The cytokine hypothesis of depression: inflammation, oxidative & nitrosative stress (IO&NS) and leaky gut as new targets for adjunctive treatments in depression.
This paper hypothesizes that inflammatory, oxidative and nitrosative (IO&NS) pathways, and an increased translocation of LPS from gram-negative bacteria are causally related to depression following external (psychological) and internal (organic) stressors and that IO&NS pathways are novel targets for antidepressant development. We review that depression is accompanied by an inflammatory reaction as indicated by an increased production of pro-inflammatory cytokines, such as interleukin-1beta (IL-1beta), IL-6, tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN)-gamma. These cytokines are stress-sensitive and may cause depressive behaviors. The latter may be induced by an increased catabolism of tryptophan, the precursor of serotonin, to neurotoxic TRYCATs (tryptophan catabolites along the indoleamine oxidase pathway). Inflammatory biomarkers are detected in animal models of depression. Newly developed animal models of depression are based on induced inflammation. Most if not all antidepressants have specific anti-inflammatory effects. Anti-inflammatory compounds may augment the clinical efficacy of antidepressants. Depression is also accompanied by an IgM-related (auto)immune response directed against disrupted lipid membrane components, such as phosphatidyl-inositol, by-products of lipid peroxidation, e.g. azelaic acid and malondialdehyde, and NO-modified amino-acids, which are normally not detected by the immune system but due to damage caused by O&NS have become immunogenic. Increased translocation of lipopolysaccharide from gram-negative bacteria, which may be induced by internal and external stressors, may further aggravate the induced IO&NS pathways.
Maes
Michael
M
Clinical Research Center for mental Health, Olmenlaan 9, 2610 Wilrijk, Belgium. crc.mh@telenet.be
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000494:pharmacology*; D015415:Biomarkers; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D016207:Cytokines / Q000502:physiology*; D003863:Depression / Q000188:drug therapy* / Q000503:physiopathology* / Q000523:psychology; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000503:physiopathology* / Q000523:psychology; D007408:Intestinal Absorption / Q000502:physiology; D007413:Intestinal Mucosa / Q000503:physiopathology*; D018384:Oxidative Stress / Q000502:physiology*; D026361:Reactive Nitrogen Species / Q000502:physiology*
D000893:Anti-Inflammatory Agents; D000928:Antidepressive Agents; D015415:Biomarkers; D016207:Cytokines; D026361:Reactive Nitrogen Species