As much as guidelines are a cornerstone in the development to a more rational and more helpful medicine, they can be a dull read. Not so the Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines for Mood Disorders¹: In relative brevity, the authors touch on an impressive array of topics and do justice to many facets of mood disorders, integrating the individual and the environment as well as the psychology and the biology. They write scientifically and down to earth at the same time—all the while in very readable style accompanied by excellent illustrations. Respect.

Naturally, in a field as vast as the disorders of the mood certain recommendations remain controversial. A case in point is the advice on how to deal with treatment failure or partial response in antidepressant pharmacotherapy, epitomized in the acronym MIDAS, reminiscent of King Midas of ancient Phrygia, in today's central Turkey. In Greek mythology, the unfortunate king stands for greed and foolishness, but the MIDAS in the Royal College's guideline means increasing the dose (ID), augment (A), and switch (S) of medication (M)—the second-step strategies recommended by the guideline (in order of recommendation). If unsuccessful, guideline authors suggest repeating the MIDAS cycle “a minimum three times.”

Why discuss this plausible set of approaches?

1 Dose increase

From clinical experience, raising the dose is very common, and every psychiatrist has seen patients getting better after their antidepressants have been elevated. Still, in practice, we never know whether this would have happened without any change anyway. Only randomizing patients to a dose increase or to a continuation treatment group can tell. Researchers have done that indeed, but, as we learned in a systematic review,² not too often: We found nine studies, all of them investigating SSRIs. When we added up the results, there was a clinically negligible, statistically nonsignificant effect (SMD: 0.05 [95% CI: −0.14; 0.25]).

In a more general way, a positive dose–response relationship is conditional to any dose escalation strategy of antidepressants. Such a relationship should show in trials randomizing patients to different doses. When scientists did just that, results turned out to be mostly negative: In meta-analyses we were unable to detect clinically meaningful or statistically significant dose–effect gradients at the level of substance groups—be it SSRIs³ or SNRIs (manuscript in submitted)—or consistent and positive evidence for specific substances. For example, 225 mg venlafaxine was not statistically significantly inferior to 375 mg, when we summarized three homogeneous studies (SMD: 0.1 [−0.15; 0.37]), neither was 75 mg venlafaxine relative to 150 mg. In fact, one of the very few statistically significant results indicated that 60 mg fluoxetine is less effective than 20 mg: SMD −0.20 [−0.01; −0.39]. It also became clear that higher doses of SSRIs and SNRIs come with more adverse events. As for tricyclics, almost all RCTs comparing different doses, conducted largely before 1990, arrived at statistically nonsignificant results.

All of this applies to doses within recommended limits, for example, 20 to 60 mg of fluoxetine, and to direct comparisons. Furukawa and colleagues employed meta-analysis to also include indirect evidence, with all the uncertainty that entails, and their results are mostly similar: Gains in effectiveness are modest at best and wide confidence intervals indicate substantial ambiguity.

2 Augmentation

While the guideline recommends lithium or antipsychotics for augmentation, there may be another worthwhile approach: the combination of antidepressants. In a meta-analysis of 20 RCTs we found a signal in favor of combination relative to monotherapy (SMD: 0.33 [0.11; 0.54])—lower, however, when only treatment resistant patients were investigated.⁴ Of note, adding antagonists of presynaptic alpha-2-autoreceptors, for example, mianserin, mirtazapine, or trazodone, to monoamine reuptake inhibitors, such as SSRIs, SNRIs, and TCAs, seems to be the effective combination (SMD: 0.54 [0.29; 0.79])

3 Switch

Switching is similar to dose escalation in that many psychiatrists remember patients responding after a switch, but proof of concept can only arise from RCTs testing switch versus continuation. I am aware of five such studies, and one, the recent SUN-D trial by Kato and coworkers, provided statistically significant evidence in favor of a switch—from sertraline to mirtazapine (SMD 0.18 [0.06; 0.30]). The other four studies remained negative and on aggregate resulted in an SMD of −0.17 [−0.59; 0.26], favoring continuation.⁵

4 MIDAS

This is not to say that what MIDAS stands for is unfounded. There are data from naturalistic and randomized trials, but supporting comparisons to antidepressant continuation are largely missing—and those are critical. From this vantage point, there is a lack of reliable evidence for increasing the dose (ID), whereas evidence for switching (S) is inconclusive, with mostly negative studies and one positive on exchanging sertraline with mirtazapine. However, combining antidepressants, particularly monoamine reuptake inhibitors plus alpha-2-autoreceptor antagonists, is an additional augmentation (A) strategy worthy of consideration.

中文翻译：

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第二步抗抑郁治疗指南建议：MIDAS 中 IDAS 的证据

尽管指南是开发更合理、更有用的药物的基石，但它们读起来可能很枯燥。并非如此澳大利亚和新西兰皇家精神病学家学院情绪障碍临床实践指南¹：相对简洁，作者触及了一系列令人印象深刻的主题，并公正对待情绪障碍的许多方面，同时整合了个人和环境如心理学和生物学。他们既科学地写作，又脚踏实地——一直以非常易读的风格伴随着出色的插图。尊重。

自然地，在情绪障碍这样广阔的领域中，某些建议仍然存在争议。一个典型的例子是关于如何处理抗抑郁药物治疗中的治疗失败或部分反应的建议，以首字母缩略词 MIDAS 为缩影，让人想起今天土耳其中部的古代弗里吉亚国王迈达斯。在希腊神话中，不幸的国王代表贪婪和愚蠢，但皇家学院指南中的 MIDAS 意味着增加剂量（ID）、增加（A）和转换（S）药物（M）——第二步策略指南推荐（按推荐顺序）。如果不成功，指南作者建议重复 MIDAS 循环“至少 3 次”。

为什么要讨论这组看似合理的方法？

1 剂量增加

从临床经验来看，提高剂量是很常见的，每个精神科医生都看到患者在抗抑郁药升高后会好转。尽管如此，在实践中，我们永远不知道如果没有任何改变，这是否会发生。只有将患者随机分配到剂量增加组或继续治疗组才能知道。研究人员确实这样做了，但是，正如我们在系统评价中了解到的，²并不常见：我们发现了 9 项研究，所有研究都在调查 SSRI。当我们将结果相加时，临床上可以忽略不计，统计学上不显着的影响（SMD：0.05 [95% CI：-0.14；0.25]）。

更一般地说，正剂量反应关系取决于抗抑郁药的任何剂量递增策略。这种关系应该在将患者随机分配到不同剂量的试验中显示出来。当科学家们这样做时，结果大多是负面的：在荟萃分析中，我们无法在物质组水平上检测到具有临床意义或统计学意义的剂量效应梯度——无论是 SSRIs ³或 SNRI（提交的手稿）——或针对特定物质的一致且积极的证据。例如，当我们总结三项均质研究（SMD：0.1 [-0.15；0.37]）时，225 mg 文拉法辛在统计学上并没有显着劣于 375 mg，相对于 150 mg，75 mg 文拉法辛也没有。事实上，极少数具有统计学意义的结果之一表明 60 mg 氟西汀的效果不如20 mg：SMD -0.20 [-0.01; -0.39]。还清楚的是，更高剂量的 SSRI 和 SNRI 会带来更多的不良事件。至于三环类药物，几乎所有比较不同剂量的随机对照试验（主要在 1990 年之前进行）都得出了统计上不显着的结果。

所有这些都适用于推荐限度内的剂量，例如 20 至 60 毫克氟西汀，并适用于直接比较。Furukawa 及其同事采用荟萃分析也包括间接证据，其中包含所有不确定性，他们的结果大多相似：有效性的增益充其量是适度的，而广泛的置信区间表明存在很大的模糊性。

2 增强

虽然该指南建议使用锂或抗精神病药进行增强，但可能还有另一种有价值的方法：抗抑郁药的组合。在对 20 项 RCT 进行的荟萃分析中，我们发现相对于单一疗法（SMD：0.33 [0.11；0.54]）有利于联合治疗的信号——然而，当仅研究耐药患者时，该信号较低。⁴值得注意的是，在单胺再摄取抑制剂（如 SSRIs、SNRIs 和 TCAs）中添加突触前 α-2-自身受体的拮抗剂（例如米安色林、米氮平或曲唑酮）似乎是有效的组合（SMD：0.54 [0.29 ; 0.79])

3 开关

转换与剂量递增相似，因为许多精神科医生记得患者在转换后有反应，但概念证明只能来自 RCT 测试转换与继续。我知道有五项这样的研究，其中一项是 Kato 和同事最近进行的 SUN-D 试验，提供了支持从舍曲林转为米氮平的统计学显着证据（SMD 0.18 [0.06; 0.30]）。其他四项研究仍然是负面的，总体上导致 SMD 为 -0.17 [-0.59; 0.26]，有利于继续。⁵

4 迈达斯

这并不是说 MIDAS 所代表的东西是没有根据的。有来自自然主义和随机试验的数据，但与抗抑郁药持续使用的支持性比较在很大程度上是缺失的——而这些数据至关重要。从这个角度来看，缺乏增加剂量 (ID) 的可靠证据，而转换 (S) 的证据尚无定论，大部分研究为阴性，一项关于将舍曲林与米氮平交换的研究为阳性。然而，联合抗抑郁药，特别是单胺再摄取抑制剂加 α-2-自身受体拮抗剂，是值得考虑的额外增强 (A) 策略。