抗抑郁药的安全性评价

综合医院抗抑郁药物治疗的风险管理,内部资料，仅供医学药学专业人士参考，严禁翻印及传播,CIPR20120504B,综合医院中多有躯体疾病伴发抑郁的患者,Sheldon H. Preskorn, et al. 2010 Guide to Psychiatric Drug Interactions. Primary Psychiatry. 2009;16(12):45-74.,提纲,综合医院抑郁症的规范治疗抗抑郁药物治疗的风险评价药物因素：药物相互作用撤药症状自杀风险患者因素：,美国精神病学会（APA）英国国家卫生与临床优化研究所（NICE）抑郁症阶梯式分层治疗策略,Practice guideline for the treatment of patients with major depressive disorder. 3rd Edition. APA. 2010.The treatment and management of depression in adults . NICE clinical guideline 90. the National Collaborating Centre for Mental Health. 2009.,*复杂的抑郁症包括多种治疗疗效不佳，还有精神病性症状，或/和伴有明显的精神病症或心理社会因素。*仅指同时有慢性躯体问题并伴功能损害。,不影响抑郁治疗的因素：抑郁症的亚型：如不典型抑郁或季节性抑郁患者人口特征：性别、种族,美国医师协会（ ACP）抑郁症全程药物治疗策略,Amir Qaseem, et al. Using Second-Generation Antidepressants to Treat Depressive Disorders: A Clinical Practice Guideline from the American College of Physicians. Ann Intern Med. 2008;149:725-733.,选择新型抗抑郁药治疗急性期抑郁症时应考察药物的不良反应、费用和患者的偏好（强烈建议）,自治疗起始1-2个星期后开始应定期评估患者状态、疗效和不良反应（强烈建议）,药物治疗6-8周仍然疗效不佳时，应考虑调整治疗方案（强烈建议）,初次发作患者治疗疗效满意后应维持治疗4-9个月；发作2次的患者则需要更长疗程。（强烈建议）,英国国家卫生与临床优化研究所（NICE）医生处方抗抑郁药时的患者教育,抗抑郁药的效果是逐渐显现的。严格按照处方医嘱用药，即使症状缓解也应维持治疗一段时间。抗抑郁药可能引起不良反应。抗抑郁药与其他药物可能有相互作用。抗抑郁药停药时会有撤药症状，应按医生建议处理。抗抑郁药不会造成成瘾。必要时提供书面教育材料。,The treatment and management of depression in adults . NICE clinical guideline 90. the National Collaborating Centre for Mental Health. 2010. P457.,提纲,综合医院抑郁症的规范治疗抗抑郁药物治疗的风险评价药物因素：药物相互作用撤药症状自杀风险患者因素：,抗抑郁药物治疗的风险多来自于治疗不当,Hanlon JT, et al. Potential underuse, overuse, and inappropriate use of antidepressants in older veteran nursing home residents. J Am Geriatr Soc. 2011 Aug;59(8):1412-20.,25.4%未服用抗抑郁药；服用抗抑郁药患者中43.1%用药不当。,42.3%处方1种抗抑郁药，其中仅4%有FDA批准适应症。,临床医生要重视安全用药,在一无所知的病人身上，用知之甚少的药治疗知之甚少的病，简直是 “灾难”“Doctors pour drugs of which they know little, to cure diseases of which they know less, into patients of whom they know nothing.”真正的多药联合应用是充满技术性的治疗组合。“The true polypharmacy is the skillful combination of remedies.”,提纲,综合医院抑郁症的规范治疗抗抑郁药物治疗的风险评价药物因素：药物相互作用撤药症状自杀风险患者因素：,药物相互作用：可预防的药物不良反应,药物相互作用的临床表现：各种严重不良反应，如猝死、惊厥、心律紊乱、5-HT综合征、高血压危象、抗精神病药物所致恶性综合征和谵妄耐受性差：患者对不良反应过于“敏感”疗效不佳出现易混淆的症状，可能导致误诊当前治疗的疾病明显恶化撤药症状或患者有觅药行为,Sheldon H. Preskorn, et al. 2010 Guide to Psychiatric Drug Interactions. Primary Psychiatry. 2009;16(12):45-74.,服用前后：制剂不相容药代动力学相互作用：胃肠道：影响药物吸收，生物利用度血浆：血浆结合蛋白（临床意义不大）肝脏：氧化、降解、共轭等CYP450（1A2、3A、2C9、2C19、2D6）肾脏：药物排泄药效学相互作用：靶器官,药物相互作用可能的环节,/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm110632.htm,新型抗抑郁药对CYP450酶系的不同影响,Greenblatt,et al. Drug interactions with newer antidepressants: role of human cytochromes P450. J Clin Phychiatry,1998,59(suppl 15):19-27 .Kelly L. Cozza, et al. Drug Interaction Principles for Medical Practice.2001.,SSRI类药的药效学相互作用,中枢神经系统：SSRI与MAOI、5-HT1A部分激动剂（如阿立哌唑）、5-HT1B/D激动剂（如舒马曲坦等）合用时可引起严重的5-HT综合征。锂盐促进5-HT释放，可增强SSRI的作用。由于5-HT抑制DA神经元放电，因此SSRI类与锂盐合用时可能增加震颤。血小板功能：SSRI可能引起出血倾向，特别是老年人或者合用其他能损害胃肠道粘膜、或干扰凝血的药物。合用NSAIDs药或阿司匹林时应考虑添加胃肠道保护药。,Sheldon H. Preskorn, et al. 2010 Guide to Psychiatric Drug Interactions. Primary Psychiatry. 2009;16(12):45-74.THE NICE GUIDELINE ON THE TREATMENT AND MANAGEMENT OF DEPRESSION IN ADULTS. UPDATED EDITION. National Institute for Health & Clinical Excellence. 2010.,避免药物相互作用的重要原则,了解并遵循临床规范避免使用多作用靶点的药物，避免不必要药物作用理性分析依据文献和数据库软件如果不确定，可低剂量起始、缓慢调整监测、预防和及时避免不良预后强效诱导剂/抑制剂治疗指数窄的药物尽可能选择低风险药物,Sheldon H. Preskorn, et al. 2010 Guide to Psychiatric Drug Interactions. Primary Psychiatry. 2009;16(12):45-74.,提纲,综合医院抑郁症的规范治疗抗抑郁药物治疗的风险评价药物因素：药物相互作用撤药症状自杀风险患者因素：,抗抑郁药可能引起的撤药症状,Sheik Hosenbocus , Raj Chahal. SSRIs and SNRIs: A review of the Discontinuation Syndrome in Children and Adolescents. J Can Acad Child Adolesc Psychiatry, 20:1, February 2011.,成年人的撤药症状差异较大，60%可能有头晕，其次是恶心（约40%）、乏力和头痛。儿童最常见的撤药症状是头晕、头重脚轻、嗜睡、注意力不集中、恶心、头痛和乏力。,SSRI“撤药症状”的判定标准,Black K, et al. Selective serotonin reuptake inhibitor discontinuation syndrome: proposed diagnostic criteria. J Psychiatry Neurosci. 2000 May;25(3):255-61.,B项条件的症状造成明显痛苦或社交、职业等重要功能损害。症状并非源于某种疾病，也不是SSRI治疗前症状的复发，或源于合用的精神兴奋物质停用/减量。,SSRI治疗至少1个月后停药或减量。符合A后1-7天内出现以下2项：头晕、头重脚轻、眩晕或晕厥感电击感或麻痹焦虑腹泻乏力步态不稳头痛失眠易激惹恶心或/和呕吐震颤视力异常,SSRI的撤药反应发生情况,Sheik Hosenbocus , Raj Chahal. SSRIs and SNRIs: A review of the Discontinuation Syndrome in Children and Adolescents. J Can Acad Child Adolesc Psychiatry, 20:1, February 2011.,不同临床研究中SSRI类药的撤药反应发生率,提纲,综合医院抑郁症的规范治疗抗抑郁药物治疗的风险评价药物因素：药物相互作用撤药症状自杀风险患者因素：,评估抑郁患者自杀风险的考虑因素,自杀观念、意图、计划、方法、行为某些精神症状：如精神病症状、严重焦虑、物质滥用整体健康状况家族史：自杀或精神疾病潜在的保护性因素：如生活愿望、社会支持,PRACTICE GUIDELINE FOR THE Treatment of Patients With Major Depressive Disorder. Third Edition. APA. Oct. 2010.,西酞普兰的自杀风险较低,Schneeweiss S, et al. Comparative safety of antidepressant agents for children and adolescents regarding suicidal acts. Pediatrics. 2010 May;125(5):876-88.,提纲,综合医院抑郁症的规范治疗抗抑郁药物治疗的风险评价药物因素：药物相互作用撤药症状自杀风险患者因素：躯体疾病影响,抗抑郁药的心血管系统风险,Practice guideline for the treatment of patients with major depressive disorder. 3rd Edition. APA. 2010. P37.PRESCRIBING AND SHARED CARE GUIDANCE FOR THE TREATMENT OF DEPRESSION IN ADULTS OVER 18 YEARS OF AGE. NHS. March, 2010,美国心脏病学会（AHA）西酞普兰是冠心病患者抑郁治疗的一线药物,西酞普兰可有效、安全地治疗冠心病患者的中度、重度和复发性抑郁。西酞普兰不会引起明显的心血管系统不良反应，包括心血管功能不稳定和服用多种药物的急性冠脉综合征（ACS）患者。,Judith H. Lichtman, et al. Depression and Coronary Heart Disease. Recommendations for Screening, Referral, and Treatment. A Science Advisory From the American Heart Association Prevention Committee of the Council on Cardiovascular Nursing, Council on Clinical Cardiology, Council on Epidemiology and Prevention, and Interdisciplinary Council on Quality of Care and Outcomes Research. Circulation. 2008;118:0-0.Bigger JT, Glassman AH.The American Heart Association science advisory on depression and coronary heart disease: An exploration of the issues raised. Cleve Clin J Med. 2010 Jul;77 Suppl 3:S12-9.,Lesperance F, et al. Effects of citalopram and interpersonal psychotherapy on depression in patients with coronary artery disease: the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial. JAMA. 2007;297:36779.,CREATE=Cardiac Randomized Evaluation of Antidepressant and PsychoTherapy Efficacy 随机、22析因研究。先按1:1随机分至人际关系心理治疗+临床处理组或单独临床处理组，随后再双盲分别分别接受西酞普兰或安慰剂治疗12周。西酞普兰平均剂量33.1mg/d。缓解定义为治疗12周后24项HAMD量表总评分8分；有效定义为治疗12周后HAMD量表总评分较之基线降低50%。,冠心病合并抑郁患者治疗12周后的心血管功能指标变化,CREATE研究：西酞普兰可有效、安全地治疗冠心病伴发抑郁,西酞普兰缓解抑郁同时改善血管内皮细胞功能,西酞普兰可显著增加冠心病合并抑郁患者血管内皮的NO合成。,Louis T. van Zyl, et al. Platelet and endothelial activity in comorbid major depression and coronary artery disease patients treated with citalopram: the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy Trial (CREATE) biomarker sub-study. J Thromb Thrombolysis (2009) 27:4856.,糖尿病患者服用抗抑郁药的风险,PRESCRIBING AND SHARED CARE GUIDANCE FOR THE TREATMENT OF DEPRESSION IN ADULTS OVER 18 YEARS OF AGE. NHS. March, 2010,西酞普兰治疗糖尿病伴发抑郁的研究,侯世芳, 周雁, 许贤豪.抗抑郁治疗对2型糖尿病痛性神经病变的影响. 中国神经免疫学和神经病学杂志. 2008, 15(6): 438-441,西酞普兰不仅可显著改善糖尿病患者的抑郁症状，还有助于缓解神经病理性疼痛症状。,随机对照治疗研究。对照组常规给予降糖药、神经营养药、止痛药、改善微循环药物治疗。治疗组在此基础上加用抗抑郁药物西酞普兰20 mg（Qd），共14d。HAMD量表：Hamilton Depression Rating Scale，汉密尔顿抑郁量表；NPI量表：Numeric Pain Intensity Scale，数字疼痛分级法。,有合并症的老年抑郁患者治疗策略,加拿大多项临床指南针对有合并症老年抑郁的干预建议：,Donatus R. Mutasingwa, et al. How applicable are clinical practice guidelines to elderly patients with comorbidities? Can Fam Physician 2011;57:e253-62.,西酞普兰显著改善老年抑郁，促进认知功能提高,Diaconescu AO, et al. Distinct functional networks associated with improvement of affective symptoms and cognitive function during citalopram treatment in geriatric depression. Hum Brain Mapp. 2011 Oct;32(10):1677-91.,英国国民保健体系（NHS）西酞普兰可有效治疗卒中后抑郁（从10mg/d起始，正常剂量范围20-40mg/d）,CLINICAL GUIDELINE FOR THE CARE AND TREATMENT OF OLDER PEOPLE WITH DEPRESSION IN A GENERAL HOSPITAL SETTING, 2nd Edition, June 2005.Andersen G, Vestergaard K, Lauritzen L. Effective treatment of poststroke depression with the selective serotonin reuptake inhibitor citalopram. Stroke. 1994 Jun;25(6):1099-104.Zittel S, Weiller C, Liepert J. Citalopram improves dexterity in chronic stroke patients. Neurorehabil Neural Repair. 2008 May-Jun;22(3):311-4.,西酞普兰可改善卒中后抑郁症状，促进精细功能恢复。,肿瘤患者如何选择抗抑郁药,大多数抗抑郁药的疗效需要3-6周才能显现。相对于肿瘤患者有限的生存期，不宜使用起效太慢的抗抑郁药。抗抑郁药不能加重现有病症，因此需要整体不良反应更少、耐受性更好的抗抑郁药。虚弱的老年患者不宜使用有抗胆碱能作用或直立性低血压的药物抗抑郁药不能与抗肿瘤药有相互作用。SSRI类抗抑郁药是肿瘤抑郁患者的首选。,Harvey Max Chochinov. Depression in cancer patients. Lancet Oncol 2001: 2: 499505.,西酞普兰适合治疗肿瘤伴发的抑郁,西酞普兰是丹麦乳癌患者使用最多的SSRI抗抑郁药。西酞普兰不影响他莫西芬的抗癌效果，不影响肿瘤复发率。,Lash TL, et al. Breast cancer recurrence risk related to concurrent use of SSRI antidepressants and tamoxifen. Acta Oncol. 2010 Apr;49(3):305-12.Lash TL, et al. Tamoxifens protection against breast cancer recurrence is not reduced by concurrent use of the SSRI citalopram. Br J Cancer. 2008 Aug 19;99(4):616-21.,ERP+/TAM+,ERP-/TAM-,丹麦1985年-2001年乳腺癌协作组DBCG在册的I-III期乳腺癌患者的病例资料，经年龄因素和其他CYP2D6抑制药物影响调整后的风险分析。ERP+/-雌激素受体表达阳性/阴性，TAM+/-他莫西芬治疗/未治疗至少1年,西酞普兰是癫痫患者抗抑郁治疗的首选,癫痫伴发的抑郁通常为轻中度，充分治疗后疗效较好。抗抑郁药会否诱发癫痫？在治疗剂量范围内，排除其他风险因素影响，抗抑郁药引发癫痫发生率0.5%。SSRI（如西酞普兰20mg/d）是癫痫患者抗抑郁治疗的首选，还需结合临床疗效和合用的抗癫痫药情况。,Mula M. Recognize and manage psychiatric comorbidities in patients with epilepsy. Panminerva Med. 2011 Dec;53(4):241-51.PRESCRIBING AND SHARED CARE GUIDANCE FOR THE TREATMENT OF DEPRESSION IN ADULTS OVER 18 YEARS OF AGE. NHS. March, 2010.,西酞普兰治疗帕金森氏病伴发抑郁的研究,Devos D, et al. Comparison of desipramine and citalopram treatments for depression in Parkinsons disease: a double-blind, randomized, placebo-controlled study. Mov Disord. 2008 Apr 30;23(6):850-7.Menza M, et al. Citalopram treatment of depression in Parkinsons disease: the impact on anxiety, disability, and cognition. J Neuropsychiatry Clin Neurosci. 2004 Summer;16(3):315-9.Rampello L, et al. The SSRI, citalopram, improves bradykinesia in patients with Parkinsons disease treated with L-dopa. Clin Neuropharmacol. 2002 Jan-Feb;25(1):21-4.,英国国民保健体系（NHS）抗抑郁药治疗痴呆患者的精神行为症状,Guidelines for Managing Behaviour Problems in Patients with Dementia (BPSD). JAPC. 2011,小结,英国国家卫生与临床优化研究所（NICE）不同抗抑郁药的临