How Inflammation Produces Depression When we started exploring how inflammation produces depression, we were convinced that depressogenic pathways unique to the immune system would be identified; leading to the conclusion that depression that occurs in response to stress or comes “out of the blue” is biologically different from depression induced by immune activation. We couldn’t have been more wrong. One of the most surprising, and consistent, findings over the last decade has been that inflammatory processes induce depression because they are capable of tapping in to every known risk pathway. In this regard, inflammation functions like psychological stress, which has similar wide-ranging, and generally depressogenic, biological effects. In fact, inflammation causes most of the same changes in the brain and body that have been repeatedly observed in animals and humans exposed to stress, especially when the stress is chronic and of a psychosocial nature. One of the best models for understanding the impact of chronic inflammation on humans has been treatment with the cytokine interferon (IFN)-alpha for either cancer or hepatitis C virus infection. IFN-alpha causes full-blown depression in a respectable minority of patients, produces depressive symptoms in a far higher percentage, and produces an improvement in mood in no one but the unfortunate few who develop mania in response to the treatment.14 Our understanding of the central-nervous-system (CNS) effects of peripheral inflammation also have been augmented by studies of humans who became acutely inflamed as a result of receiving a dose of lipopolysaccharide or a typhoid vaccine. Figure 2 (see below) provides a schematic of the neurobiological pathways known to be influenced by both acute and chronic inflammatory stimuli in humans, ultimately leading to alterations in neurocircuitry and behavior. Neuroimaging studies reliably indicate that peripheral inflammation targets brain regions repeatedly implicated in the pathophysiology of depression, especially the anterior cingulate cortex (ACC) and basal ganglia. Depending on the nature of the stimulus, the impact of cytokines on the ACC is seen most strongly in either the subgenual or the dorsal area.Cytokine-induced increases in neural activity in these regions have been associated with the development of mood and anxiety symptoms. On the other hand, peripheral immune activation has been shown repeatedly to impair basal ganglia functioning in ways that are consistent with the known inhibitory effects of cytokines on dopamine signaling in the CNS. Reductions in basal ganglia activity have been noted in more posterior regions, where they associate with fatigue, and in more ventral regions (such as the nucleus accumbens), where they have been associated with the development of anhedonia, a psychological condition characterized by an inability to experience enjoyment in normally pleasurable acts. Regarding the mechanisms of the effects of cytokines on these and other brain regions, cytokines have been shown repeatedly to alter neurotransmitter signaling in the CNS in ways that are relevant to the pathophysiology of depression and its treatment. For example, through activation of the intracellular signaling pathway mitogen-activated protein kinase, cytokines can increase the number and function of the reuptake pumps for serotonin, norepinephrine, and dopamine, which in turn can reduce the availability of these neurotransmitters within the synaptic cleft. This is relevant to depression and its treatment given that most currently available antidepressants act by blocking these reuptake pumps to increase neurotransmitter availability in the synapse. Cytokines have other effects known to impact neurotransmitter availability. Indeed, by activating enzyme indoleamine 2, 3-dioxygenase, cytokines can shunt tryptophan away from the production of serotonin and into the production of kynurenine. Kynurenine is transported to the brain and can be converted by activated microglia (innate cells in the brain) to the neurotoxic metabolite quinolinic acid. The clinical relevance of this process has been shown by the association between cerebrospinal fluid levels of kynurenine and quinolinic acid, and the development of depression during treatment with IFN-alpha.1 Moreover, increased quinolinic acid has been found in activated microglia in the ACC of suicide victims who were depressed. Quinolinic acid can impact glutamate signaling in ways relevant to depression, including the stimulation of extrasynaptic N-methyl-D-aspartate (NMDA) receptors, which lead to the downregulation of the production of brain-derived neurotrophic factor (BDNF), a potent inducer of neurogenesis. Consistent with this and other activities of inflammatory cytokines, animal and human studies have demonstrated that increased inflammatory cytokines can reduce central levels of BDNF and neurogenesis, leading to depressive-like behavior.20 Depression is not just a brain disease. Indeed, many of the depression-related physiological abnormalities identified at the dawn of biological psychiatry involved the body’s stress system and especially the hypothalamic-pituitary-adrenal (HPA) axis. As a group, depressed individuals have been repeatedly reported to demonstrate increased circulating cortisol and concomitant glucocorticoid resistance (e.g. decreased sensitivity to the inhibitory effects of glucocorticoids on HPA axis regulation and inflammation). Depressed patients also show a flatter diurnal pattern of cortisol secretion than do healthy control subjects. Strikingly, inflammatory cytokines have been shown to be capable of producing all these abnormalities, including glucocorticoid resistance, and in the context of treatment with IFN-alpha, flattening of the cortisol slope strongly predicts the development of depression.
Posted on: Fri, 02 Aug 2013 22:38:14 +0000
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