The pathogenesis of clinical depression: stressor- and cytokine-induced alterations of neuroplasticity.
Stressful events promote neurochemical changes that may be involved in the provocation of depressive disorder. In addition to neuroendocrine substrates (e.g. corticotropin releasing hormone, and corticoids) and central neurotransmitters (serotonin and GABA), alterations of neuronal plasticity or even neuronal survival may play a role in depression. Indeed, depression and chronic stressor exposure typically reduce levels of growth factors, including brain-derived neurotrophic factor and anti-apoptotic factors (e.g. bcl-2), as well as impair processes of neuronal branching and neurogenesis. Although such effects may result from elevated corticoids, they may also stem from activation of the inflammatory immune system, particularly the immune signaling cytokines. In fact, several proinflammatory cytokines, such as interleukin-1, tumor necrosis factor-alpha and interferon-gamma, influence neuronal functioning through processes involving apoptosis, excitotoxicity, oxidative stress and metabolic derangement. Support for the involvement of cytokines in depression comes from studies showing their elevation in severe depressive illness and following stressor exposure, and that cytokine immunotherapy (e.g. interferon-alpha) elicited depressive symptoms that were amenable to antidepressant treatment. It is suggested that stressors and cytokines share a common ability to impair neuronal plasticity and at the same time altering neurotransmission, ultimately contributing to depression. Thus, depressive illness may be considered a disorder of neuroplasticity as well as one of neurochemical imbalances, and cytokines may act as mediators of both aspects of this illness.
Hayley
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Institute of Neuroscience, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario, Canada K1S 5B6. shayley@ccs.carleton.ca
Poulter
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MO
Merali
Z
Z
Anisman
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H
D000818:Animals; D016207:Cytokines / Q000378:metabolism / Q000502:physiology*; D003863:Depression / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D009414:Nerve Growth Factors / Q000378:metabolism / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology*; D013315:Stress, Psychological / Q000378:metabolism / Q000503:physiopathology*
D016207:Cytokines; D009414:Nerve Growth Factors