 11. As time progress, time, GNB3 genotype, and time×GNB3 genotype effect on lipid profile.............72
Figure 12. As time progress, time, GNB3 genotype, and time×GNB3 genotype effect on sugar profile.............74
Figure 13. As time progress, time, GNB3 genotype, and time×GNB3 genotype effect on leptin and CRP............76
Figure 14. As time progress, time, GNB3 genotype, and time×GNB3 genotype effect on the change of disease severity.............77
Figure 15. As time progress, time, GNB3 genotype, and time×GNB3 genotype effect on the change of BMI and waist circumference.............78
Figure 16. As time progress, time, GNB3 genotype, and time×GNB3 genotype effect on the change of lipid profile	.............79
Figure 17. As time progress, time, GNB3 genotype, and time×GNB3 genotype effect on the change of sugar profile	.............81
Figure 18. As time progress, time, GNB3 genotype, and time×GNB3 genotype effect on the change of leptin and CRP	.............83
Figure 19. As time progress, time, GNB3 genotype, and time ×GNB3 on cognitive function.............84
Figure 20. ROC curve for CRP cut-off point............129
Figure 21. As time progress, time, memantine, and time × memantine effect on disease severity, CRP cut-off point	.............150
Figure 22. As time progress, time, memantine, and time × memantine effect on BMI and waist circumference, CRP cut-off point.............152
Figure 23. As time progress, time, memantine, and time × memantine effect on lipid profile, CRP cut-off point..153
Figure 24. As time progress, time, memantine, and time × memantine effect on sugar profile, CRP cut-off point	.............156
Figure 25. As time progress, time, memantine, and time × memantine effect on leptin and CRP, CRP cut-off point...........159
Figure 26. As time progress, time, memantine, and time × memantine on cognitive function, CRP cut-off point....160
Figure 27. As time progress, time, GNB3 genotype & CRP cut-off point effect on VPA level.............187
Figure 28. As time progress, time, GNB3 genotype & CRP cut-off point effect on disease severity.............188
Figure 29. As time progress, time, GNB3 genotype & CRP cut-off point effect on BMI and waist circumference	.............190
Figure 30. As time progress, time, GNB3 genotype & CRP cut-off point effect on lipid profile.............192
Figure 31. As time progress, time, GNB3 genotype & CRP cut-off point effect on sugar profile.............197
Figure 32. As time progress, time, GNB3 genotype & CRP cut-off point effect on leptin and CRP.............202
Figure 33. As time progress, time, GNB3 genotype & CRP cut-off point effect on the change of disease severity	.............204
Figure 34. As time progress, time, GNB3 genotype & CRP cut-off point effect on the change of BMI and waist circumference.............206
Figure 35. As time progress, time, GNB3 genotype & CRP cut-off point effect on the change of lipid profile	.............208
Figure 36. As time progress, time, GNB3 genotype & CRP cut-off point effect on the change of sugar profile	.............213
Figure 37. As time progress, time, GNB3 genotype & CRP cut-off point effect on the change of leptin and CRP	.............218
Figure 38 Summary of the current study.............235


                                    

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