抗抑郁治疗的遗传药理学.ppt

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,抗抑郁治疗的遗传药理学,抑郁症的终身患病率为,10%20%,，时点患病率为,2%5%,，在世界十大常见疾病中该病排行第四。,预计在,2020,年，抑郁障碍在疾病总负担中位居第二。,抑郁症流行情况,Diagnostic Criteria for Major depression,(DSM-IV),Depressed mood,Feelings of hopelessness,worthlessness and guilt,Inability to think or concentrate,Diminished interest or pleasure,Decreased or increased appetite,Weight loss or weight gain,Insomnia or hypersomina,Fatigue or loss of energy,Psychomotor retardation or agitation,Recurrent thought of death or suicide,Five(or more)of the above symptoms,Persist longer than 2 weeks,Significant impairment in social,occupational or other important area of functioning,抑郁症诊断,美国精神障碍诊断与统计手册第,4,版,Drug type,Mechanism,MAOi,Irreversible inhibition of MAOA and B.,TCA,Nonselective inhibition of NA,5-HT and dopamine reuptake,SSRI,Selection inhibition of 5-HT reuptake,SNRI,Selection inhibition of NA and 5-HT reuptake,NARI,Selection inhibition of NA reuptake,NaSSA,Enhancement of 5-HT and NA release by blockage of presynaptic,2 adrenergic receptor,SARI,Blockage of 5-HT2 receptor and inhibition of 5-HT reuptake,MAOi,monoamine oxidase inhibitors;SSRI selective 5-HT reuptake inhibitors;,SNRI,5-HT and NA reuptake inhibitors;NARI:NA uptake inhibitors;,NaSSA,noradrenergic and specific 5-HT antidepressants;,SARI,5-HT antagonist and reuptake inhibitors,临床上治疗药物,中国精神障碍分类与诊断标准第,3,版（,CCMD-3,）推荐一线药物,(Geddes JR et al.2003 Lancet),治疗失败,30-40%,部分显效,30-40%,显著疗效,35-45%,Nemeroff CB et al.2002 Nat Neurosci,Tsai SJ et al.2003 Current pharmacogenomics,Stimpson et al.,2003 the Cochrane Database Review,About,30-40%,of MDD patients do not respond sufficiently to SSRIs,(Tsai SJ et al.Current pharmacogenomics 2003).,Approximately,30%,of people suffering from clinically significant depressive illness do not respond to the usually recommended dose of antidepressants,(Stimpson et al.the Cochrane Database Review 2003),.,Antidepressants:current limitations,All approved classes of antidepressants act in one of,three ways:,Blockage of presynaptic monoamine transporters,Inhibition of monoamine oxidase,Inhibition/excitation of pre/post synaptic receptors that regulate monoamine transmitter release and/or neuronal firing rates,(Nemeroff CB et al.2002 Nat Neurosci),MAOA,-VNTR in,promotor,:,DRD2,Ser311Cys,DRD4,exon,4 VNTR,5HT,1A,C-1018G,5HT,2A,T102C,5HT,2,A,G-1438A,5HT,2C,5HT,6,T267C*,ACE,I/D*,G-protein,3 C825T,ADRB1,G1165C,NOS1,C276T*,IL-1,C-511T*,BDNF,V66M*,（,脑源神经营养因子）,Phase-II enzymes,CYP1A2,CYP2B6,CYP3A4,CYP2D6,CYP2C19,CYP2C9,Pharmacogenetic studies about antidepressant responsiveness,Pharmacogenetic studies of Antidepressant:,Focusing on SSRI response,Serotonin transporter promoter function in,human JAR placental choriocarcinoma cell,Heils A et al.,J.Neurochem.,1996,Serotonin transporter promoter function in,human lymphoblast cell,Lesch et al.,Science.,1996,Pharmacogenetic study of SSRI response and serotonin transporter genetic variations,Smeraldi et al.,Mol.Psychiatry.,1998,Copyright restrictions may apply.,Murphy,G.M.et al.Arch Gen Psychiatry 2004;61:1163-1169.,Survival curves showing discontinuations due to adverse events for paroxetine and mirtazapine,stratified by Serotonin Transporter Gene Promoter Polymorphism type,S:short form;L:long form,%pts,dis-,continuing,treatment,121,Major depression patients(age=44.7(16.7),M/F=70/51)treated with fluoxetine,Measuring HDRS-21 at baseline(18)and 4,th,week.,Responder:=50%decrease in HDRS-21,Remitter:HDRS-217 at 4,th,week.,MAOA,-VNTR in,promotor,:,DRD2,Ser311Cys,DRD4,exon,4 VNTR,5HT,1A,C-1018G,5HT,2A,T102C,5HT,2,A,G-1438A,5HT,2C,5HT,6,T267C*,ACE,I/D*,G-protein,3 C825T,ADRB1,G1165C,NOS1,C276T*,IL-1,C-511T*,BDNF,V66M*,（,脑源神经营养因子）,Phase-II enzymes,CYP1A2,CYP2B6,CYP3A4,CYP2D6,CYP2C19,CYP2C9,Pharmacogenetic studies about antidepressant responsiveness,Toxic level,Minimum,therapeutic level,Cp,time,Therapeutic window,Amitriptyline,阿米替林,Citalopram,西酞普兰,Desipramine,地昔帕明,Doxepin,多虑平,Duloxetine,度洛西汀,Fluoxetine,氟西汀,Fluvoxamine,氟伏沙明,Imipramine,丙咪嗪,Maprotiline,马普替林,Mianserin,米安色林,Mirtazapine,米氮平,Moclobemide,吗氯贝胺,Nefazodone,萘法唑酮,Nortriptyline,去甲替林,Paroxetine,帕罗西丁,Sertraline,舍曲林,Trazodone,曲唑酮,Trimipramine,三甲丙咪嗪,Venlafaxine,文拉法辛,Phenelzine,苯乙肼,Tranylcypromine,反苯环丙胺,Bupropion,丁氨苯丙酮,Tianeptine,噻萘普丁,Reboxetine,瑞波西汀,T,hank all of you so much for attention!,