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Inflammation and Treatment Resistance in Major Depression: The Perfect Storm

Inflammation and Treatment Resistance in Major Depression: The Perfect Storm

Clinical predictors of treatment resistance related to inflammationTable 1
Cytokines circumvent mechanisms of action of conventional antidepressantsreFigure 2
Translational targets for inflammation and treatment-resistant depressionTable 2

CME credit for this article is now expired. It appears here for informational purposes. Some of the material may have changed.

At the end of this article, readers should be able to:

1. Understand the correlation between inflammation and treatment-resistant depression.

2. Describe the clinical factors associated with treatment non-response and how these factors correlate with inflammation.

3. Identify the mechanisms that lead to nonresponse.

 

Major depression is a disease that affects approximately 20 million adults in the US and has a devastating impact on personal and public health.1 Although successful treatment substantially reduces functional impairment and economic burden, up to one-third of depressed patients are resistant to treatment with conventional antidepressants (eg, serotonin and/or norepinephrine reuptake inhibitors), even in the context of standardized attempts such as switching medications and/or augmenting with thyroid hormone, mood stabilizers, and atypical antipsychotics.2 Thus, roughly 7 million adults in the US are considered to have treatment-resistant depression (TRD), which emphasizes the need to develop new conceptual frameworks and new therapeutic targets to improve treatment outcome.

One factor that has received increasing attention regarding TRD is inflammation. A significant percentage of patients with TRD exhibit increased markers of inflammation, and clinical factors that are linked with treatment nonresponse are associated with inflammation. Inflammatory cytokines, which are critical mediators of the inflammatory response, have been found to sabotage and circumvent many of the mechanisms of action of conventional antidepressants. These findings provide powerful evidence that inhibition of inflammation or its downstream effects on mood may open up a host of new approaches to treatment for depression, especially for patients with TRD.

Invaluable to survival in the short term, chronic inflammation can lead to significant damage to multiple organ systems in the body—including the brain. Recognizing chronic inflammation as a common mechanism of disease, including cardiovascular disease, diabetes, and cancer, is one of the major insights of the past decade.3 Nevertheless, psychiatry began recognizing the role of inflammation in TRD only recently—as both the problem and a solution.

The correlation between TRD and inflammation

A number of clinical factors have been associated with TRD, including obesity, childhood maltreatment, anxiety disorders, personality disorders/neuroticism, bipolar disorder, and medical comorbidities (Table 1). Data show a dose-response relationship between BMI and TRD—the higher the BMI, the lower the response rate.4 Early life stress is also associated with poor treatment outcome. Childhood maltreatment has been associated with a significantly decreased likelihood of response or remission during antidepressant treatment.5 Likewise, anxiety disorders, including PTSD, obsessive-compulsive disorder, generalized anxiety disorder, and panic disorder, were found to be negative predictors of response in step 1 and especially in step 2 of the STAR*D.6

Comorbid personality disorders and high levels of neuroticism have also been shown to predict TRD.7 In addition, a significant percentage of patients with TRD have hidden bipolar disorder, for which antidepressants are often less effective and poorly tolerated.8 A dose-response relationship appears to exist between severity or degree of medical comorbidity and treatment resistance. For each organ system affected by illness, there is an approximately 20% decrease in the likelihood of antidepressant treatment response.9

Not only is there a dose-response relationship between BMI and a number of inflammatory markers, but also there is an array of inflammatory mediators that are released by fat cells, including the inflammatory cytokines tumor necrosis factor (TNF)-α, and interleukin (IL)-6 as well as the chemokine monocyte chemoattractant protein-1, which is a potent attractant for macrophages that accumulate in fatty tissue and sustain inflammatory responses.10 Childhood maltreatment has also been associated with increased markers of inflammation in depression, under resting conditions, and following stress. Depressed patients with a history of childhood maltreatment were found to exhibit increased plasma levels of the acute phase protein C-reactive protein (CRP), which is released by the liver during an inflammatory response.11 After exposure to a laboratory psychosocial stressor, persons with a history of childhood maltreatment showed increased plasma IL-6 levels and increased DNA binding of nuclear factor-κB (NF-κB) in peripheral blood mononuclear cells compared with controls.12 NF-κB is a lynchpin signaling molecule in the inflammatory cascade.

An increase of inflammatory markers has also been seen in patients with anxiety and personality disorders. Bipolar disorder has been associated with increased blood inflammatory markers as well as increased inflammatory cytokines, NF-κB, and markers of microglial activation in postmortem brain tissue.13 Patients with medical illnesses are well known to exhibit increased inflammation secondary to infection and the tissue damage and destruction that can activate the inflammatory response. The data indicate that treatment resistance may be in part a function of activation of inflammatory pathways. The clinical factors that may alert the clinician to which patients are most likely to exhibit increased inflammatory biomarkers and risk for treatment resistance include obesity, childhood maltreatment, bipolar disorder, and comorbid medical illness (Figure 1).



Multiple lifestyle, environmental, psychiatric, and medical factors contribute to and are a function of an inflammatory milieu associated with increased inflammatory cytokines, which can reduce the availability of monoamines, inhibit neurogenesis, and increase glutamate. Conventional antidepressants act on monoamine pathways to increase monoamine availability and require neurogenesis for efficacy. Moreover, glutamate is not a primary target of conventional antidepressant therapy. Cytokine effects on these biological processes thus conspire to sabotage and circumvent the mechanism of action of conventional antidepressants, leading to treatment resistance.

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