Treatment of difficult-to-treat depression – clinical guideline for selected interventions

Difficult-to-treat-depression (DTD) is a clinical challenge. The interventions that are well-established for DTD are not suitable or effective for all the patients. Therefore, more treatment options are highly warranted. We formulated an evidence-based guideline concerning six interventions not well-established for DTD in Denmark.
Selected review questions were formulated according to the PICO principle with specific definitions of the patient population (P), the intervention (I), the comparison (C), and the outcomes of interest (O), and systematic literature searches were performed stepwise for each review question to identify relevant systematic reviews/meta-analyses, and randomized controlled trials. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to assess the methodological quality of the included studies. Clinical recommendations were formulated based on the evidence, the risk-benefit ratio, and perceived patient preferences.
We found sufficient evidence for a weak recommendation of repetitive transcranial magnetic stimulation (rTMS) and cognitive behavioural analysis system of psychotherapy (CBASP). The use of bright light therapy in DTD was not sufficiently supported by the evidence, but should be considered as good clinical practice. The interventions should be considered in addition to ongoing antidepressant treatment. We did not find sufficient evidence to recommend intravenous ketamine/esketamine, rumination-focused psychotherapy, or cognitive remediation to patients with DTD.
The evidence supported two of the six reviewed interventions, however it was generally weak which emphasizes the need for more good quality studies. This guideline does not cover all treatment options and should be regarded as a supplement to relevant DTD-guidelines.

难治性抑郁症（Difficult-to-treat-depression, DTD）是临床诊疗中的一大难题。目前已确立的针对DTD的干预手段并非适用于所有患者，且疗效未必理想，因此亟需开发更多可供选择的治疗方案。本研究针对丹麦地区6种尚未被充分确立疗效的DTD干预手段制定了循证指南。
本次研究依据PICO原则设定了精选的评审问题，对患者人群（P）、干预措施（I）、对照方案（C）与关注结局（O）进行了明确定义；并针对每个评审问题逐步开展系统性文献检索，以识别相关的系统性综述/元分析及随机对照试验。研究采用推荐分级、评估、制定与评价（GRADE）系统，对纳入研究的方法学质量进行评估。临床推荐意见基于现有证据、风险获益比以及患者偏好制定。
研究结果显示，现有证据足以支持对重复经颅磁刺激（repetitive transcranial magnetic stimulation）与认知行为分析系统心理治疗（cognitive behavioural analysis system of psychotherapy）给出弱推荐。针对DTD的强光疗法虽未获得足够证据支持，但可作为优质临床实践方案予以考虑。上述干预手段应在患者正在接受抗抑郁药物治疗的基础上额外使用。本研究未发现足够证据支持向DTD患者推荐静脉注射氯胺酮/艾司氯胺酮、反刍思维聚焦心理治疗或认知矫正治疗。
本次针对6种干预手段的回顾分析显示，仅2种获得了证据支持，但整体证据强度均较弱，这凸显了开展更多高质量研究的必要性。本指南并未覆盖全部治疗选择，仅可作为相关DTD临床指南的补充参考。