臺灣博碩士論文加值系統

背景：精神分裂症患者心因性猝死的機會較一般人高，而猝死又與副交感神經功能低下有關。抗精神病藥物被認為是精神分裂症患者心因性猝死的惡化因子。我們藉著心律變異分析評估，來偵測抗精神病藥物對自主神經功能可能的影響。

方法：在A研究中，我們利用電腦輔助的心律變異分析，來偵測精神分裂症個案中，接受第一代抗精神病藥物治療，因為出現遲發性運動不能的副作用，而轉換到第二代抗精神病藥物（首利安與金菩薩）治療。有十五位換成首利安，十八位換成金菩薩，心律變異於換藥前，換藥後一個月、二個月、三個月進行評估。在B研究中，我們對實驗大鼠進行腹腔藥物注射五天，注射藥物分別有好度、理思必妥、可致律與空白對照組。大鼠分別於給藥前，給藥後每天，紀錄六小時心律變異分析資料，供作自主神經功能分析。在C研究中，我們對實驗大鼠進行腹腔可致律注射十四天，之後讓大鼠停藥休息七天。我們利用無線訊號記錄系統，記錄了大鼠給藥前，給藥後，停藥後的心律變異分析資料，每天二十四小時，供作自主神經功能分析。

結果：在A研究中，我們發現相較於金菩薩，首利安有較強的迷走功能促進作用，暗示在這個三個月的換藥觀察研究中，首利安相較於金菩薩有較佳的心血管安全性。在B研究中，我們發現可致律藉著抑制了交感與副交感神經活性，讓大鼠的心跳速率增加。好度傾向減低心跳速率，而理思必妥略為增加心跳速率，但並不如可制律那樣顯著。在C研究中，我們發現可致律對大鼠的影響大約可持續六小時，而且這個抑制作用在停藥後是可逆的。

結論：當精神分裂症患者由第一代抗精神病藥物轉換到第二代抗精神病藥物的觀察研究中，首利安相較於金菩薩有較佳的心血管安全性。抗精神病藥物的動物實驗中，好度相較於理思必妥與可致律呈現較佳的心血管安全性，而可致律在三者間心血管安全性是最差的。不過我們的動物研究也顯示，可致律對自主神經功能活性的抑制是可逆的，因此對心血管功能不佳的病人，及早停用可致律可能對心血管安全有幫助。

Background: Sudden cardiac death is higher among schizophrenic patients and is associated with parasympathetic hypoactivity. Antipsychotic agents are highly suspected to be a precipitating factor. We use the measurement of heart rate variability (HRV) as a tool to detect the possible influences of antipsychotic agents to autonomic function.

Methods: In study A, we used a computer-assisted 5-min measurement of resting HRV in schizophrenic patients who were switched to atypical antipsychotic agents (amsulpride and olanzapine) due to tardive dyskinesia. In 15 patients who switched to amisulpride and 18 to olanzapine, HRV was evaluated before the medication was switched, and patients were followed up every month for 3 month after switch. In study B, haloperidol, risperidone and clozapine were given separately by intraperitoneal injection to male Wistar-Kyoto (WKY) rats for 5 days. Cardiac autonomic function was assessed 6 hours a day by using HRV analysis. In study C, clozapine were given by intraperitoneal injection to male WKY rats for 14 days then rest seven days, cardiac autonomic function was assessed 24 hours a day by wireless system.

Results: In the study A, we found the amisulpride have a more vagotonic effect, suggesting a more cardiovascular safety than that on typical antipsychotic agents or olanzapine during the 3 months observation. In the study B, we found clozapine increase heart rate and suppressed cardiac sympathetic parasympathetic activity. Haloperidol tend to decrease heart rate while risperidone mildly increased heart rate, their effect were less obvious than those of clozapine. In study C, we found the effect of clozapine had just about 6 hours effect after clozapine was injected in WKY rat, and the autonomic activity was just reversible after stopping clozapine usage.

Conclusions: Amsulpride may have more cardiovascular safety than olanzapine when switched from typical antipsychotic agents. Haloperidol may have a better level of cardiovascular safety than risperidone or clozapine. Clozapine may have higher cardiovascular risk, but the suppression of autonomic function is just reversible. Stopping using clozapine as soon as possible when patients are poor cardiovascular situation may be helpful.

Table of contents
General Introduction…………………………………………………. …1
1. Schizophrenia…………………………………………………………..………..1
1.1 Neurotransmitters abnormality in schizophrenia……...……………………..…1
1.2 Antipsychotics and schizophrenia………………………...…………………….2
2. Autonomic nervous system……………………………………………………...3
2.1 Autonomic dysfunction in schizophrenia………………..……………………..4
2.2 Measurements of autonomic nervous function………..………………..………5
2.3 Autonomic imbalance and disease…………………………………..………….5
3. Sudden cardiac death in schizophrenia…………………………………………7
3.1 Higher sudden cardiac death in schizophrenia……………………………..…...7
3.2 Cardiovascular safety of antipsychotics……………………………………..….8
4. Clozapine………………………………………………………………………….9
4.1 Clinical use of clozapine………………………..………………………………9
4.2 Side effects of clozapine………………………………...……………………..10
5. Background……………………………………………………………………...11
The Aim of study A………………………………………………………………..12
The Aim of study B………………………………………………………………..12
The Aim of study C………………………………………………………………..13
Study A - Heart rate variability in schizophrenic patients switched from typical antipsychotic agents to amisulpiride and olanzapine: 3 months followed up…….…14
1. Materials and methods………………………………………………………….14
1.1 Subjects…………………………………………………..……………………14
1.2 Processing of electrocardiogram signals…..……………………..……………16
1.3 Frequency-domain analysis of HRV……………………………………..……16
1.4 Statistical analysis……………………………………………………………17 2. Results…………………………………………………………………………...17
3. Discussion………………………………………………………………………..19
Study B - The Influences of Antipsychotic Agents on the Heart Rate Variability in Male WKY Rats: Implications for Cardiovascular Safety…………………………………………………...22
1. Materials and methods…………………………………………………………22
1.1 Animal preparation and antipsychotics treatment……………………..………22
1.2 Electrophysiological recordings………..……………………………………...24
1.3 Sleep analysis………………………………..………………………………...24
1.4 HRV analysis…………………………………………………..………………25
1.5 Statistical analysis……………………………………………………………26 2. Results…………………………………………………………………………...27
2.1 The effects of antipsychotic agents on HRV indexes (without sleep staging)...27
2.2 The effects of antipsychotic agents on sleep patterns……………..……..……28
2.3 The interaction between drug and stage in the HRV changes……………..…..29
3. Discussion…………………………………………………………..……………30
3.1 Cardiovascular safety and autonomic functions…………………………..…...30
3.2 Hazardous effects of clozapine on cardiovascular function………………...…31
3.3 Haloperidol is relatively beneficial……………………………..……………..32
3.4 Sleep pattern and antipsychotics…………..……………………..……………32
3.5 Limitations…………………………………………..…………………...……33
Study C – Continuously monitored the clozapine-induced autonomic activity suppression in male WKY rats………….35
1. Materials and methods………………………………………………….………35
1.1 Animal preparation and clozapine treatment…………………………..………35
1.2 Data acquisition and storages…………………………..……………………...36
1.3 HRV analysis…………………………………..………………………………37
1.4 Statistical analysis………………………..……………………………………38 2. Results……………………………………………………………...……………39
3. Discussion………………………………………………………………….……40
Conclusions……………………………………………………………………42
Future work………………………………………………………………...…44
Tables……………………………………………………………………………..45
Table 1. Demographic data of the two groups of schizophrenic patients in Study
A……………………………………………………………..…….…45
Table 2. HRV change from before to after treatment with antipsychotics or
saline for five days in Study B……………………………………….46
Table 3. Two way mixed design ANOVA results of the HRV changes (within
groups factor: stage; between groups factors: drug) in Study B …….48
Table 4. Simple main effect analysis of the factors stage and drug in Study B.49
Figures……………………………………………………………………………50
Figure 1. HRV changes in Study A………………………………………….…50
Figure 2. Protocol of Study B……………………………………………….…51
Figure 3. Continuous and stimultaneous analysis of polysomnogram and HRV in an example rat……………………………………………………52
Figure 4. Baseling HRV in different sleep stage………………………………53
Figure 5. HRV changes in antipsychotic treatment rat in Study B................…54
Figure 6. Proportion of sleep stage in antipsychotic treatment rat in Study B..55
Figure 7. Protocol of Study C…………………….……………………………56
Figure 8. HRV changes in clozapine treatment in Study C……………………57
Figure 9. Daily RR changes during clozapine treatment and withdrawal……..58
Figure 10. Daily HF changes during clozapine treatment and withdrawal……59
Figure 11. Daily LF% changes during clozapine treatment and withdrawal….60
Figure 12. 24 hours RR changes during clozapine treatment………………….61
Figure 13. 24 hours HF changes during clozapine treatment………………….62
Figure 14. 24 hours LF% changes during clozapine treatment………………..63
References……………………………………………………………………...64
Appendix A - Subscales of The Brief Psychiatric Rating Scale (BPRS) applied in
Study A………………………………………………………..……….78
Appendix B - Institutional Review Board Approval of Study A…………....………..79
Appendix C - Institutional Review Board Approval of animal study............………..80
Appendix D - The bioelectrical signals recording over rat head……………………..81
Appendix E - Ying-Chieh Wang’s publication list during 2004-2012………….…....82

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