Inflammation and depression

Many explanations have been proposed for the occurrence of comorbid depression in diabetes, from the psychological burden of the disease itself to a number of possible biological mechanisms including autonomic dysfunction, disrupted sleep patterns, altered activity of the hypothalamo-pituitary-adrenal axis, and chronic inflammation [1]. The possibility that inflammation is a key pathogenic factor common to both diabetes and depression has received much interest lately.

Diabetes is associated with chronic inflammation. Part of this inflammation is caused by activation of the receptor for advanced glycation end products. Inflammation is a key pathogenic factor in the association between obesity and type 2 diabetes as it contributes to the development of insulin resistance [2]. Like in other chronic inflammatory conditions, inflammation associated with diabetes is able to affect all organs of the body including the brain [3]. Peripheral inflammatory mediators do not cross the blood-brain barrier but instead activate immune-to-brain communication pathways. Circulating danger signals activate innate immune cells that are located in brain areas devoid of an intact blood-brain barrier, the so-called circumventricular organs. The inflammatory cytokines that are produced in circumventricular organs diffuse in the extracellular milieu into the brain parenchyma. A number of cytokines produced at the periphery can be transported actively across the blood-brain barrier. In addition, peripheral cytokines activate cytokine receptors on afferent nerve fibers. All this allows the systemic immune signal to reach the brain. In response to peripheral inflammatory signals, brain innate immune cells including perivascular and meningeal macrophages and parenchymal microglia, produce and release inflammatory cytokines. Brain inflammatory cytokines ultimately act on neuronal functions to induce the symptoms of sickness (lethargy, fatigue, decreased appetite, increased sleep, cognitive dysfunction) and depression.

A close association between inflammation and symptoms of depression has been reported in many clinical studies carried out in people with various chronic inflammatory conditions including diabetes. Most studies are cross-sectional, which limits their consideration for determining whether inflammation is responsible for depression or vice versa. The causal role of inflammation is more readily apparent in prospective studies. In one of the few prospective studies available, higher levels of interleukin-6 measured at age 9 years were associated with subsequent risk of depression at age 18 years (adjusted odds-ratio 1.55; 95% confidence interval, 1.32-2.14, based on 4500 children from the Avon Longitudinal Study of Parents and Children) [4]. Chronic inflammation, as measured by plasma levels of C-reactive protein higher than 3 mg/ml, was also found to lead to increased risk of diabetes when associated with elevated depressive symptoms (adjusted odds ratio 2.03, 95% CI 1.14-3.61, 4955 participants aged 50 years and older and followed over 63 months in the English Longitudinal Study of Ageing) [5].

At the preclinical level there is some evidence that diabetes is associated with increased inflammatory cytokine signaling in the brain and a more intense sickness response to systemic inflammation. We have in particular shown that non-obese pre-diabetic mice, a genetic model of type 1 diabetes, are more sensitive to the sickness-inducing effects of interleukin-1 than mice from the control ICR strain despite having a similar distribution and density of brain interleukin-1 receptors [6]. In a similar manner, diabetic db/db mice that are deficient for the leptin receptor show an enhanced sickness response to systemic administration of lipopolysaccharide, the active fragment of endotoxin [7]. The enhanced sickness displayed by db/db mice is associated with increased expression of inflammatory cytokines in their brains.

The mechanisms of the relationship between inflammation and depression have been elucidated during the last ten years. Brain inflammatory cytokines act directly or indirectly on neurons, by modifying the neuronal environment. Dopaminergic neurons of the basal ganglia are very sensitive to inflammation. For instance, people with hepatitis C virus infection who are treated with chronic administration of interferon-alpha show increased glucose metabolism in basal ganglia nuclei probably as a result of the increased oscillatory burst activity of neurons that are normally inhibited by dopamine [8]. More direct evidence for inflammation-induced dopaminergic deficiency comes from the observation of decreased activation of the ventral striatum in response to cues associated with a monetary reward in volunteers injected with a low dose of endotoxin [9]. A possible mechanism for these neurotoxic effects of inflammation is the activation of the kynurenine metabolism pathway. The kynurenine metabolism pathway is activated by inflammation and it promotes the development of immunotolerance [10]. Inflammatory mediators activate the tryptophan degrading enzyme indoleamine 2,3 dixoygenase. This results in the formation of kynurenine that is transported into the brain where it is further metabolized in various kynurenine metabolites under the influence of several enzymes. Some of these metabolites such as kynurenic acid are neuroprotective. However, other metabolites such as 3-hydroxy kynurenine and quinolinic acid are neurotoxic. Inflammation is associated with an increased in the ratio of neurotoxic to neuroprotective kynurenine metabolites, which therefore promotes neurodegeneration. One of the neurotoxic metabolite of kynurenine, quinolinic acid, is able to activate the N-methyl-D-aspartic acid (NMDA) glutamatergic receptor. In addition activated microglia release glutamate in the extracellular milieu, which contributes to excitotoxicity. We have shown that NMDA receptors with ketamine, a NMDA receptor antagonist, abrogates the depression-like behavior that is induced in mice by a systemic administration of lipopolysaccharide at sub-septic doses [11].

Depression and sickness are closely related. Inflammation induces symptoms of sickness in all individuals but depression develops over this background of sickness in only 20 to 40 percent of the cases. Fatigue is the predominant symptom of sickness and does not respond to antidepressant therapy in contrast to the cognitive and psychological symptoms of depression (anhedonia, depressed mood, feelings of worthlessness and guilt). The transition from sickness to depression is dependent on the presence of risk factors for depression. These risk factors have mainly been studied in people infected with hepatitis C virus and treated with interferon-alpha as the sample size of this population is large enough for genetic association studies. The main risk factors are represented by single nucleotide polymorphisms of genes enhancing the production of inflammatory cytokines (e.g., the interferon-gamma gene that regulates the production of interferon-gamma) and modulating the level of neurotransmitters (e.g., the gene of the serotonin-1A receptor that regulates serotonin release) [12][13].

The existence of an association between inflammation and depression opens new possibilities for the treatment of depression in people with inflammatory conditions [14]. An obvious treatment strategy is the administration of anti-inflammatory drugs. A few add-on studies on inhibitors of the synthesis of prostaglandins indicate a possible beneficial effect of inhibitors of cyclo-oxygenase 2 as adjuncts to antidepressant therapy. However, possible adverse effects of non-steroidal anti-inflammatory drugs on response to antidepressants have also been noted. The administration of cytokine antagonists appears to be beneficial, as several studies show a rapid improvement in fatigue and depression in people with chronic inflammatory conditions when treated with an antagonist of tumor necrosis factor-alpha (TNF). This type of approach needs to be used with precaution, however, as a recent proof-of-principle clinical trial in people with depression but without any comorbid medical condition showed beneficial effects of the anti-TNF agent etanercept only in those who had relatively high circulating levels of C-reactive protein. Symptoms of depression actually increased in those who had low circulating levels of C-reactive protein.

Several antidepressant drugs have anti-inflammatory properties. However, the contribution of these effects to their antidepressant activity has never been tested. The involvement of the kynurenine metabolism pathway in the pathogenesis of inflammation-induced depression indicates that there is certainly a potential for the use of compounds that block the formation of kynurenine, prevent its transport across the blood-brain barrier, or normalizes the ratio of neuroprotective to neurotoxic kynurenine metabolites. Blocking the NMDA receptor activation is another approach to be considered although the development of drugs that target glutamatergic neurotransmission has been fraught with many problems so far.

In summary, there is much evidence to point to inflammation as a risk factor for depression in chronic inflammatory conditions. This does not mean that the usual psychosocial factors that increase the risk of depression, e.g., early physical abuse, low socio-economic status, poor social support) have to be neglected. There is actually more and more evidence that they exert their non-specific influence on morbidity and mortality by promoting inflammation.


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