Trends in Immunology
Volume 27, Issue 1, January 2006, Pages 24-31
Journal home page for Trends in Immunology

Cytokines sing the blues: inflammation and the pathogenesis of depression

https://doi.org/10.1016/j.it.2005.11.006Get rights and content

Increasing amounts of data suggest that inflammatory responses have an important role in the pathophysiology of depression. Depressed patients have been found to have higher levels of proinflammatory cytokines, acute phase proteins, chemokines and cellular adhesion molecules. In addition, therapeutic administration of the cytokine interferon-α leads to depression in up to 50% of patients. Moreover, proinflammatory cytokines have been found to interact with many of the pathophysiological domains that characterize depression, including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity and behavior. Stress, which can precipitate depression, can also promote inflammatory responses through effects on sympathetic and parasympathetic nervous system pathways. Finally, depression might be a behavioral byproduct of early adaptive advantages conferred by genes that promote inflammation. These findings suggest that targeting proinflammatory cytokines and their signaling pathways might represent a novel strategy to treat depression.

Section snippets

Evidence for increased inflammation in depression

Patients with major depression who are otherwise medically healthy have been repeatedly observed to have activated inflammatory pathways, as manifested by increased proinflammatory cytokines, increased acute-phase proteins and increased expression of chemokines and adhesion molecules 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22. Increased serum and/or plasma concentrations of interleukin (IL)-6 and/or C-reactive protein have been most frequently observed 6, 7, 8, 9, 10, 11, 12

Questions and controversies: does association imply causality?

Although several studies support the idea that inflammatory processes contribute to the pathogenesis of major depression, other studies have failed to find an association between the two 37, 38 and, in some cases, associations have been attenuated or obviated when potential mediating or moderating factors (e.g. body mass index, gender or personality) have been included in the analyses 8, 13, 14, 39. Some positive studies have failed to find a correlation between inflammation and depressive

Pathophysiological mechanisms: immunological pathways to psychopathology

A rich neuropsychiatric literature attests to fundamental mechanisms that conspire to cause the syndrome of major depression. At a neurobiological level, alterations in neurotransmitter function involving serotonin, norepinephrine and dopamine are well known to induce depression and are primary targets for currently available psychopharmacological (antidepressant) treatments [41]. Abnormalities in neuropeptide function are also believed to contribute. Indeed, hypersecretion of the neuropeptide

At the interface between immunology and behavior

Given the primary factors that are associated with the pathophysiology of depression, it is intriguing that peripherally released inflammatory cytokines can access the brain and influence all of the relevant pathophysiological domains (Figure 1). Because of the large size of cytokines and their resultant inability to readily penetrate the blood–brain barrier, attention has been paid to routes by which cytokines access the brain, including (i) entry through leaky regions in the blood–brain

Interferon-α: a clinical model of cytokine-induced depression

To study the effects of innate immune cytokines on behavior in humans, several investigators have seized upon the profound clinical observation that a high percentage of patients who are administered the cytokine interferon (IFN)-α for the treatment of infectious diseases or cancer develop a behavioral syndrome that is strikingly similar to major depression (Figure 2). IFN-α is a potent inducer of proinflammatory cytokines, including IL-6 and, to lesser extent, IL-1 β and TNF-α [54].

Stress and immunity: a crucial link in the cytokine–depression chain

Inflammation is the sine qua non of pathology, so it is understandable that proinflammatory cytokines might contribute to depression in the context of medical illness, thus potentially accounting for the five–tenfold greater prevalence of depression in individuals with a wide range of medical disorders [5]. Nevertheless, it is not as readily apparent what might drive increased inflammation in patients with major depression who are presumably physically healthy. One possibility is the impact of

Evolutionary perspectives

The relationship between depression and activation of innate immune responses might have its roots in the evolutionary advantages of a behavioral repertoire that enables diversion of crucial energy resources to the metabolic demands of fever during times of pathogen exposure. In addition, pathophysiological changes central to depression might protect inflammatory responses from negative regulation by neuroendocrine (glucocorticoid) responses 48, 80 (Box 1). Thus, depression might have been a

Treatment implications

Because paradigm shifts within medicine are judged (finally) by their clinical utility, it is encouraging that important treatment implications have already emerged from our nascent understanding of the role of inflammation in the pathogenesis of major depression. Indeed, data increasingly suggest that inflammatory processes contribute to the therapeutic effects of the currently available antidepressants and could provide targets for novel pharmacological and nonpharmacological treatment

Conclusion

A great amount of compelling data suggest that inflammatory innate immune responses might contribute to the development of depression, in part through complex interactions with stress-responsive pathways involving the neuroendocrine and autonomic nervous systems. The role of the immune system in the pathophysiology of depression probably derives from evolutionary imperatives, and presents intriguing and unique therapeutic opportunities to expand the treatment targets for this disabling and

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