| P M I D |
37713557 |
| 发表年份 |
2023.09 |
| 发表杂志 |
World psychiatry |
| 影响因子 |
73.3 |
| JCR分区 |
Q1 |
作者团队
Michael E Thase
研究方向
难治性抑郁症
论文题目
Recent developments pertaining to treatment-resistant depression: a 40-year perspective
论文摘要
With the increasing recognition that major depressive disorder (MDD) is one of the world greatest public health problems1, 2, there have recently been concerted efforts to ensure that people suffering from this condition are promptly recognized, accurately diagnosed, and vigorously treated. Indeed, a relatively wide range of proven treatments are now available to help depressed people, and health care systems and agencies throughout the world have prioritized implementation strategies to efficiently deliver cost-effective interventions1. Without established primary prevention strategies to reduce the incidence of MDD, maximizing access to treatment and ensuring optimal delivery of care represents the best way to reduce the morbidity, mortality, and personal and societal costs of this common condition1.
That said, no more than one half of people who receive an adequate course of a first-line antidepressant medication will obtain an acceptable response (i.e., at least a 50% reduction in depressive symptom severity, coupled with a tolerable level of side effects) and, as illustrated by the results of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study3, the likelihood of benefit diminishes substantially after the second sequential treatment trial. Episodes that follow this course are commonly called treatment-resistant depression (TRD), and account for a disproportionately large proportion of the illness burden associated with MDD1. This is the subject of the excellent paper by McIntyre et al4, which provides a concise, yet comprehensive review of the topic, including up-to-date summaries of the best studied and most promising treatment strategies.
The concept of TRD is nearly as old as the first generation of effective treatments for depression, namely electroconvulsive therapy (ECT), tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). The first papers using that concept were published in the 1970s5. In that era, an almost intuitive hierarchy emerged on the basis of the clinical effort needed to implement the treatment: TCAs were generally used first, MAOIs second and ECT third for most patients. There were no randomized controlled trials (RCTs) of TRD in that era, though clinical wisdom taught that MAOIs worked in about one half of the cases in which TCAs failed, and ECT was expected to benefit at least 80% of antidepressant non-responders5. As a result, clinicians might have predicted that 70-90% of depressed patients could be treated effectively with this three-step proto-algorithm.
By the mid-1990s, selective serotonin reuptake inhibitors (SSRIs) and several other newer-generation antidepressants had supplanted the TCAs as first-line treatments, expanding that intuitive algorithm to four levels of treatment. When we first reviewed the growing literature on this topic, 6, we reached a similar conclusion: a four-step treatment algorithm, in theory, might be expected to yield up to a 90% cumulative response rate. Yet, the 1980s and 1990s ushered in an era of increasing methodological rigor, and the first RCTs of TRD began to emerge. Results indicated that our estimates were overly optimistic, and methodological conventions such as intention-to-treat analyses, which account for the impact of attrition on response rates, and use of “blinded” evaluators to minimize expectancy biases, revealed more sobering estimates of benefit. For example, in the STAR*D trial, the cumulative response to a sequence of four treatment trials was in the order of 50-60%.
So, the public health problem of TRD turned out to be much larger than anticipated and, as reviewed by McIntyre et al, subsequent methods to refine and expand upon the simple hierarchical system that we had proposed have strengthened our ability to assess and classify depressions that do not respond to standard therapies. The introduction of a broader and more inclusive term, difficult-to-treat depression, further enriches the conceptual framework of understanding the clinical context of non-response to antidepressants: there are many reasons that might explain why an antidepressant will not deliver the desired result, and only some of them pertain to neuropharmacological actions of our medications.
Nearly 20 years have passed since the publication of the main findings of the STAR*D trial. In the post-STAR*D era, it can be argued that the greatest unmet need in the psychopharmacology of depression is for antidepressants that work via mechanisms other than modulation of monoaminergic neurotransmission. McIntyre et al provide a particularly useful summary of the data on several of the more recent therapeutic developments that have truly improved the outcomes of some people who do not respond to standard antidepressants.
Switching antidepressants, which was once the quintessential second step in most algorithms, is now more of a default option for patients who have tolerability issues with the index antidepressant, and only rarely are patients switched to an MAOI. More commonly used second-line options include combinations of SSRIs and either mirtazapine or bupropion, and several adjunctive strategies. Among the adjunctive options, a large amount of empirical data supports use of a group of second-generation antipsychotics (SGAs). Given the well-known risk of weight gain, the potential for other metabolic side effects, and a small but real ultimate risk of tardive dyskinesia, more extensive data from longer-term studies are sorely needed to help to more accurately gauge the relative merits and cost-effectiveness of this adjunctive strategy.
Although clinically tested and widely used, combining antidepressants and adjunctive therapy with SGAs can be thought of as incremental options, because they target somewhat complementary monoaminergic mechanisms and require that patients continue to take an SSRI or other newer antidepressant. There was a frustratingly long pause between the introduction of the various members of the so-called “newer” generation of antidepressants – it is, after all, more than 35 years since the US Food and Drug Administration (FDA) first approved fluoxetine – and the discovery of interventions with truly novel mechanisms of action. Fortunately things are changing, with the serendipitous observation that a sub-anesthetic intravenous dose of ketamine could have large and remarkably rapid antidepressant effects. Now confirmed by the findings of a large number of RCTs in patients with various forms of TRD8, the relatively rapid acceptance of this “off-label” use of intravenous ketamine has opened the gates to a new wave of potential therapies that target glutamatergic neurotransmission.
While it remains to be seen whether intravenous ketamine or intranasal esketamine – the first FDA-approved therapy to result from these observations – will continue to be widely used a decade from now, it is a fact that the paradigm for drug discovery for TRD has changed for the foreseeable future. In this respect, the path for studying the therapeutic potential of neurosteroid drugs such as zuranolone, which is thought to indirectly affect glutamatergic neurotransmission through GABA-A receptor positive allosteric modulation, has been much less arduous than previously possible. Likewise, the paradigm change determined by the proven efficacy of intravenous ketamine, a controlled substance with abuse liability and characteristic dissociative effects, has prepared the field for a new wave of studies examining the therapeutic benefit of psilocybin and related psychedelic compounds that were once considered essentially off limits for therapeutic research. Finally, descendants of transcranial magnetic stimulation, including intermittent theta burst stimulation (iTBS) and an accelerated high-dose iTBS protocol utilizing magnetic resonance imaging to guide or target functional connectivity9, have given hope for the possibility of viable alternate neuromodulation strategies for patients with more advanced levels of TRD.
McIntyre et al's outline of the evidence concerning TRD, therefore, is timely and provides a thought-provoking overview of an exciting new era in the therapeutics of depression.
随着越来越多的人认识到重性抑郁障碍（MDD）是世界上最大的公共卫生问题之一，近来人们一致努力确保患有这种疾病的患者得到及时发现、准确诊断和积极治疗。事实上，目前有相对广泛的经过验证的治疗方法可以帮助抑郁症患者，世界各地的卫生保健系统和机构已优先考虑实施战略，以有效地提供具有成本效益的干预措施。在没有确立降低MDD发病率的初级预防策略的情况下，最大限度地获得治疗并确保最佳的医疗服务是降低这一常见疾病发病率、死亡率以及个人和社会成本的最佳方式。
也就是说，在接受足够疗程一线抗抑郁药治疗的患者中，不超过一半的人会获得可接受的应答（即抑郁症状严重程度降低至少50%，并且伴有可容忍的副作用），而且正如STAR*D（缓解抑郁的顺序治疗替代方案）研究结果所示，在第二次顺序治疗试验后，获益的可能性大幅降低。遵循这一过程的发作通常被称为难治性抑郁症（TRD），并且在与MDD相关的疾病负担中占不成比例的很大比例。这是McIntyre等人发表的一篇优秀论文的主题，该论文对该主题进行了简明而全面的回顾，包括最新的最佳研究和最有希望的治疗策略总结。
TRD的概念几乎与第一代有效的抑郁症治疗方法一样古老，即电休克疗法（ECT）、三环抗抑郁药（TCAs）和单胺氧化酶抑制剂（MAOIs）。使用这一概念的第一篇论文发表于20世纪70年代。在那个时代，基于实施治疗所需的临床努力，出现了一个很直观的分级制度：大多数患者通常首先使用TCAs，其次是MAOIs，第三是ECT。在那个时代，没有TRD的随机对照试验（RCTs），但临床经验告诉我们，MAOIs在大约一半的TCAs失败的病例中有效，而ECT预计至少对80%的抗抑郁无效患者有益。因此，临床医生可能已经预测，70-90%的抑郁症患者可以通过这个三步算法原型得到有效治疗。
到20世纪90年代中期，选择性5-羟色胺再摄取抑制剂（SSRIs）和其他几种新一代抗抑郁药已取代TCAs作为一线治疗方法，将这一直观算法扩展到4个治疗级别。当我们第一次回顾关于这一主题的越来越多的文献时，得出了类似的结论：理论上，四步治疗算法有望产生高达90%的累积缓解率。然而，20世纪80年代和90年代迎来了方法学日益严格的时代，第一批TRD的RCTs开始出现。结果表明，我们的估计值过于乐观，而意向性治疗分析（解释对应答率的损耗率的影响）和使用“盲法”评估器来最小化预期偏倚等方法学惯例显示，揭示了更清醒的获益估计。例如，在STAR*D试验中，对连续4项治疗试验的累积应答率约为50%~60%。
因此，TRD的公共卫生问题比预期的要大得多，正如McIntyre等人所回顾的那样，在我们提出的简单等级系统的基础上改进和扩展的后续方法加强了我们对标准治疗无效的抑郁症进行评估和分类的能力。引入一个更广泛、更包容的术语“难治性抑郁症”，进一步丰富了理解抗抑郁药无反应的临床背景的概念框架：有许多原因可以解释为什么抗抑郁药不能达到预期的效果，其中只有一些与我们的药物的神经药理作用有关。
自STAR*D试验的主要结果发表以来，已经过去了近20年。在后STAR*D时代，可以认为，抑郁症精神药理学中最大的未满足需求是通过单胺能神经传递调节以外的机制起作用的抗抑郁药。McIntyre等人提供了一个特别有用的数据总结，总结了一些最近的治疗进展，这些进展确实改善了一些对标准抗抑郁药没有反应的人的治疗效果。
更换抗抑郁药曾是大多数算法中最典型的第二步，但现在更多的是对抗抑郁药有耐受性问题的患者的默认选项，只有极少数患者会更换为MAOI。更常用的二线治疗方案包括SSRI与米氮平或安非他酮的联合使用，以及几种辅助治疗策略。在辅助治疗方案中，大量经验数据支持使用一组第二代抗精神病药（SGAs）。考虑到众所周知的体重增加风险、其他代谢副作用的潜在风险，以及迟发性运动障碍的微小但真实的最终风险，我们迫切需要来自长期研究的更广泛数据来帮助更准确地评估这一辅助策略的相对优点和成本效益。
虽然已在临床上得到检验并广泛应用，联合抗抑郁药和SGAs辅助治疗可被视为一个渐进的方案，因为它们针对的是某种互补的单胺能机制，并且要求患者继续服用SSRI或其他新型抗抑郁药。从引入所谓的“新”一代抗抑郁药的各种成员到发现具有真正新颖作用机制的干预措施之间，有一个令人沮丧的长时间停顿——毕竟，自美国食品和药物管理局（FDA）首次批准氟西汀以来，已经超过35年了。幸运的是，情况正在改变，偶然观察到亚麻醉剂量的静脉注射氯胺酮可以产生显著且快速的抗抑郁作用。目前，在各种形式的TRD患者中进行的大量RCTs结果证实了这一点，人们相对快速地接受了这种“标签外”静脉使用氯胺酮，为靶向谷氨酸能神经传递的新一波潜在疗法打开了大门。
虽然静脉注射氯胺酮或滴鼻艾氯胺酮（FDA根据这些观察结果批准的第一种治疗方法）是否会在10年后继续广泛使用仍有待观察，但事实是，在可预见的未来，TRD药物发现的范式已经发生了变化。在这方面，研究神经类固醇药物（如卓拉诺酮，被认为通过GABA-A受体阳性变构调节间接影响谷氨酸能神经传递）的治疗潜力的途径比以前要容易得多。同样，静脉注射氯胺酮（一种受管制的药物，具有滥用风险和典型的分离效应）已证实的疗效决定了范式的变化，这为研究赛洛西宾和相关致幻化合物的治疗效果的新一波研究奠定了基础，这些化合物曾被认为是治疗性研究的基本禁忌。最后，经颅磁刺激的后续疗法（包括间歇性θ短阵脉冲刺激(iTBS)和利用磁共振成像指导或靶向功能连接的加速大剂量iTBS方案）为更晚期TRD患者提供了可行的替代神经调节策略的可能性。
因此，McIntyre等人关于TRD证据的概述是及时的，并提供了一个令人兴奋的抑郁症治疗新时代的发人深省的概述。
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