北医药物治疗学-抗抑郁药课件
Depression,王天晟, Pharm.D., R.Ph. 北京大学药学院,Additional Resources: 1. Mann JJ. The Medical Management of Depression. New England Journal of Medicine 2005;353:1819-34 2. Gelenberg AJ, Hopkins HS. Assessing and Treating Depression in Primary Care Medicine. American Journal of Medicine. 2007; 120:105-108 3. The Texas Implementation of Medication Algorithms: Update to the Algorithms for Treatment of Bipolar I Disorder. Suppes T., et al. Journal of Clinical Psychiatry 2005; 66: 870-886,Neurotransmitter,synthesizing packaging releasing binding removal,Epidemiology,occurs in 1 in 8 individuals during their lifetime 2-3% of males; 5-9% of females comorbidities: anxiety impulse control disorder substance abuse Average Onset: mid-20s, but can manifest at any age,Epidemiology,triggering factors: death of loved one, divorce, chronic medical conditions endocrine disorder: Cushings dz, Addisons dz, Implication: 50% of completed suicides involve depression annual cost: $44 billion,Epidemiology,Course of illness single episode recurrent episodes 60% of Pts w/ single episode: develop a 2nd episode Pts w/ 2nd episode: 70% chance of having a 3rd episode Pts w/ 3rd episode: 90% chance of having a 4th episode,Epidemiology,5-10% of Pts w/ single depressive episode: will eventually experience manic episode Ps w/ residual symptoms more likely to suffer from future depressive episodes,Pathophysiology,exact etiology unknown most likely multifactorial: genetic, environmental, biological 1st degree relative w/ depression 1.5-3 times more likely to develop brain imaging has identified numerous regions of altered structure activity,Pathophysiology,Positron Emission Tomography(PET) studies in 5-HT transporters altered post-synaptic 5-HT-receptor binding Pts suffering w/ depression brain 5-HT and NE levels: DO NOT differ from controls 5-HT and NE transmission: DOES treat symptoms.,Diagnosis,depressed mood lack of interest/pleasure almost daily 2 weeks. also must have 4 additional symptoms (SIGECAPS),Diagnosis,SIGECAPS: must be accompanied by significant impairment in functioning. cannot be due to effects of substance abuse, drug side effect, toxin exposure bereavement (within 2 months of loss).,General Treatment Principles,Duration of Use,所有ADs需要 4周治疗(最好8周)足够剂量 治疗剂量持续6-9个月, 更多建议为12个月 维持治疗2年: 针对复发/慢性抑郁 候选患者： 3 episodes of major depression 2 episodes + 1 of the following: *情绪障碍家族史，快速复发，年老/严重发作 维持治疗=同样药物/同样剂量,Response,Response: 50% in symptoms 50% of Pts will still have residual symptoms Predictors of response absence of neurovegetative symptoms past response familial response patients adherence with visits and meds,6-12 weeks,4-9 months,1 year,Response vs. Remission,Discontinuation/Withdrawal syndrome,戒断症状 vivid dreams, 恶梦, 颤动, 头晕, 头痛, 电休克感, 恶心 不建议立即停药, (逐渐减小剂量7-10天） 例外：氟西汀(Fluoxetine),Suicidality,Black Box Warning: 治疗,Introduction of Fluoxtine and other ADs in late 1980s,Serotonin Syndrome,惶惑 烦躁不安 肌阵挛 反射亢进 出汗 颤动 颤抖 痢疾 轻度狂躁 不协调性 .,Serotonin Syndrome,5-HT综合征 (5-HT storm) 可以 5-HT 水平的药物都有此风险 very rare, 1%, especially with monotherapy 两种5-HT药物合用时风险 can be life threatening,Video,Antidepressants (ADs),Tricyclic Antidepressants,三环类 (TCAs) 阿米替林(amitriptyline) 去甲替林(nortriptyline) 丙咪嗪(imipramine) desipramine clomipramine,TCAs,1线用药：1960s-1980s 不同程度上阻断NE和5HT重吸收,TCAs,“dirty receptor binding”: 同时阻断其他受体 组胺 胆碱 alpha肾上腺素 肝代谢 剂量： large interpatient pharmacokinetic variability, serum levels play a large role in determining dose,Disadvantages,抗胆碱(anticholinergic)副作用 口干燥 视力模糊 尿潴留 便秘 中枢神经(激动、错觉、烦躁不安) Desipramine & 去甲替林(nortriptyline): less anticholinergic 通常不用于老年患者,Disadvantages,心血管副作用: 最好避免用于潜在心血管疾病患者 直立性低血压 心跳加速 传导延时 5-HT副作用 增加癫痫发作的可能性 转换为狂躁: 10% of patients can switch rapidly 过量剂量可致命,Advantages,廉价 long track record plasma levels are useful in monitoring 也可用于治疗 疼痛、 焦虑、 失眠， 预防偏头痛,Selective Serotonin Reuptake Inhibitors,选择性5-HT再摄取抑制剂(SSRIs) 氟西汀(fluoxetine) 帕罗西汀(paroxetine) 舍曲林(sertraline) 西酞普兰(citalopram) 艾司西酞普兰(escitalopram) fluvoxamine,MOA,抑制5-HT在突出的重吸收 对组胺、胆碱、或肾上腺素受体无吸引力 5-HT1A = antidepressant action 5-HT2 & 5-HT3 = 胃肠和性功能副作用,Treatment of Choice,Advantages over TCAs 过量剂量不会致命 镇静作用更少 体重增加更少 无心血管副作用 心脏传导改变 直立性低血压 尿潴留,Treatment of Choice,effective for several comorbidites as well 广泛性焦虑症 社交恐惧症 强迫症 贪食, 经前期烦躁不安的紊乱 血浆浓度和临床效果无关 给药: 每日一次,5-HT Side effects,Early onset 恶心: 特别是舍曲林(sertraline), 1-2星期产生耐受性 焦虑&激动: 初始明显，然后减弱， 氟西汀(fluoxetine) & sertraline最明显：,5-HT Side effects,Late onset 失眠: 初始可能镇静，特别是帕罗西汀(paroxetine) 体重改变: 初始可能体重，后期, 特别是paroxetine 性功能障碍: 性欲，性快感，阳痿，特别是sertraline,Interactions,MAOI 2星期清空期(wash out period), Fluoxetine需5星期 fluoxetineMAOIs: 5weeks MAOISfluoxetine：2weeks,Interactions,其他可能5-HT水平的药物 曲马多(tramadol), 哌替啶(meperidine), triptan, e.g. 舒马普坦(sumatriptan), rizatriptan. TCAs, SNRI others due to cytochrome P450 effects: e.g. fluoxetine maycarbamazepine, alprazolam, phenytoin concentrations,Dosing,开始低剂量 逐渐剂量：频率小于每周 (no sooner than weekly) 4-6 周后评价效果 some symptoms may respond in 1-2weeks aim for remission of symptoms and/or target dose
