posted on July 20, 2010 | E-mail | |

July 22, 2010

Question:
"Is major depression an inflammatory disease?"

Vladimir Maletic, MD:
I believe that we have strong evidence that inflammation is a relevant pathophysiological mechanism contributing to the development, severity, and persistence of major depression (MDD).^1,2,3 Is it not the same as saying that MDD is an inflammatory disease? Not, exactly. Rheumatoid arthritis and ulcerative colitis would be good examples of inflammatory disorders. Inflammation is the fundamental mechanism of etiopathogenesis in these conditions and the primary target of successful treatments. By comparison, inflammation has a significant role in etiology and propagation of malignant disorders. Yet cancers are not commonly considered as a primarily inflammatory condition, nor are the anti-inflammatory agents the mainstay of treatment.

Let us now examine the evidence linking depression and inflammation. Stress and medical illness are the principal precipitants of depression, both are associated with immune activation and elevated inflammation.^1,3 Compromised cortico-limbic regulation of mood and stress response appears to be the central feature of a depressive episode, most likely giving rise to neuropsychiatric symptoms of depression.^1,3 The brain responds to a depressed state in a manner that is very similar to a moderate “fight or flight” response: inadequate hypothalamic-pituitary-adrenal regulation, sympathetic activation combined with diminished parasympathetic tone, and, lastly, inflammation!^1,3

Evidence links elevation of proinflammatory cytokines in the context of depression to multiple somatic and psychiatric manifestations, such as change in sleep and appetite, aches, fatigue, irritability, sadness, impaired concentration and cognition, and even suicidal ideation.^1,3-6 Interferon therapy and experimentally induced inflammation are independently recognized as precipitants of depression and anxiety.^1,3 Inflammation is also a purported “missing link” explaining the synergistic impact of sleep disturbance, medical illness, and chronic stress on mood. The impact of inflammation on brain circuitry, intracellular signaling, and neuroplasticity will be discussed next month.

References

1. Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009;65(9):732-741.
2. Sjögren E, Leanderson P, Kristenson M, Ernerudh J. Interleukin-6 levels in relation to psychosocial factors: studies on serum, saliva, and in vitro production by blood mononuclear cells. Brain Behav Immun. 2006;20(3):270-278.
3. Maletic V, Raison CL. Neurobiology of depression, fibromyalgia and neuropathic pain. Front Biosci. 2009;14:5291-5338.
4. Harrison NA, Brydon L, Walker C, et al. Inflammation causes mood changes through alterations in subgenual cingulated activity and mesolimbic connectivity. Biol Psychiatry. 2009;66(5):407-414.
5. Alesci S, Martinez PE, Kelkar S, et al. Major depression is associated with significant diurnal elevations in plasma interleukin-6 levels, a shift of its circadian rhythm, and loss of physiological complexity in its secretion: clinical implications. J Clin Endocrinol Metab. 2005;90(5):2522-2530.
6. Kim YK, Na KS, Shink KH, et al. Cytokine imbalance in the pathophysiology of major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31(5):1044-1053.

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