Replication and reproducibility issues in the relationship between C-reactive protein and depression: A systematic review and focused meta-analysis

Abstract

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.

Association between C Reactive Protein and Depression in a Population of Healthy Adults: The Cooper Center Longitudinal Study

“…In the largest study to date, we found hs-CRP was not associated with depression among generally healthy adults after controlling for BMI. Our findings are consistent with prior population-based studies that found no significant association between CRP and depression independent of BMI 12 15. Our findings also align with other studies that found no association between CRP and depression independent of other covariates related to depression, including antidepressant use and chronic illness 10 11 13 16 27…”

Large-scale evidence for an association between low-grade peripheral inflammation and brain structural alterations in major depression in the BiDirect study

“…First, we studied a well-powered, homogeneous sample of patients with MDD. Second, we investigated high-sensitivity CRP (hsCRP) levels, a serum marker that has frequently been shown to provide reliable assessments of peripheral inflammation in MDD 23 as well as in other psychiatric disorders, such as bipolar disorder 24 and psychosis, 25 and that has repeatedly been associated with brain structural alterations. 16,20,22,26 Third, we used a voxel-based morphometry approach, which does not rely on a priori selection of regions of interest, allowing us to investigate structural alterations across the entire brain.…”

How handling extreme C-reactive protein (CRP) values and regularization influences CRP and depression criteria associations in network analyses

“…In fact, elevated inflammation is associated with treatment-resistant depression (Yang et al, 2019). In particular, the acute phase reactant Creactive protein (CRP) arguably is the most researched inflammatory index in depression research (Horn et al, 2018;Howren et al, 2009). CRP is a non-specific pentameric protein synthesized in the liver that is upregulated during the acute phase of inflammation in response to stimulation from other proinflammatory proteins (e.g., interleukin (IL)-6 and IL-1 ; Du Clos, 2000).…”