Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration.
Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration.
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DOI：
10.1371/journal.pmed.0050045
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发表时间：
2008-02
期刊：
影响因子：
15.8
通讯作者：
Johnson, Blair T.
中科院分区：
文献类型：
--
作者：
Kirsch, Irving;Deacon, Brett J.;Huedo-Medina, Tania B.;Scoboria, Alan;Moore, Thomas J.;Johnson, Blair T.
抗抑郁药物的荟萃分析显示，与安慰剂治疗相比，仅具有适度的益处，并且当纳入未发表的试验数据时，其益处低于公认的临床意义标准。然而，抗抑郁药的疗效也可能取决于初始抑郁评分的严重程度。该分析的目的是使用已发表和未发表的临床试验的相关数据集来建立基线严重程度和抗抑郁疗效的关系。我们获得了向美国食品和药物管理局 (FDA) 提交的四种新一代抗抑郁药许可的所有临床试验的数据，并提供了完整的数据集。然后，我们使用荟萃分析技术来评估初始严重程度对药物组和安慰剂组改善评分以及药物与安慰剂差异评分的线性和二次影响。药物与安慰剂的差异随着初始严重程度的增加而增加，从中等水平初始抑郁症的几乎没有差异上升到对于非常严重抑郁症患者的相对较小的差异，仅对于处于非常严重抑郁症类别高端的患者达到临床意义的常规标准。荟萃回归分析表明，药物组中基线严重程度与改善的关系呈曲线关系，而安慰剂组中则显示出强烈的负线性成分。药物与安慰剂的抗抑郁疗效差异随着基线严重程度的增加而增加，但即使对于严重抑郁患者来说，差异也相对较小。初始严重程度与抗抑郁疗效之间的关系可归因于非常严重的抑郁症患者对安慰剂的反应性降低，而不是对药物的反应性增加。 Kirsch 及其同事表明，在抗抑郁试验中，对于更严重的抑郁患者，药物和安慰剂之间的疗效存在更大差异。然而，这种差异似乎是由于抑郁症患者对安慰剂的反应较差所致。每个人都会偶尔感到痛苦。但对于一些患有抑郁症的人来说，这些悲伤的感觉会持续数月或数年，并干扰日常生活。抑郁症是一种严重的疾病，由调节情绪的大脑化学物质失衡引起。它会影响六分之一的人一生中的某个时期，让他们感到绝望、毫无价值、没有动力，甚至有自杀倾向。医生使用“汉密尔顿抑郁量表”(HRSD)（一份包含 17-21 项的问卷）来衡量抑郁症的严重程度。每个问题的答案都会给出一个分数，问卷总分超过18分表示患有严重抑郁症。轻度抑郁症通常通过心理疗法或谈话疗法来治疗（例如，认知行为疗法可以帮助人们改变消极的思维和行为方式）。对于更严重的抑郁症，目前的治疗通常是心理治疗和抗抑郁药物的结合，假设这种药物可以使影响情绪的大脑化学物质正常化。抗抑郁药包括“三环类药物”、“单胺氧化酶”和“选择性血清素再摄取抑制剂”(SSRI)。 SSRI 是最新的抗抑郁药，包括氟西汀、文拉法辛、奈法唑酮和帕罗西汀。尽管美国食品和药物管理局 (FDA)、英国国家健康与临床卓越研究所 (NICE) 和其他许可机构已批准 SSRIs 用于治疗抑郁症，但对其临床疗效仍存在一些疑问。在批准抗抑郁药用于患者之前，必须进行临床试验，将其改善患者 HRSD 评分的能力与安慰剂（一种不含药物的虚拟药片）进行比较。每项单独的试验都提供了有关新药有效性的一些信息，但通过将所有试验的结果合并到“荟萃分析”中可以获得更多信息，“荟萃分析”是一种结合许多研究结果的统计方法。先前发表的对在许可期间提交给 FDA 的 SSRI 已发表和未发表试验的荟萃分析表明，这些药物仅具有边际临床益处。平均而言，SSRIs 比安慰剂使患者的 HRSD 评分提高了 1.8 分，而 NICE 将抗抑郁药的显着临床益处定义为药物与安慰剂在 HRSD 评分改善方面的差异为 3 分。然而，平均改善分数可能会掩盖不同患者群体之间的有益效果，因此在本文的荟萃分析中，研究人员调查了抑郁症的基线严重程度是否会影响抗抑郁药的疗效。研究人员获得了向 FDA 提交氟西汀、文拉法辛、奈法唑酮和帕罗西汀许可的所有临床试验的数据。然后，他们使用荟萃分析技术来调查抑郁症的初始严重程度是否影响这些试验中药物组和安慰剂组的 HRSD 改善评分。他们首先证实这些新一代抗抑郁药的总体效果低于推荐的临床意义标准。然后他们发现，对于中度抑郁症患者来说，药物和安慰剂的改善分数实际上没有差异，而对于非常严重的抑郁症患者来说，只有很小的、临床上不显着的差异。然而，对于初始 HRSD 评分超过 28 的患者（即最严重的抑郁患者），抗抑郁药和安慰剂之间的改善差异达到了临床意义。其他分析表明，抗抑郁药在这些最严重抑郁症患者中的明显临床效果反映了对安慰剂的反应性降低，而不是对抗抑郁药的反应性增加。这些发现表明，与安慰剂相比，新一代抗抑郁药不会对最初患有中度甚至非常重度抑郁症的患者产生临床上显着的抑郁症改善，但仅对最严重的抑郁症患者显示出显着效果。研究结果还表明，这些患者的效果似乎是由于对安慰剂的反应降低，而不是对药物的反应增加。鉴于这些结果，研究人员得出结论，除了最严重的抑郁症患者之外，没有什么理由给任何人开新一代抗抑郁药物，除非替代疗法无效。此外，与不太严重抑郁的患者相比，极度抑郁的患者对安慰剂的反应较差，但对抗抑郁药的反应相似，这一发现对于抑郁症患者如何对抗抑郁药和安慰剂的反应具有潜在的重要意义，应进一步研究。请通过此摘要的在线版本访问这些网站：http://dx.doi.org/10.1371/journal.pmed.0050045。 MedlinePlus 百科全书包含有关抑郁症的页面（英语和西班牙语）。患者和护理人员可以从美国国家医疗健康研究所和英国国家卫生服务直接健康百科全书中获取有关抑郁症各个方面（包括症状和治疗）的详细信息。直接健康百科全书 MedlinePlus 提供了有关抑郁症的更多信息的链接列表。英国国家健康和临床卓越研究所为专业人士、患者、护理人员和公众提供了临床指南。
Meta-analyses of antidepressant medications have reported only modest benefits over placebo treatment, and when unpublished trial data are included, the benefit falls below accepted criteria for clinical significance. Yet, the efficacy of the antidepressants may also depend on the severity of initial depression scores. The purpose of this analysis is to establish the relation of baseline severity and antidepressant efficacy using a relevant dataset of published and unpublished clinical trials. We obtained data on all clinical trials submitted to the US Food and Drug Administration (FDA) for the licensing of the four new-generation antidepressants for which full datasets were available. We then used meta-analytic techniques to assess linear and quadratic effects of initial severity on improvement scores for drug and placebo groups and on drug–placebo difference scores. Drug–placebo differences increased as a function of initial severity, rising from virtually no difference at moderate levels of initial depression to a relatively small difference for patients with very severe depression, reaching conventional criteria for clinical significance only for patients at the upper end of the very severely depressed category. Meta-regression analyses indicated that the relation of baseline severity and improvement was curvilinear in drug groups and showed a strong, negative linear component in placebo groups. Drug–placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients. The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication. Kirsch and colleagues show that, in antidepressant trials, there is a greater difference in efficacy between drug and placebo amongst more severely depressed patients. However, this difference seems to result from a poorer response to placebo amongst more depressed patients. Everyone feels miserable occasionally. But for some people—those with depression—these sad feelings last for months or years and interfere with daily life. Depression is a serious medical illness caused by imbalances in the brain chemicals that regulate mood. It affects one in six people at some time during their life, making them feel hopeless, worthless, unmotivated, even suicidal. Doctors measure the severity of depression using the “Hamilton Rating Scale of Depression” (HRSD), a 17–21 item questionnaire. The answers to each question are given a score and a total score for the questionnaire of more than 18 indicates severe depression. Mild depression is often treated with psychotherapy or talk therapy (for example, cognitive–behavioral therapy helps people to change negative ways of thinking and behaving). For more severe depression, current treatment is usually a combination of psychotherapy and an antidepressant drug, which is hypothesized to normalize the brain chemicals that affect mood. Antidepressants include “tricyclics,” “monoamine oxidases,” and “selective serotonin reuptake inhibitors” (SSRIs). SSRIs are the newest antidepressants and include fluoxetine, venlafaxine, nefazodone, and paroxetine. Although the US Food and Drug Administration (FDA), the UK National Institute for Health and Clinical Excellence (NICE), and other licensing authorities have approved SSRIs for the treatment of depression, some doubts remain about their clinical efficacy. Before an antidepressant is approved for use in patients, it must undergo clinical trials that compare its ability to improve the HRSD scores of patients with that of a placebo, a dummy tablet that contains no drug. Each individual trial provides some information about the new drug's effectiveness but additional information can be gained by combining the results of all the trials in a “meta-analysis,” a statistical method for combining the results of many studies. A previously published meta-analysis of the published and unpublished trials on SSRIs submitted to the FDA during licensing has indicated that these drugs have only a marginal clinical benefit. On average, the SSRIs improved the HRSD score of patients by 1.8 points more than the placebo, whereas NICE has defined a significant clinical benefit for antidepressants as a drug–placebo difference in the improvement of the HRSD score of 3 points. However, average improvement scores may obscure beneficial effects between different groups of patient, so in the meta-analysis in this paper, the researchers investigated whether the baseline severity of depression affects antidepressant efficacy. The researchers obtained data on all the clinical trials submitted to the FDA for the licensing of fluoxetine, venlafaxine, nefazodone, and paroxetine. They then used meta-analytic techniques to investigate whether the initial severity of depression affected the HRSD improvement scores for the drug and placebo groups in these trials. They confirmed first that the overall effect of these new generation of antidepressants was below the recommended criteria for clinical significance. Then they showed that there was virtually no difference in the improvement scores for drug and placebo in patients with moderate depression and only a small and clinically insignificant difference among patients with very severe depression. The difference in improvement between the antidepressant and placebo reached clinical significance, however, in patients with initial HRSD scores of more than 28—that is, in the most severely depressed patients. Additional analyses indicated that the apparent clinical effectiveness of the antidepressants among these most severely depressed patients reflected a decreased responsiveness to placebo rather than an increased responsiveness to antidepressants. These findings suggest that, compared with placebo, the new-generation antidepressants do not produce clinically significant improvements in depression in patients who initially have moderate or even very severe depression, but show significant effects only in the most severely depressed patients. The findings also show that the effect for these patients seems to be due to decreased responsiveness to placebo, rather than increased responsiveness to medication. Given these results, the researchers conclude that there is little reason to prescribe new-generation antidepressant medications to any but the most severely depressed patients unless alternative treatments have been ineffective. In addition, the finding that extremely depressed patients are less responsive to placebo than less severely depressed patients but have similar responses to antidepressants is a potentially important insight into how patients with depression respond to antidepressants and placebos that should be investigated further. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050045. The MedlinePlus encyclopedia contains a page on depression (in English and Spanish) Detailed information for patients and caregivers is available on all aspects of depression (including symptoms and treatment) from the US National Institute of Medical Health and from the UK National Health Service Direct Health Encyclopedia MedlinePlus provides a list of links to further information on depression Clinical Guidance for professionals, patients, caregivers and the public is provided by the UK National Institute for Health and Clinical Excellence
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DOI：
10.2307/1165136
发表时间：
1993-09-01
期刊：
JOURNAL OF EDUCATIONAL STATISTICS
影响因子：
--
作者：
GIBBONS, RD;HEDEKER, DR;DAVIS, JM
通讯作者：
DAVIS, JM
影响因子：
2.9
作者：
Ballenger, JC
通讯作者：
Ballenger, JC
影响因子：
7.2
作者：
Furukawa, TA;Barbui, C;Watanabe, N
通讯作者：
Watanabe, N
DOI：
10.1097/00004850-199206004-00006
发表时间：
1992-06-01
影响因子：
2.6
作者：
CLAGHORN, J
通讯作者：
CLAGHORN, J
影响因子：
39.2
作者：
Hansen, RA;Gartlehner, G;Carey, TS
通讯作者：
Carey, TS