Inflammation and treatment resistance: Mechanisms and treatment implications

Introduction

Increasing data indicate that the immune system in general and inflammation in particular may play a role in the pathophysiology of psychiatric disorders including depression and anxiety ( ). These data include evidence of low-grade inflammation in subgroups of patients with a variety of psychiatric diseases as well as effects of inflammatory mediators on neurotransmitter systems and neurocircuits that regulate behavior ( ). Interestingly, there appears to be a special relationship between increased inflammation and treatment response, best documented in depression ( ; ; ; ). Data indicate that increased inflammatory markers prior to initiation of therapy predict poor treatment response to conventional antidepressants ( ; ), and treatment-resistant depressed patients exhibit increased markers of inflammation ( ; ; ). Moreover, a rich literature describes the multiple pathways by which inflammatory factors can disrupt neurotransmitter metabolism and growth factors and ultimately neurocircuits that are the foundations of treatment response to conventional antidepressant medications ( ; ). Increased inflammation is also associated with a better response to ketamine and electroconvulsive therapy (ECT) ( ; ), suggesting that a primary effect of inflammation is to undermine the efficacy of conventional antidepressant treatments, while increasing the responsiveness to alternative treatment strategies.

Given the relationship between inflammation and pathophysiologic mechanisms related to depression and other psychiatric disorders, studies using drugs with antiinflammatory properties have been investigated ( ). In general, there is modest evidence that antiinflammatory therapies may have potential to treat depression including treatment-resistant depression (TRD). However, due to multiple confounds involving both the designs and the drugs used in these studies, the results are almost impossible to interpret, and therefore, the field is bereft of meaningful clinical trial data to serve as the foundation for future research ( ; ; ).

The goal of this chapter is to first provide the basis for the hypothesis that inflammation plays a role in depression, including a review of the neurobiological and immunological mechanisms involved. Next, we will address the special relationship between inflammation and treatment resistance. Finally, we will review relevant clinical trials that have targeted inflammation in depression including TRD and make recommendations regarding the drugs and clinical trials’ designs of future studies in this area. It is the position of the authors that there is great promise in further understanding the translational relevance of the rich database that has been developed regarding the impact of inflammation on the brain and behavior. Indeed, as will be described, patients with increased inflammation can be readily identified, and given our knowledge regarding inflammatory pathways to pathology, we believe that targeting inflammation and/or its downstream effects on the brain will provide an important platform for precision psychiatry. By the same token, we also recognize that failure to integrate what is known about inflammation and its role in depression and other psychiatric disorders will result in a missed opportunity based on outdated clinical trial methodologies, drugs with multiple off-target effects, and outcomes that are not well-aligned with our understanding of the impact of inflammation on the brain.

Foundation for the hypothesis of inflammation’s role in depression

Patients with depression exhibit all the cardinal features of a chronic inflammatory response

The earliest studies examining the relationship between the immune system and depression were derived from human and laboratory animal studies demonstrating that a variety of stressors could inhibit lymphocyte proliferation in vitro ( ). Indeed, numerous studies demonstrated that peripheral blood immune cells from depressed patients exhibited decreased in vitro B- and T-cell responses as well as decreased natural killer (NK) cell activity ( ). These data suggested that depression was associated with suppression of acquired immune responses. Interestingly, however, data began to surface that in contrast to acquired immune responses, there was evidence of activation of the innate immune response as revealed by increased concentrations of acute phase proteins ( ). This early work served as the foundation for subsequent studies demonstrating increased markers of an activated innate immune inflammatory response including increased inflammatory cytokines, increased chemokines, and increased cellular adhesion molecules as well as increased acute phase proteins. Hundreds of papers have been published in this area, and meta-analyses of the literature have established reliable elevations of the inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF) and the acute phase protein C-reactive protein (CRP) in the peripheral blood of depressed patients ( ; ). Postmortem studies have also revealed evidence of an inflammatory response in the brain of depressed suicide victims including increased expression of toll-like receptors (TLRs) and other inflammatory signaling molecules in brain parenchyma ( ), activation of microglia and astrocytes ( ; ; ), and the presence of perivascular monocytes ( ; ). In addition, positron emission tomography (PET) using ligands that bind to the translocator protein (TSPO), which is expressed in microglia as well as other cell types in the brain, has provided evidence of microglial activation in depression ( ), although the specificity of these findings for neuroinflammation has yet to be established ( ). Finally, several large, longitudinal, epidemiological studies have shown that CRP and other inflammatory mediators can predict the development of depression, with less compelling data suggesting that depression leads to increased inflammation ( ).

Relationship with treatment nonresponse

Relevant to the response to antidepressants, a meta-analysis of the literature suggested that increased inflammatory biomarkers prior to treatment with conventional antidepressants (e.g., selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs)) is predictive of a reduced therapeutic response in ambulatory depressed patients ( ). Moreover, studies have indicated that treatment-resistant depressed patients exhibit increased inflammatory markers including IL-6, TNF, and CRP ( ; ). Molecular markers of inflammation including mRNA for the purinergic receptor P2RX7, IL-1beta, TNF, the CXC chemokine CXCL12, and migration inhibitory factor have also been shown to predict antidepressant nonresponse to SSRIs and SNRIs ( ). In addition, two studies have suggested that CRP may predict a differential response to antidepressants, with both studies finding a poor response to escitalopram in individuals with a CRP > 1 mg/L ( ; ). One of these studies found bupropion and the other found nortriptyline to lead to better responsiveness in the subgroup with CRP > 1 mg/L. Interestingly, increased inflammatory markers also have been found to predict a positive response to ketamine and ECT ( ; ). It should be noted, however, that most studies identifying inflammatory markers as predictors of treatment response have used post hoc analyses. Few studies have a priori determined that inflammatory markers can predict response to antidepressant or antiinflammatory treatment. Taken together, these data suggest that inflammatory markers have the potential to help guide treatment decision-making, especially as it relates to treatment response. Moreover, as discussed below, increased inflammatory markers appear to have special relevance to well-known predictors of treatment nonresponse including obesity, early life stress, medical illnesses, and anxiety ( ; ).

Administration of inflammatory cytokines/stimuli causes depressive symptoms

A second major body of data that supports the relationship between inflammation and depression, while also addressing the cause-and-effect nature of this relationship, is work demonstrating that administration of inflammatory cytokines (e.g., interferon (IFN)-alpha) or inflammatory stimuli (e.g., endotoxin or typhoid or influenza vaccination) leads to behavioral changes that are consistent with those seen in patients with depression ( ). For example, chronic treatment with IFN-alpha leads to symptoms that meet criteria for major depression in 30%–50% of subjects (e.g., patients with cancer or infectious diseases) depending on the dose ( ; ). Moreover, comparison of symptoms induced by IFN-alpha with symptoms from otherwise healthy depressed individuals yield few meaningful differences between the two, although IFN-alpha-treated patients exhibit an overrepresentation of neurovegetative symptoms ( ). Endotoxin and typhoid and influenza vaccination, typically administered acutely to healthy volunteers in laboratory settings, also lead to symptoms of depression, albeit short-lived ( ; ; ). The capacity of these inflammatory stimuli to induce a behavioral syndrome like depression provides compelling data that inflammation can cause depression. Based on these data, much has been learned about the central nervous system (CNS) mechanisms by which inflammation affects neurotransmitter systems and neurocircuits in the brain to change behavior ( ).

Inhibition of inflammation reduces depressive symptoms

Further supporting the cause-and-effect relationship between inflammation and depression are studies indicating that inhibition of inflammation can reduce depressive symptoms. The most convincing data come from patients with autoimmune and inflammatory disorders who have been treated with anticytokine therapies that both reduce inflammation and reduce depressive symptoms ( ; ). In many of the studies, the decrease in depressive symptoms is independent of the improvement in disease activity, although the possibility that behavioral effects are tied to the response of the underlying disease process remains a consideration. Studies also suggest that drugs with antiinflammatory properties including celecoxib, aspirin, minocycline, statins, pioglitazone, and omega-3 fatty acids have antidepressant effects in otherwise healthy individuals ( ). Nevertheless, as indicated earlier, there are many complications in the clinical trial designs and the drugs used that make interpretation of these data challenging ( ; ; ).

Clinical predictors of treatment resistance and inflammation

Several clinical factors have been shown to be predictors of antidepressant treatment nonresponse and are related to inflammation. These include obesity, early life stress, medical illness, and anxiety ( ; ). There is a dose-response relationship between body mass index and inflammatory markers. In addition, early life stress has been reliably associated with increased inflammation and an increased inflammatory response to stress in exposed individuals ( ). A rich literature also describes the strong relationship between markers of inflammation and medical illnesses including diabetes, cardiovascular disease, and cancer ( ). Indeed, elevated CRP has been shown to be a reliable predictor of the development of these disorders, and the American Heart Association has defined levels of inflammatory risk based on CRP with a CRP < 1 mg/L representing low risk, a CRP between 1 and 3 mg/L representing moderate risk, and a CRP > 3 mg/L representing high risk ( ). Finally, data also strongly implicate increased inflammatory markers in patients with anxiety disorders ( ).

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