Department of Psychological Medicine, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
Children and Young People Satellite, Cochrane Common Mental Disorders, The University of Auckland, Auckland, New Zealand.
Cochrane Database Syst Rev. 2021 May 24;5(5):CD013674. doi: 10.1002/14651858.CD013674.pub2.
Major depressive disorders have a significant impact on children and adolescents, including on educational and vocational outcomes, interpersonal relationships, and physical and mental health and well-being. There is an association between major depressive disorder and suicidal ideation, suicide attempts, and suicide. Antidepressant medication is used in moderate to severe depression; there is now a range of newer generations of these medications.
To investigate, via network meta-analysis (NMA), the comparative effectiveness and safety of different newer generation antidepressants in children and adolescents with a diagnosed major depressive disorder (MDD) in terms of depression, functioning, suicide-related outcomes and other adverse outcomes. The impact of age, treatment duration, baseline severity, and pharmaceutical industry funding was investigated on clinician-rated depression (CDRS-R) and suicide-related outcomes.
We searched the Cochrane Common Mental Disorders Specialised Register, the Cochrane Library (Central Register of Controlled Trials (CENTRAL) and Cochrane Database of Systematic Reviews (CDSR)), together with Ovid Embase, MEDLINE and PsycINFO till March 2020.
Randomised trials of six to 18 year olds of either sex and any ethnicity with clinically diagnosed major depressive disorder were included. Trials that compared the effectiveness of newer generation antidepressants with each other or with a placebo were included. Newer generation antidepressants included: selective serotonin reuptake inhibitors; selective norepinephrine reuptake inhibitors (SNRIs); norepinephrine reuptake inhibitors; norepinephrine dopamine reuptake inhibitors; norepinephrine dopamine disinhibitors (NDDIs); and tetracyclic antidepressants (TeCAs).
Two reviewers independently screened titles/abstracts and full texts, extracted data, and assessed risk of bias. We analysed dichotomous data as Odds Ratios (ORs), and continuous data as Mean Difference (MD) for the following outcomes: depression symptom severity (clinician rated), response or remission of depression symptoms, depression symptom severity (self-rated), functioning, suicide related outcomes and overall adverse outcomes. Random-effects network meta-analyses were conducted in a frequentist framework using multivariate meta-analysis. Certainty of evidence was assessed using Confidence in Network Meta-analysis (CINeMA). We used "informative statements" to standardise the interpretation and description of the results.
Twenty-six studies were included. There were no data for the two primary outcomes (depressive disorder established via clinical diagnostic interview and suicide), therefore, the results comprise only secondary outcomes. Most antidepressants may be associated with a "small and unimportant" reduction in depression symptoms on the CDRS-R scale (range 17 to 113) compared with placebo (high certainty evidence: paroxetine: MD -1.43, 95% CI -3.90, 1.04; vilazodone: MD -0.84, 95% CI -3.03, 1.35; desvenlafaxine MD -0.07, 95% CI -3.51, 3.36; moderate certainty evidence: sertraline: MD -3.51, 95% CI -6.99, -0.04; fluoxetine: MD -2.84, 95% CI -4.12, -1.56; escitalopram: MD -2.62, 95% CI -5.29, 0.04; low certainty evidence: duloxetine: MD -2.70, 95% CI -5.03, -0.37; vortioxetine: MD 0.60, 95% CI -2.52, 3.72; very low certainty evidence for comparisons between other antidepressants and placebo). There were "small and unimportant" differences between most antidepressants in reduction of depression symptoms (high- or moderate-certainty evidence). Results were similar across other outcomes of benefit. In most studies risk of self-harm or suicide was an exclusion criterion for the study. Proportions of suicide-related outcomes were low for most included studies and 95% confidence intervals were wide for all comparisons. The evidence is very uncertain about the effects of mirtazapine (OR 0.50, 95% CI 0.03, 8.04), duloxetine (OR 1.15, 95% CI 0.72, 1.82), vilazodone (OR 1.01, 95% CI 0.68, 1.48), desvenlafaxine (OR 0.94, 95% CI 0.59, 1.52), citalopram (OR 1.72, 95% CI 0.76, 3.87) or vortioxetine (OR 1.58, 95% CI 0.29, 8.60) on suicide-related outcomes compared with placebo. There is low certainty evidence that escitalopram may "at least slightly" reduce odds of suicide-related outcomes compared with placebo (OR 0.89, 95% CI 0.43, 1.84). There is low certainty evidence that fluoxetine (OR 1.27, 95% CI 0.87, 1.86), paroxetine (OR 1.81, 95% CI 0.85, 3.86), sertraline (OR 3.03, 95% CI 0.60, 15.22), and venlafaxine (OR 13.84, 95% CI 1.79, 106.90) may "at least slightly" increase odds of suicide-related outcomes compared with placebo. There is moderate certainty evidence that venlafaxine probably results in an "at least slightly" increased odds of suicide-related outcomes compared with desvenlafaxine (OR 0.07, 95% CI 0.01, 0.56) and escitalopram (OR 0.06, 95% CI 0.01, 0.56). There was very low certainty evidence regarding other comparisons between antidepressants.
AUTHORS' CONCLUSIONS: Overall, methodological shortcomings of the randomised trials make it difficult to interpret the findings with regard to the efficacy and safety of newer antidepressant medications. Findings suggest that most newer antidepressants may reduce depression symptoms in a small and unimportant way compared with placebo. Furthermore, there are likely to be small and unimportant differences in the reduction of depression symptoms between the majority of antidepressants. However, our findings reflect the average effects of the antidepressants, and given depression is a heterogeneous condition, some individuals may experience a greater response. Guideline developers and others making recommendations might therefore consider whether a recommendation for the use of newer generation antidepressants is warranted for some individuals in some circumstances. Our findings suggest sertraline, escitalopram, duloxetine, as well as fluoxetine (which is currently the only treatment recommended for first-line prescribing) could be considered as a first option. Children and adolescents considered at risk of suicide were frequently excluded from trials, so that we cannot be confident about the effects of these medications for these individuals. If an antidepressant is being considered for an individual, this should be done in consultation with the child/adolescent and their family/caregivers and it remains critical to ensure close monitoring of treatment effects and suicide-related outcomes (combined suicidal ideation and suicide attempt) in those treated with newer generation antidepressants, given findings that some of these medications may be associated with greater odds of these events. Consideration of psychotherapy, particularly cognitive behavioural therapy, as per guideline recommendations, remains important.
重度抑郁症对儿童和青少年有重大影响，包括对教育和职业成果、人际关系以及身心健康和幸福的影响。重度抑郁症与自杀意念、自杀企图和自杀有关。抗抑郁药用于中重度抑郁症；现在有一系列更新的药物。
通过网络荟萃分析（NMA），调查在患有经临床诊断的重度抑郁症（MDD）的儿童和青少年中，不同新一代抗抑郁药在抑郁、功能、自杀相关结果和其他不良结果方面的相对有效性和安全性。研究了年龄、治疗持续时间、基线严重程度和制药行业资助对临床医生评定的抑郁（CDRS-R）和自杀相关结果的影响。
我们检索了 Cochrane 常见精神障碍专业注册库、Cochrane 图书馆（CENTRAL 和 CDSR）、Ovid Embase、MEDLINE 和 PsycINFO，检索截止日期为 2020 年 3 月。
入选年龄在 6 至 18 岁、任何种族的临床试验，且患有临床诊断的重度抑郁症。入选的试验将比较新一代抗抑郁药彼此之间或与安慰剂的有效性。新一代抗抑郁药包括：选择性 5-羟色胺再摄取抑制剂；选择性去甲肾上腺素再摄取抑制剂（SNRIs）；去甲肾上腺素再摄取抑制剂；去甲肾上腺素多巴胺再摄取抑制剂；去甲肾上腺素多巴胺抑制剂（NDDIs）；和四环抗抑郁药（TeCAs）。
两名审查员独立筛选标题/摘要和全文，提取数据，并评估偏倚风险。我们分析了二分类数据作为优势比（ORs），并分析了连续数据作为抑郁症状严重程度（临床评定）、抑郁症状缓解或缓解、抑郁症状严重程度（自我评定）、功能、自杀相关结果和总体不良结果的均数差（MD）。使用多变量荟萃分析在一个频率主义框架中进行了随机效应网络荟萃分析。使用“信息性陈述”来标准化结果的解释和描述。
共纳入 26 项研究。由于没有关于两个主要结局（通过临床诊断访谈确定的抑郁障碍和自杀）的数据，因此，结果仅包括次要结局。与安慰剂相比，大多数抗抑郁药可能与抑郁症状（范围为 17 至 113）的“小而不重要”降低有关（高确定性证据：帕罗西汀：MD-1.43，95%CI-3.90，1.04；维拉佐酮：MD-0.84，95%CI-3.03，1.35；文拉法辛：MD-0.07，95%CI-3.51，3.36；中度确定性证据：舍曲林：MD-3.51，95%CI-6.99，-0.04；氟西汀：MD-2.84，95%CI-4.12，-1.56；依他普仑：MD-2.62，95%CI-5.29，0.04；低确定性证据：度洛西汀：MD-2.70，95%CI-5.03，-0.37；伏硫西汀：MD0.60，95%CI-2.52，3.72；非常低确定性证据比较其他抗抑郁药与安慰剂之间的差异）。与安慰剂相比，大多数抗抑郁药在降低抑郁症状方面可能存在“小而不重要”的差异（高或中度确定性证据）。在大多数其他获益结果中也存在相似的结果。在大多数研究中，自杀相关结果的风险是研究的排除标准。大多数纳入研究的自杀相关结果的比例较低，所有比较的 95%置信区间都很宽。关于米氮平（OR0.50，95%CI0.03，8.04）、度洛西汀（OR1.15，95%CI0.72，1.82）、维拉佐酮（OR1.01，95%CI0.68，1.48）、文拉法辛（OR0.94，95%CI0.59，1.52）、西酞普兰（OR1.72，95%CI0.76，3.87）或伏硫西汀（OR1.58，95%CI0.29，8.60）的自杀相关结果，关于自杀相关结果的证据非常不确定。有低确定性证据表明，依他普仑可能“至少略微”降低自杀相关结果的几率（OR0.89，95%CI0.43，1.84）。有低确定性证据表明，氟西汀（OR1.27，95%CI0.87，1.86）、帕罗西汀（OR1.81，95%CI0.85，3.86）、舍曲林（OR3.03，95%CI0.60，15.22）和万拉法辛（OR13.84，95%CI1.79，106.90）可能“至少略微”增加自杀相关结果的几率与安慰剂相比。有中度确定性证据表明，与度洛西汀（OR0.07，95%CI0.01，0.56）和依他普仑（OR0.06，95%CI0.01，0.56）相比，文拉法辛可能“至少略微”增加自杀相关结果的几率。关于抗抑郁药之间的其他比较，有非常低确定性的证据。
总体而言，随机试验的方法学缺陷使得难以解释新一代抗抑郁药物在疗效和安全性方面的发现。研究结果表明，与安慰剂相比，大多数新一代抗抑郁药可能会以小而不重要的方式减轻抑郁症状。此外，大多数抗抑郁药之间可能存在小而不重要的抑郁症状缓解差异。然而，我们的发现反映了抗抑郁药的平均效果，由于抑郁症是一种异质性疾病，一些人可能会有更大的反应。指南制定者和其他提出建议的人可能因此考虑是否为某些人在某些情况下推荐使用新一代抗抑郁药。我们的研究结果表明，舍曲林、依他普仑、度洛西汀以及目前唯一推荐用于一线治疗的氟西汀可能被视为首选药物。在试验中，经常排除考虑自杀的儿童和青少年，因此我们不能确定这些药物对这些人的疗效。如果正在考虑为个人开抗抑郁药，应与儿童/青少年及其家人/照顾者一起进行，并且仍然至关重要的是，要密切监测接受新一代抗抑郁药治疗的个体的治疗效果和自杀相关结果（结合自杀意念和自杀企图），因为研究结果表明，一些此类药物可能与这些事件的几率增加有关。考虑心理治疗，特别是认知行为疗法，仍然是符合指南建议的。
