Elsevier

Biological Psychiatry

Volume 65, Issue 9, 1 May 2009, Pages 732-741
Biological Psychiatry

Review
Inflammation and Its Discontents: The Role of Cytokines in the Pathophysiology of Major Depression

https://doi.org/10.1016/j.biopsych.2008.11.029Get rights and content

Recognition that inflammation may represent a common mechanism of disease has been extended to include neuropsychiatric disorders including major depression. Patients with major depression have been found to exhibit increased peripheral blood inflammatory biomarkers, including inflammatory cytokines, which have been shown to access the brain and interact with virtually every pathophysiologic domain known to be involved in depression, including neurotransmitter metabolism, neuroendocrine function, and neural plasticity. Indeed, activation of inflammatory pathways within the brain is believed to contribute to a confluence of decreased neurotrophic support and altered glutamate release/reuptake, as well as oxidative stress, leading to excitotoxicity and loss of glial elements, consistent with neuropathologic findings that characterize depressive disorders. Further instantiating the link between inflammation and depression are data demonstrating that psychosocial stress, a well-known precipitant of mood disorders, is capable of stimulating inflammatory signaling molecules, including nuclear factor kappa B, in part, through activation of sympathetic nervous system outflow pathways. Interestingly, depressed patients with increased inflammatory biomarkers have been found to be more likely to exhibit treatment resistance, and in several studies, antidepressant therapy has been associated with decreased inflammatory responses. Finally, preliminary data from patients with inflammatory disorders, as well as medically healthy depressed patients, suggest that inhibiting proinflammatory cytokines or their signaling pathways may improve depressed mood and increase treatment response to conventional antidepressant medication. Translational implications of these findings include the unique opportunity to identify relevant patient populations, apply immune-targeted therapies, and monitor therapeutic efficacy at the level of the immune system in addition to behavior.

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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