With 7 meta-analyses published on this topic between 2009 and 2017, there is little doubt that patients with major depression have, on average, have increased activity of the inflammatory system.1 This is indicated by raised circulating levels of proinflammatory cytokines, such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α, and of acute phase proteins such as c-reactive protein (CRP). However, not all depressed patients have increased inflammation.
Using the American Heart Association definition of high cardiovascular risk (CRP >3 mg/L) to identify “inflamed” depressed patients, only approximately one-fourth to one-half of all depressed patients reach this threshold. Raison and colleagues2 report that 45% of treatment-resistant depressed patients in a clinical trial with infliximab had a CRP concentration greater than 3 mg/L. Similar findings were seen by Rethorst and colleague.3 A slightly lower rate was found by Wysokinski.4 Remarkably, we still do not know the factors that lead to increased inflammation in these depressed patients.
The role of early life stress
Results from our research show increased inflammation not only in depressed patients who have a history of childhood maltreatment but also in persons who have experienced maltreatment but who are not depressed.5 These findings suggest that exposure to childhood maltreatment is a potential risk factor for depression.
In a subsequent study, we found that inflammation is increased also in depressed patients with lower socioeconomic status in childhood or adulthood, and in patients with more cardiovascular risk factors, such as being overweight or having high blood pressure, high total cholesterol, and high glycated hemoglobin.6 However, early life stress increases CRP levels over and above these other confounders.
Professor Pariante has received consultation fees from Eleusis Ltd, research funding from Johnson & Johnson as part of a program of research on depression and inflammation, and research funding from the Medical Research Council (UK) and the Wellcome Trust for research on depression and inflammation as part of two large consortia that also include Johnson & Johnson, GSK, and Lundbeck.
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2. Raison CL, Rutherford RE, Woolwine BJ, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013;70:31-41.
3. Rethorst CD, Bernstein I, Trivedi MH. Inflammation, obesity, and metabolic syndrome in depression: analysis of the 2009-2010 National Health and Nutrition Examination Survey (NHANES). J Clin Psychiatry. 2014;75:e1428-1432.
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