ReviewInflammation and Its Discontents: The Role of Cytokines in the Pathophysiology of Major Depression
Section snippets
Evidence for a Cytokine Basis for Major Depression
When compared with nondepressed individuals, both medically ill and medically healthy patients with major depression have been found to exhibit all of the cardinal features of inflammation, including elevations in relevant inflammatory cytokines and their soluble receptors in peripheral blood and cerebrospinal fluid (CSF), as well as elevations in peripheral blood concentrations of acute phase proteins, chemokines, adhesion molecules, and inflammatory mediators such as prostaglandins (5, 6).
Mechanisms and Mediators of Cytokine-Induced Behavioral Change
Studies have addressed fundamental pathways by which cytokines may contribute to depression. In general, cytokines have been shown to access the brain and interact with virtually every pathophysiologic domain relevant to depression, including neurotransmitter metabolism, neuroendocrine function, and neural plasticity (5, 17). However, it remains unclear whether activation of inflammatory pathways in the central nervous system (CNS) during depression originate primarily in the periphery (e.g.,
Cytokine Effects on Neurotransmitter Metabolism
Once cytokine signals reach the brain, they have the capacity to influence the synthesis, release, and reuptake of mood-relevant neurotransmitters including the monoamines (30). There is a rich animal literature demonstrating that administration of cytokines or cytokine inducers can profoundly affect the metabolism of serotonin, norepinephrine, and dopamine (DA) (31, 32). Moreover, drugs (serotonin and norepinephrine reuptake inhibitors) and gene polymorphisms (serotonin transporter gene) that
Cytokine Effects on Neuroendocrine Function
Some of the earliest observed effects of cytokines on mechanisms relevant to major depression involved their impact on the hypothalamic-pituitary-adrenal (HPA) axis (49). Cytokines, especially when administered acutely, have been shown to stimulate the expression and release of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH), as well as cortisol, all of which have been found to be elevated in patients with depression (49, 50). Although acute activation of the HPA
Cytokine Effects on Neural Plasticity
Cytokines such as IL-1, IL-6, and TNF-alpha that subserve inflammation in the periphery have complex and Janus-faced functional roles in the CNS. Under physiological conditions, these cytokines are important for providing trophic support to neurons and enhancing neurogenesis, while contributing to normal cognitive functions such as memory in laboratory animals (62, 63). However, significant data indicate that in the context of excessive and/or prolonged activation, cytokine networks in the CNS
Cytokines, Stress, and Depression
The source of inflammation is clear when depression occurs in the context of medical illnesses in which there is an infectious, autoimmune, or inflammatory component or when there is tissue damage and/or destruction, all of which are associated with activation of peripheral, and in some cases, central inflammatory responses. However, in the case of presumably medically healthy depressed individuals, the source of inflammation is less apparent, albeit nascent inflammatory processes secondary to
Neuroanatomical Substrates of Cytokine Effects on the Brain
An emerging literature is beginning to identify brain regions that may be targets of the effects of cytokines in humans. One important area in this regard is the basal ganglia. Both IFN-alpha and typhoid vaccination have been associated with psychomotor slowing and/or fatigue in association with changes in neuronal activity in the substantia nigra, putamen, and nucleus accumbens, as measured by functional magnetic resonance imaging (fMRI) and positron emission tomography (16, 100). Given the
Translational Implications
Relevant to the potential clinical applications of the association between inflammation and depression, data indicate that inflammatory biomarkers may identify depressed patients who are less likely to respond to conventional antidepressant treatment and may provide an indicator of treatment response. For example, patients with evidence of increased inflammatory activity prior to treatment have been reported to be less responsive to antidepressants, lithium, or sleep deprivation (a potent
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