第一选择
艾司西酞普兰
:
起始剂量 10 mg,口服,每日一次,根据反应逐渐增加,最大剂量为 20 mg/日
或
度洛西汀
:
初始剂量为 30-60 mg 口服,每日一次,根据反应逐渐增加剂量,最大剂量为 120 mg/天
或
文拉法辛
:
初始剂量为37.5至75mg 口服(延释剂),每日一次,根据反应逐渐增加剂量,最大剂量为 225 mg/天
第二选择
丁螺环酮
:
起始剂量 7.5 mg,口服,每日两次,根据反应逐渐增加,最大剂量是 60 mg/日
或
舍曲林
:
初始剂量为25 mg 口服,每日一次,根据反应逐渐增加,最大剂量为 200 mg/日
或
氟西汀
:
初始剂量为10- 20 mg 口服(常释剂),每日一次,根据反应逐渐增加剂量,最大剂量为 60 mg/日
或
或
第三选择
普瑞巴林
:
初始剂量为 75 mg 口服(速释剂),每日两次,根据反应逐渐增加剂量,最大剂量为 600 mg/日
或
帕罗西汀
:
初始剂量为 20 mg 口服(速释剂),每日一次,根据反应逐渐增加剂量,最大剂量为 50 mg/日
或
氯硝西泮
:
起始剂量 0.25 mg,口服,每日两次,根据反应逐渐增加,最大剂量是 4 mg/日
或
地西泮
:
初始剂量为 2-10 mg 口服,每日2-4次,根据反应逐渐增加剂量,最大剂量为 40 mg/日
药物选择依据包括:疾病严重程度、患者痛苦程度、躯体疾病情况、物质滥用与否、患者意愿以及不良作用耐受。[32]Gale C, Oakley-Browne M. Generalized anxiety disorder. Clin Evid. 2005 Dec;(14):1253-69.http://www.ncbi.nlm.nih.gov/pubmed/16620453?tool=bestpractice.com 监测副作用,改变剂量和转换药物可改善疗效和患者依从性(例如,一些抗抑郁药可能引起烦躁,这可能使得焦虑症状恶化)。[57]Sinclair LI, Christmas DM, Hood SD, et al. Antidepressant-induced jitteriness/anxiety syndrome: systematic review. Br J Psychiatry. 2009 Jun;194(6):483-90.http://www.ncbi.nlm.nih.gov/pubmed/19478285?tool=bestpractice.com
一些指南提出了关于 GAD 药物治疗选择不同细节的建议。[35]Andrews G, Bell C, Boyce P, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the treatment of panic disorder, social anxiety disorder and generalised anxiety disorder. Aust N Z J Psychiatry. 2018 Nov;52(12):1109-72.https://journals.sagepub.com/doi/10.1177/0004867418799453[55]Bandelow B, Sher L, Bunevicius R, et al; WFSBP Task Force on Mental Disorders in Primary Care; WFSBP Task Force on Anxiety Disorders, OCD and PTSD. Guidelines for the pharmacological treatment of anxiety disorders, obsessive-compulsive disorder and posttraumatic stress disorder in primary care. Int J Psychiatry Clin Pract. 2012 Jun;16(2):77-84.http://www.wfsbp.org/fileadmin/user_upload/Treatment_Guidelines/Bandelow_et_al_01.pdfhttp://www.ncbi.nlm.nih.gov/pubmed/22540422?tool=bestpractice.com[58]Baldwin DS, Anderson IM, Nutt DJ, et al. Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: a revision of the 2005 guidelines from the British Association for Psychopharmacology. J Psychopharmacol. 2014 May;28(5):403-39.http://www.ncbi.nlm.nih.gov/pubmed/24713617?tool=bestpractice.com 本主题中的建议基于2019年进行的药物治疗网络荟萃分析,其被该主题作者认为是该主题发表时最为全面的证据。网络荟萃分析囊括了 89 项试验和随机分配到22种不同的活性药物治疗组或安慰剂组的 25,441名患者。度洛西汀、普瑞巴林、文拉法辛、艾司西酞普兰较安慰剂更为有效,且接受度更好。米氮平、舍曲林、氟西汀、丁螺环酮和阿戈美拉汀也同样有效,并可良好耐受,但这些结论基于较少的研究和较小的样本量。帕罗西汀和苯二氮卓类药物通过汉密尔顿焦虑评定量表(HAM-A)测量是有效的,但与安慰剂相比耐受性较差。[56]Slee A, Nazareth I, Bondaronek P, et al. Pharmacological treatments for generalised anxiety disorder: a systematic review and network meta-analysis. Lancet. 2019 Feb 23;393(10173):768-77.http://www.ncbi.nlm.nih.gov/pubmed/30712879?tool=bestpractice.com 关于苯二氮䓬类药物在治疗GAD的长期疗效尚缺少足够信息。
治疗选择包括 SSRI(例如艾司西酞普兰、舍曲林、氟西汀、帕罗西汀)、SNRI(例如度洛西汀、文拉法辛)、具有非典型作用模式的抗抑郁药( 例如米氮平、丁螺环酮、阿戈美拉汀),或抗惊厥药普瑞巴林。苯二氮卓类药物(如地西泮、氯硝西泮)也是部分患者的一种治疗选择。
SSRIs 治疗GAD的效力在老年患者,[55]Bandelow B, Sher L, Bunevicius R, et al; WFSBP Task Force on Mental Disorders in Primary Care; WFSBP Task Force on Anxiety Disorders, OCD and PTSD. Guidelines for the pharmacological treatment of anxiety disorders, obsessive-compulsive disorder and posttraumatic stress disorder in primary care. Int J Psychiatry Clin Pract. 2012 Jun;16(2):77-84.http://www.wfsbp.org/fileadmin/user_upload/Treatment_Guidelines/Bandelow_et_al_01.pdfhttp://www.ncbi.nlm.nih.gov/pubmed/22540422?tool=bestpractice.com 以及儿童和青少年中得到证明[60]Ipser, JC, Stein DJ, Hawkridge S, et al. Pharmacotherapy for anxiety disorders in children and adolescents. Cochrane Database Syst Rev. 2009 Jul 8;(3):CD005170.http://cochranelibrary-wiley.com/doi/10.1002/14651858.CD005170.pub2/fullhttp://www.ncbi.nlm.nih.gov/pubmed/19588367?tool=bestpractice.com[61]Dobson ET, Strawn JR. Pharmacotherapy for pediatric generalized anxiety disorder: a systematic evaluation of efficacy, safety and tolerability. Paediatr Drugs. 2016 Feb;18(1):45-53.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4925147/http://www.ncbi.nlm.nih.gov/pubmed/26660158?tool=bestpractice.com 在 GAD 短期治疗和预防复发中的效力亦得到证明。[58]Baldwin DS, Anderson IM, Nutt DJ, et al. Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: a revision of the 2005 guidelines from the British Association for Psychopharmacology. J Psychopharmacol. 2014 May;28(5):403-39.http://www.ncbi.nlm.nih.gov/pubmed/24713617?tool=bestpractice.com[62]Khan AY, Macaluso M. Duloxetine for the treatment of generalized anxiety disorder: a review. Neuropsychiatr Dis Treat. 2009;5:23-31.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2695226/http://www.ncbi.nlm.nih.gov/pubmed/19557096?tool=bestpractice.com[63]Brawman-Mintzer O, Knapp RG, Rynn M, et al. Sertraline treatment for generalized anxiety disorder: a randomized, double-blind, placebo-controlled study. J Clinical Psychiatry. 2006 Jun;67(6):874-81.http://www.ncbi.nlm.nih.gov/pubmed/16848646?tool=bestpractice.com[64]Allgulander C, Florea I, Huusom AK. Prevention of relapse in generalized anxiety disorder by escitalopram treatment. Int J Neuropsychopharmacol. 2006 Oct;9(5):495-505.http://www.ncbi.nlm.nih.gov/pubmed/16316482?tool=bestpractice.com 无论焦虑的基线严重程度如何,GAD 的抗抑郁药物似乎都一贯有效。[65]de Vries YA, de Jonge P, van den Heuvel E, et al. Influence of baseline severity on antidepressant efficacy for anxiety disorders: meta-analysis and meta-regression. Br J Psychiatry. 2016 Jun;208(6):515-21.http://www.ncbi.nlm.nih.gov/pubmed/26989093?tool=bestpractice.com
丁螺环酮的应用在一些患者中被认为有效。[66]Chessick CA, Allen MH, Thase M, et al. Azapirones for generalized anxiety disorder. Cochrane Database Syst Rev. 2006 Jul 19;(3):CD006115.https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006115/fullhttp://www.ncbi.nlm.nih.gov/pubmed/16856115?tool=bestpractice.com 由于它也不成瘾,对于有吸毒或酗酒史的患者较为有利但由于常见恶心,故使用受限。近期使用过苯二氮䓬类药物可能削弱其疗效。[32]Gale C, Oakley-Browne M. Generalized anxiety disorder. Clin Evid. 2005 Dec;(14):1253-69.http://www.ncbi.nlm.nih.gov/pubmed/16620453?tool=bestpractice.com
普瑞巴林可单独用药,也可作为增效剂与其他药物联合使用。[72]Rickels K, Shiovitz TM, Ramey TS, et al. Adjunctive therapy with pregabalin in generalized anxiety disorder patients with partial response to SSRI or SNRI treatment. Int Clin Psychopharmacol. 2012 May;27(3):142-50.http://www.ncbi.nlm.nih.gov/pubmed/22302014?tool=bestpractice.com 一项系统评价发现,在 GAD 患者中,普瑞巴林优于安慰剂, 在临床反应上与苯二氮卓类药物相当,但药物退出率较其更低。[73]Generoso MB, Trevizol AP, Kasper S, et al. Pregabalin for generalized anxiety disorder: an updated systematic review and meta-analysis. Int Clin Psychopharmacol. 2017 Jan;32(1):49-55.http://www.ncbi.nlm.nih.gov/pubmed/27643884?tool=bestpractice.com 但是,普瑞巴林用药需谨慎,因为它可能导致肾功能损害,特别是对于有肾功能损害危险因素的患者(例如,年龄较大、药物滥用、合并用药如抗高血压药物和某些抗生素),以及存在意识模糊的持续风险。[74]Buoli M, Caldiroli A, Serati M. Pharmacokinetic evaluation of pregabalin for the treatment of generalized anxiety disorder. Expert Opin Drug Metab Toxicol. 2017 Mar;13(3):351-9.http://www.ncbi.nlm.nih.gov/pubmed/28075650?tool=bestpractice.com
虽然苯二氮卓类药物可能有效,但它们也与有害的副作用呈现相关(例如更为频繁的跌倒;记忆障碍,特别是新的学习;增加事故风险;和药物依赖)。[67]Donnelly K, Bracchi R, Hewitt J, et al. Benzodiazepines, Z-drugs and the risk of hip fracture: a systematic review and meta-analysis. PLoS One. 2017 Apr 27;12(4):e0174730.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407557/http://www.ncbi.nlm.nih.gov/pubmed/28448593?tool=bestpractice.com[68]Née M, Avalos M, Luxcey A, et al. Prescription medicine use by pedestrians and the risk of injurious road traffic crashes: A case-crossover study. PLoS Med. 2017 Jul 18;14(7):e1002347.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515401/http://www.ncbi.nlm.nih.gov/pubmed/28719606?tool=bestpractice.com 临床医生和患者面临的关键问题是衡量风险与获益。苯二氮卓类药物在基线严重程度较高的人群中应用更为有效。[69]Gale C, Glue P, Guaiana G, et al. Influence of covariates on heterogeneity in Hamilton Anxiety Scale ratings in placebo-controlled trials of benzodiazepines in generalized anxiety disorder: systematic review and meta-analysis. J Psychopharmacol. 2019 Jan 24 [Epub ahead of print].http://www.ncbi.nlm.nih.gov/pubmed/30676225?tool=bestpractice.com 它们通常不会影响QTc间期,但过量服用,或与阿片类药物联用时,可能导致呼吸抑制和死亡。[70]Petrushevska T, Jakovski Z, Poposka V, et al. Drug-related deaths between 2002 and 2013 with accent to methadone and benzodiazepines. J Forensic Leg Med. 2015 Apr;31:12-8.http://www.ncbi.nlm.nih.gov/pubmed/25735778?tool=bestpractice.com[71]Lintzeris N, Nielsen S. Benzodiazepines, methadone and buprenorphine: interactions and clinical management. Am J Addict. 2010 Jan-Feb;19(1):59-72.http://www.ncbi.nlm.nih.gov/pubmed/20132123?tool=bestpractice.com 如果患者有物质滥用病史或有此类风险,应避免使用苯二氮卓类药物。
由于副作用风险(例如QTc延长和代谢综合征),勿提供抗精神病药如喹硫平作为GAD的初始治疗。[75]LaLonde CD, Van Lieshout RJ. Treating generalized anxiety disorder with second generation antipsychotics: a systematic review and meta-analysis. J Clin Psychopharmacol. 2011 Jun;31(3):326-33.http://www.ncbi.nlm.nih.gov/pubmed/21508847?tool=bestpractice.com[79]Maneeton N, Maneeton B, Woottiluk P, et al. Quetiapine monotherapy in acute treatment of generalized anxiety disorder: a systematic review and meta-analysis of randomized controlled trials. Drug Des Devel Ther. 2016 Jan 12;10:259-76.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4716733/http://www.ncbi.nlm.nih.gov/pubmed/26834458?tool=bestpractice.com[80]National Institute for Health and Care Excellence. Generalised anxiety disorder and panic disorder in adults: management in primary, secondary and community care. Jan 2011 [internet publication].https://www.nice.org.uk/guidance/cg113/chapter/guidance
合并抑郁患者的治疗方法与无抑郁患者的治疗方法相同;但是,不建议使用丁螺环酮和普瑞巴林。SNRIs类抗抑郁药对焦虑共病抑郁的患者有明确疗效。[82]Mancini M, Perna G, Rossi A, et al. Use of duloxetine in patients with an anxiety disorder, or with comorbid anxiety and major depressive disorder: a review of the literature. Expert Opin Pharmacother. 2010 May;11(7):1167-81.http://www.ncbi.nlm.nih.gov/pubmed/20402555?tool=bestpractice.com
药物治疗时限长短未在文献中被具体提及。获益应在6-8周被观察到。如若不然,应给予替代性抗抑郁药。一项针对 28 项研究的系统评价和荟萃分析结果显示,抗抑郁药物治疗至少一年方与复发率降低相关,且耐受性良好。除此而外,尚缺乏更长时间应用治疗效果和耐受性的证据,但这不应被理解为1年后即终止抗抑郁药治疗的明确提议。[81]Batelaan NM, Bosman RC, Muntingh A, et al. Risk of relapse after antidepressant discontinuation in anxiety disorders, obsessive-compulsive disorder, and post-traumatic stress disorder: systematic review and meta-analysis of relapse prevention trials. BMJ. 2017 Sep 13;358:j3927.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596392/http://www.ncbi.nlm.nih.gov/pubmed/28903922?tool=bestpractice.com 根据作者临床经验,建议对GAD抗抑郁治疗有反应的患者,应继续药物治疗至少1年。此后可基于药物不良反应或其他因素与医生讨论是否继续使用。如患者因为生活压力减轻而希望尝试停药。[30]Fricchione G. Generalized anxiety disorder. N Engl J Med. 2004 Aug 12;351(7):675-82.http://www.ncbi.nlm.nih.gov/pubmed/15306669?tool=bestpractice.com 如果就抗抑郁药物减量和停用达成一致,需缓慢进行,并密切监测症状复发。
若患者选择药物治疗作为一线治疗,也可提供全方位的非药物辅助治疗,用作其治疗的组成部分。[35]Andrews G, Bell C, Boyce P, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the treatment of panic disorder, social anxiety disorder and generalised anxiety disorder. Aust N Z J Psychiatry. 2018 Nov;52(12):1109-72.https://journals.sagepub.com/doi/10.1177/0004867418799453
在实践中常使用较低的起始剂量(有时低于许可剂量),以降低不良反应风险。应从低剂量起始,根据患者反应以及药物处方信息逐渐增加。