Stress–immune interactions and depression. (a) Activation of NF-κB through Toll-like receptors (TLR) during immune challenge leads to an inflammatory response including (b) the release of the proinflammatory cytokines TNF-α, IL-1 and IL-6. (c) These cytokines, in turn, access the brain via leaky regions in the blood–brain barrier, active transport molecules and afferent nerve fibers (e.g. sensory vagus), which relay information through the nucleus tractus solitarius (NTS) [48]. (d) Once in the brain, cytokine signals participate in pathways (indicated in orange) known to be involved in the development of depression, including: (i) altered metabolism of relevant neurotransmitters such as serotonin (5HT) and dopamine (DA) [50,51]; (ii) activation of CRH in the paraventricular nucleus (PVN) and the subsequent production and/or release of ACTH and glucocorticoids (cortisol) [52,53] and (iii) disruption of synaptic plasticity through alterations in relevant growth factors [e.g. brain-derived neurotrophic factor (BDNF)] [59,60]. (e) Exposure to environmental stressors promotes activation of inflammatory signaling (NF-κB) through increased outflow of proinflammatory sympathetic nervous system responses [release of norepinephrine (NE), which binds to α (αAR) and β (βAR) adrenoceptors] (orange). (f) Stressors also induce withdrawal of inhibitory motor vagal input [release of acetylcholine (ACh), which binds to the α7 subunit of the nicotinic acetylcholine receptor (α7nAChR)] (blue) [73,77]. (g) Activation of the mitogen activated protein kinase pathways, including p38 and Jun amino-terminal kinase (JNK), inhibit the function of glucocorticoid receptors (GR), thereby releasing NF-κB from negative regulation by glucocorticoids released as a result of the HPA axis in response to stress (blue) [55,56].

IFN-α: modeling of cytokine-induced depression. Therapeutic administration of IFN-α is associated with depression in 30–50% of patients, depending on the dose [61,62]. IFN-α-induced depression is associated with pathophysiological changes that overlap with those found in medically healthy depressed patients, including activation of neuroendocrine (HPA axis) pathways (a), alterations in neurotransmitter metabolism (b), responsiveness to antidepressant treatment (c) and alterations in brain circuitry relevant to information processing (d). (a) The initial injection of IFN-α to patients with malignant melanoma is associated with a marked induction of ACTH and cortisol, which was significantly higher in patients who eventually developed depression (blue) than in those who never became depressed during IFN-α treatment (red). a, significantly different from 0 hours; P<0.01; b, significant difference between groups, P<0.01. (b) The relationship between the severity of depressive symptoms [as measured by the Montgomery–Asberg Depression Rating Scale (MADRS)] and changes in plasma tryptophan (TRP) concentrations during IFN-α therapy for cancer. TRP is the primary amino acid precursor of serotonin, a major regulator of limbic brain circuitry that subserves emotion. Decreases in TRP were significantly correlated (R=−0.50, P<0.05) with increases in depression severity scores during IFN-α treatment. (c) Patients who received the serotonin reuptake inhibitor paroxetine, a commonly used antidepressant, before and during IFN-α therapy for malignant melanoma (red triangles), were significantly more likely to remain free of depression during IFN-α administration than a placebo-treated control group (black squares). (d) Significantly greater activation (yellow and orange) of the dorsal ACC, as measured by functional magnetic resonance imaging (fMRI) during a task of visuospatial attention was found in IFN-α-treated patients compared with controls. (e) A significant linear relationship was found between activation of the ACC and the number of task-related errors in IFN-α-treated patients (red stars) but not in control subjects (black triangles). Increased ACC activation in response to relatively low task error rates has been associated with cognitive styles that predispose to anxiety and depression, suggesting that IFN-α-induced changes in ACC function might represent a cognitive pathway to psychopathology [65]. Reproduced, with permission, from (a) Ref. [63], (b) Ref. [62], (c) Ref. [61] and (d,e) Ref. [65].

Acute and chronic immune and inflammatory processes, combined with relevant contributions from immunogenetics (such as polymorphisms in cytokine genes) and past immune experiences (such as prior infections and vaccination history) (orange) interact with acute and chronic stressors combined with relevant contributions from psychiatric genetics (such as polymorphisms in neurotransmitter transporter genes) and past emotional experiences (such as adversity in early life) (yellow) to promote the syndrome of major depression (brown). A diagnosis of major depression is based on the presence of five of the following symptoms: depressed mood, anhedonia, fatigue, guilt and/or worthlessness, suicidal ideation, impaired concentration and/or memory, psychomotor retardation and/or agitation and disturbances of sleep or appetite. Symptoms must persist for at least two weeks and cause significant functional impairment [91].