Abstract
Low-grade inflammation plays a role not only in the pathogenesis of major depressive disorder (MDD) but probably also in the poor responsiveness to regular antidepressants. There are also indications that anti-inflammatory agents improve the outcomes of antidepressants. Aim: To study whether the presence of low-grade inflammation predicts the outcome of antidepressants, anti-inflammatory agents, or combinations thereof. Methods: We carried out a systematic review of the literature on the prediction capability of the serum levels of inflammatory compounds and/or the inflammatory state of circulating leukocytes for the outcome of antidepressant/anti-inflammatory treatment in MDD. We compared outcomes of the review with original data (collected in two limited trials carried out in the EU project MOODINFLAME) on the prediction capability of the inflammatory state of monocytes (as measured by inflammatory gene expression) for the outcome of venlafaxine, imipramine, or sertraline treatment, the latter with and without celecoxib added. Results: Collectively, the literature and original data showed that: 1) raised serum levels of pro-inflammatory compounds (in particular of CRP/IL-6) characterize an inflammatory form of MDD with poor responsiveness to predominately serotonergic agents, but a better responsiveness to antidepressant regimens with a) (add-on) noradrenergic, dopaminergic, or glutamatergic action or b) (add-on) anti-inflammatory agents such as infliximab, minocycline, or eicosapentaenoic acid, showing—next to anti-inflammatory—dopaminergic or lipid corrective action; 2) these successful anti-inflammatory (add-on) agents, when used in patients with low serum levels of CRP/IL-6, decreased response rates in comparison to placebo. Add-on aspirin, in contrast, improved responsiveness in such “non-inflammatory” patients; 3) patients with increased inflammatory gene expression in circulating leukocytes had a poor responsiveness to serotonergic/noradrenergic agents. Conclusions: The presence of inflammation in patients with MDD heralds a poor outcome of first-line antidepressant therapies. Immediate step-ups to dopaminergic or glutamatergic regimens or to (add-on) anti-inflammatory agents are most likely indicated. However, at present, insufficient data exist to design protocols with reliable inflammation parameter cutoff points to guide such therapies, the more since detrimental outcomes are possible of anti-inflammatory agents in “non-inflamed” patients.
Highlights
It is well accepted that immune dysregulation plays an important role in the pathogenesis of at least a proportion of patients with major depressive disorder (MDD) [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16]
We indicate in the result section (Table 1C, marked with B and C) which studies included bipolar depressed patients, and we discuss in the Discussion section putative differences stemming from this inclusion. [4] the absence of severe somatic diseases; [5] the assessment of immune biomarkers; [6] the use of first-line or other antidepressant agents or the use of an anti-inflammatory agent added to antidepressant treatment or alone; [7] the assessment of symptom reduction with standardized measure [e.g., Hamilton Rating Scale for Depression (HAMD), Montgomery–Asberg Depression Rating Scale (MADRS), Beck’s depression inventory (BDI)] and [8] the analysis of responder and non-responder subgroups
The data of the systematic review and experimental monocyte data, as presented in this study, collectively point in the direction that the state of so-called low-grade inflammation does play a role in the outcome of antidepressant therapy of patients with MDD
Summary
It is well accepted that immune dysregulation plays an important role in the pathogenesis of at least a proportion of patients with major depressive disorder (MDD) [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16]. Special interest has been raised for the role of low-grade inflammation in the immune system dysregulation of MDD. Thirdline agents are drugs with a predominantly noradrenergic/ dopaminergic action, such as mirtazapine or bupropion, or agents with other mechanisms of action, such as ketamine [i.e., an N-methyl-d-aspartate (NMDA) receptor antagonist, elevating glutamate levels]. Despite this wide range of medications, response rates to treatment are still insufficient, with about half of the patients not responding adequately to an installed treatment [26, 27]
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