Treatment-resistant depression (TRD) is an ongoing area of concern in public health, with increasing interest in the psychiatric scientific community, given its great personal and societal costs. Its prevalence is high, and up to a third of patients do not respond to four consecutive antidepressants. Patients with TRD experience significant loss in quality of life, high costs, and hospitalizations, and are estimated to be twice as likely to attempt suicide at least once during their lifetime than non-resistant depressed patients, and 15 times more likely than the general population. Despite multiple antidepressant treatment options, patients with TRD encounter growing difficulties to maintain a relief of symptoms with subsequent episodes. This is true as well for newer treatments such as ketamine and esketamine. Electroconvulsive therapy (ECT) is very effective in depression, with remission rates of 60–90% reported in clinical trials, but relapse rates are high, and long courses of ECT have cumulative cognitive side effects that many times become intolerable for patients. Non-pharmacological treatments besides ECT have been available for years, with the main example being repetitive transcranial magnetic stimulation (rTMS); multiple metaanalysis have demonstrated efficacy of rTMS by stimulation of the dorsolateral prefrontal cortex (DLPFC). However, rTMS is a burdensome treatment (daily 40-minute sessions for up to 6 weeks), and patients with high levels of treatment resistance are less likely to respond. Vagus nerve stimulation (VNS) was approved for use in TRD in 2005. The device delivers low-frequency, chronic, intermittent-pulsed electrical signals to the left cervical vagus nerve. Studies have described a slow but sustained clinical response, mostly shown by long-term naturalistic follow-up of patients rather than in the primary end points of the clinical trials. Sadly, insurance coverage by third-party payers has been limited; therefore, the number of patients benefitting from this treatment option is low despite 15 years of commercial availability. Deep brain stimulation (DBS) has the potential to provide a new treatment for TRD once other strategies have ceased to work. DBS may provide faster relief than VNS, as well as a sustained response for extended periods of time. Besides VNS, no other treatment option has been studied in long-term results (over 1 year). The conceptualization of psychiatric disorders as circuit-based, and the formulation of depression as the manifestation of dysfunctional brain networks, with support from neuroimaging, enabled the introduction of DBS in depression, modeled after its success in movement disorders. DBS is the most invasive of the neuromodulatory approaches, requiring neurosurgical implantation of bilateral electrodes in the selected area of interest. However, it provides a unique opportunity to achieve sustained control of symptoms of depression. Since the first report of DBS in depression in 2005, multiple targets have been investigated, with promising results. The largest clinical samples have studied the subcallosal cingulate white matter (SCC), nucleus accumbens (NAc), ventral capsule/ventral striatum (VC/VS), and medial forebrain bundle (MFB). Different open-label case series have reported response in around 40–70% of patients. The enthusiasm of these reports led to large randomized clinical trials (RCTs) in the SCC and VC/VS, which unfortunately did not meet their primary clinical endpoints. These trials were terminated early after interim analyses determined low likelihood of a positive result with completion of the desired recruitment goals. Many opinions were expressed regarding potential causes for these failures. One main concern has been directed at the trial design: primary endpoints were reportedly too early to identify a difference between active stimulation and placebo. Supporting this hypothesis, the results from a different trial showed that discontinuation of stimulation after a period of optimization was better suited to identify a difference between active and sham stimulation. Bergfeld et al. described a 40% overall response rate in 25 patients during the open-label phase; then, a number of participants entered a randomized crossover period, in which all responders experienced return of symptoms within less than 2 weeks once stimulation was discontinued. Other groups identified that the possible reason for failure of larger RCTs was the surgical protocol to determine the ideal region for implantation. Initially through retrospective analysis of white matter connectivity in patients who responded to SCC DBS, and then through prospective identification of the target using diffusion

中文翻译：

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为什么对难治性抑郁症的深部脑刺激是一种必要的治疗选择？

难治性抑郁症 (TRD) 是公共卫生中一个持续关注的领域，鉴于其巨大的个人和社会成本，精神病学界对它的兴趣越来越大。它的患病率很高，多达三分之一的患者对连续使用四种抗抑郁药没有反应。TRD 患者的生活质量显着下降、费用高昂和住院治疗，据估计，他们一生中至少尝试自杀一次的可能性是非抵抗性抑郁症患者的两倍，是普通人群的 15 倍. 尽管有多种抗抑郁治疗选择，但 TRD 患者在后续发作时仍难以维持症状缓解。对于氯胺酮和艾氯胺酮等较新的治疗方法也是如此。电休克疗法 (ECT) 对抑郁症非常有效，临床试验报告的缓解率为 60-90%，但复发率高，且长期 ECT 具有累积的认知副作用，很多时候患者无法忍受。除 ECT 以外的非药物治疗已经存在多年，主要的例子是重复经颅磁刺激 (rTMS)；多项荟萃分析通过刺激背外侧前额叶皮层 (DLPFC) 证明了 rTMS 的功效。然而，rTMS 是一种繁重的治疗（每天 40 分钟的疗程，持续长达 6 周），并且治疗抵抗力高的患者不太可能有反应。迷走神经刺激 (VNS) 于 2005 年被批准用于 TRD。该设备提供低频、慢性、向左颈迷走神经发出间歇性脉冲电信号。研究描述了缓慢但持续的临床反应，主要表现在对患者的长期自然随访，而不是临床试验的主要终点。可悲的是，第三方付款人的保险范围有限；因此，尽管已有 15 年的商业可用性，但受益于该治疗方案的患者数量很少。一旦其他策略停止工作，深部脑刺激 (DBS) 有可能为 TRD 提供新的治疗方法。DBS 可以提供比 VNS 更快的缓解，以及长时间的持续响应。除了 VNS，在长期结果（超过 1 年）方面还没有研究过其他治疗方案。精神障碍的概念化为基于电路的，在神经影像学的支持下，将抑郁症表述为大脑网络功能障碍的表现，使得 DBS 能够在抑郁症中引入，模仿其在运动障碍中的成功。DBS 是最具侵入性的神经调节方法，需要在选定的感兴趣区域内进行双侧电极的神经外科植入。然而，它提供了一个独特的机会来实现对抑郁症状的持续控制。自 2005 年首次报告 DBS 治疗抑郁症以来，已对多个靶点进行了研究，并取得了可喜的成果。最大的临床样本研究了胼胝体扣带回白质 (SCC)、伏隔核 (NAc)、腹侧囊/腹侧纹状体 (VC/VS) 和内侧前脑束 (MFB)。不同的开放标签病例系列报告了大约 40-70% 的患者有反应。这些报告的热情导致了 SCC 和 VC/VS 的大型随机临床试验 (RCT)，不幸的是，这些试验没有达到他们的主要临床终点。在中期分析确定在完成预期招募目标后出现阳性结果的可能性较低后，这些试验提前终止。对于这些故障的潜在原因，人们表达了许多意见。一个主要的担忧是针对试验设计：据报道主要终点还为时过早，无法确定主动刺激和安慰剂之间的差异。支持这个假设，不同试验的结果表明，在优化一段时间后停止刺激更适合识别主动刺激和假刺激之间的差异。伯格菲尔德等人。在开放标签阶段描述了 25 名患者的 40% 总体反应率；然后，许多参与者进入了一个随机交叉期，在该期中，一旦停止刺激，所有响应者都会在不到 2 周的时间内出现症状恢复。其他小组确定较大 RCT 失败的可能原因是确定植入的理想区域的手术方案。最初通过对 SCC DBS 有反应的患者的白质连通性进行回顾性分析，然后通过使用扩散对目标进行前瞻性识别 在开放标签阶段描述了 25 名患者的 40% 总体反应率；然后，许多参与者进入了一个随机交叉期，在该期中，一旦停止刺激，所有反应者都会在不到 2 周的时间内经历症状的恢复。其他小组认为，较大 RCT 失败的可能原因是确定理想植入区域的手术方案。最初通过对 SCC DBS 有反应的患者的白质连通性进行回顾性分析，然后通过使用扩散对目标进行前瞻性识别 在开放标签阶段描述了 25 名患者的 40% 总体反应率；然后，许多参与者进入了一个随机交叉期，在该期中，一旦停止刺激，所有响应者都会在不到 2 周的时间内出现症状恢复。其他小组认为，较大 RCT 失败的可能原因是确定理想植入区域的手术方案。最初通过对 SCC DBS 有反应的患者的白质连通性进行回顾性分析，然后通过使用扩散对目标进行前瞻性识别 其他小组认为，较大 RCT 失败的可能原因是确定理想植入区域的手术方案。最初通过对 SCC DBS 有反应的患者的白质连通性进行回顾性分析，然后通过使用扩散对目标进行前瞻性识别 其他小组确定较大 RCT 失败的可能原因是确定植入的理想区域的手术方案。最初通过对 SCC DBS 有反应的患者的白质连通性进行回顾性分析，然后通过使用扩散对目标进行前瞻性识别