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1、氯胺酮與抑郁癥,背景介紹,新藥氯胺酮,總結(jié),提綱,1,2,3,背景介紹 概況,抑郁癥是一種常見的心境障礙，以顯著而持久的心境低落為主要臨床特征，且心境低落與其處境不相稱，嚴重者可出現(xiàn)自殺念頭和行為。,單相性抑郁癥(即重性抑郁癥和精神抑郁癥)、適應(yīng)性障礙、輕微抑郁癥、季節(jié)情感性精神障礙(SAD)，經(jīng)前期焦慮癥(PMDD)、產(chǎn)后抑郁癥、非典型抑郁癥及雙相性精神障礙、躁郁癥等,1、定義,2、分類,又稱躁狂抑郁癥：一種能夠引起患者心情大起大落變化的疾病?；颊叩男那榭赡芫蜁袠O度亢奮突然轉(zhuǎn)變?yōu)闃O度憂傷抑郁，即在心情的兩極間波動。平時患者則是正常的。,3、雙相抑郁癥,精力 減退,抑郁 心境,興趣 喪失,自

2、我 評價低,抑郁癥,睡眠 障礙,食欲 下降,自殺 觀念,精神 運動 遲滯,抑郁癥,背景介紹 臨床癥狀,腦中單胺遞質(zhì)去甲腎上腺素(NE)和5羥色胺(5-HT)功能不足,環(huán)境及個體心理因素行為認知、精神衛(wèi)生等,背景介紹 發(fā)病機制,單胺遞質(zhì)理論,神經(jīng)遞質(zhì)理論,單相性抑郁癥(即重性抑郁癥和精神抑郁癥)、適應(yīng)性障礙、輕微抑郁癥、季節(jié)情感性精神障礙(SAD)，經(jīng)前期焦慮癥(PMDD)、產(chǎn)后抑郁癥、非典型抑郁癥及雙相性精神障礙、躁郁癥等,神經(jīng)回路學(xué)說,背景介紹 現(xiàn)狀,世界衛(wèi)生組織2005年統(tǒng)計，各種抑郁癥的患病率約占全球人口的11%。在中國，目前抑郁癥的患病率約為3%5%，抑郁癥患者估計有3600萬人。抑郁

3、癥已成為世界第4大疾患,預(yù)計到2020年,可能成為僅次于冠心病的第二大疾病。 與高發(fā)病率形成鮮明反差的是，目前全國地市級以上醫(yī)院對抑郁癥的識別率不到20%。而在現(xiàn)有抑郁癥患者中，只有不到10%的人接受了相關(guān)藥物治療。抑郁癥在我國造成的直接經(jīng)濟負擔約為141億元，間接經(jīng)濟損失約481億元，總經(jīng)濟負擔達到621億元。,背景介紹 現(xiàn)狀,圖一：20072011年全球抗抑郁藥物市場規(guī)模,背景介紹 現(xiàn)狀,圖一：20052011年我國抗抑郁藥物市場規(guī)模及增長率,心理學(xué)治療,光療法,睡眠剝奪法,電休克治療,音樂療法,運動療法,藥物治療,背景介紹 治療方法,發(fā)現(xiàn)第一代抗抑郁藥TCAs、MAOIs,“單胺假說”和

4、抑郁患者腦中缺少5-HT和/或NE 的假說得到明確,雙重作用的抗抑郁藥被研發(fā)出來,請在此添加文字,新的抗抑郁藥SSRIs被研發(fā)出來,新的可能的藥物靶點被發(fā)現(xiàn),背景介紹 藥物治療抗抑郁藥的發(fā)展,三環(huán)類抗抑郁藥（TCAs） 第一代抗抑郁藥。TCAs阻斷突觸前膜對神經(jīng)遞質(zhì)5-HT、NE的再攝取減少對5-HT、NE的攝取提高在突觸間隙中 的濃度加強神經(jīng)傳導(dǎo)抗抑郁,非三環(huán)類抗抑郁藥 SSRIs、 SNRIs、 NDRIs、 SARIs、 NaSSAs等。新一代抗抑郁藥，曲唑酮、馬普替林、阿莫沙平、舍曲林、米氮平、帕羅西汀、氟西汀等,單胺氧化酶抑制藥（MAOI） 抑制MAO5-HT、NE、DA等神經(jīng)遞質(zhì)氧

5、化脫氨降解作用減少單胺在組織中、神經(jīng)元突觸間隙中含量增 多，濃度升高治療抑郁癥,其他 神經(jīng)營養(yǎng)因子類抗抑郁藥 植物類抗抑郁藥 P物質(zhì)拮抗藥,抗抑 郁藥,背景介紹 藥物治療抗抑郁藥分類,新藥氯胺酮 必要性,Existing therapies for major depression and bipolar depression have a lag of onset of action of several weeks, resulting in considerable morbidity. Exploring pharmacological strategies that have rap

6、id onset of antidepressant effects within a few days and that are sustained would have an enormous impact on patient care. Reasons for this lack of better medications of Depression SoWe need a new Drug!,新藥氯胺酮 發(fā)現(xiàn)過程,For example, postmortem studies have reported altered NMDA-receptor complexes in the b

7、rain tissue of patients with Depression,How to begin? Converging lines of evidencesuggest the role of the glutamatergic system in the pathophysiology and treatment of mood disorders. Particularly the N-methyl-D-aspartate (NMDA)receptor complexmay play an important role in the pathophysiology of Depr

8、ession At the genetic level, polymorphisms of the GRIN1 and GRIN2B genes coding for the NR1 and NR2B subunits, respectively, have been associated with Depression. We know that ketamine is a NMDA antagonist!,新藥氯胺酮 發(fā)現(xiàn)過程,For example, postmortem studies have reported altered NMDA-receptor complexes in t

9、he brain tissue of patients with Depression,Lets Begin Can ketamine produce a rapid antidepressant effects in subjects with major depression ？ Design:A randomized, placebo-controlled, double-blind Study Patients:Eighteen subjects with DSM-IV major depression (treatment-resistant) Age:1865 Main Outco

10、me Measures : 21-item Hamilton Depression Rating Scale,新藥氯胺酮 發(fā)現(xiàn)過程,Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the dr

11、ug difference was very large after 24 hours,新藥氯胺酮 發(fā)現(xiàn)過程,A, Proportion of responders (50% improvement on 21-item Hamilton Depression Rating Scale28 HDRS) to ketamine and placebo treatment from minute 40 to day 7 postinfusion (n=18). B, Proportion of remitters (HDRS score 7) to ketamine and placebo tre

12、atment from minute 40 to day 7 postinfusion (n=18),新藥氯胺酮 發(fā)現(xiàn)過程,To my knowledge, this is the first report of any medication or other treatment that results in such a pronounced, rapid, prolonged response with a single dose. These were very treatment-resistant patients,NIMH director Dr. Thomas Insel,Co

13、nclusion: Robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-Daspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week.,新藥氯胺酮 發(fā)現(xiàn)過程,Can ketamine produce a rapid antidepressant effects in subjects with b

14、ipolar depression ？ Design:A randomized, placebo-controlled, double-blind Study Patients:Eighteen subjects with DSM-IV bipolar depression (treatment-resistant). Age：1865 Main Outcome Measures :Montgomery-Asberg Depression Rating Scale,新藥氯胺酮 發(fā)現(xiàn)過程,Change in depression scale scores during 2 weeks in pa

15、tients with bipolar disorder given placebo and ketamine (n=18).,新藥氯胺酮 發(fā)現(xiàn)過程,Proportion of responders and remitters after ketamine or placebo infusion by Montgomery-Asberg Depression Rating Scale (MADRS) score. A, Proportion of responders (50% improvement on MADRS) from 40 minutes to day 14 postinfusi

16、on (n=18). B, Proportion of remitters (MADRS score 10) from 40 minutes to day 14 postinfusion (n=18).,新藥氯胺酮 發(fā)現(xiàn)過程,From the figure,we can see that: Within 40 minutes, depressive symptoms significantly improved in subjects receiving ketamine compared with placebo this improvement remained significant t

17、hrough day 3.the drug difference effect size was largest at day 2. So we can come to a conclusion : In patients with treatment-resistant bipolar depression, robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-Daspartate antagonistketamine.,新藥氯胺酮 發(fā)現(xiàn)過程,How ke

18、tamine exert its function？ Ketamine causes a significant increase (more than 60%) in glutamate (Glu) and gamma aminobutyric acid (GABA) levels in the front of the brain. The investigators hypothesize that this increase in Glu and GABA levels, is responsible for the antidepressant action of the medic

19、ation. But the mechanism remain unknown!,新藥氯胺酮 發(fā)現(xiàn)過程,What adverse effects ketamine cause? Subjects with major depression: perceptual disturbances, confusion, elevations in blood pressure, euphoria, dizziness, and increased libido. The majority of these adverse effects ceased within 80 minutes after t

20、he infusion. Subjects with bipolar depression: transitory perceptual and dissociative disturbances. Although most ketamine patients experienced such changes, those changes were not associated with antidepressant response; furthermore, some patients who responded to ketamine had no substantial dissociative symptoms.,新藥氯胺酮 結(jié)論,Conclusion:,Ketamine can produce rapid antidepressant effects in subjects with treatment-resistant major depression or treatment-resistant bipolar depression,NIMH director Dr. Thomas Insel,Fantastic ketamine !,新藥氯胺酮 結(jié)論,But there remain some quest