It Is Too Early to Put Delirium Prophylaxis to Bed: Stronger Evidence Is Needed for Suvorexant.
It Is Too Early to Put Delirium Prophylaxis to Bed: Stronger Evidence Is Needed for Suvorexant.
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DOI：
10.4088/jcp.20lr13818
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发表时间：
2021-04
期刊：
影响因子：
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通讯作者：
J. Brooks;Jennifer L. Kruse
中科院分区：
文献类型：
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作者：
J. Brooks;Jennifer L. Kruse
致编辑：在精神病学和医学疾病的交叉点，很少有像谵妄这样令人沮丧的疾病预防或治疗。除了解决谵妄的根本原因外，还不存在适当的对症治疗。以前的主要治疗手段，如抗精神病药物，在短期和长期都不是统一有效的我们热情地支持对谵妄的潜在干预的研究，然而干预需要严格的支持，即使在缺乏替代方案的情况下。因此，我们对最近发表在JCP上的两篇关于使用suvorexant作为谵妄的有效预防的文章进行评论。Suvorexant是一种食欲素受体拮抗剂，根据减少睡眠中断可能减轻谵妄症状的逻辑，已被认为是治疗或预防谵妄的潜在药物。荟萃分析的结果还没有为临床应用提供坚实的基础，因为它们依赖于有样本选择问题和小效应量的研究。最近的两项研究表明，suvorexant在预防和治疗谵妄方面是有效的：Hatta等人的一项前瞻性病例对照研究3研究了ramelteon/suvorexant联合用于预防谵妄，Izuhara等人的一项回顾性队列研究4探讨了suvorexant作为谵妄治疗的作用。虽然这两项研究都增强了我们对suvorexant治疗谵妄的潜在作用的认识，但我们警告说，这两项研究都没有为临床应用提供足够的证据。两份报告都采用了自然主义的方法，这是值得称赞的，但不幸的是引入了混淆，限制了作者对因果关系的归因。据Izuhara等人报道，回顾性队列研究提供了信息，但由于非随机分组和缺乏安慰剂对照，无法建立因果关系。在Izuhara及其同事的研究中，抗抑郁药是由临床酌情决定的，这可能会导致系统的群体差异，而这种差异无法通过分析中包含协变量来纠正。同样，Hatta等人也将是否接受ramelteon/ suvoreant的决定留给了临床医生和/或患者自行决定。两项研究中产生的药物选择偏倚可能反映了现实世界的实践，排除了对治疗组的非随机分配，因此无法得出与其他未测量因素相反的过量因素导致组差异的结论。在两项研究中，增生性治疗组和非增生性治疗组之间的差异（作者注意到了这一点）给解释研究结果带来了挑战。例如，在Izuhara和他的同事的研究中，在谵妄发作之前，接受过右美托咪定、氟哌啶醇、利培酮、曲唑酮和/或雷美替宁治疗的患者是正常组的1.2-3.5倍。这些药物被用于预防、5和/或治疗谵妄，取得了不同程度的成功，6这表明，在接受抗抑郁药之前，抗抑郁药组的患者可能已经对谵妄的早期或前驱症状进行了预防性或预防性治疗。研究开始前的治疗也表明，早期和/或轻微症状可能促使临床决定开抗抑郁药。同样，在Hatta等人的研究中，治疗组和非治疗组在苯二氮卓类药物和类固醇的使用以及是否紧急住院方面存在差异。在非随机研究中，这些和其他未知因素可以通过复杂的相互作用影响谵妄的可能性，并且不容易通过将其作为简单协变量纳入回归中来解决。总的来说，两项研究中对患者的非随机分配治疗并不能得出明确的结论，即瑞美替宁或瑞美替宁/瑞美替宁联合用药能减轻谵妄症状。也就是说，如果拉美替恩没有足够的催眠作用，患者可以选择服用抗抑郁药。虽然自然研究有助于确定suvorexant在谵妄预防中的功效，但匹配的队列样本可能提供了更容易解释的关系。不幸的是，自我选择或临床医生选择受试者的问题并不能为治疗推荐提供充分的依据。在Hatta和他的同事的ramelteon/过度预防研究中，受试者选择过程的几个方面进一步限制了结果的普遍性。例如，尽管作者将受试者分为谵妄组和非谵妄组，但似乎所有患者在研究开始时实际上都是谵妄的，因为他们在研究开始前表现出过度活跃的谵妄，或者至少是睡眠/觉醒周期失调。被归类为非谵妄的受试者可能处于衰弱阶段。因此，这一问题提出了将suvorexant视为“预防”剂的挑战。Hatta等人认为，与未接受药物治疗的患者相比，ramelteon/suvorexant改善了睡眠-觉醒周期。在他们的研究中，suvorexant被作为ramelteon（一种褪黑激素受体1型激动剂）之后的二线治疗（由临床医生和患者自行决定）。然而，在基线时，服用suvorexant/ ramelteon的患者比未服用的患者有更大的睡眠-觉醒周期障碍。这种不平等造成了统计学上的悖论，被称为“向均值回归”，即得分较高的患者比得分较低的患者更有可能在随后的测试中有所改善。因此，睡眠-觉醒周期的改善可能部分反映了统计伪象。在解释Izuhara等人提供的Cox回归分析结果时，应注意几个方面，因为84例患者接受了suvorexant治疗，615例患者没有。当纳入协变量时，回归模型的稳定性不幸在5天（n = 26/n = 148；过度/非过度），甚至在10天（n = 8/n = 42）和30天（n = 1/n = 3）时迅速恶化。因此，这些数据足以支持前5天过量服用和谵妄发生率下降之间的联系，但不支持30天。虽然有有限的证据表明第二代抗精神病药物与某些患者谵妄的减少有关，但在一般预防措施中颠覆谵妄仍有争议因此，新的预防谵妄的方法是非常重要的，值得进一步研究。我们认为，虽然Izuhara等人和Hatta等人的数据为suvorexant改变谵妄或其病程的潜力提供了额外的证据，但需要更明确的数据来确定suvorexant在临床护理中的使用。
To the Editor: At the intersection of psychiatric and medical disorders, few conditions are as frustrating to prevent or treat as delirium. Aside from addressing underlying causes of delirium, adequate symptomatic treatments do not exist. Previous treatment mainstays, such as antipsychotics, are not uniformly effective in either the shortor longer-term.1 We enthusiastically support the search for potential interventions for delirium, yet interventions require rigorous support even when there is a paucity of alternatives. Thus, we provide a comment on 2 recent articles published in JCP regarding the use of suvorexant as an effective prophylaxis of delirium. Suvorexant, which is an orexin receptor antagonist, has been suggested as a potential agent to treat or prevent delirium, guided by the logic that lessening sleep disruptions may reduce delirium symptoms. Meta-analytic findings2 have not provided a firm basis for clinical use because of their reliance on studies with sample selection issues and small effect sizes. Two recent studies have suggested that suvorexant is effective in preventing and treating delirium: a prospective case-control study by Hatta et al3 examined a ramelteon/suvorexant combination for delirium prophylaxis, and a retrospective cohort study by Izuhara et al4 explored suvorexant as a treatment for delirium. While both studies enhance our knowledge of the potential role for suvorexant in treating delirium, we caution that neither study provides sufficient evidence for clinical application. Both reports employed naturalistic approaches, which is laudable, but unfortunately introduced confounds that restricted the attributions of causality made by the authors. Retrospective cohort studies, as reported by Izuhara et al,4 are informative but cannot establish causal relations because of non-random group assignment and lack of placebo controls. In Izuhara and colleagues’ study, suvorexant was initiated at clinical discretion, which can induce systematic group differences that cannot be corrected by the inclusion of covariates in analyses. Similarly, Hatta et al3 left the decision to receive ramelteon/suvorexant to the discretion of the clinician and/or patient. The resulting medication selection bias in both studies, which may reflect real-world practice, precluded non-random assignment to treatment group and thus prevents the conclusion that suvorexant, as opposed to other unmeasured factors, resulted in group differences. Differences between the suvorexant and non-suvorexant treatment groups in both studies (which were noted by the authors) create challenges when interpreting the studies’ results. For example, in Izuhara and colleagues’ study, patients in the suvorexant group were 1.2–3.5 times more likely to have received dexmedetomidine, haloperidol, risperidone, trazodone, and/or ramelteon prior to the onset of delirium. These medications are used, with varying degrees of success, to prevent1,5 and/or to treat delirium,6 which suggests that patients in the suvorexant group may have been treated either preventatively or preemptively for early or prodromal symptoms of delirium prior to receiving suvorexant. Treatment prior to study entry also suggests that early and/or subtle symptoms may have spurred clinical decisions to prescribe suvorexant. Similarly, treatment and non-treatment groups in the study by Hatta et al differed with respect to benzodiazepine and steroid use and whether the hospitalization had been emergent. These and other unknown factors in non-randomized studies can affect the likelihood of delirium through complex interactions and are not readily addressed by their inclusion as simple covariates in a regression. Collectively, the non-randomized assignment of patients to treatment in both studies does not allow for the definitive conclusion that suvorexant or the combination of ramelteon/ suvorexant lessens the symptoms of delirium. That is, patients were provided with the option of taking suvorexant if ramelteon was not sufficiently hypnotic. Although naturalistic studies are helpful in determining the efficacy of suvorexant in delirium prophylaxis, a matched cohort sample may have provided a more readily interpretable relation. Unfortunately, the issue of self-selection or clinician selection of subjects does not provide a sufficient basis for treatment recommendation. Several aspects of the subject selection process in Hatta and coworkers’ ramelteon/suvorexant prophylaxis study further limit the generalizability of the results. For example, although the authors divided subjects into groups with and without delirium, it would appear that all patients were in fact delirious at study entry as they exhibited hyperactive delirium, or at the very least sleep/wake cycle dysregulation, prior to study entry. Subjects classified as without delirium may have been in a waning phase. Consequently, this issue presents challenges in considering suvorexant as a “preventative” agent. Hatta et al suggested that ramelteon/suvorexant improved the sleep-wake cycle compared with patients who did not receive the did not receive the medications. In their study, suvorexant was administered as second-line treatment (at clinician and patient discretion) following ramelteon, which is a melatonin receptor type 1 agonist. At baseline, however, patients who took suvorexant/ ramelteon had greater sleep-wake cycle disturbance than those patients who did not. This inequality creates a statistical paradox known as “regression toward the mean,” in which the patients with more extreme scores are more likely to improve on a subsequent measure than those with less extreme scores. Thus, the improvement in sleep-wake cycle attributed to suvorexant/ramelteon may in part reflect statistical artifact. Caution should be exercised in several areas when interpreting the results of the Cox regression analysis that Izuhara et al provided, as 84 patients received suvorexant and 615 did not. The stability of the regression model, when incorporating the covariates, unfortunately deteriorates rapidly at 5 days (n = 26/n = 148; suvorexant/nonsuvorexant) and even further by 10 days (n = 8/n = 42) and 30 days (n = 1/n = 3). Thus, the data are sufficient to support an association between suvorexant and decreased rates of delirium during the first 5 days, but not through 30 days. While there is limited evidence that second-generation antipsychotics are associated with reduced delirium in certain patient profiles,7 in general prophylactic efforts to subvert delirium are debated.1 Thus, novel means of delirium prophylaxis are highly important and deserve further study. We suggest that while the data of both Izuhara et al and Hatta et al provide additional evidence of the potential for suvorexant to alter delirium or its course, more definitive data are necessary to establish the use of suvorexant in clinical care.