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Replication and reproducibility issues in the relationship between C-reactive protein and depression: A systematic review and focused meta-analysis
Open accessAbstract
One of the most common inflammatory markers examined in depression is C-reactive protein (CRP). However, the magnitude of the association between CRP and depression when controlling for potentially confounding factors such as age, sex, socio-economic status, body mass index, medication and other substance use, and medical illness, is unclear. Inconsistencies in other methodological practices, such as sample collection, assaying, and data cleaning and transformation, may contribute to variations in results. We aggregate studies that examined the association between CRP and depression in two ways. First, a systematic review summarizes how studies of CRP and depression have reported on methodological issues. Second, a tiered meta-analysis aggregates studies that have adhered to various levels of methodological rigor. Findings from the systematic review indicate a lack of protocol detail provided. The effect between depression and CRP was small, but highly significant across all stages of the meta-analysis (p < 0.01). The effect size in the most methodologically rigorous stage of the meta-analysis, which included studies controlling for age, sex, obesity, medical conditions and substance, medication, or psychosocial factors, was small (r = 0.05). There were also only 26 articles in this stage (13% of studies from the systematic review), suggesting that more studies that consistently account for these confounding factors are needed. Additionally, an a priori quality score of methodological rigor was a significant moderator in this stage of the meta-analysis. The effect size was strikingly attenuated (r = 0.005) and non-significant in studies with higher quality scores. We describe a set of recommended guidelines for future research to consider, including sample collection and assaying procedures, data cleaning and statistical methods, and control variables to assess.
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“Based on prior work,12,45,46 we controlled for extraneous factors associated with inflammation.”
From Social Media Use and Its Link to Physical Health Indicators (2022) · cites this paper as [45]
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“Based on prior work (Horn et al., 2018; Lee and Way, 2019; O'Connor et al., 2009), we controlled for extraneous factors that have been associated with inflammation.”
From Social media use and systemic inflammation: The moderating role of self-esteem (2021) · cites this paper as Horn et al., 2018
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“as they have been shown to have anti-inflammatory properties (see Horn et al., 2018).”
From Social media use and systemic inflammation: The moderating role of self-esteem (2021) · cites this paper as Horn et al., 2018
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“Furthermore, neurovascular damage induced by the peripheral myeloid cells, pro-inflammatory cytokines, and the dysregulation of the complement pathways could be a further potential mechanism of action [36,37,38].”
From C-Reactive protein as a biomarker for major depressive disorder? (2022) · cites this paper as [38]
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Metadata
- Authors
- Horn, S. R., Long, M. M., Nelson, B. W., Allen, N. B., Fisher, P. A., & Byrne, M. L.
- Affiliations
- University of Oregon (US)
- Leiden University (NL)
- Corresponding author
- Horn, Sarah R.
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2018-10
- Volume
- 73
- Pages
- 85-114
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC6800199
- OpenAlex
- W2809379956
- Cited by
- 129
- References
- 258
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 14 · 2023: 18 · 2022: 21 · 2021: 19 · 2020: 19 · 2019: 16 · 2018: 4
- FWCI
- 1.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Brain Behavior and Immunity (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Science Foundation Graduate Research Fellowship Program (2017244647)
- NIH (R01 HD075716, P50 DA035763)
- National Institute of Mental Health of the National Institutes of Health (K01MH111951)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- C-reactive protein, depression, inflammation, replication, reproducibility, confounding adjustment, methodological quality, data cleaning, quality scores
- MeSH terms
- C-Reactive Protein, Depression, Depressive Disorder, Female, Humans, Inflammation, Male, Reproducibility of Results, Biomarkers, Comorbidity, Confounding Factors, Epidemiologic
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