Assessing 42 inflammatory markers in 321 control subjects and 887 major depressive disorder cases: BMI and other confounders and overall predictive ability for current depression

Abstract

Inflammatory markers such as cytokines represent potential biomarkers for major depressive disorder (MDD). Many, generally small studies have examined the role of single markers and found significant associations. We assessed 42 inflammatory markers, namely cytokines, in the blood of 321 control subjects and 887 MDD cases. We tested whether individual inflammatory marker levels were significantly affected by MDD case/control status, current episode, or current depression severity, covarying for age, sex, body mass index (BMI), smoking, current antidepressant use, ethnicity, assay batch and study effects. We further used machine learning algorithms to investigate if we could use our data to blindly discriminate MDD patients, or those in a current episode. We found broad and powerful influences of confounding factors on log-protein levels. Notably, IL-6 levels were very strongly influenced by BMI (p = 1.37 x 10 -43 , variance explained = 18%), while Interleukin-16 was the most significant predictor of current depressive episode (p = 0.003, variance explained = 0.9%, q < 0.1). No single inflammatory marker predicted MDD case/control status when a subject was not in a depressed episode, nor did any predict depression severity. Machine learning results revealed that using inflammatory marker data with clinical confounder information significantly increased precision for differentiating MDD patients who were in an episode. To conclude, a wide panel of inflammatory markers alongside clinical information may aid in predicting the onset of symptoms, but no single inflammatory protein is likely to represent a clinically useful biomarker for MDD diagnosis or prognosis.We note that the potential influence of physical health related and population stratification related confounders on inflammatory biomarker studies in psychiatry is considerable.

Associations between childhood maltreatment and inflammatory markers

“… 20 – 22 Indeed, we have recently reported major influences of BMI (as well as other factors) on inflammatory marker levels, namely CRP and IL-6, which once covaried for, removes MDD case–control differences in inflammatory marker levels. 18 Here, we replicate the effects of BMI on CRP and IL-6 levels in the ADD study, confirming the necessity to appropriately covary for BMI and other confounders in statistical models relating to inflammatory measures.…”

“…Upon use, serum was thawed at room temperature and 41 inflammatory markers were quantified simultaneously using multiplex enzyme-linked immunosorbent assay-based technology provided by the Meso Scale Discovery V-PLEX Plus Human Biomarker 40-Plex kit, and a customised human duplex kit assaying brain-derived neurotrophic factor and interferon-alpha, as described previously. 18 Seven-point standard curves were run in duplicate on each plate in order to calculate absolute pg/mL values for the 80 samples assayed per plate, and a no-template control was used to correct for background fluorescence. Case and control groups were randomised across batches, and plates were scanned on the Mesoscale Scale Discovery Meso Quickplex SQ 120 reader at the Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London.…”

“…Socioeconomic status was determined based on an individual's type of employment: manual work, non-manual work, unemployed and economically inactive (such as retired, full-time parents, students or those unable to work because of disability). Based on our previous work (which included SELCoH), 18 we also attempted to replicate the effects of BMI on levels of CRP and IL-6 (commonly shown to be associated with maltreatment and MDD) in the ADD study, using the same model as above.…”

Cerebrospinal fluid markers of inflammation and infections in schizophrenia and affective disorders: a systematic review and meta-analysis

“…Seventh, several studies did not match on important factors such as age or gender (eTable 4) and did not control for important confounders such as BMI, smoking or diet. These confounding factors have been shown to largely influence the associations between at least peripheral inflammatory markers and depression [96], which need to be considered in future studies also for CSF inflammatory markers. Finally, we had no knowledge regarding longitudinal data relating to clinical state and severity of the disorder or response to medications.…”

Genetic risk for severe COVID‐19 correlates with lower inflammatory marker levels in a SARS‐CoV‐2‐negative cohort

“…As a secondary aim, we considered how genetic risk interacted with age and body mass index (BMI) to affect inflammatory marker levels. We investigated this because the risk of severe COVID‐19 and associated mortality is higher amongst elderly and obese individuals, and because we have previously demonstrated a substantial influence of age and BMI on inflammatory marker levels 9‐12 . Our results shed important new insights into possible immunological mechanisms moderating risk for severe COVID‐19.…”