The serotonin hypothesis of depression is still influential. We aimed to synthesise and evaluate evidence on whether depression is associated with lowered serotonin concentration or activity in a systematic umbrella review of the principal relevant areas of research. PubMed, EMBASE and PsycINFO were searched using terms appropriate to each area of research, from their inception until December 2020. Systematic reviews, meta-analyses and large data-set analyses in the following areas were identified: serotonin and serotonin metabolite, 5-HIAA, concentrations in body fluids; serotonin 5-HT_1A receptor binding; serotonin transporter (SERT) levels measured by imaging or at post-mortem; tryptophan depletion studies; SERT gene associations and SERT gene-environment interactions. Studies of depression associated with physical conditions and specific subtypes of depression (e.g. bipolar depression) were excluded. Two independent reviewers extracted the data and assessed the quality of included studies using the AMSTAR-2, an adapted AMSTAR-2, or the STREGA for a large genetic study. The certainty of study results was assessed using a modified version of the GRADE. We did not synthesise results of individual meta-analyses because they included overlapping studies. The review was registered with PROSPERO (CRD42020207203). 17 studies were included: 12 systematic reviews and meta-analyses, 1 collaborative meta-analysis, 1 meta-analysis of large cohort studies, 1 systematic review and narrative synthesis, 1 genetic association study and 1 umbrella review. Quality of reviews was variable with some genetic studies of high quality. Two meta-analyses of overlapping studies examining the serotonin metabolite, 5-HIAA, showed no association with depression (largest n = 1002). One meta-analysis of cohort studies of plasma serotonin showed no relationship with depression, and evidence that lowered serotonin concentration was associated with antidepressant use (n = 1869). Two meta-analyses of overlapping studies examining the 5-HT_1A receptor (largest n = 561), and three meta-analyses of overlapping studies examining SERT binding (largest n = 1845) showed weak and inconsistent evidence of reduced binding in some areas, which would be consistent with increased synaptic availability of serotonin in people with depression, if this was the original, causal abnormaly. However, effects of prior antidepressant use were not reliably excluded. One meta-analysis of tryptophan depletion studies found no effect in most healthy volunteers (n = 566), but weak evidence of an effect in those with a family history of depression (n = 75). Another systematic review (n = 342) and a sample of ten subsequent studies (n = 407) found no effect in volunteers. No systematic review of tryptophan depletion studies has been performed since 2007. The two largest and highest quality studies of the SERT gene, one genetic association study (n = 115,257) and one collaborative meta-analysis (n = 43,165), revealed no evidence of an association with depression, or of an interaction between genotype, stress and depression. The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations. Some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentration.

抑郁症的血清素假说仍然有影响力。我们的目的是通过对主要相关研究领域的系统性综述，综合和评估抑郁症是否与血清素浓度或活性降低有关的证据。从 PubMed、EMBASE 和 PsycINFO 自成立到 2020 年 12 月，使用适合每个研究领域的术语进行了搜索。确定了以下领域的系统评价、荟萃分析和大数据集分析：血清素和血清素代谢物、5-HIAA ，体液中的浓度；血清素 5-HT _1A受体结合；通过成像或尸检测量血清素转运蛋白 (SERT) 水平；色氨酸消耗研究；SERT 基因关联和 SERT 基因-环境相互作用。与身体状况和抑郁症特定亚型（例如双相抑郁症）相关的抑郁症研究被排除在外。两名独立评审员使用 AMSTAR-2、改良版 AMSTAR-2 或用于大型遗传研究的 STREGA 提取数据并评估纳入研究的质量。研究结果的确定性使用修改后的 GRADE 版本进行评估。我们没有综合各个荟萃分析的结果，因为它们包括重叠的研究。该审查已在 PROSPERO 注册（CRD42020207203）。纳入 17 项研究：12 项系统评价和荟萃分析、1 项协作荟萃分析、1 项大型队列研究荟萃分析、1 项系统评价和叙述综合、1 项遗传关联研究和 1 项总体评价。一些高质量的基因研究的评论质量参差不齐。对检查血清素代谢物 5-HIAA 的重叠研究进行的两项荟萃分析显示，与抑郁症没有关联（最大n  = 1002）。一项对血浆血清素队列研究的荟萃分析显示，血清素浓度与抑郁症没有关系，并且有证据表明血清素浓度降低与抗抑郁药物的使用相关（n  = 1869）。对检查 5-HT _1A受体（最大n = 561）的重叠研究进行的两项荟萃分析以及对检查 SERT 结合（最大n = 1845） 的重叠研究进行的三项荟萃分析 显示，某些区域的结合减少的证据微弱且不一致，如果这是最初的因果异常，那么这与抑郁症患者突触可用血清素的增加是一致的。然而，不能可靠地排除先前使用抗抑郁药物的影响。色氨酸消耗研究的一项荟萃​​分析发现，对大多数健康志愿者（n  = 566）没有影响，但有微弱的证据表明对有抑郁症家族史的人（n  = 75）有影响。另一项系统评价 ( n  = 342) 和十个后续研究的样本 ( n = 407）发现对志愿者没有影响。自 2007 年以来，尚未对色氨酸消耗研究进行过系统回顾。两项最大且质量最高的 SERT 基因研究，一项基因关联研究 ( n  = 115,257) 和一项协作荟萃分析 ( n  = 43,165)，没有发现任何证据表明与抑郁症的关联，或基因型、压力和抑郁症之间的相互作用。血清素研究的主要领域没有提供一致的证据证明血清素与抑郁症之间存在关联，也没有支持抑郁症是由血清素活性或浓度降低引起的假设。一些证据与长期使用抗抑郁药会降低血清素浓度的可能性相一致。