Carmine M. Pariante, MD, PhD

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.

 This is indicated by raised circulating levels of proinflammatory cytokines, such as interleukin (IL)-6 and tumor necrosis factor (TNF)-Î±, 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 colleagues

 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.

 A slightly lower rate was found by Wysokinski.

 Remarkably, we still do not know the factors that lead to increased inflammation in these depressed patients.

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.

 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.

 However, early life stress increases CRP levels over and above these other confounders.

These findings were replicated in other studies. In a meta-analysis of the literature on the effects of early life stress on inflammation, early (mostly pre-pubertal) exposure to physical and sexual violence, or severe social deprivation increased inflammation in young adults-especially (but not only) if depressed.

More recently, we have been able to replicate the association between early life stress and increased inflammation in young adults who have been exposed to stress not in childhood but in utero because of maternal depression in pregnancy.

 We evaluated the offspring from the South London Child Development Cohort, a longitudinal sample of depressed women who were recruited and assessed during pregnancy. We found that offspring exposed to maternal depression, now young adults, have increased inflammation as shown by raised CRP levels, in the absence of any depressive symptoms. Thus, exposure to stress in utero is associated with increased inflammation in adulthood as a risk factor for depression, rather than being a consequence of depression.

We recently reviewed the effects of immune gene variants on depression’s severity and response to antidepressant treatment.

 Based largely on candidate-gene studies, findings indicate that common genetic variants are involved in both immune activation and depression. The most replicated and relevant genetic variants include single nucleotide polymorphisms (SNPs) in the genes for interleukin (IL)-1Î², IL-6, IL-10, TNF-Î±, phospholipase A2, and CRP.

Moreover, a number of studies have shown that the effects of some SNPs may only become evident in the presence of life stressors, through a “gene-environment” interaction. For example, KovÃ¡cs and colleagues

 report that the high-IL-1Î² T allele of the rs16944 SNP leads to increased depressive symptoms in adults, but only in individuals exposed to early life stress. Similarly, we have recently found that a polymorphism in the alpha-2-macroglobulin, an acute phase protein that is activated during inflammation, leads to depressive symptoms but only in the presence of a history of early life stress.

The BanI polymorphism of the cytosolic phospholipase A2 (cPLA2) gene and the rs4648308 polymorphism in the cyclooxygenase 2 (COX-2) gene regulate the risk for depression in patients exposed to interferon (INF)-Î±.

 Interestingly, carriers of the 2 genotypes were found to have lower levels of the omega-3 fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), before and during IFN-Î± treatment.

Considering the putative antidepressants and anti-inflammatory action of these omega-3 fatty acids, we speculated that genetically driven low levels of these endogenous anti-inflammatory compounds increase the risk of inflammation-induced depression. We followed-up this initial observation with a clinical trial, which showed that prophylactic treatment with EPA and DHA (filling the putative endogenous anti-inflammatory reserve) prevents or delays the onset of INF-Î± induced depression.

Our findings are consistent with a recent clinical trial by Rapaport and colleagues

 who used immune biomarkers to predict treatment response to EPA (vs placebo) as nutritional treatment for depression. Participants with increased inflammation improved more on EPA than placebo. These findings confirmed the notion that increased inflammation can characterize a group of depressed patients who are more likely to benefit from treatment with omega-3 fatty acids. It is interesting to note that subjects with no inflammation did better on placebo than on EPA.

Depressed patients who are resistant to conventional antidepressants tend to have higher concentrations of immune biomarkers, both as plasma/serum proteins and as blood mRNA levels. Blood mRNA levels of 2 pro-inflammatory cytokines-macrophage inhibiting factor (MIF) and IL-1Î²-are accurate and reliable prospective predictors of antidepressant response.

 We independently replicated these findings in 2 clinical samples. Both samples demonstrated identical positive predictive values and specificity of 100% for future non-responders.

A larger, GENDEP sample, provides evidence that increased inflammation can predict better response to some antidepressants.

 High levels of serum CRP predicted lack of treatment response to the SSRI, escitalopram, but not to the tricyclic (and noradrenergic uptake inhibitor) nortriptyline. The researchers explain this by speculating that antidepressants with a noradrenergic action may have anti-inflammatory properties and are thus more likely to be effective in patients with high inflammation.

Interestingly, molecular analyses can explain why 2 immune biomarkers (MIF and IL-1Î²) may be better predictors than one biomarker alone (CRP). Functionally, CRP is only loosely connected with IL-1Î² (it is not connected with MIF), which indicates that patients with high levels of CRP may be different from those with high levels of MIF or IL-1Î². CRP levels in the study undertaken by Uher and colleagues16 predicted a response by only about 11% compared with 40% to 50% of the variance explained by cytokines mRNA levels in our study.

Because MIF and IL-1Î² are functional neighbor target’, it is possible that having high levels of either of these cytokines is enough to activate downstream targets of both, thus affecting the neuroplasticity targets of MIF and the neurodegeneration targets of IL-1Î². These widespread molecular abnormalities would likely inhibit the response to a wide range of antidepressants.

These findings and those for omega-3 fatty acids confirm the notion that high levels of inflammation identify a group of depressed patients who are less likely to respond to conventional antidepressants. Indeed, these patients can benefit from nutritional interventions or from specific antidepressants that may have anti-inflammatory properties.

Perhaps the strongest evidence that supports the role of immune biomarkers in personalizing the treatment of depression comes from the clinical trial in which infliximab was used as an adjuvant strategy to treat severe, treatment-resistant depressed patients.

 The study found that only depressed patients with high levels of inflammation (in this case, CRP > 5 mg/L) respond to infliximab, while the anti-inflammatory is detrimental to mental health in patients with no inflammation, who respond better to placebo. These findings are similar to those of Rapaport and colleagues,

 who found that patients with increased inflammation improve more on EPA than placebo, and patients with no inflammation improve more on placebo than on EPA. Ongoing clinical trials are attempting to replicate these findings using adjuvant treatment with other anti-inflammatories such as sirukumab (ClinicalTrials.gov Identifier: NCT02473289) or minocycline (EudraCT Number: 2015-003413-26).

Together, the studies reviewed in this article provide a new model for clinical practice-one where the treatment of depressed patients is not governed by trial and error, but rather where patients with treatment-resistant depression can access new interventions sooner. This model would allow patients with inflammation above certain thresholds access to more assertive antidepressant strategies, including augmentation with antidepressants and nutritional strategies, or directly with anti-inflammatory drugs. Patients with inflammation below the suggested cutoffs could be directed toward usual care.

Randomized controlled trials that test the efficacy of using blood-based biomarkers compared with treatment as usual need to be undertaken that can provide clear guidelines for a personalized approach. We still do not know if there is a difference in the potential antidepressant action of different anti-inflammatories; we do know that there is an increased risk of adverse effects, such as gastric bleeding, when combining most conventional antidepressants with anti-inflammatories. Therefore, we are still a long-way from prescribing or advising patients to take aspirin for their depression. In the meantime, high-dose EPA (at least 1 g/d) is a safer, and thus more routinely advisable, adjuvant strategy for depressed patients with high inflammation until we have such clear guidelines.

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.

 KÃ¶hler CA, Freitas TH, Maes M, et al. Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. 

 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. 

 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). 

 Wysokinski A, Margulska A, Strzelecki D, Kloszewska I. Levels of C-reactive protein (CRP) in patients with schizophrenia, unipolar depression and bipolar disorder. 

 Danese A, Moffitt TE, Pariante CM, et al. Elevated inflammation levels in depressed adults with a history of childhood maltreatment. 

 Danese A, Moffitt TE, Harrington H, et al. Adverse childhood experiences and adult risk factors for age-related disease: depression, inflammation, and clustering of metabolic risk markers. 

 Baumeister D, Akhtar R, Ciufolini S, et al. Childhood trauma and adulthood inflammation: a meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-Î±. 

 Plant DT, Pawlby S, Sharp D, et al. Prenatal maternal depression is associated with offspring inflammation at 25 years: a prospective longitudinal cohort study. 

 Barnes J, Mondelli V, Pariante CM. Genetic contributions of inflammation to depression. Neuropsychopharmacol. 2017;42:81-98.

 Kovacs D, Eszlari N, Petschner P, et al. Effects of IL1B single nucleotide polymorphisms on depressive and anxiety symptoms are determined by severity and type of life stress. 

 Cattaneo A, Cattane N, Malpighi C, et al. FoxO1, A2M and TGF-B1: three novel genes predicting depression in gene X environment interactions are identified using cross-species and cross-tissues transcriptomic and miRNomic analyses. 

 Su KP, Huang SY, Peng CY, et al. Phospholipase A2 and cyclooxygenase 2 genes influence the risk of interferon-alpha-induced depression by regulating polyunsaturated fatty acids levels. 

 Su KP, Lai HC, Yang HT, et al. Omega-3 fatty acids in the prevention of interferon-alpha-induced depression: results from a randomized, controlled trial.

 Rapaport MH, Nierenberg AA, Schettler PJ, et al. Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof-of-concept study. 

 Cattaneo A, Ferrari C, Uher R, et al, for the MRC ImmunoPsychiatry Consortiu. Absolute measurements of macrophage migration inhibitory factor and interleukin-1-Î² mRNA levels accurately predict treatment response in depressed patients.

 Uher R, Tansey KE, Dew T, et al. An inflammatory biomarker as a differential predictor of outcome of depression treatment with escitalopram and nortriptyline. 

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The studies reviewed in this article provide a new model for clinical practice-one where the treatment of depressed patients is not governed by trial and error, but rather where patients can access new interventions sooner.

Carmine M. Pariante, MD, PhD

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