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研究生：	黃立中 Huang, Li-Chung
論文名稱：	治療頑固型思覺失調症患者認知功能、臨床症狀及合併治療與谷胺酸(glutamate)濃度變化之相關研究 Cognitive function, symptoms severity and the augmentation therapy are associated with glutamatergic variations in the patients of treatment resistant schizophrenia
指導教授：	楊延光 Yang, Yen-Kuang 江伯敏 Chiang, Po-Min
學位類別：	博士 Doctor
系所名稱：	醫學院 - 臨床醫學研究所 Institute of Clinical Medicine
論文出版年：	2022
畢業學年度：	110
語文別：	英文
論文頁數：	61
中文關鍵詞：	治療頑固型思覺失調症、谷胺酸神經傳導物質分布、功能性核磁共振、認知功能、sodium benzoate (苯甲酸鈉)
外文關鍵詞：	treatment resistant schizophrenia, glutamatergic distribution, 1-H MRS, cognition function, sodium benzoate
相關次數：	點閱：127 下載：21
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中文摘要
背景:
治療頑固型思覺失調症(treatment resistant schizophrenia,TRS)的定義為對大多數藥物反應不佳的思覺失調症，這些病人常伴隨認知退化及精神症狀惡化。多巴胺假說可以解釋大部分思覺失調症的病理及藥物作用機轉，但無法解釋藥物治療後頑固型思覺失調症之持續症狀惡化，而glutamate (谷胺酸)可能是詮釋治療頑固型的思覺失調症的機轉之一。Sodium benzoate(苯甲酸鈉)作用在D-amino acid oxidase inhibitors上是目前被嘗試用來治療治療頑固型思覺失調症的合併藥物之一。其機轉是在調整anterior cingulate cortex(前扣帶迴,ACC) 和medial prefrontal cortex (中前額葉,MPFC)的谷胺酸濃度，也可能由此進一步改善認知功能及臨床症狀。本研究的目的有四,目的一: 探討治療頑固型思覺失調症之glutamate是否異常?及glutamate與認知功能及臨床症狀之關係;目的二: 檢定sodium benzoate治療頑固型思覺失調症合併原有抗精神病藥物治療療效;考量到偵測腦中glutamate濃度的替代方法進行兩個研究;目的三:分析腦中glutamate濃度與周邊血液glutamate濃度的相關及目的四:分析治療頑固型思覺失調症的ACC谷胺酸濃度與ACC與其它腦區的功能性連結之相關。
方法:
本研究分為橫斷性及介入性兩部分進行多年期的試驗，第一部分收集38位頑固型思覺失調症病人、35位非頑固型思覺失調症病人及19位健康受試者。分析三組在認知功能、臨床症狀及在腦部谷胺酸濃度的差異性及彼此之間的相關性，同時收集病人之ACC對於其他腦區的功能性連結。第二部分試驗招募12位治療頑固型思覺失調症病患以2:1的比例隨機雙盲持續給予苯甲酸鈉每日2g或安慰劑六個週，原本服用的藥物不變。並於未給藥(sodium benzoate)前、給藥後2週及給藥後6週重測認知功能、臨床症狀及核磁共振檢測腦部谷胺酸濃度;。第二部分目前已完成6週藥物研究者為8人，安慰劑組為4人。
結果:
橫斷性研究顯示治療頑固型思覺失調症患者ACC的谷胺酸(Glx/NAAx)濃度比非治療頑固型思覺失調症患者高;非治療頑固型思覺失調症患者Glx/NAAx濃度在前扣帶迴和工作記憶呈負相關的關聯性，同樣的狀態並沒有在頑固型思覺失調症患者和健康組被觀察到。週邊血液的谷胺酸濃度無法推估腦部谷胺酸濃度,但是ACC對於其他腦區的功能性連結可以成為腦中谷胺酸濃度推估替代方法。第二部分結果顯示服用藥物組病人呈現臨床症狀 (PANSS),正性及負性症狀的改善。
總結:
病人腦中之 ACC 的谷胺酸濃度可能是思覺失調症的亞型分類方式之一; sodium benzoate的合併療法在治療頑固型思覺失調症具療效。TRS 患者的谷胺酸和工作記憶 (working memory index, WMI)的關聯可能為預測疾病發展的分類因子。以周邊血液glutamate濃度推估腦中glutamate (谷胺酸)濃度的替代方法並未成功。 ACC對於其它腦區的功能性連結可能是預測腦中glutamate (谷胺酸)濃度方法之一。

關鍵詞：治療頑固型思覺失調症，谷胺酸神經傳導物質分布，功能性核磁共振，認知功能，sodium benzoate (苯甲酸鈉)

Abstract
Backgrounds:
Treatment-resistant schizophrenia (TRS) is a drug-refractory subtype of schizophrenia in which cognitive function gradually declines and clinical symptoms worsen. The dopaminergic hypothesis is a plausible neurochemical model of schizophrenia; however, it cannot adequately explain the occurrence of TRS. Other neurotransmitters, such as glutamatergic metabolites, have also been found to be involved in the pathophysiology of TRS. Sodium benzoate, a D-amino acid oxidase inhibitor (DAAO inhibitor), is considered an effective glutamatergic modulator for add-on therapy of schizophrenia and TRS. It works by modulating glutamate levels in the anterior cingulate cortex (ACC) and medial prefrontal cortex (MPFC), which may in turn improve cognitive function and clinical symptoms. There are four aims of the study: Aim 1: To explore the differences in glutamatergic levels between schizophrenia subgroups and the association between glutamatergic concentration and cognition and clinical symptoms. Aim 2: To examine the efficacy of sodium benzoate as an add-on therapy for TRS. Aim 3: To analyse the correlation between peripheral plasma glutamate and brain glutamate levels using magnetic resonance spectroscopy (MRS). Aim 4: To detect the association between brain glutamate levels and functional connectivity between brain regions in TRS, by using anterior cingulate cortex (ACC) as seed region.
Methods:
The study was divided into two parts: (1) a cross-sectional study; and (2) an interventional study. In the first part (Study 1) 38 treatment-resistant schizophrenia (TRS) patients, 35 treatment responsive schizophrenia patients (non-TRS), and 19 healthy controls each for both TRS and non-TRS groups were recruited. The differences among the subgroups were compared. The functional connectivity between brain regions was also analysed by ACC-seeding. In the second part (Study 2), 12 TRS patients were randomly and double blindly divided into two groups with a 2:1 (sodium benzoate 2 g/day: placebo) ratio. This augmentation treatment study was performed for 6 weeks. The observation time points were at baseline, 2 weeks, and 6 weeks after augmentations. We measured cognitive function, symptom changes, and glutamate levels using the MRS.
Results:
In the cross-sectional study, patients with TRS showed higher Glx/NAAx levels in the ACC than the non-TRS patients and healthy controls. The working memory index (WMI) was negatively associated with Glx/NAAx in the ACC areas only in non-TRS patients, while any such association was not found in TRS patients and healthy controls. The plasma glutamatergic concentration was not associated with brain glutamate levels measured by MRS; however, some tracts of the ACC seeded functional connectivity were correlated with glutamate levels in the ACC. In the Study 2, improvements in the total PANSS (the Positive and Negative Symptoms Scale) score were noted in the active treatment arm.
Conclusion:
Our findings indicate that glutamatergic levels in the ACC could be a potential marker for subtyping of TRS and non-TRS. Sodium benzoate add-on therapy may be a potentially effective treatment for TRS. The associations between glutamatergic complex levels and WMI might lead to the development of novel of predictor or classification biomarkers for TRS patients. This study also reported that alternative method for determination of peripheral glutamatergic levels used in this research is not efficient and reliable. Some tracts of functional connectivity seeded from the ACC to other brain regions might be predictors of ACC glutamatergic concentrations in MRS.

Key words: treatment resistant schizophrenia; glutamatergic distribution; 1-H MRS; cognition function; sodium benzoate.

Contents
中文摘要	I
Abstract	III
誌 謝	V
List of tables	VIII
List of figures	IX
Abbreviations lists	X
Chapter 1. Introduction	1
1.1 Monoamine imbalance in patients with treatment-resistant schizophrenia (TRS)	1
1.2 The roles of integrated glutamatergic and dopamine hypothesis in patients with TRS	2
1.2.1 Glutamatergic markers and interventions in patients with TRS	2
1.2.2 Cognitive function in patients with schizophrenia and TRS.	3
1.3. The glutamatergic neurometabolites detected by 1-H magnetic resonance spectroscopy (MRS) in patients with schizophrenia	4
1.4 Glutamatergic modulator augmented therapy and sodium benzoate in TRS patients	4
1.5 Alterations in peripheral glutamate levels among the schizophrenia subgroups and	5
1.6 The association between resting-state functional connectivity and glutamate levels in patients with TRS	5
1.7 Hypothesis and specific aims	6
Chapter 2. Methods	8
2.1. The cross-sectional study (Study 1)	8
2.1.1 Participants	8
2.1.2. Measurements	9
2.1.3. Image parameters	10
2.1.4. Glutamate assay kit	12
2.2 The interventional study (Study 2)	12
2.2.1 Participants	12
2.2.2 Measurements and visits	12
2.3 Statistical analysis	12
Chapter 3 Results	16
3.1 Demographic data and glutamatergic concentrations in MRS among the three subgroups of Study 1	16
3.2. The association between cognitive function and glutamatergic neurometabolites	16
3.3 Sodium benzoate trial (Study 2)	35
3.3.1 Clinical improvements after sodium benzoate administration	35
3.3.2 The pre-treatment glutamate complex levels in ACC	38
3.3.3 Cognitive function improvement after sodium benzoate administration	39
3.4 Peripheral glutamate concentrations in TRS (Study 1)	40
3.5 Resting state functional connectivity associated with Glx levels in TRS (Study1)	42
Chapter 4. Discussion, limitations and conclusions	47
4.1. The findings of present study	47
4.1.1 The role of glutamatergic concentration in ACC in patients with schizophrenia	47
4.1.2 The efficacy of add-on therapy of sodium benzoate in improving clinical symptoms and cognition functions	48
4.1.3 The peripheral plasma glutamatergic levels in clinical practice	49
4.1.4 Association between the ACC seed functional connectivity and the glutamatergic levels	49
4.2. Clinical and scientific implications	50
4.3 Limitations	51
4.4 Conclusions	51
Publications list	53
References	54

List of tables
Table 1. The biomarkers and treatment choices of glutamatergic theory.	2
Table 2. Procedures and measurements for Study 2	15
Table 3. Clinical characteristics and demographic data of the study participants classified into three groups (Study 1)	18
Table 4. Medication categories classified by antipsychotic agents and mood stabilizers in the non-TRS and TRS groups	19
Table 5. Group comparison of the glutamatergic concentrations in ACC and MPFC after adjusting for covariates	20
Table 6. The relationships between demographic characters and glutamatergic levels in ACC brain region of all three groups	22
Table 7. Analysis of covariance (ANCOVA) for testing the group difference in Glx/NAAx level in the ACC, adjusting for age and sex	24
Table 8. ANCOVA for testing the group difference in Glx/NAAx level in the ACC, adjusting for age, sex, educational level, smoking status, and cognitive function	25
Table 9. ANCOVA for testing the group difference in Glx/NAAx level in the MPFC, adjusting for age and sex	26
Table 10. ANCOVA for testing the group difference in Glx/NAAx level in the MPFC, adjusting for age, sex, educational level, smoking status, and cognitive function	27
Table 11. ANCOVA for testing the group difference in Glx/NAAx level in the ACC, adjusting for age, sex, lithium usage proportion, and mood stabilizer proportion	28
Table 12. ANCOVA for testing the group difference in Glx/NAAx level in the ACC, adjusting for age, sex, 1st generation antipsychotic usage proportion, 2nd generation antipsychotic proportion, and combined antipsychotic proportion	29
Table 13. ANCOVA for testing of the group difference in Glx/NAAx level in the ACC, controlling for age, sex, clozapine usage proportion and clozapine-like agent proportion	30
Table 14. Baseline characteristics of the 12 patients randomly assigned to treatment groups.	36
Table 15. Symptom reduction in lower and higher pre-treatment Glx level groups.	38
Table 16. Demographic data and peripheral glutamatergic concentration of study participants	41
Table 17. Demographic data of study participants with both MRS and resting state data	43
Table 18. Clusters of significant group differences in the ACC seeded resting state functional connectivity	44
Table 19. Clusters of functional connectivity significantly associated with Glx in ACC	46 
List of figures
Figure 1. Dopamine activity and glutamate concentration in schizophrenia patient subgroups.	3
Figure 2. The flow chart and sample sizes for each aim in the cross-sectional study (Study 1)	9
Figure 3. Locations and placement procedures for the 1H-MRS voxels	11
Figure 4. The scheme of the interventional study (Study 2)	14
Figure 5. The significant association between anterior cingulate Glx /NAAx ratio and cognition function (WMI) in the non-TRS group	31
Figure 6. The association between anterior cingulate Gln /NAAx ratio and cognition function (WMI) in the non-TRS group	32
Figure 7. The association between anterior cingulate Gln /NAAx ratio and cognition function (PSI) in the non-TRS group	33
Figure 8. The association between anterior cingulate Glx /NAAx ratio and cognition function (VCI) in the TRS group	34
Figure 9. a.b.c. Total PANSS scores, positive symptoms and negative symptoms between the active and placebo groups	37
Figure 10. The variations and pre-treatment glutamate levels associated with reduction in negative symptoms	39
Figure 11. WMI and reduction rate among the active and placebo groups	40
                                    

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