查找资料PPT制作.ppt

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,Existingtherapiesformajordepressionandbipolardepressionhavealagofonsetofactionofseveralweeks,resultinginconsiderablemorbidity.Exploringpharmacologicalstrategiesthathaverapidonsetofantidepressanteffectswithinafewdaysandthataresustainedwouldhaveanenormousimpactonpatientcare.ReasonsforthislackofbettermedicationsofDepressionSoWeneedanewDrug!,新药氯胺酮发现过程,Forexample,postmortemstudieshavereportedalteredNMDA-receptorcomplexesinthebraintissueofpatientswithDepression,Howtobegin?Converginglinesofevidencesuggesttheroleoftheglutamatergicsysteminthepathophysiologyandtreatmentofmooddisorders.ParticularlytheN-methyl-D-aspartate(NMDA)receptorcomplexmayplayanimportantroleinthepathophysiologyofDepressionAtthegeneticlevel,polymorphismsoftheGRIN1andGRIN2BgenescodingfortheNR1andNR2Bsubunits,respectively,havebeenassociatedwithDepression.WeknowthatketamineisaNMDAantagonist!,新药氯胺酮发现过程,Forexample,postmortemstudieshavereportedalteredNMDA-receptorcomplexesinthebraintissueofpatientswithDepression,LetsBeginCanketamineproducearapidantidepressanteffectsinsubjectswithmajordepression？Design:Arandomized,placebo-controlled,double-blindStudyPatients:EighteensubjectswithDSM-IVmajordepression(treatment-resistant)Age:1865MainOutcomeMeasures:21-itemHamiltonDepressionRatingScale,新药氯胺酮发现过程,Subjectsreceivingketamineshowedsignificantimprovementindepressioncomparedwithsubjectsreceivingplacebowithin110minutesafterinjection,whichremainedsignificantthroughoutthefollowingweek.Theeffectsizeforthedrugdifferencewasverylargeafter24hours,新药氯胺酮发现过程,A,Proportionofresponders(50%improvementon21-itemHamiltonDepressionRatingScale28HDRS)toketamineandplacebotreatmentfromminute40today7postinfusion(n=18).B,Proportionofremitters(HDRSscore7)toketamineandplacebotreatmentfromminute40today7postinfusion(n=18),新药氯胺酮发现过程,Tomyknowledge,thisisthefirstreportofanymedicationorothertreatmentthatresultsinsuchapronounced,rapid,prolongedresponsewithasingledose.Thesewereverytreatment-resistantpatients,NIMHdirectorDr.ThomasInsel,Conclusion:RobustandrapidantidepressanteffectsresultedfromasingleintravenousdoseofanN-methyl-Daspartateantagonist;onsetoccurredwithin2hourspostinfusionandcontinuedtoremainsignificantfor1week.,新药氯胺酮发现过程,Canketamineproducearapidantidepressanteffectsinsubjectswithbipolardepression？Design:Arandomized,placebo-controlled,double-blindStudyPatients:EighteensubjectswithDSM-IVbipolardepression(treatment-resistant).Age：1865MainOutcomeMeasures:Montgomery-AsbergDepressionRatingScale,新药氯胺酮发现过程,Changeindepressionscalescoresduring2weeksinpatientswithbipolardisordergivenplaceboandketamine(n=18).,新药氯胺酮发现过程,ProportionofrespondersandremittersafterketamineorplaceboinfusionbyMontgomery-AsbergDepressionRatingScale(MADRS)score.A,Proportionofresponders(50%improvementonMADRS)from40minutestoday14postinfusion(n=18).B,Proportionofremitters(MADRSscore10)from40minutestoday14postinfusion(n=18).,新药氯胺酮发现过程,Fromthefigure,wecanseethat:Within40minutes,depressivesymptomssignificantlyimprovedinsubjectsreceivingketaminecomparedwithplacebothisimprovementremainedsignificantthroughday3.thedrugdifferenceeffectsizewaslargestatday2.Sowecancometoaconclusion:Inpatientswithtreatment-resistantbipolardepression,robustandrapidantidepressanteffectsresultedfromasingleintravenousdoseofanN-methyl-Daspartateantagonistketamine.,新药氯胺酮发现过程,Howketamineexertitsfunction？Ketaminecausesasignificantincrease(morethan60%)inglutamate(Glu)andgammaaminobutyricacid(GABA)levelsinthefrontofthebrain.TheinvestigatorshypothesizethatthisincreaseinGluandGABAlevels,isresponsiblefortheantidepressantactionofthemedication.Butthemechanismremainunknown!,新药氯胺酮发现过程,Whatadverseeffectsketaminecause?Subjectswithmajordepression:perceptualdisturbances,confusion,elevationsinbloodpressure,euphoria,dizziness,andincreasedlibido.Themajorityoftheseadverseeffectsceasedwithin80minutesaftertheinfusion.Subjectswithbipolardepression:transitoryperceptualanddissociativedisturbances.Althoughmostketaminepatientsexperiencedsuchchanges,thosechangeswerenotassociatedwithantidepressantresponse;furthermore,somepatientswhorespondedtoketaminehadnosubstantialdissociativesymptoms.,新药氯胺酮结论,Conclusion:,Ketaminecanproducerapidantidepressanteffectsinsubjectswithtreatment-resistantmajordepressionortreatment-resistantbipolardepression,NIMHdirectorDr.ThomasInsel,Fantasticketamine!,新药氯胺酮结论,Butthereremainsomequestio