Abstract
抽象

Background
背景

This systematic review evaluated St. John’s wort (SJW) for the treatment of Major Depressive Disorder (MDD). The objectives of this review are to (1) evaluate the efficacy and safety of SJW in adults with MDD compared to placebo and active comparator and (2) evaluate whether the effects vary by severity of MDD.
本系统评价评估了圣约翰草 （SJW） 治疗重度抑郁症 （MDD） 的效果。本综述的目的是 （1） 与安慰剂和活性对照剂相比，评估 SJW 在成人 MDD 患者中的疗效和安全性，以及 （2） 评估效果是否因 MDD 的严重程度而异。

Methods
方法

We searched PubMed, CINAHL, PsycINFO, CENTRAL, Embase, AMED, MANTIS, Web of Science, and ICTRP and existing reviews to November 2014. Two independent reviewers screened the citations, abstracted the data, and assessed the risk of bias. We included randomized controlled trials (RCTs) examining the effect of at least a 4-week administration of SJW on depression outcomes against placebo or active comparator in adults with MDD. Risk of bias was assessed using the Cochrane Risk of Bias tool and USPSTF criteria. Quality of evidence (QoE) was assessed using the GRADE approach.
我们检索了截至2014年11月的PubMed、CINAHL、PsycINFO、CENTRAL、Embase、AMED、MANTIS、Web of Science和ICTRP以及现有综述。两名独立评价员筛选引文，提取数据，并评估偏倚风险。我们纳入了随机对照试验 （RCTs），这些试验研究了至少 4 周的 SJW 给药与安慰剂或阳性对照药物对成人 MDD 患者抑郁结局的影响。使用 Cochrane 偏倚风险工具和 USPSTF 标准评估偏倚风险。使用 GRADE 方法评估证据质量 （QoE）。

Results
结果

Thirty-five studies examining 6993 patients met inclusion criteria; eight studies evaluated a hypericum extract that combined 0.3 % hypericin and 1–4 % hyperforin. The herb SJW was associated with more treatment responders than placebo (relative risk [RR] 1.53; 95 % confidence interval [CI] 1.19, 1.97; I² 79 %; 18 RCTs; N = 2922, moderate QoE; standardized mean differences [SMD] 0.49; CI 0.23, 0.74; 16 RCTs; I² 89 %, N = 2888, moderate QoE). Compared to antidepressants, SJW participants were less likely to experience adverse events (OR 0.67; CI 0.56, 0.81; 11 RCTs; moderate QoE) with no difference in treatment effectiveness (RR 1.01; CI 0.90, 1.14; 17 RCTs, I² 52 %, moderate QoE; SMD −0.03; CI −0.21, 0.15; 14 RCTs; I² 74 %; N = 2248, moderate QoE) in mild and moderate depression.
35 项研究涉及 6993 名患者，符合纳入标准;8 项研究评估了一种金丝桃提取物，该提取物结合了 0.3 % 金丝桃素和 1-4 % 金丝桃素。与安慰剂相比，草药 SJW 与更多的治疗反应者相关 （相对风险 [RR] 1.53;95 % 置信区间 [CI] 1.19， 1.97;I² 79 %;18 项随机对照试验; N=2922，中等 QoE;标准化平均差 [SMD] 0.49;CI 0.23， 0.74;16 项随机对照试验;I² 89 %， N=2888，中等 QoE）。与抗抑郁药相比，SJW 参与者发生不良事件的可能性较小 （OR 0.67;CI 0.56， 0.81;11 项随机对照试验;中等 QoE），治疗效果无差异 （RR 1.01;CI 0.90， 1.14;17 项随机对照试验，I² 52 %，中等 QoE;表面贴花 −0.03;CI -0.21， 0.15;14 项随机对照试验;I² 74 %; N=2248，中度 QoE）在轻度和中度抑郁症中。

Conclusions
结论

SJW monotherapy for mild and moderate depression is superior to placebo in improving depression symptoms and not significantly different from antidepressant medication. However, evidence of heterogeneity and a lack of research on severe depression reduce the quality of the evidence. Adverse events reported in RCTs were comparable to placebo and fewer compared with antidepressants. However, assessments were limited due to poor reporting of adverse events and studies were not designed to assess rare events. Consequently, the findings should be interpreted with caution.
SJW 单药治疗轻度和中度抑郁症在改善抑郁症状方面优于安慰剂，与抗抑郁药物没有显着差异。然而，异质性的证据和缺乏对严重抑郁症的研究降低了证据的质量。RCT 中报告的不良事件与安慰剂相当，与抗抑郁药相比更少。然而，由于不良事件的报告不佳，评估受到限制，并且研究并非旨在评估罕见事件。因此，应谨慎解释这些发现。

Systematic review registration
系统综述注册

PROSPERO CRD42015016406.

Electronic supplementary material
电子辅助材料

The online version of this article (doi:10.1186/s13643-016-0325-2) contains supplementary material, which is available to authorized users.
本文的在线版本 （doi：10.1186/s13643-016-0325-2） 包含补充材料，可供授权用户使用。

Keywords: St. John’s wort, Major depressive disorder, Complementary and alternative medicine, Herb, Systematic review, Meta-analysis, Antidepressant
关键词： 圣约翰草， 重度抑郁症， 补充和替代医学， 草药， 系统评价， 荟萃分析， 抗抑郁药

Background
背景

Depressive disorders are one of the largest sources of disease burden. More than 350 million people worldwide suffer from depression at any one time, and this number appears to be on the rise [1]. The condition affected approximately 15 million individuals in the USA in the last year, with a 12-month prevalence of 4.8 % in men and 8.2 % in women, yet the condition remains underdiagnosed and undertreated [2]. Depression has severe consequences for the lives of individuals. Nearly 43 % of those with severe depression in the USA report serious difficulties with work, home, or social activities [3]. Depression is also linked to an estimated productivity loss of 5.6 h per week and $40 billion a year [4].
抑郁症是疾病负担的最大来源之一。全世界任何时候都有超过 3.5 亿人患有抑郁症，而且这个数字似乎还在上升 [1]。去年，该病在美国影响了大约 1500 万人，其中 12 个月的患病率为男性 4.8 %，女性为 8.2 %，但该病症仍然诊断不足和治疗不足 [2]。抑郁症对个人的生活有严重的后果。在美国，近 43 % 的重度抑郁症患者报告在工作、家庭或社交活动方面存在严重困难 [3]。抑郁症还与估计每周 5.6 小时的生产力损失和每年 400 亿美元的生产力损失有关 [4]。

Pharmacotherapy and psychotherapy are established treatments and have been shown to be effective to treat depressive disorders, such as major depressive disorder (MDD). However, stigma, costs, discomfort with, or lack of availability of, mental health treatment, side effects of medication, and other factors cause many individuals to
药物治疗和心理治疗是公认的治疗方法，并已被证明可有效治疗抑郁症，例如重度抑郁症 （MDD）。然而，耻辱感、费用、对心理健康治疗的不适或缺乏可用性、药物的副作用和其他因素导致许多人not seek standard treatments. For centuries, extracts of the herb St. John’s wort (botanical name 
不寻求标准治疗。几个世纪以来，草本圣约翰草（植物学名称Hypericum perforatum
贯叶连翘 L., SJW) have been used to treat various conditions, including depressive disorders. Existing clinical practice guidelines vary in their recommendations to include SJW as a treatment option for treating depressive disorders [
L.， SJW） 已被用于治疗各种疾病，包括抑郁症。现有的临床实践指南在将 SJW 作为治疗抑郁障碍的治疗选择方面存在差异 [5]. A Cochrane Review of SJW for depression documented available research studies published to 2008 and found a beneficial effect compared to both placebo and other antidepressant therapies across 29 double-blind randomized controlled trials (RCTs) [
].SJW 治疗抑郁症的 Cochrane 综述记录了截至 2008 年发表的现有研究，并在 29 项双盲随机对照试验 （RCT） 中发现与安慰剂和其他抗抑郁疗法相比，具有有益效果 [6]. The review concluded that the available evidence suggested that hypericum extracts tested in the included trials are superior to placebo and patients with major depression and are similarly effective as standard antidepressants, and have fewer side effects than standard antidepressants. Overall, SJW has been considered safe but side effects have been noted, including photosensitivity, elevated thyroid stimulating hormones, hypertensive crisis, and induction of mania [
].本综述得出的结论是，现有证据表明，在纳入的试验中测试的金丝桃提取物优于安慰剂和重度抑郁症患者，与标准抗抑郁药相似有效，并且比标准抗抑郁药的副作用更少。总体而言，SJW 被认为是安全的，但已注意到副作用，包括光敏性、促甲状腺激素升高、高血压危象和躁狂诱导 [7]. In addition, preparations of SJW vary in the amounts of active compounds they contain, which may make it difficult to compare across studies [
].此外，SJW 制剂所含活性化合物的量各不相同，这可能使得难以在研究之间进行比较 [8].

In recent years, more research on SJW has been published in the international literature testing not only its effectiveness compared to placebo conditions but testing also its comparative effectiveness and comparative safety compared with standard antidepressant treatment. This review aims to synthesize all available RCTs in a comprehensive systematic review in order to provide reliable and current estimates of the effectiveness and comparative effectiveness and safety of SJW compared to placebo or antidepressant treatment in the treatment of adults with MDD (see Additional file 1 for PRISMA checklist).
近年来，国际文献中发表了更多关于 SJW 的研究，不仅测试了它与安慰剂条件相比的有效性，还测试了它与标准抗抑郁治疗相比的比较有效性和相对安全性。本综述旨在综合所有可用的随机对照试验，进行全面的系统评价，以便对SJW与安慰剂或抗抑郁治疗治疗成人MDD相比的有效性、比较有效性和安全性提供可靠和最新的估计（PRISMA检查表见附加文件1 ）。

We set out to answer the following review questions:
我们着手回答以下评论问题：

What are the efficacy and safety of SJW in adults with MDD compared to placebo and active comparator?
与安慰剂和活性对照剂相比，SJW 对成人 MDD 患者的疗效和安全性如何？

Is there a difference in effect, depending on the type of MDD (i.e., mild, moderate, severe)?
根据 MDD 的类型（即轻度、中度、重度），效果是否有差异？

Methods
方法

Search strategy
检索策略

We searched the electronic databases PubMed, CINAHL (Cumulative Index to Nursing and Allied Health Literature), PsycINFO, CENTRAL (Cochrane
我们检索了电子数据库 PubMed、CINAHL （Cumulative Index to Nursing and Allied Health Literature）、PsycINFO、CENTRAL （CochraneCentral Register of Controlled Trials), Embase, AMED (Allied and Complementary Health Database), MANTIS (Manual, Alternative, and Natural Therapy Index System), Web of Science, and ICTRP (International Clinical Trials Registry Platform) without language restriction from January 2007 to November 2014 to identify recent reports of RCTs testing the efficacy and safety of SJW—used adjunctively or as monotherapy—to treat adults with MDD. RCTs published earlier than 2007 were identified through reference mining of included studies and previous systematic reviews related to SJW, including a Cochrane review that included trials on SJW for MDD published to July 2007 [
对照试验中心注册库（Central Register of Controlled Trials）、Embase、AMED（联合和补充健康数据库）、MANTIS（手动、替代和自然疗法索引系统）、Web of Science 和 ICTRP（国际临床试验注册平台），在 2007 年 1 月至 2014 年 11 月期间没有语言限制，以确定最近关于测试 SJW 疗效和安全性的 RCT（辅助或作为单一疗法）治疗成人 MDD 的报告。2007 年之前发表的 RCT 是通过对纳入的研究和与 SJW 相关的先前系统评价的参考挖掘来确定的，包括截至 2007 年 7 月发表的关于 SJW 治疗 MDD 的试验的 Cochrane 评价 [6]. The Cochrane review conducted a comprehensive search to locate SJW RCTs in the Clinical Trials Register of the Cochrane Collaboration Depression Anxiety & Neurosis Group (CCDANTR) until 2007, in PubMed until 2008, in the database of the Cochrane Field for Complementary Medicine, in the Medline SilverPlatter CD-ROM from 1983 onwards, in Embase from 1989 onward, in the Psychlit and Psychindex 1987–1997 CD-ROM, and in Phytodok [
].Cochrane综述进行了全面的搜索，以在Cochrane协作抑郁焦虑与神经症小组（CCDANTR）的临床试验注册中查找SJW RCTs，直到2007年在PubMed中，在Cochrane补充医学领域的数据库中，从1983年开始在Medline SilverPlatter CD-ROM中，从1989年开始在Embase中，在Psychlit和Psychindex 1987-1997 CD-ROM中， 在 Phytodok [6]. We screened all studies identified in the systematic searches, i.e., studies included or excluded from the Cochrane review. All studies included in the 2008 Cochrane review were eligible for inclusion, but our review also identified head-to-head trials comparing different St. John’s wort extracts, different dosage, and standard antidepressant interventions (including psychotherapy). Our search was not limited to peer-reviewed literature; we included grey literature, such as conference abstracts. We contacted authors to obtain full-text publications cited in other reviews or indexed in databases that were not available through information retrieval services or the original publisher; but, due to resource restrains, we did not systematically contact all authors for potential additional studies or data. The search strategy is available online. (see Additional file 
].我们筛选了系统检索中确定的所有研究，即纳入或排除在 Cochrane 综述中的研究。2008年Cochrane系统综述中纳入的所有研究均符合纳入标准，但我们的系统综述还确定了比较不同圣约翰草提取物、不同剂量和标准抗抑郁药干预（包括心理治疗）的头对头试验。我们的检索不仅限于同行评审的文献;我们纳入了灰色文献，例如会议摘要。我们联系了作者，以获取其他综述中引用的全文出版物，或在无法通过信息检索服务或原始出版商获得的数据库中编入索引的全文出版物;但是，由于资源限制，我们没有系统地联系所有作者以获取潜在的额外研究或数据。检索策略可在线获取。（请参阅附加文件2).

Eligibility criteria
资格

The inclusion and exclusion criteria for this review were developed using the framework of participants, interventions, comparators, outcomes, timing, settings, and study design or PICOTSS:
本综述的纳入和排除标准是使用受试者、干预措施、对照、结局、时间、设置和研究设计或 PICOTSS 的框架制定的：

Participants: Studies in adults, male and female, 18 years of age and over, with a diagnosis of MDD were eligible for inclusion in the review. In studies not referring to a clinical diagnosis based on Diagnostic and Statistical Manual of Mental Disorders (DSM) or International Classification of Diseases (ICD) criteria, we applied a specified threshold on validated depression scales (see Additional file 3). Studies that enrolled individuals with other comorbid conditions, such as traumatic brain injury, were eligible for inclusion. Studies in participants in postnatal depression were included if the criteria were in accordance with DSM-V criteria for MDD (i.e., peripartum onset or 4 weeks following delivery). Studies in individuals with diagnoses of dysthymia, bipolar disorder, or schizophrenia, alone or in combination with major depression, were excluded in accordance with DSM-V criteria. Studies evaluating multiple psychiatric conditions were included if the data for patients with MDD were presented separately.
参与者：针对 18 岁及以上被诊断为 MDD 的成人、男性和女性的研究符合纳入条件。在未参考基于 精神障碍 诊断与统计手册 （DSM） 或国际疾病分类 （ICD） 标准的临床诊断的研究中，我们在经过验证的抑郁量表上应用了指定的阈值（见附加文件 3）。招募患有其他合并症（如创伤性脑损伤）的个体的研究符合纳入标准。如果标准符合 MDD 的 DSM-V 标准（即围产期发病或分娩后 4 周），则纳入对产后抑郁参与者的研究。根据 DSM-V 标准，单独或联合重度抑郁症排除了诊断为心境恶劣、双相情感障碍或精神分裂症的个体的研究。如果 MDD 患者的数据单独呈报，则纳入评估多种精神疾病的研究。

Interventions: Studies that administered a supplement that contained a known amount of SJW, and the amount and type of active compounds contained in the SJW supplement that was specified (i.e., naphthodianthrones, hypericin, pseudohypericin, flavonoids, phloroglucinols, hyperforin, and adhyperforin), were eligible. SJW could be evaluated alone or in conjunction with pharmacologic and/or psychotherapy.
干预措施：使用含有已知量 SJW 的补充剂的研究，以及指定的 SJW 补充剂中所含活性化合物的数量和类型（即萘啶、金丝桃素、假金丝桃素、类黄酮、根皮葡萄糖醇、金丝桃素和超贯叶素）的研究，均符合条件。SJW 可以单独评估，也可以与药物和/或心理治疗联合评估。

Comparator: Studies comparing SJW with placebo or with active comparators, or against another amount or extract of SJW, were eligible.
对照：将 SJW 与安慰剂或活性对照剂，或与其他量或提取物的 SJW 进行比较的研究符合条件。

Outcomes: Studies that reported Hamilton clinical rating scale for depression (HAMD) scores or other validated depression scale scores were eligible for inclusion as well as studies that reported other changes in depressive symptoms (e.g., suicidal ideation) or the rate of treatment responders. Studies that reported the number of patients in remission or rates of depression relapse were also eligible. Studies that reported adverse events in adults taking SJW for MDD were included if adverse events were reported by study arm. Studies that reported on biomarkers alone without reporting efficacy for depression outcomes were excluded. Only studies that at least reported outcome assessments at baseline and at the end of treatment for both study arms were included. Studies of healthcare provider outcomes, acceptance, prevalence, use, costs, study design features, and intervention features not reporting patient health outcomes were excluded.
结局： 报告汉密尔顿抑郁临床评定量表 （HAMD） 评分或其他经过验证的抑郁量表评分的研究以及报告抑郁症状（例如自杀意念）或治疗反应率其他变化的研究均符合纳入标准。报告缓解患者人数或抑郁复发率的研究也符合条件。如果研究组报告了不良事件，则纳入报告服用 SJW 治疗 MDD 的成人不良事件的研究。仅报告生物标志物而不报告抑郁结局疗效的研究被排除在外。仅纳入至少报告了两个研究组在基线和治疗结束时结局评估的研究。排除了关于医疗保健提供者结局、接受度、患病率、使用、成本、研究设计特征和干预特征的研究，这些研究未报告患者健康结局。

Timing: Only studies with a treatment duration of 4 weeks or longer were eligible.
时间：只有治疗持续时间为 4 周或更长时间的研究才符合条件。

Setting: Studies were not limited by setting (e.g., country, physical location of treatment).
地点：研究不受地点限制（例如，国家、治疗的物理位置）。

Study design: Included studies were limited to RCTs.
研究设计： 纳入的研究仅限于 RCT。

Inclusion screening
纳入筛选

All article screening and abstraction was conducted using the systematic review software DistillerSR (Evidence Partners, Ottawa, Canada). Two independent reviewers screened titles and abstracts of retrieved citations. Citations judged as potentially eligible by one or both reviewers were obtained as full text. The full-text publications were screened against the specified inclusion criteria by the two independent reviewers using a standardized and pilot-tested form; any disagreements were resolved through discussion within the review team.
所有文章筛选和摘要均使用系统评价软件 DistillerSR （Evidence Partners， Ottawa， Canada） 进行。两名独立评价员筛选了检索到的引文的标题和摘要。被一位或两位评价员判断为可能符合条件的引文以全文形式获得。两位独立评价员使用标准化和试点测试的表格，根据规定的纳入标准筛选全文出版物;任何分歧都通过审核小组内部的讨论来解决。

Studies reporting on the same participants were counted as one study regardless of the number of publications the results were presented in. All study-related publications were considered and contributed to the data extraction.
报告相同受试者的研究被算作一项研究，无论结果在多少出版物中呈现。所有与研究相关的出版物都被考虑并有助于数据提取。

Data extraction
数据提取

Two reviewers abstracted study-level information. Categorical data concerning study details were abstracted independently by both reviewers; free text information concerning study details were abstracted by one reviewer and checked by the review lead. The reviewers pilot-tested the data collection forms prior to data extraction to ensure agreement of interpretation. Numerical outcome data were abstracted and checked by a single biostatistician.
两名评价员提取了研究层面的信息。两位评价员独立提取有关研究细节的分类数据;有关研究细节的自由文本信息由一名评价员提取，并由评价负责人检查。审查员在数据提取之前对数据收集表进行了试点测试，以确保解释一致。数值结果数据由一名生物统计学家提取和检查。

The following information was abstracted from each study:
从每项研究中摘录了以下信息：

Participants: MDD diagnostic criteria, baseline measure of depression symptoms, depression severity (mild, moderate, or severe) using the authors’ description, depression history (e.g., recurrent), comorbidities, mean age and age range, gender
参与者：MDD 诊断标准、抑郁症状的基线测量、使用作者描述的抑郁严重程度（轻度、中度或重度）、抑郁病史（例如，复发性）、合并症、平均年龄和年龄范围、性别

Interventions: details including amount and type of active compounds contained in the SJW supplement, dosage, co-intervention(s)
干预措施：详细信息，包括 SJW 补充剂中所含活性化合物的数量和类型、剂量、共同干预措施

Comparators: type and description of comparator
Comparators：比较器的种类和描述

Outcomes assessed: assessment measures and primary endpoint, method of data expression (e.g., mean difference), results (effect estimate, precision)
评估的结果：评估措施和主要终点、数据表达方法（例如，平均差）、结果（效果估计、精度）

Timing: time-points of outcome assessment, duration of intervention
时间：结果评估的时间点、干预持续时间

Setting: country
设置：国家/地区

Study design: aim of study, inclusion and exclusion criteria, sample size and reported power calculations, funding source.
研究设计：研究目的、纳入和排除标准、样本量和报告的功效计算、资金来源。

Outcome data were based on intention-to-treat (ITT) analyses. In the absence of reported ITT data, we used the number randomized as the denominator; in the absence of the number randomized, we used the number of participants at follow-up. All studies were analyzed using the latest reported follow-up; however, studies reporting follow-up only for a subsample of treatment responders were not considered. Follow-up used the baseline as the point of reference, not the end of treatment; most studies assessed treatment effects directly after the end of treatment but treatment duration varied. When multiple depression measures were available, we used HAMD scores to assess treatment effects on depression symptoms. We used the authors’ definition of response to treatment, usually reflecting a 50 % decrease in HAMD scores. We used the authors’ definition of remission, usually reflecting a HAMD score of less than seven or eight. We computed standardized mean differences (SMDs) for studies reporting continuous outcomes, relative risks (RRs) for treatment effect estimates, and odds ratios (ORs) for rare adverse events, together with the 95 % confidence interval (CI).
结局数据基于意向性治疗 （ITT） 分析。在没有报告的 ITT 数据的情况下，我们使用随机化的数字作为分母;在没有随机人数的情况下，我们使用了随访中的受试者人数。所有研究都使用最新报告的随访进行分析;然而，未考虑仅报告治疗反应者子样本随访的研究。随访使用基线作为参考点，而不是治疗结束;大多数研究在治疗结束后立即评估治疗效果，但治疗持续时间各不相同。当有多种抑郁指标可用时，我们使用 HAMD 评分来评估治疗对抑郁症状的影响。我们使用了作者对治疗反应的定义，通常反映 HAMD 评分下降了 50%。我们使用了作者对缓解的定义，通常反映 HAMD 评分小于 7 或 8。我们计算了报告连续性结局的研究的标准化均数差（standardized mean differences， SMDs）、治疗效果估计的相对风险（relative risk， RRs）、罕见不良事件的比值比（odds ratios， ORs），以及95%置信区间（confidence interval， CI）。

Risk of bias
偏倚风险

Two reviewers independently assessed the risk of bias of included studies using the Cochrane Risk of Bias tool [9] and criteria used by the US Preventative Services Task Force [10]. We assessed random sequence generation (selection bias); allocation concealment (selection bias); blinding of participants and providers (performance bias); blinding of outcome assessors (detection bias); completeness of reporting outcome data (attrition bias); selective outcome reporting (reporting bias); whether treatment group received plus treatment as usual SJW and the control group received treatment as usual plus no additional treatment (“add-on trial”); washout periods or exclusion of individuals taking personal supplement; equal distribution among groups of potential confounders at baseline; crossovers or contamination between groups; equal, reliable, and valid outcome measurement; clear definitions of interventions; and ITT analysis. The criteria were used to rate the quality of individual studies using the following guidelines [10, 11]:
两位评价员使用Cochrane偏倚风险工具[9]和美国预防服务工作组使用的标准[10]独立评估纳入研究的偏倚风险。我们评估了随机序列生成（选择偏倚）;分配隐藏（选择偏倚）;参与者和提供者的盲法（实施偏倚）;结局评价者的盲法（检测偏倚）;报告结局数据的完整性（失访偏倚）;选择性结局报告（报告偏倚）;治疗组是否接受常规加常规治疗 SJW，对照组是否接受常规治疗加无额外治疗（“附加试验”）;清除期或排除服用个人补充剂的个人;基线时潜在混杂因素组之间的平均分配;组间交叉或污染;平等、可靠和有效的结果测量;明确的干预措施定义;和 ITT 分析。这些标准用于使用以下指南对单个研究的质量进行评分 [10， 11]：

Good: Comparable groups are initially assembled and maintained throughout the study with at least 80 % follow-up; reliable, valid measurement is used and applied equally to all groups; interventions are clearly described; all important outcomes are considered; appropriate attention is given to confounders in analysis; and ITT analysis is used.
良好：在整个研究过程中，最初收集并维持可比组，至少 80 % 的随访;使用可靠、有效的测量方法并平等地应用于所有组;清楚地描述了干预措施;考虑了所有重要结果;在分析中适当关注混杂因素;并使用 ITT 分析。

Fair: One or more of the following issues is found in the study: some though not major differences between groups exist at follow-up; measurement instruments are acceptable but not ideal, though are generally applied equally; some but not all important outcomes are considered; some but not all potential confounders are accounted for in analyses. ITT analysis must be done.
公平：在研究中发现了以下一个或多个问题： 随访时组之间存在一些但不主要的差异;测量工具是可以接受的，但并不理想，尽管通常应用相同;考虑一些但不是所有重要结果;在分析中考虑了一些但不是所有潜在的混杂因素。必须进行 ITT 分析。

Poor: One or more of the following “fatal flaws” is found in the study: initially assembled groups are not comparable or maintained throughout the study; unreliable or invalid measurements are used or applied unequally across groups; key confounders are given little to no attention in analyses; ITT analysis is not used.
差：在研究中发现了以下一个或多个“致命缺陷”：最初组合在一起的组在整个研究中没有可比性或维护性;不可靠或无效的测量方法在各组之间使用或应用不均;在分析中很少或没有关注关键的混杂因素;不使用 ITT 分析。

Critical appraisal assessments were used for sensitivity analyses by excluding poor quality studies to evaluate the robustness of findings.
通过排除低质量研究来评估结果的稳健性，采用关键评价评估进行敏感性分析。

Data synthesis
数据合成

The primary aim of this systematic review was to determine effects of SJW on depressive symptoms, quality of life, and adverse events compared with placebo and active comparators. We differentiated effectiveness and comparative effectiveness analyses. Placebo trials were used to estimate the treatment effect of SJW by demonstrating effects that go beyond placebo effects. A further key aim of the review was to determine the comparative effectiveness of SJW compared with standard antidepressant treatment (both psychotherapy or antidepressant medication). Comparative effectiveness results and equivalence assessments of the efficacy and safety took the consistency of effects across individual studies and the statistical power to detect a statistically significant difference between treatment groups into account. For all efficacy outcomes and the number of patients with adverse events, we used the Hartung-Knapp-Sidik-Jonkman method for a random effects meta-analysis [12–14]. For specific adverse events, many of which are very rare, we used exact conditional methods to estimate ORs and CIs. Heterogeneity was assessed using the I² statistic and values above 75 % were interpreted as possibly representing considerable heterogeneity.
本系统综述的主要目的是确定与安慰剂和活性对照相比，SJW 对抑郁症状、生活质量和不良事件的影响。我们区分了有效性分析和比较有效性分析。安慰剂试验用于通过证明超越安慰剂效应的效果来估计 SJW 的治疗效果。本综述的另一个关键目的是确定SJW与标准抗抑郁治疗（心理治疗或抗抑郁药物）相比的比较效果。疗效和安全性的比较有效性结果和等效性评估考虑了单个研究之间的效果一致性以及检测治疗组之间具有统计学意义差异的统计能力。对于所有疗效结局和不良事件患者数量，我们使用 Hartung-Knapp-Sidik-Jonkman 方法进行随机效应荟萃分析 [12–14]。对于特定的不良事件，其中许多非常罕见，我们使用精确的条件方法来估计ORs和CIs。使用 I² 统计量评估异质性，高于 75 % 的值被解释为可能代表相当大的异质性。

We conducted preplanned subgroup analyses for different patient groups depending on the severity of depression. In studies comparing SJW to antidepressant medication we differentiated selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (imipramine, amitriptyline), and other (e.g., maprotiline, Deanxit). Further meta-regressions were conducted to identify sources of heterogeneity across studies where appropriate. We conducted sensitivity analyses to test the robustness of results (e.g., to test effects in studies with sufficient power to detect effect differences between study arms or excluding poor quality studies). Publication bias was assessed with the Begg and Egger tests; in the case of indications for bias, treatment estimates were estimated using the trim-and-fill method.
我们根据抑郁的严重程度对不同的患者群体进行了预先计划的亚组分析。在将 SJW 与抗抑郁药物进行比较的研究中，我们区分了选择性 5-羟色胺再摄取抑制剂 （SSRIs）、三环类抗抑郁药（丙咪嗪、阿米替林）和其他药物（例如马普替林、Deanxit）。在适当的情况下，进行了进一步的 meta 回归分析，以确定研究间异质性的来源。我们进行了敏感性分析以测试结果的稳健性（例如，在具有足够把握度来检测研究组之间效果差异或排除低质量研究的研究中测试效果）。使用 Begg 和 Egger 检验评估发表偏倚;在偏倚指征的情况下，使用 trim-and-fill 方法估计治疗估计值。

Quality of evidence
证据质量

The quality of evidence was assessed using the GRADE approach [15]. The body of evidence was evaluated on the following dimensions: study limitations, inconsistency, directness, and precision. The quality was downgraded when results were primarily based on studies with substantial limitations and suspected risk of bias; when results were inconsistent across individual studies or the result was based on a single study without replication in an independent research study; in the presence of substantial heterogeneity in pooled analyses and variation in the direction of effects; when conclusions were based on indirect evidence (e.g., effects bases on subgroup analyses or meta-regressions in the absence of head-to-head comparisons); and when pooled results were imprecise estimates of the treatment effect with wide confidence intervals spanning effect sizes with different clinical conclusions. The quality of evidence was graded on a 4-item scale:
使用 GRADE 方法评估证据质量 [15]。根据以下维度评估证据主体： 研究局限性、 不一致性、 直接性和 精确性。当结果主要基于具有重大局限性和疑似偏倚风险的研究时，质量被降级;当单个研究的结果不一致或结果基于单个研究而没有在独立研究中重复时;在汇总分析中存在大量异质性和效应方向的变化;当结论基于间接证据时（例如，在没有头对头比较的情况下，效果基于亚组分析或 meta 回归）;当合并结果对治疗效果的估计不精确时，具有不同临床结论的效应大小的宽置信区间。证据质量按 4 项量表进行分级：

High indicates that review authors are very confident that the effect estimate lies close to the true effect for a given outcome, as the body of evidence has few or no deficiencies. As such, the reviewers believe the findings are stable and further research is very unlikely to change confidence in the effect estimate.
高 表示综述作者非常有信心，即效应估计接近给定结局的真实效应，因为证据主体很少或没有缺陷。因此，评价员认为研究结果是稳定的，进一步的研究不太可能改变对效果估计的信心。

Moderate indicates that the review authors are moderately confident that the effect estimate lies close to the true effect for a given outcome, as the body of evidence has some deficiencies. As such, the reviewers believe that the findings are likely to be stable, but further research may change confidence in the effect estimate and may even change the estimate.
中等 表示综述作者对效应估计接近给定结局的真实效应有中等信心，因为证据体存在一些缺陷。因此，评价员认为研究结果可能是稳定的，但进一步的研究可能会改变对效果估计的信心，甚至可能改变估计。

Low indicates that the review authors have limited confidence that the effect estimate lies close to the true effect for a given outcome, as the body of evidence has major or numerous (or both) deficiencies. As such, the reviewers believe that additional evidence is needed before concluding either that the findings are stable or that the effect estimate lies close to the true effect.
低 表示综述作者对效应估计接近给定结局的真实效应的信心有限，因为证据主体存在重大或大量（或两者兼而有之）缺陷。因此，评价员认为，在得出结论结论之前，需要额外的证据来证明研究结果稳定或效果估计值接近真实效果。

Very low indicates that the review authors have very little confidence that the effect estimate lies close to the true effect for a given outcome, as the body of evidence has very major deficiencies. As such, the true effect is likely to be substantially different from the estimated effect; thus, any estimate of effect is very uncertain.
Very low 表示综述作者对效应估计接近给定结局的真实效应几乎没有信心，因为证据主体存在非常重大的缺陷。因此，真实效果可能与估计效果有很大不同;因此，任何效果估计都是非常不确定的。

This review was registered in PROSPERO CRD42015016406.
本综述已注册在 PROSPERO CRD42015016406。

Results
结果

We identified 594 potentially relevant citations through the electronic database search and reference mining. We obtained 93 studies as full text. In total, 35 studies met inclusion criteria (see Fig. 1 for PRISMA diagram) [16–50]. All studies addressed the efficacy of SJW reporting on the rate of treatment responders, mean scores on depression scales, or the number of patients in remission. Very few studies reported on relapse and quality of life and studies. In total, 34 studies addressed safety and reported on the number of patients with adverse events or the frequency of individual events. Risk of bias in included studies varied: ten studies were rated “good,” 14 “fair,” and 11 “poor” quality (see Table 1). Table 2 shows key characteristics of the included studies.
我们通过电子数据库检索和参考文献挖掘确定了 594 篇可能相关的引文。我们获得了 93 项研究的全文。总共有35项研究符合纳入标准（PRISMA图见图1  ）[16–50]。所有研究都讨论了 SJW 报告治疗反应率、抑郁量表平均评分或缓解患者人数的疗效。很少有研究报告复发和生活质量以及研究。总共有 34 项研究涉及安全性，并报告了发生不良事件的患者人数或个体事件的频率。纳入研究的偏倚风险各不相同：10项研究被评为“良好”，14项为“一般”，11项为“差”质量（见表 1）。表 2 显示了纳入研究的主要特征。

Fig. 1.
图 1.

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Article flow diagram
文章流程图

Table 1.
表 1.

Study quality/risk of bias for individual included studies
纳入个体研究的研究质量/偏倚风险

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SJW St. John’s wort, ITT intention-to-treat analysis, TAU treatment as usual
SJW 圣约翰草， ITT 意向治疗分析， TAU 治疗照常进行

Table 2.
表 2.

Evidence table
证据表