An intriguing and hitherto unexplained co-occurrence: Depression and chronic fatigue syndrome are manifestations of shared inflammatory, oxidative and nitrosative (IO&NS) pathways Michael Maes ⁎ Maes Clinics @ TRIA, 998 Rimklongsamsen Road, Bangkok 10310, Thailand abstract article info Article history: Received 17 March 2010 Received in revised form 19 June 2010 Accepted 26 June 2010 Available online 4 July 2010 Keywords: Chronic fatigue syndrome Cytokines Depression Inflammation Oxidative stress Mitochondria There is a significant ‘comorbidity’ between depression and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Depressive symptoms frequently occur during the course of ME/CFS. Fatigue and somatic symptoms (F&S), like pain, muscle tension, and a flu-like malaise, are key components of depression. At the same time, depression and ME/CFS show major clinical differences, which allow to discriminate them with a 100% accuracy. This paper aims to review the shared pathways that underpin both disorders and the pathways that discriminate them. Numerous studies have shown that depression and ME/CFS are characterized by shared aberrations in inflammatory, oxidative and nitrosative (IO&NS) pathways, like systemic inflammation and its long-term sequels, including O&NS-induced damage to fatty acids, proteins and DNA; dysfunctional mitochondria; lowered antioxidant levels, like zinc and coenzyme Q10; autoimmune responses to neoepitopes formed by O&NS; lowered omega-3 polyunsaturated fatty acid levels; and increased translocation of gram-negative bacteria. Some IO&NS-related pathways, like the induction of indoleamine 2-3-dioxygenase, neurodegeneration and decreased neurogenesis, are more specific to depression, whereas other pathways, like the 2′-5′ oligoadenylate synthetase/RNase L pathway, are specific to ME/CFS. Most current animal models of depression, e.g. those induced by cytokines, are not reminiscent of human depression but reflect a mixture of depressive and F&S symptoms. The latter symptoms, sometimes called sickness behavior, differ from depression and ME/CFS because the former is a (sub)acute response to infection-induced pro-inflammatory cytokines that aims to enhance recovery, whereas the latter are characterized by long-term sequels in multiple IO&NS pathways. Depression and ME/CFS are not ‘comorbid’ disorders, but should be regarded as ‘co-associated disorders’ that are clinical manifestations of shared pathways. © 2010 Elsevier Inc. All rights reserved. 1. Introduction: “comorbidity” between depression and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) Depression and myalgic encephalomyelitis/chronic fatigue syn- drome (ME/CFS) are considered to be comorbid disorders. Thus, depression frequently occurs during the course of ME/CFS (Skapinakis et al., 2003, 2004). Other authors suggest that ME/CFS is a form fruste of depression, because fatigue syndromes often accompany comorbid affective disorders, including depression (Roy-Byrne et al., 2002). Harvey and Wessely (2009) even suggest that depression is the most common comorbid disorder in ME/CFS. They conclude therefore that if depression is present, a mental state examination remains the best investigation in persons with unexplained fatigue. Rating scales used to measure the severity of ME/CFS, such as the 12-item Fibromyalgia and Chronic Fatigue Syndrome Rating (FF) Scale include depressive symptoms, such as sadness (Zachrisson et al., 2002). Functional, psychosomatic or somatoform symptoms, such as chronic fatigue, loss of energy, pain, muscle aches, paraesthesiae, irritable bowel, sexual inhibition, headache, vertigo and other Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 784–794 Abbreviations: ME/CFS, myalgic encephalomyelitis/chronic fatigue syndrome; FF, Fibromyalgia and Chronic Fatigue Syndrome Rating Scale; HDRS, Hamilton Depression Rating Scale; BDI, Beck Depression Inventory; F&S, fatigue and somatic; IO&NS, inflammatory, oxidative and nitrosative stress; TNF, tumor necrosis factor; IL, interleukin; NFκB, nuclear factor κB; COX-2, cyclo-oxygenase 2; iNOS, inducible nitric oxide synthase; ROS, radical oxygen species; NO, nitric oxide; MDA, malondialdehyde; LDL, low density lipoprotein; TBARS, thiobarbituric acid reactive substances; GPX, glutathione peroxidase; TAS, total antioxidant capacity; DHEA, dehydroepiandroster- one; mtDNA, mitochondrial DNA; CMS, chronic mild stress; PUFA, polyunsaturated fatty acids; EPA, eicosapetanoic acid; DHA, docosahexaenoic acid; AA, arachidonic acid; IFN, interferon; IDO, indoleamine oxidase; TRYCATs, tryptophan catabolites along the IDO pathway; BDNF, brain-derived neurotrophic factor; OAS/RNase, the 2′-5′ oligoadenylate (2-5 A) synthetase/RNase L; EBV, Epstein Barr virus; MS, multiple sclerosis; IBD, inflammatory bowel disease; RA, rheumatoid arthritis; IgIV, immuno- glubolin intravenously; SNPs, single nucleotide polymorphisms; OB, olfactory bulbectomized. ⁎ Tel.: +66 2 6602728, +32 3 4809282; fax: +32 3 2889185. E-mail address: crc.mh@telenet.be. URL: http://www.michaelmaes.com. 0278-5846/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2010.06.023 Contents lists available at ScienceDirect Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp