Inflammation, glutamate, and glia in depression: a literature review

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McNally L, Bhagwagar Z, Hannestad J. CNS Spectr. 2008;13(6):501-510

Immunologic abnormalities, especially indices of excess inflammation, are a common finding in patients with depression. Although the causal direction of these associations are unclear, there is increasing evidence suggesting that inflammation could, in a subgroup of patients and in some medical conditions, contribute to the pathogenesis of depression. This may occur through interference with monoaminergic, glutamatergic, and neurotrophic systems.


Multiple lines of evidence suggest that inflammation and glutamate dysfunction contribute to the pathophysiology of depression. In this review we provide an overview of how these two systems may interact. Excess levels of inflammatory mediators occur in a subgroup of depressed patients. Studies of acute experimental activation of the immune system with endotoxin and of chronic activation during interferon-? treatment show that inflammation can cause depression. Peripheral inflammation leads to microglial activation which could interfere with excitatory amino acid metabolism leading to inappropriate glutamate receptor activation. Loss of astroglia, a feature of depression, upsets the balance of anti- and pro-inflammatory mediators and further impairs the removal of excitatory amino acids. Microglia activated by excess inflammation, astroglial loss, and inappropriate glutamate receptor activation ultimately disrupt the delicate balance of neuroprotective versus neurotoxic effects in the brain, potentially leading to depression.

Depression is a common and debilitating disorder for which current treatments are inadequate. The pathogenesis of depression is not well understood. The annual prevalence of depression is 7% and the lifetime prevalence is 16%.1,2 In addition to significant disability,3 depression is associated with excess mortality,4,5 particularly from cardiovascular disease.6 Current antidepressants, which target monoamines, only produce remission in 30% of patients. Part of the problem lies in the fact that the pathophysiology of depression has not been elucidated, and treatments are based on empirical data, not mechanisms of action. It remains unclear how these drugs actually work, since their ability to increase synaptic concentrations of monoamines is immediate, while their clinical effects take 2–4 weeks to become apparent.7 The aim of this article is to provide an overview of studies implicating inflammation in depression, and propose a model of how excess inflammation may interact with glutamate and glia to cause depression.

Inflammation in Depression
Immunologic alterations in depression have been described for over 2 decades8 and the current hypothesis is that excess inflammation plays a role.9,10 The innate immune system can favor a T helper cell type 1 (Th1) or a Th2 response. During a Th1 response activated macrophages secrete so-called pro-inflammatory mediators, such as interferon-? (IFN-?), tumor necrosis factor (TNF), and interleukin-1 (IL-1) and IL-2. A Th2 response is characterized by antibody production and anti-inflammatory mediators, IL-4, IL-5, and IL-10, which inhibit the Th1 response. This balance is essential to prevent excess inflammation which can have deleterious consequences. It has been repeatedly shown that a subgroup of patients with depression has elevated plasma levels of pro-inflammatory mediators, including IL-1, IL-2, IL-6, TNF, and C-reactive protein.8,11-14 In patients with depression the ratio of IFN-? to IL-4 was elevated, and this ratio decreased with antidepressant treatment.15 Multiple studies14,16-18 have shown that there is a decrease in Th1 mediator levels with antidepressant treatment, indicating that one potential mechanism of action of antidepressant treatments is decreased inflammation. Researchers19 have found that higher levels of TNF at baseline may predict a poor response to escitalopram. In a rare prospective study,20 an increased inflammatory state at baseline (elevated levels of C-reactive protein and increased capacity of leukocytes to produce IL-1) predicted later onset of depression in elderly individuals without a prior history of depression, suggesting that excess inflammation precedes depression. In summary, inflammatory mediator levels are elevated in depression, the Th1:Th2 balance is off, and such excess inflammation may play a role in the development of depression and contribute to poor response to antidepressants.

It is important to keep in mind that the peripheral and central inflammatory systems operate in parallel. In rodents, peripheral inflammatory stimuli induce expression of inflammatory mediators in the brain.9 Conversely, over-expression of IL-1 in the rodent brain led to increased peripheral production of inflammatory mediators,21 highlighting this bi-directional communication between central and peripheral inflammatory systems. In monkeys, intravenous administration of IL-1 led to increases in IL-6 in cerebrospinal fluid (CSF),22 and in hepatitis C patients receiving IFN-? treatment, CSF levels of IL-6 increased during treatment (A. Miller, MD, et al, written communication, 2007), demonstrating that, as seen in rodents, peripherally activating the immune system activates inflammatory pathways in the primate brain. Consistent with this, in patients with depression levels of IL-1 in CSF are also elevated,23 suggesting that, in depression, there is excess inflammation both centrally and peripherally. Because an appropriate Th1:Th2 balance is of crucial importance to avoid the deleterious effects of excess inflammation, several redundant mechanisms regulate this balance. For example, a recent study24 demonstrated that repeated endotoxin stimulation of monocytes induced chromatin modifications which silenced the transcription of inflammatory genes, while priming the transcription of antimicrobial genes. It is possible this or other regulatory mechanisms are deficient in depression, leading to excessive inflammation.

In patients with hepatitis C treated with IFN-? up to 45% develop depression.25 IFN-?-induced depression is associated with increases in plasma levels of IL-6 and TNF,26 inflammatory mediators commonly elevated in depression. As previously described, IL-6 levels also increase in CSF. On functional magnetic resonance imaging, IFN-? treatment is associated with hypometabolism in prefrontal and temporal regions, findings similar to those in depression27,28 demonstrating that peripherally administered IFN-? affects brain regions implicated in depression. Endotoxin, a cell-wall component of gram-negative bacteria, is a potent stimulus of the innate immune system. In rodents, administration of endotoxin leads to a constellation of behaviors, including decreased sucrose preference (akin to human anhedonia, a core symptom of depression), reduced exploratory and social behaviors, reduced food intake, and increased sleep.9 In humans, endotoxin at doses from 2–4 ng/kg causes influenza-like symptoms, such as fever, chills, headache, and myalgias.29,30 Lower doses of endotoxin (0.8 ng/kg) are insufficient to cause sickness symptoms, but do cause depressive symptoms.31 Another non-sickness-inducing inflammatory stimulus, Salmonella typhi vaccine, also induces negative mood.32
Inflammatory stimuli can induce psychiatric symptoms that are not dependent on the physical discomfort associated with inflammation and do not require a full-blown sickness syndrome.

Anti-inflammatory Agents Have Antidepressant Effects
If depression is associated with excess inflammation, one would expect that inhibiting inflammation would reduce depressive symptoms. Eicosanoids are inflammatory mediators that mediate fever, vascular permeability, and neutrophil chemotaxis. The enzyme that converts arachidonic acid to eicosanoids is called cyclooxygenase-2, and inhibition of this enzyme reduces inflammation. In a randomized, placebo-controlled trial of the cyclooxygenase-2 inhibitor celecoxib in depressed patients treated with reboxetine,33 celecoxib augmentation was more efficacious than placebo. Another anti-inflammatory medication used in various forms of arthritis is etanercept, an antagonist of the inflammatory mediator TNF. In a trial in patients with psoriasis,34 it was demonstrated that etanercept reduced depressive symptoms independent of improvement in psoriatic symptoms, such as skin involvement and joint pain. This study suggests that blocking TNF can treat depressive symptoms, which is consistent with elevations in TNF plasma levels seen in depression, the fact that such levels go down with treatment, and the fact that knocking-out TNF receptors in mice reduces depressive-like behaviors. 34

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