抗抑郁治疗的遗传药理学.ppt

抗抑郁治疗的遗传药理学 王连生 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。 Relapse rate with drug vs. placebo in continuation studies (Dunner DL. 2001 J Clin Psychiatry) Antidepressants: current limitations 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 The history of good response to that agent by a person or a family member (Synopsis of Psychiatry. 8th). A familial tendency to respond to specific antidepressants or antidepressant groups. (O’Reilly RL et al. 1994 Biol Psychiatry) Genetic factors play a substantial role in antidepressant response (Tsai SJ et al. Current pharmacogenomics 2003)(O’Reilly RL et al. 1994 Biol Psychiatry) 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) Pharmacogenetic studies about antidepressant responsiveness MAOA-VNTR in promotor: DRD2 Ser311Cys, DRD4 exon 4 VNTR 5HT1A C-1018G, 5HT2A T102C, 5HT2A G-1438A, 5HT2C, 5HT6 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 Selective Serotonin Reuptake Inhibitors Use as first-line medication for MDD Fluoxetine (Prozac) was first introduced in 1988, setraline, paroxetine, fluvoxamine, citalopram also with similar property Inhibiting serotonin reuptake by presynaptic neuron 60-70% of MDD patients may response to the SSRI Pharmacogenetic studies of Antidepressant: Focusing on SSRI