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1、氯胺酮与抑郁症,背景介绍,新药氯胺酮,总结,提纲,1,2,3,背景介绍 概况,抑郁症是一种常见的心境障碍，以显著而持久的心境低落为主要临床特征，且心境低落与其处境不相称，严重者可出现自杀念头和行为。,单相性抑郁症(即重性抑郁症和精神抑郁症)、适应性障碍、轻微抑郁症、季节情感性精神障碍(SAD)，经前期焦虑症(PMDD)、产后抑郁症、非典型抑郁症及双相性精神障碍、躁郁症等,1、定义,2、分类,又称躁狂抑郁症：一种能够引起患者心情大起大落变化的疾病。患者的心情可能就会有极度亢奋突然转变为极度忧伤抑郁，即在心情的两极间波动。平时患者则是正常的。,3、双相抑郁症,精力 减退,抑郁 心境,兴趣 丧失,自

2、我 评价低,抑郁症,睡眠 障碍,食欲 下降,自杀 观念,精神 运动 迟滞,抑郁症,背景介绍 临床症状,脑中单胺递质去甲肾上腺素(NE)和5羟色胺(5-HT)功能不足,环境及个体心理因素行为认知、精神卫生等,背景介绍 发病机制,单胺递质理论,神经递质理论,单相性抑郁症(即重性抑郁症和精神抑郁症)、适应性障碍、轻微抑郁症、季节情感性精神障碍(SAD)，经前期焦虑症(PMDD)、产后抑郁症、非典型抑郁症及双相性精神障碍、躁郁症等,神经回路学说,背景介绍 现状,世界卫生组织2005年统计，各种抑郁症的患病率约占全球人口的11%。在中国，目前抑郁症的患病率约为3%5%，抑郁症患者估计有3600万人。抑郁

3、症已成为世界第4大疾患,预计到2020年,可能成为仅次于冠心病的第二大疾病。 与高发病率形成鲜明反差的是，目前全国地市级以上医院对抑郁症的识别率不到20%。而在现有抑郁症患者中，只有不到10%的人接受了相关药物治疗。抑郁症在我国造成的直接经济负担约为141亿元，间接经济损失约481亿元，总经济负担达到621亿元。,背景介绍 现状,图一：20072011年全球抗抑郁药物市场规模,背景介绍 现状,图一：20052011年我国抗抑郁药物市场规模及增长率,心理学治疗,光疗法,睡眠剥夺法,电休克治疗,音乐疗法,运动疗法,药物治疗,背景介绍 治疗方法,发现第一代抗抑郁药TCAs、MAOIs,“单胺假说”和

4、抑郁患者脑中缺少5-HT和/或NE 的假说得到明确,双重作用的抗抑郁药被研发出来,请在此添加文字,新的抗抑郁药SSRIs被研发出来,新的可能的药物靶点被发现,背景介绍 药物治疗抗抑郁药的发展,三环类抗抑郁药（TCAs） 第一代抗抑郁药。TCAs阻断突触前膜对神经递质5-HT、NE的再摄取减少对5-HT、NE的摄取提高在突触间隙中 的浓度加强神经传导抗抑郁,非三环类抗抑郁药 SSRIs、 SNRIs、 NDRIs、 SARIs、 NaSSAs等。新一代抗抑郁药，曲唑酮、马普替林、阿莫沙平、舍曲林、米氮平、帕罗西汀、氟西汀等,单胺氧化酶抑制药（MAOI） 抑制MAO5-HT、NE、DA等神经递质氧

5、化脱氨降解作用减少单胺在组织中、神经元突触间隙中含量增 多，浓度升高治疗抑郁症,其他 神经营养因子类抗抑郁药 植物类抗抑郁药 P物质拮抗药,抗抑 郁药,背景介绍 药物治疗抗抑郁药分类,新药氯胺酮 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!,新药氯胺酮 发现过程,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!,新药氯胺酮 发现过程,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,新药氯胺酮 发现过程,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,新药氯胺酮 发现过程,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),新药氯胺酮 发现过程,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.,新药氯胺酮 发现过程,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,新药氯胺酮 发现过程,Change in depression scale scores during 2 weeks in pa

15、tients with bipolar disorder given placebo and ketamine (n=18).,新药氯胺酮 发现过程,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).,新药氯胺酮 发现过程,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.,新药氯胺酮 发现过程,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!,新药氯胺酮 发现过程,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.,新药氯胺酮 结论,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 !,新药氯胺酮 结论,But there remain some quest