Ostuzzi Giovanni, Matcham Faith, Dauchy Sarah, Barbui Corrado, Hotopf Matthew
Department of Neuroscience, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, Policlinico "GB Rossi", Piazzale L.A. Scuro, 10, Verona, Italy, 37134.
Cochrane Database Syst Rev. 2018 Apr 23;4(4):CD011006. doi: 10.1002/14651858.CD011006.pub3.
Major depression and other depressive conditions are common in people with cancer. These conditions are not easily detectable in clinical practice, due to the overlap between medical and psychiatric symptoms, as described by diagnostic manuals such as the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Diseases (ICD). Moreover, it is particularly challenging to distinguish between pathological and normal reactions to such a severe illness. Depressive symptoms, even in subthreshold manifestations, have been shown to have a negative impact in terms of quality of life, compliance with anti-cancer treatment, suicide risk and likely even the mortality rate for the cancer itself. Randomised controlled trials (RCTs) on the efficacy, tolerability and acceptability of antidepressants in this population are few and often report conflicting results.
To assess the efficacy, tolerability and acceptability of antidepressants for treating depressive symptoms in adults (aged 18 years or older) with cancer (any site and stage).
We searched the following electronic bibliographic databases: the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 6), MEDLINE Ovid (1946 to June week 4 2017), Embase Ovid (1980 to 2017 week 27) and PsycINFO Ovid (1987 to July week 4 2017). We additionally handsearched the trial databases of the most relevant national, international and pharmaceutical company trial registers and drug-approving agencies for published, unpublished and ongoing controlled trials.
We included RCTs comparing antidepressants versus placebo, or antidepressants versus other antidepressants, in adults (aged 18 years or above) with any primary diagnosis of cancer and depression (including major depressive disorder, adjustment disorder, dysthymic disorder or depressive symptoms in the absence of a formal diagnosis).
Two review authors independently checked eligibility and extracted data using a form specifically designed for the aims of this review. The two authors compared the data extracted and then entered data into Review Manager 5 using a double-entry procedure. Information extracted included study and participant characteristics, intervention details, outcome measures for each time point of interest, cost analysis and sponsorship by a drug company. We used the standard methodological procedures expected by Cochrane.
We retrieved a total of 10 studies (885 participants), seven of which contributed to the meta-analysis for the primary outcome. Four of these compared antidepressants and placebo, two compared two antidepressants, and one three-armed study compared two antidepressants and placebo. In this update we included one additional unpublished study. These new data contributed to the secondary analysis, while the results of the primary analysis remained unchanged.For acute-phase treatment response (6 to 12 weeks), we found no difference between antidepressants as a class and placebo on symptoms of depression measured both as a continuous outcome (standardised mean difference (SMD) -0.45, 95% confidence interval (CI) -1.01 to 0.11, five RCTs, 266 participants; very low certainty evidence) and as a proportion of people who had depression at the end of the study (risk ratio (RR) 0.82, 95% CI 0.62 to 1.08, five RCTs, 417 participants; very low certainty evidence). No trials reported data on follow-up response (more than 12 weeks). In head-to-head comparisons we only retrieved data for selective serotonin reuptake inhibitors (SSRIs) versus tricyclic antidepressants, showing no difference between these two classes (SMD -0.08, 95% CI -0.34 to 0.18, three RCTs, 237 participants; very low certainty evidence). No clear evidence of a beneficial effect of antidepressants versus either placebo or other antidepressants emerged from our analyses of the secondary efficacy outcomes (dichotomous outcome, response at 6 to 12 weeks, very low certainty evidence). In terms of dropouts due to any cause, we found no difference between antidepressants as a class compared with placebo (RR 0.85, 95% CI 0.52 to 1.38, seven RCTs, 479 participants; very low certainty evidence), and between SSRIs and tricyclic antidepressants (RR 0.83, 95% CI 0.53 to 1.30, three RCTs, 237 participants). We downgraded the certainty (quality) of the evidence because the included studies were at an unclear or high risk of bias due to poor reporting, imprecision arising from small sample sizes and wide confidence intervals, and inconsistency due to statistical or clinical heterogeneity.
AUTHORS' CONCLUSIONS: Despite the impact of depression on people with cancer, the available studies were very few and of low quality. This review found very low certainty evidence for the effects of these drugs compared with placebo. On the basis of these results, clear implications for practice cannot be deduced. The use of antidepressants in people with cancer should be considered on an individual basis and, considering the lack of head-to-head data, the choice of which agent to prescribe may be based on the data on antidepressant efficacy in the general population of individuals with major depression, also taking into account that data on medically ill patients suggest a positive safety profile for the SSRIs. To better inform clinical practice, there is an urgent need for large, simple, randomised, pragmatic trials comparing commonly used antidepressants versus placebo in people with cancer who have depressive symptoms, with or without a formal diagnosis of a depressive disorder.
重度抑郁症和其他抑郁状况在癌症患者中很常见。由于医学症状和精神症状存在重叠，正如《精神疾病诊断与统计手册》（DSM）和《国际疾病分类》（ICD）等诊断手册所描述的那样，这些状况在临床实践中不易被察觉。此外，区分对如此严重疾病的病理反应和正常反应极具挑战性。即使是阈下表现的抑郁症状，也已显示出对生活质量、抗癌治疗依从性、自杀风险甚至癌症本身的死亡率都有负面影响。关于抗抑郁药在该人群中的疗效、耐受性和可接受性的随机对照试验（RCT）很少，且结果往往相互矛盾。
评估抗抑郁药对患有癌症（任何部位和分期）的成年人（18岁及以上）抑郁症状的疗效、耐受性和可接受性。
我们检索了以下电子文献数据库：Cochrane对照试验中心注册库（CENTRAL 2017年第6期）、MEDLINE Ovid（1946年至2017年第4周）、Embase Ovid（1980年至2017年第27周）和PsycINFO Ovid（1987年至2017年第4周）。我们还手工检索了最相关的国家、国际和制药公司试验注册库以及药物审批机构的试验数据库，以查找已发表、未发表和正在进行的对照试验。
我们纳入了比较抗抑郁药与安慰剂，或抗抑郁药与其他抗抑郁药的随机对照试验，试验对象为任何原发性癌症诊断且伴有抑郁症（包括重度抑郁症、适应障碍、心境恶劣障碍或无正式诊断的抑郁症状）的成年人（18岁及以上）。
两位综述作者独立检查入选资格，并使用专门为本综述目的设计的表格提取数据。两位作者比较提取的数据，然后使用双录入程序将数据录入Review Manager 5。提取的信息包括研究和参与者特征、干预细节、每个感兴趣时间点的结局指标、成本分析以及制药公司的资助情况。我们采用了Cochrane预期的标准方法程序。
我们共检索到10项研究（885名参与者），其中7项对主要结局进行了荟萃分析。其中4项比较了抗抑郁药与安慰剂，2项比较了两种抗抑郁药，1项三臂研究比较了两种抗抑郁药和安慰剂。在本次更新中，我们纳入了1项额外的未发表研究。这些新数据用于二次分析，而主要分析结果保持不变。对于急性期治疗反应（6至12周），我们发现作为一个类别，抗抑郁药与安慰剂在作为连续结局测量的抑郁症状方面没有差异（标准化均值差（SMD）-0.45，95%置信区间（CI）-1.01至0.11，5项随机对照试验，266名参与者；极低确定性证据），在研究结束时仍有抑郁的人群比例方面也没有差异（风险比（RR）0.82，95% CI 0.62至1.08，5项随机对照试验，417名参与者；极低确定性证据）。没有试验报告随访反应（超过12周）的数据。在直接比较中，我们仅检索到选择性5-羟色胺再摄取抑制剂（SSRI）与三环类抗抑郁药的数据，显示这两类药物之间没有差异（SMD -0.08，95% CI -0.34至0.18，3项随机对照试验，237名参与者；极低确定性证据）。我们对二次疗效结局（二分结局，6至12周时的反应，极低确定性证据）的分析未发现抗抑郁药与安慰剂或其他抗抑郁药相比有明显有益效果的证据。在因任何原因退出研究方面，我们发现作为一个类别，抗抑郁药与安慰剂之间没有差异（RR 0.85，95% CI 0.52至1.38，7项随机对照试验，479名参与者；极低确定性证据），SSRI与三环类抗抑郁药之间也没有差异（RR 0.83，95% CI 0.53至1.30，3项随机对照试验，237名参与者）。我们降低了证据的确定性（质量），因为纳入的研究由于报告不佳、样本量小导致的不精确性和宽置信区间以及统计或临床异质性导致的不一致性，存在不清楚或高偏倚风险。
尽管抑郁症对癌症患者有影响，但现有研究很少且质量较低。本综述发现与安慰剂相比，这些药物效果的证据确定性极低。基于这些结果，无法得出明确的实践意义。癌症患者使用抗抑郁药应个体化考虑，鉴于缺乏直接比较的数据，开哪种药物的选择可能基于重度抑郁症普通人群中抗抑郁药疗效的数据，同时考虑到内科疾病患者的数据表明SSRI具有良好的安全性。为了更好地为临床实践提供信息，迫切需要进行大型、简单、随机、实用的试验，比较常用抗抑郁药与安慰剂对有抑郁症状的癌症患者（无论是否有抑郁障碍的正式诊断）的效果。
