27/03/2019

從基礎到臨床,褪黑激素致效劑與晝夜節律失調的臨床及分子效應

從基礎到臨床,褪黑激素致效劑與晝夜節律失調的臨床及分子效應

蘇冠賓
中國醫藥大學 醫學院副院長
精神醫學及神經科學教授

精神障礙的臨床表現及發病機制與晝夜節律失調有關。由內生性褪黑激素所研發出之受體致效劑,在基礎研究中呈現有抗發炎、逆轉過度氧化作用、並減緩神經退化,在臨床的應用上,也有治療憂鬱焦慮及預防譫妄症的效果。實驗室最近在相關的主題上的試驗成果,利用兩篇原著論文和一篇回顧論文,從基礎到臨床,把晝夜節律失調在憂鬱及焦慮的疾患問題,做深入之探討。

Reference:
1.        Satyanarayanan SK, Shih YH, Chien YC, Huang SY, Gałecki P, Kasper S, Chang JPC, Su KP*. Anti-oxidative effects of melatonin receptor agonist and omega-3 polyunsaturated fatty acids in neuronal SH-SY5Y cells: Deciphering synergic effects on antidepressant mechanisms. Molecular Neurobiology 2018 Feb 3. doi: 10.1007/s12035-018-0899-x. [Epub ahead of print] (IF=6.19, R/C= 25/259, NEUROSCIENCE 9%)
2.        Satyanarayanan SK, Chien YC, Chang JPC, Huang SY, Guu TW, Su HX, Su KP*. Melatonergic agonist regulates circadian clock genes and peripheral inflammatory and neuroplasticity markers in patients with depression and anxiety. Brain Behavior and Immunity (In Press)  (IF=6.128, R/C= 27/252, NEUROSCIENCES)
3.        Satyanarayanan SK, , Su HX, Lin YW, Su KP*. Circadian Rhythm and Melatonin in the Treatment of Depression. Curr Pharm Des. 2018;24(22):2549-2555. 

精神障礙的臨床表現及發病機制與晝夜節律失調有關。由內生性褪黑激素所研發出之受體致效劑,在基礎研究中呈現有抗發炎、逆轉過度氧化作用、並減緩神經退化;而在臨床試驗上顯示可以透過調整晝夜節律的相位,成為治療焦慮、憂鬱及睡眠障礙的新療法。此外,愈來愈多的基礎及臨床研究也發現,抗鬱天然物omega-3多元不飽和脂肪酸(omega-3 PUFAs)有抗發炎、逆轉氧化作用、減緩神經退化及臨床的抗憂鬱效果我們最近的使用神經細胞的毒性研究模式,發現褪黑激素致效劑與omega-3 PUFAs對神經保護、抗氧化及抗發炎具有協同加強的作用,這項研究最大的目的,是希望能做為未來合併兩種天然抗鬱物質,進行下一步的臨床試驗,以實驗來推廣營養醫學在憂鬱症之治療與預防的概念。
  • The results demonstrated that RMT and EPA synergistically provide effective neuroprotective, anti-oxidative/inflammatory effect against oxidative stress. (意即在細胞層面,RMT/EPA combination對於神經細胞保護有加成的效果)
  • Cell viability: Rescue (RMT+EPA; FLX+N3; EPA); Prevention (RMT, RMT+EPA; EPA). (意即RMT/EPA combination, 藥物/N3 combination & EPA有類似治療的效果;而對於RMT, RMT/EPA combination; EPA有類似預防的效果)
  • ROS: Rescue (DHA-, RMT-0, FLX+); Prevention (EPA-, DHA-, RMT-)
  • NFkB translocation: Rescue (RMT+, FLX-, EPA-, DHA-); Prevention (All +)
最近我們更進一步透過臨床研究,探討褪黑激素致效劑之改善睡眠及抗憂鬱的臨床療效,以及其在神經保護(BDNF & GDNF)、神經內分泌(melatonin & cortisol)、抗神經發炎(IL-1beta, TNF-alpha & IL-10)、和對生物週期基因(CLOCK, PER1, PER2, CRY1, CRY2, NR1D1, NR1D2, DEC1 & TIMELESS)的調節機制




28/02/2019

譫妄症藥物治療的新指引(論文簡介及中英文新聞稿)

譫妄症藥物治療的新指引(論文簡介及中英文新聞稿)

蘇冠賓
中國醫藥大學 醫學院副院長
精神醫學及神經科學教授


由中國醫藥大學精神醫學教授蘇冠賓高雄文信診所曾秉濤醫師、與林口長庚復健科吳易澄醫師等人主導,結合日本國家癌症中心、英國倫敦國王學院及加拿大多倫多大學之國際知名團隊,對精神疾病的最嚴重之類型「譫妄症」的所有藥物治療納入研究主題,最新研究結果發表在國際知名期刊JAMA Psychiatry!他們的發現除了替臨床醫師帶來治療藥物選擇的根據之外,也為未來的譫妄症研究和治療指引提供新的方向!
A recent paper published in JAMA Psychiatry provides important findings of the missing piece of clinical uncertainty about treatment and prevention in delirium.
Delirium, commonly known as acute confusional state, can often be caused by one or more contributing factors, such as a severe or chronic medical illness, changes in metabolic balance, adverse effects from medication, systemic infection, surgery, or alcohol or drug intoxication or withdrawal. It’s critically important to identify and treat delirium because some of the contributing factors could be life-threatening. However, there is no sufficient evidence for choice of medication to treat or prevent the symptoms of delirium. 
A recent paper, Association of Delirium Response and Safety of Pharmacological Interventions for the Management and Prevention of Delirium A Network Meta-analysis, published in JAMA Psychiatry provides important findings of this missing piece in that important clinical uncertainty. The leading author of an international collaboration, Professor Kuan-Pin Su, at the China Medical University in Taichung, Taiwan, concludes the main finding about treatment/prevention of delirium: “In this report, we found that the combination of haloperidol and lorazepam demonstrated the best option for treatment of delirium, while ramelteon for prevention against delirium.” Hopefully, our findings would revise the chapter of treatments and prevention of delirium in the treatment guidelines. (https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2726609).
In addition to the superiority of “haloperidol plus lorazepam” and “ramelteon” in treatment and prevention to delirium, the paper also revealed an important result that both of these regimens did not associate with higher all-cause mortality rate than placebo/control did. That is, the safety of such regimen was similar with that of placebo/control, in aspect of risk of mortality.
Delirious symptoms have profound negative impacts to patients and their caregivers, and significant increase the mortality and morbidity. According to another main author, Dr Ping-Tao Tseng from the WinShine Clinics in Kaohsiung, Taiwan, “it is equally important to treat underlying diseases (e.g. dehydration, adverse drug reaction, or metabolic imbalances) and to treat the neuropsychiatric symptoms (psychosis, irritable and unstable mood, agitated and destructive behaviors… etc.) of delirium. Therefore, the rationale of this work was to provide a general principle of medication prescription to manage the delirium symptoms rather than the etiology behind the delirium.” In another word, the results of current network meta-analysis were aiming to delirious symptoms but not targeting their underlying causes as the recruited subjects had different baseline condition among these 58 RCTs.
In addition to the superiority of “haloperidol plus lorazepam” and “ramelteon” in treatment and prevention to delirium, the paper also revealed the important findings about safety. Their result revealed that both of these regimens did not associate with higher all-cause mortality rate than placebo/control.
In the study by Wu and colleagues in a coming issue of JAMA Psychiatry, the authors use a variant of meta-analysis (network meta-analysis [NMA]) to explore pharmacologic interventions for delirium. Another main author, Dr Yi-Cheng Wu, from the Chang Gung Memorial Hospital in Linkou, Taiwan, added, “single randomized controlled trial or traditional pairwise meta-analysis provides less information than NMA to synthesize direct and indirect evidence for decision-making.”
The Editorial in the same issue by Professor Blazer from Duke University Medical Center, North Carolina, pointed out that this NMA is of importance for at least 2 reasons. First, non-pharmacological approaches for delirium are time-consuming and costly to implement. A safe and effective pharmacologic intervention would be welcomed. Second, new agents and new approaches to pharmacologic treatment have emerged that can be empirically investigated for efficacy and safety in the treatment of delirium (https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2726605).
Indeed, non-pharmacological treatments are always important in the treatment and prevention in delirium. In fact, in this current NMA in JAMA Psychiatry, the authors have reported that the ramelteon, a melatonergic agonist, was ranked the best preventive regimen against delirium prevention. The authors added, “the action of melatonin agonists like ramelteon is to re-establish the disturbed circadian rhythm. Interestingly, the combination of simple behavioral interventions (e.g. exposure to diurnal light-dark cycles, familiar objects, clocks/calendars, …etc.) has been commonly advised to help to prevent delirium in clinical settings.

中國醫藥大學蘇冠賓教授領導國際跨院合作之團隊研究提供譫妄治療新發現!

由中國醫藥大學精神醫學教授蘇冠賓以及幾位台灣精神科醫師主導,結合國際知名研究團隊,對精神疾病的最嚴重之類型「譫妄症」的所有藥物治療納入研究主題,最新研究結果發表在國際知名期刊JAMA Psychiatry!他們的發現除了替臨床醫師帶來治療藥物選擇的根據之外,也為未來的譫妄症研究和治療指引提供新的方向!

譫妄 (delirium)在重症治療中是一個相當重要的症候群,主要症狀包括突然其來嚴重的聽幻覺、視幻覺、及怪異妄想,合併意識混亂,讓照顧者以為患者中邪了。最新研究的報告指出(Pérez-Ros et al. Diseases 2019 Jan 30),譫妄在住院中老人盛行率高達27%,在其他重症病人中也非常常見(加護病房高達 35%, 如果使用上呼吸器更上達 80%;一般低風險手術後12%-13%;高風險手術後更高,例船冠狀心血管手術29%、重大腹部手術50%、心臟手術 51%;臨終病人高達85%!)由於譫妄患者死亡率高達20-30% (Lipowski NEJM 1989),其臨床意義非常重要,代表個案的病情相當嚴重,不容輕忽!

目前醫學界公認對於治療譫妄最重要的就是找出潛在生理病因並盡快矯正(例如藥物中毒或戒斷、代謝系統異常、急慢性內外科疾病或感染病…等等)。然而,譫妄症狀(例如幻覺及妄想所造成的對自我及他人之危險以及治療和照顧上的困難),嚴重影響病人的預後,雖然其病因仍未完全明朗,研究認為譫妄幻覺妄想症狀與腦內多巴胺、乙醯膽鹼、GABA等神經傳導物質異常、以及生物節律與醒睡中樞異常有關。遺憾的是,目前臨床研究證據相當有限,療效不足、副作用、都增加臨床治療困難;此外,譫妄的預防更是讓臨床醫師爭論不休的議題。臨床治療指引 (clinical guideline) 都強調:目前的臨床研究證據不足,無法有足夠確實的結論!

中國醫藥大學精神醫學教授蘇冠賓醫師、林口長庚復健科吳易澄醫師、與高雄文信診所曾秉濤醫師等人主導,結合日本國家癌症中心、英國倫敦國王學院及加拿大多倫多大學之國際知名團隊,把現存所有譫妄藥物治療納入研究主題,利用網路統合分析(NMA)的最新方法,發現:褪黑激素受體藥物ramelteon對於預防重病患者產生譫妄症有顯著的功效!在由於褪黑激素受體藥物可以矯正生物節率和晝夜週期(circadian rhythm),其效果類似其他矯正譫妄症的非藥物療法,例如光照療法、利用時鐘或日曆強化人時地定向感…等,因此藥物如果可以有效地達到類似的效果,應該具有相當重要的臨床價值。生物的晝夜週期(circadian rhythm)的正常運作,不僅是身心健康的重要指標、是大腦記憶功能的守門員、更是維持代謝、免疫、心血管、骨骼肌肉功能的重要生理機能。此外,蘇教授團隊更首度證實Haloperidol與lorazepam兩藥物的組合最能改善譫妄症的症狀,這份重大突破的研究成果也獎刊登在國際知名期刊JAMA Psychiatry!這樣的結果,甚至獲得國外審查專家的評論:「做為未來臨床指引制定之重要根據!」

Notes:

1. Lipowski, Z.J. Delirium in the elderly patient. N. Engl. J. Med. 1989, 320, 578–582. 
[The outcome for the majority of patients is full recovery, but in 20 to 30 percent, delirium is followed by death], [About 40 percent of patients with dementia who were 55 years of age or older were delirious on admission to the hospital, whereas 25 percent of those who were delirious had dementia], [In older long-term care residents, the reported prevalence varies between 15% and 70%]

2. Pérez-Ros P, Martínez-Arnau FM. Delirium Assessment in Older People in Emergency Departments. A Literature Review. Diseases. 2019 Jan 30;7(1). pii: E14. doi: 10.3390/diseases7010014.
[The prevalence of delirium in end-of-life patients approaches 85%], [In hospitalized older patients, delirium is the most frequent complication, with an approximate prevalence of 27%], [In postsurgical patients, the general surgery pose lesser risk, with a prevalence of 12%-13%, whereas the patients subjected to aortic, major abdominal, or cardiac surgery is much higher, up to 29%, 50%, and 51%, respectively], [In the ICU, the prevalence varies between 31% and 35%, being higher in patients subjected to mechanical ventilation and with comorbidities (up to 80%)], [The probability of delirium increasing by 45% in moderate dementias and 58% in severe dementias]. 


REPLY to valuable comments about the limitation of NMA:



Dear ~,
I am also very delighted to receive many valuable comments from excellent clinicians like you about our NMA in JAMA Psychiatry. They correctly pointed out the limitation of NMA and the caution of using FGS (haloperidol/lorazepem). I actually agree them all as well as the Editorial by Blazer in the same issue.
Although our study is strengthened by comparing different drugs with NMA, the generalization of our results are still highly limited and depending on the studies included in the NMA and the possible comparisons given the studies available. For example, there were many studies using haloperidol but only only one study compared haloperidol/lorazapam versus haloperidol/placebo. The result showing haloperidol/lorazapam the best because this combination was doing very well in Richmond Agitation-Sedation Scale (RASS) scores as compared to haloperidol/placebo in that single study.
In conclusion, we should always consider specific treatments in specific clinical conditions rather than applying only one general principle from a big picture of our NMA.


轉自共同作者曾秉濤醫師部落格:臨床困境與實證醫學的應用:譫妄症新紀元
https://tsengpt.blogspot.com/2019/02/blog-post.html

最近美國醫學會系列期刊 JAMA Psychiatry 刊出一篇非常重要的網路統合分析 (Network Meta-Analysis) 研究,這篇文章結合了來自世界各地許多位專家學者資深經驗薈萃,給出了許多關於臨床處理譫妄症狀 (delirium) 的重要臨床建議! 

譫妄症狀 (delirium) 是什麼?

患者因為內外科問題而導致身體狀況惡化時,有一定機率會出現譫妄症狀的併發症,這時患者會出現急性且起起伏伏的躁動 (agitation) 、幻覺 (hallucination) 、妄想 (delusion) 、日夜混亂 (circadian disturbance)、胡言亂語 (irrelevant and incoherent speech) 等,而這些症狀出現時,往往代表患者的身體出現重大狀況!



實證醫學告訴我們什麼:治療譫妄症方面

在我們這篇最新的研究中,我們發現到Haloperidol與lorazepam的組合,是所有藥物處方中最能緩解譫妄症狀的處方,另一方面,如果不考慮複方,Haloperidol則是所有單方 (single regimen) 裡面效果最好的處方!而且根據統計,這些處方和安慰劑/對照組 (placebo/control) 比較起來,並不會因此造成更高的患者最終死亡率 (all-cause mortality rate)。

實證醫學告訴我們什麼:預防譫妄症方面

另一方面,我們也嘗試討論是否有任何處方能夠預防 (或減少) 譫妄症的發生,我們的研究發現ramelteon 這個藥物對於預防譫妄症狀的發生,是所有處方之中效果最好的,而Olanzapine則是所有抗精神病劑 (antipsychotics) 中預防效果最好的,而且這兩種藥物和安慰劑/對照組 (placebo/control) 比較起來,並不會因此造成更高的患者最終死亡率 (all-cause mortality rate)。 (圖片資料整理自原始文章)

處理譫妄症狀的過程還是需要回歸根本

但是,我們還是要提醒所有臨床工作者,譫妄症狀的源頭還是來自於「患者的身體出狀況」,因此上述處方藥物只是協助緩解譫妄症狀的表面症狀,臨床工作人員還是要同時積極尋找與解決患者潛藏的身體問題,這才是治本之道! 

至於其餘各種藥物 (例如大家常用的quetiapine) 的效果,以及各種藥物的使用劑量與時間等細節,就請有興趣的讀者自行上雜誌網站買全文來看了! 最後,也提醒民眾,若真有遇到譫妄症狀的問題,切勿自行使用藥物,而應配合醫師接受積極檢查與治療方為上策唷! 

25/02/2019

中醫大 MD/PhD千里馬計畫

Cultivating Physician Scientists for Future Medicine 

MD/PhD Program @ CMU

蘇冠賓
中國醫藥大學 醫學院副院長
精神醫學及神經科學教授
身心介面實驗室主持人

目標
  • 培育菁英學生及一流之醫師科學家,解決重大醫學難題,具有臨床或基礎醫學研究和生技產業之國際影響力。
  • 培育新世代優質醫療人才,解決未來醫療及健康政策面、產學研發面、醫學教育面、醫學人文面的問題和困境。
  • 培育中醫大永續經營的領導人才,乃至於台灣及國際醫學領域之領袖。

CMU MD/PhD 千里馬計畫
  • 整合高中入學、醫、中及牙醫學系
    1. 每年10位(五位高中入學,吸引頂尖學生;五位大四入選,激勵校內菁英學生卓越)
    2. 新生入學前暑假提供啟蒙指導教授和實驗室研究;跨系所Project-based learning Independence Study、進入傑出實驗室參與專題研究、科技部大專生計畫(大二)及參加預研學程(大二~四)
      • 指導教授、生涯導師及頂尖研究機構之訓練:
      1. 根據學生興趣和研究表現,協助媒合指導教授及生涯導師,以師徒制的精神,提供學生獨一無二的適才適性研究訓練
      2. 頂尖研究機構訓練:結合國內外頂尖的研究機構(例如中研院)訓練2~4年;補助海外研實習與修讀雙聯學位(例如美國安德森癌症中心、加州大學爾灣分校、持續新增)
        • 學位後培育(國內外):
        1. 畢業後持續協助畢業生,留任本校之醫療科部及研究單位,或進入「國際一流訓練醫院和研究機構」,進行專科及次專科的臨床訓練(七至十年)及博士後(二至三年)的研究訓練 。
        2. 本校將和訓練醫院科部和機構簽署共同培育領袖人才的合作備忘錄,以確定訓練理念之延續。 

          16/02/2019

          馬勒、佛洛伊德與精神分析(演講摘要)

          馬勒、佛洛伊德與精神分析
          蘇冠賓
          中國醫藥大學 醫學院副院長
          精神醫學及神經科學教授

          「自由,
心靈的自由」
           

          面對未知所產生的直覺就是「神」,有人投射對未知的恐懼和慾望,所以產生制定所有規範和教條的神;有人則窮盡一生去追求真象,當對宇宙的未知產生越多的了解,就會發現有更多的未知,然後就會轉向宗教或心靈的探索,去接近靈性的智慧。人類受限於感官和思考的種種框架,無法體驗宇宙及生命的所有面向、全貌及本質。詩人、作家、藝術家如濟慈、莎士比亞、梵谷「啟發我們心靈和感知」,接觸文學和藝術使我們「超越視野的局限」。

          二十一世紀的今天,佛洛依德理論已經不是醫學的主流,但精神分析最後仍然勝出。不僅是現代「藝術、文學、音樂、電影…」等創作的基礎,更化身為「高度精神壓力工作者」的身心修練之道。企業的CEO、頂尖運動員、卓越的演員、不再僅僅只能透過「靈性」的宗教,現在更常常透過「科學性」的精神分析,深入「探索自我」,查察「潛意識」對生活和工作的影響,進而突破自我的迷宮,作出別具洞見的決策,成就出不凡的表現。感受生命、表達自我、表現藝術,都會反映出內在動機和深層情感,所以具備這種洞察能力,可以讓人的心靈層次更加提升。在二十一世紀在物質文明的對比之下,更突顯了精神層次的匱乏,Freudian的智慧如空谷足音,聽來倍覺溫暖充實。


          創作者或許能體驗群體潛意識中的禁忌、壓抑和慾求,用作品投射出群體潛意識,進而引發時代的共鳴、恐懼、和精神張力的渲洩。所以,作品是創作者的白日夢,也讓觀眾能夠看到自己的夢;是潛意識的溝通、更是曝露自己潛意識的「危險行為」。



          Ich bin der Welt abhanden gekommen, 我被世界所遺棄,
          Denn wirklich bin ich gestorben der Welt. 我確實從這世界死去。
          Ich bin gestorben dem Weltgetuemmel, 我已經在庸碌世間中死去,
          Und ruh' in einem stillen Gebiet! 安眠在寧靜的角落!
          Ich leb' allein in meinem Himmel, 我獨自活在我的天堂,
          In meinem Lieben, in meinem Lied! 在我的愛,在我的歌中!



          作曲家馬勒在音樂上表現的死亡、陰暗、掙扎、憂鬱、神經質、自怨自艾、焦慮和厭世,作品直接的心理揭露呈現前所未有的強烈震撼。馬勒終其一身深受精神官能症狀所苦,最後終於在婚姻危機的嚴重問題之下,決定求助於佛洛依德。 一開始馬勒似乎對於就醫有所抗拒,取消兩次預約,但最後終於忍受不了巨大的身心疼痛,還是坐了二十六小時的火車,在1910年8月26日荷蘭的Leiden向佛洛依德求助。事實上,馬勒當時正忙著準備他「最重要」的第八號交響曲之首演,而佛洛依德只是到Leiden開會做短暫的停留。所以「患者」應該是感到有迫切的需要,才會不辭辛勞趕緊就診。 兩位大師見面,留下歷史上有名的一個長達四小時的心理治療面談(2010年德國電影 Mahler auf der Couch就是以虛構的情節在描述這段經過)!






            
          In 1925 Freud told his pupil Marie Bonaparte about the meeting

          • Mahler and Freud immediately understood each other
          • Both spoke German (wit regional coloring), had the same social, historical and cultural background from Vienna (Congruence of cognition), both had an international reputation, been in America, studied Philosophy, were fascinated by Dostoyevsky and both had a morbid fear of death

          In a letter to Theodor Reik (1934), Freud noted…

          • ‘“brilliant faculty of comprehension, I had plenty of opportunity to admire the capability for psychological understanding of this man of genius…”
          • “No light fell on the symptomatic facade of his obsessional neurosis. It was as if you would dig a single shaft through a mysterious building…”
          • The day after the meeting, Mahler wrote a telegram to Alma ‘‘I’m filled with joy.”

          馬勒對精神分析的奧祕很快可以掌握,對自我的心理狀態也有高度的洞察力,能查覺早年影響;不必針對外顯官能症狀工作,直接在神祕建築物內投入強光,也為馬勒帶來心理衝突的解脫。馬勒生命中最後的九個月,即使經歷生理極端的痛苦,但心理上卻獲得靈性的圓滿。馬勒離世之前給予「心愛的人完全的自由」,也同時象徵給予「受困於馬勒潛意識中犧牲付出的母親」自由,同時
也就帶給自己「心靈全面的自由」!




          文獻及論文
          • Gustav-Mahler.eu
          • Starcevic V. Gustav Mahler as Freud's patient. Australas Psych 2013
          • Garcia EE. Gustav Mahler's choice. Psychoanal Study Child. 2000
          • Kuehn JL. Encounter at Leyden: Mahler consults Freud. Psychoanal Rev 1965
          • Mijolla A. Int Dictionary Psychoanalysis, 2005
          • Garcia EE. Gustav Mahler's Choice: A Note on Genius, and Psychosomatics. Psychoanalysis Child 2000 
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