Supplementary Material for: INTEGRATIVE SYSTEMATIC REVIEW ON PHARMACOLOGICAL, PSYCHOTHERAPEUTIC AND NEUROSTIMULATORY TREATMENT OPTIONS IN TREATMENT-RESISTANT ANXIETY DISORDERS

Treatment resistance in anxiety disorders (TR-AD) constitutes a major clinical challenge conferring a considerable burden regarding quality of life and societal health costs. This systematic review provides an overview of pharmacological, psychotherapeutic and neurostimulatory treatment options in adults with treatment-resistant generalized anxiety disorder (TR-GAD), panic disorder (TR-PD) / agoraphobia and social anxiety disorder (TR-SAD). A total of 26 randomised controlled trials (RCTs) and 36 open label studies were identified, with, however, mostly small sample sizes and several methodological limitations. According to RCTs, selective serotonin reuptake inhibitors (SSRI) or clomipramine are effective in TR-PD after failure to respond to cognitive behavioral therapy (CBT). In pharmacological TR-SAD, switching from one SSRI to another or to venlafaxine was found helpful in open label trials. RCTs further suggest augmentation with quetiapine, risperidone, olanzapine or pregabalin in TR-GAD, pindolol in TR-PD and clonazepam in TR-SAD. Open label studies in TR-AD provide preliminary evidence for ketamine or augmentation with nefazodone, reboxetine, buspirone, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone, divalproex sodium, levetiracetam, zonisamide, flumazenil, pregabalin, cannabidiol and acamprosate. For pharmacological TR, CBT was effective in several RCTs. Following non-response to CBT, first evidence suggests effectiveness of Acceptance and Commitment Therapy and Mindfulness-Based Cognitive Therapy. Only inconclusive support was identified for repetitive transcranial magnetic stimulation (rTMS) in TR-AD. In summary, this integrative review may provide an evidence base for expert recommendations, inform clinical guidelines, and inspire further research into innovative, personalized treatment of TR-AD increasing response rates and lowering the considerable individual and public health burden of anxiety disorders.

焦虑障碍难治性（Treatment-resistant anxiety disorders, TR-AD）是一项重大临床挑战，会显著降低患者生活质量，并给社会医疗成本带来沉重负担。本系统综述概述了针对成人难治性广泛性焦虑障碍（Treatment-resistant generalized anxiety disorder, TR-GAD）、难治性惊恐障碍（Treatment-resistant panic disorder, TR-PD）/广场恐惧症以及难治性社交焦虑障碍（Treatment-resistant social anxiety disorder, TR-SAD）的药物治疗、心理治疗及神经调控治疗方案。本研究共纳入26项随机对照试验（randomised controlled trials, RCTs）与36项开放标签研究，但多数研究样本量较小，且存在多项方法学局限。根据随机对照试验结果，在认知行为疗法（cognitive behavioral therapy, CBT）应答失败后，5-羟色胺再摄取抑制剂（selective serotonin reuptake inhibitors, SSRI）或氯米帕明对TR-PD具有确切疗效。针对药物难治性TR-SAD，开放标签试验显示，将一种SSRI更换为另一种SSRI或文拉法辛可带来临床获益。随机对照试验还提示，针对TR-GAD可采用喹硫平、利培酮、奥氮平或普瑞巴林进行增效治疗，针对TR-PD可采用吲哚洛尔进行增效治疗，针对TR-SAD可采用氯硝西泮进行增效治疗。针对TR-AD的开放标签研究为氯胺酮单药治疗，或联用奈法唑酮、瑞波西汀、丁螺环酮、阿立哌唑、奥氮平、喹硫平、利培酮、齐拉西酮、双丙戊酸钠、左乙拉西坦、唑尼沙胺、氟马西尼、普瑞巴林、大麻二酚及阿坎酸提供了初步循证证据。针对药物难治性焦虑障碍，多项随机对照试验显示认知行为疗法有效。在认知行为疗法应答失败后，现有初步证据表明接纳与承诺疗法及正念认知疗法具有临床疗效。针对TR-AD的重复经颅磁刺激（repetitive transcranial magnetic stimulation, rTMS）仅获得了证据效力尚不明确的支持证据。综上，本整合性综述可为专家推荐意见提供循证依据，为临床指南制定提供参考，并为探索焦虑障碍难治性病例的创新、个性化治疗方案提供研究方向，以期提高治疗应答率，减轻焦虑障碍给患者个体及公共健康带来的沉重负担。