Findings from animal studies also suggest that stress-induced increases in catecholamines stimulate the release of monocytes from the bone marrow.2 Once in the blood, these monocytes encounter danger- or microbial-associated molecular patterns derived from stress-induced alterations in metabolism or microbial products from the gut that in turn activate inflammatory signaling pathways such as nuclear factor κB (BF-κB) leading to TNF and IL-6 as well as the imflammasome, which leads to the production of IL-1. TNF in turn has been shown to activate microglia to produce MCP-1, attracting monocytes to the brain notably in areas that regulate fear and anxiety including the amygdala.11 Recent data indicate that chronic social stress in laboratory animals can also lead to permeability in the blood – brain barrier that allows peripheral inflammatory signals including IL-6 to enter the brain in regions relevant to motivation and reward.12 Consistent with these laboratory animal data, peripheral blood immune cells from depressed patients have shown evidence of activation of both nuclear factor κB and the inflammasome.13
Despite evidence that monocytes and the innate immune response play a pivotal role in effects of inflammation on the brain, there is growing evidence to suggest that T cells and the adaptive immune response may also be involved.14 Decreased anti-inflammatory T regulatory cells and increased hyperinflammatory Th17 cells have been described in depressed patients and animal models of depression.13-15 Moreover, T cells and their production of IL-4 have been associated with resilience to stress and depression in laboratory animal models.1,14,16 These data are especially intriguing given recent characterization of the lymphatic system within CNS that allows the T cells to patrol the brain.17 Whether inflammatory responses are primarily driven by innate immune responses and monocytes versus the adaptive immune response and T cells will have profound implications for immunotherapeutic targeting of the immune system to treat depression.
Inflammation is related to treatment response
A major advantage of a pathophysiologic process that is believed to largely emanate from the periphery and spread to the brain is the opportunity to use blood tests to identify specific individuals for treatment targeting and ultimately precision care. Indeed, inflammatory markers alone or in combination have been shown to predict treatment response to conventional antidepressants and psychotherapy as well as advanced treatment strategies such as ketamine and anti-cytokine immunotherapy.13,18 Unfortunately, these studies are post hoc in nature, and no study has yet to prospectively assign patients with one or more level of inflammatory marker to a given treatment and predict response.
The greatest challenge is to determine which inflammatory marker(s) exhibits the greatest predictive value, while also being readily available for clinical application. Findings suggest that individuals with a CRP >1mg/L, which is the cut off for moderate inflammation, were less likely to respond to SSRIs.19,20 High CRP was also shown to predict response to the anti-inflammatory drug infliximab, an inhibitor of TNF.1 Given the relative availability of CRP in clinics and hospitals throughout the US and elsewhere, it may be that until other data are available, clinicians can use CRP as a general yardstick for inflammatory load.
There has been recent interest in identifying inflammation directly in the brain of depressed patients using positron emission tomography to identify activated microglia reflected by upregulation of the translocator protein (TSPO).21 Although there has been an assumption that increased TSPO binding signals neuroinflammation, the TSPO ligand is not able to distinguish microglia that are activated to perform important neuroprotective and neuroregulatory functions from microglia that are inflammatory. Therefore, these ligands are not ready for prime time, and results from the published literature using TSPO ligands should be interpreted with caution.
Therapeutic implications are imminent
Clearly, there is much to be learned about the relationship between depression and inflammation. Nevertheless, the most exciting aspects of this work are the clear therapeutic implications ranging from blocking inflammation to targeting the downstream effects of inflammation on neurotransmitter systems and neurocircuits to implementing lifestyle interventions that reduce inflammation (Table 2).
Several clinical trials are underway using immunotherapies that target TNF and IL-6. In each instance, a precision medicine approach is being taken: individuals with increased inflammation of CRP >3 mg/L are being treated. Whether targeting these cytokines versus targeting T cell-derived cytokines such as IL-17 is more efficacious and for whom remains to be determined. In addition, studies have suggested that both minocycline, which blocks microglial activation, and inhibitors of the inflammatory mediator cyclooxygenase (COX)-2 have antidepressant efficacy.18 However, more data are needed, given that precision targeting of patient populations with high inflammation has not been incorporated into the clinical trial design of these studies. Based on the impact of inflammation on dopaminergic and glutamatergic pathways, drugs that enhance dopamine signaling or block glutamate receptors may be especially relevant for patients with depressive symptoms and increased inflammation.
Dr Miller reports no conflicts of interest concerning the subject matter of this article.
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