title: Cumulative meta-analysis of interleukins 6 and 1β, tumour necrosis factor α and C-reactive protein in patients with major depressive disorder.
abstract: Cumulative meta-analyses are used to evaluate the extent to which further studies are needed to confirm or refute a hypothesis. We used this approach to assess observational evidence on systemic inflammation in individuals with major depressive disorder. We identified 58 studies of four common inflammatory markers in a literature search of PubMed, Embase and PsychInfo databases in May 2014. Pooled data from the earliest eight studies already showed an association between interleukin-6 concentrations and major depression; 23 more recent studies confirmed this finding (d=0.54, p<0.0001). A significant association between C-reactive protein levels and major depression was noted after 14 studies and this did not change after addition of six more studies (d=0.47, p<0.0001). For these two inflammatory markers, there was moderate heterogeneity in study-specific estimates, subgroup differences were small, and publication bias appeared to be an unlikely explanation for the findings. Sensitivity analyses including only high-quality studies and subjects free of antidepressant medication further verified the associations. While there was a link between tumour necrosis factor-α levels and major depression (d=0.40, p=0.002), the cumulative effect remained uncertain due to the extensive heterogeneity in study-specific estimates and inconsistencies between subgroups. No evidence was found for the association between interleukin-1β levels and major depression (d=-0.05, p=0.86). In conclusion, this cumulative meta-analysis confirmed higher mean levels of interleukin-6 and C-reactive protein in patients with major depression compared to non-depressed controls. No consistent association between tumour necrosis factor-α, interleukin-1β and major depression was observed. Future studies should clarify the specific immune mechanisms involved as well as continue testing anti-inflammatory therapies in patients suffering from major depression.
authors.affiliation: Department of Epidemiology and Public Health, University College London, London, UK; Finnish Institute of Occupational Health, Systems Toxicology Unit, Centre of Expertise for Health and Work Ability, Helsinki, Finland; Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK. Electronic address: r.haapakoski@ucl.ac.uk.
authors.forename: Rita
authors.initials: R
authors.lastname: Haapakoski
authors.affiliation: Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK; Université Pierre et Marie Curie, Paris, France.
authors.forename: Julia
authors.initials: J
authors.lastname: Mathieu
authors.affiliation: Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.
authors.forename: Klaus P
authors.initials: KP
authors.lastname: Ebmeier
authors.affiliation: Finnish Institute of Occupational Health, Systems Toxicology Unit, Centre of Expertise for Health and Work Ability, Helsinki, Finland.
authors.forename: Harri
authors.initials: H
authors.lastname: Alenius
authors.affiliation: Department of Epidemiology and Public Health, University College London, London, UK; Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Mika
authors.initials: M
authors.lastname: Kivimäki
mesh_terms: D000328:Adult; D002097:C-Reactive Protein / Q000276:immunology* / Q000378:metabolism; D003865:Major Depressive Disorder / Q000097:blood / Q000150:complications / Q000276:immunology*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000150:complications / Q000276:immunology*; D018836:Inflammation Mediators / Q000097:blood / Q000276:immunology; D053583:Interleukin-1beta / Q000097:blood / Q000276:immunology*; D015850:Interleukin-6 / Q000097:blood / Q000276:immunology*; D008297:Male; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000276:immunology*
chemical_list: D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein
keywords: C-reactive protein; Cumulative meta-analysis; Inflammation; Interleukin-1β; Interleukin-6; Major depression; Tumour necrosis factor-α