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Depression, the Metabolic Syndrome and Neurodegeneration

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Immunology and Psychiatry

Part of the book series: Current Topics in Neurotoxicity ((Current Topics Neurotoxicity,volume 8))

Abstract

The review summarises the evidence that chronic low grade inflammation triggers a number of metabolic changes that are ultimately responsible for the physical ill-health (such as type 2 diabetes, heart disease and cancer) which frequently characterise major depression.

The possible mechanisms involve a dysfunction of glucose metabolism due to an insensitivity of insulin receptor signalling which results from the action of superoxide radicals produced by intermediates of the tryptophan–kynurenine pathway. Additional metabolic changes occur as a result of a decrease in mitochondrial activity.

Increasing epidemiological and clinical evidence suggests that chronic depression is often a prelude to dementia in later life. Possible metabolic mechanisms whereby this occurs involve the neurodegenerative effects of pro-inflammatory cytokines, the consequences of oxidative stress and the action of the neurotoxins formed by the tryptophan–kynurenine pathway. The review concludes with a summary of some of the nutritional factors that may have a neuroprotective action, largely due to their anti-inflammatory effects.

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References

  • Almeida OP, Marsh K, Alfonso H, Flicker L, et al. B vitamins reduce the long-term risk of depression after stroke: the VITATOPS-DEP trial. Ann Neurol. 2010;68:503–10.

    Article  CAS  PubMed  Google Scholar 

  • Balkwill F, Burke F, Talbot D. Evidence of TNF/cachectin production in cancer. Lancet. 1990;2:1229–32.

    Google Scholar 

  • Barber-Gateau P, Latenneur L, Deschamps V, et al. Fish, meat and risk of dementia: cohort study. Br Med J. 2002;325:932–3.

    Article  Google Scholar 

  • Barnes DE, Alexopoulos GS, Lopez OL, et al. Depressive symptoms, vascular disease and mild cognitive impairment: findings from the cardiovascular health study. Arch Gen Psychiatry. 2006;63:273–9.

    Article  PubMed  Google Scholar 

  • Bluthe RM, Castanon N, Pousset F, et al. Central injection of IL-10 antagonises the behavioural effects of lipopolysaccharide in rats. Psychoneuroendocrinology. 1999;24:301–11.

    Article  CAS  PubMed  Google Scholar 

  • Byers AL, Yaffe K. Depression and risk of developing dementia. Nat Rev Neurol. 2011;7:323–31.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Calder PC. The relationship between the fatty acid composition of immune cells and their function. Prostaglandins Leukot Essent Fatty Acids. 2008;79:101–8.

    Article  CAS  PubMed  Google Scholar 

  • Campayo A, de Jonge P, Roy JF, Saz P, et al. Depressive disorder and incident diabetes mellitus: the effect of characteristics of depression. Am J Psychiatry. 2010;167:580–8.

    Article  PubMed  Google Scholar 

  • Chen P, Ganguli M, Mubant BH, De Korsky ST. The temporal relationship between depressive symptoms and dementia: a community based prospective study. Arch Gen Psychiatry. 1999;56:261–6.

    Article  CAS  PubMed  Google Scholar 

  • Cuzzocrea S, Riley DP, Capute AP, Salvemini D. Antioxidant therapy: a new approach to shock, inflammation and ischaemia/reperfusion injury. Pharmacol Rev. 2001;53:135–59.

    CAS  PubMed  Google Scholar 

  • Devanand DP, Sano M, Tang MX, et al. Depressed mood and the incidence of Alzheimer’s disease in elderly living in the community. Arch Gen Psychiatry. 1996;53:175–82.

    Article  CAS  PubMed  Google Scholar 

  • Dilman M, Lapin IP, Oxenkrug GF. Serotonin and ageing. In: Essman W, editor. Serotonin in health and disease, vol. 5. London: Spectrum Press; 1979. p. 111–23.

    Google Scholar 

  • Dotson VM, Beydoun MA, Zonderman AB. Recurrent depressive symptoms and the incidence of dementia and mild cognitive impairment. Neurology. 2010;75:27–34.

    Article  PubMed Central  PubMed  Google Scholar 

  • Douglas RG, Shaw JHF. Metabolic response to sepsis and trauma. Br J Surg. 1989;76:115–20.

    Article  CAS  PubMed  Google Scholar 

  • Fuchs D, Avanzas P. The role of neopterin in atherosclerosis and cardiovascular risk assessment. Curr Med Chem. 2009;16:4644–53.

    Article  CAS  PubMed  Google Scholar 

  • Gal EM, Sherman AD. l-Kynurenine: its synthesis and possible regulatory function in brain. Neurochem Res. 1980;5:223–39.

    Article  CAS  PubMed  Google Scholar 

  • Geerlings MI, Schoevers RA, Bechman AT, et al. Depression and the risk of cognitive decline in Alzheimer’s disease: results of 2 prospective community based studies in the Netherlands. Br J Psychiat. 2000;176:568–75.

    Google Scholar 

  • Gimble RF. Dietary manipulation of the inflammatory cascade. Proc Nutr Soc. 1992;51:285–93.

    Article  Google Scholar 

  • Gimble RF. Nutritional modulation of cytokine biology. Nutrition. 1998;14:634–40.

    Article  Google Scholar 

  • Griffin DE, Moser HW, Mendoza Q, Moench TR, et al. Identification of the inflammatory cells in the CNS of patients with adrenoleukodystrophy. Ann Neurol. 1985;18:660–4.

    Article  CAS  PubMed  Google Scholar 

  • Grunfeld C, Feingold KR. TNF, interleukin and interferon induce changes in lipid metabolism as part of host defence. Proc Soc Exp Biol Med. 1992;200:224–30.

    Article  CAS  PubMed  Google Scholar 

  • Guillemin GJ, Brew BJ. Implications of the kynurenine pathway and quinolinic acid in Alzheimer’s disease. Redox Rep. 2002;7:199–206.

    Article  CAS  PubMed  Google Scholar 

  • Han Q, Tao C, Tagle DA, Li J. Structure, expression and function of kynurenine aminotransferase in human and rodent brains. Cell Mol Life Sci. 2010;67:353–68.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hattori M, Kotake Y. Studies on the urinary excretion of xanthenuric acid in diabetics. Acta Vitaminol Enzymol. 1984;16:221–8.

    Google Scholar 

  • Jiang H, Hempel D, Prvulovic D, et al. Elevated CSF levels of TACE activity and soluble TNF receptors in subjects with mild cognitive impairment and patients with Alzheimer’s disease. Mol Neurodegener. 2011;6:69–77.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jorm AF. History of depression as a risk factor for dementia: an update. Aust N Z J Psychiatry. 2001;35:776–81.

    Article  CAS  PubMed  Google Scholar 

  • Kalmijn S, van Boxtel MP, Ocke M, et al. Dietary intake of fatty acids and fish in relationship to cognitive performance at middle-age. Neurology. 2004;62:275–80.

    Article  CAS  PubMed  Google Scholar 

  • Kim Y-K, Na KS, Shin KH, Jung HY, et al. Cytokine imbalance in the pathophysiology of major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:1044–53.

    Article  CAS  PubMed  Google Scholar 

  • Kotaki Y, Ueda T, Mori T, Igali S, et al. Abnormal tryptophan metabolism and experimental diabetes by xanthenuric acid. Acta Vitaminol Enzymol. 1975;29:2369.

    Google Scholar 

  • Lam CK, Chari M, Su BB, Cheung GW, et al. Activation of N-methyl-d-aspartate receptors in the dorsal vagal complex lowers glucose production. J Biol Chem. 2010;285:21913–21.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lapin IP. Kynurenines as probable participants of depression. Pharmakopsychiatr Neurop sychopharmakol. 1973;6:273–9.

    Google Scholar 

  • Lapin IP, Oxenkrug GF. Intensification of the central serotonergic processes as possible determinants of the thymoleptic effect. Lancet. 1969;1:32–9.

    Google Scholar 

  • Launer LJ. Demonstrating the case that Alzheimer’s disease is a vascular disease: epidemiologic evidence. Ageing Res Rev. 2002;1:61–77.

    Article  PubMed  Google Scholar 

  • Lee S, Tong M, Hang S, et al. Cerebrospinal fluid and brain indices in insulin resistance, oxidative stress and neuroinflammation in early and late Alzheimer’s disease. Alzheimer’s disease and Parkinsonism. 2013. doi:10.4172/2161-0460.1000128.

  • Leonard BE. Changes in the immune system in depression and dementia. Int J Dev Neurosci. 2001a;19:305–21.

    Article  CAS  PubMed  Google Scholar 

  • Leonard BE. Brain cytokines and the psychopathology of depression. In: Leonard BE, editor. Antidepressants. Basel: Birkhauser Verlag; 2001b. p. 109–20.

    Chapter  Google Scholar 

  • Leonard BE. The concept of depression as a dysfunction of the immune system. Curr Immunol Rev. 2010;6:205–12.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Leonard BE. Inflammation as the cause of the metabolic syndrome in depression. Mod Trends Pharmacopsychiatri. 2013;28:117–26.

    Article  CAS  PubMed  Google Scholar 

  • Leonard BE. Impact of inflammation on neurotransmitter changes in major depression: an insight into the action of antidepressants. Prog Neuropsychopharmacol Biol Psychiatry. 2014; 48:261–7.

    Article  CAS  PubMed  Google Scholar 

  • Leonard BE, Myint A-M. Inflammation and depression: is there a causal connection with dementia? Neurotox Res. 2006;10:149–60.

    Article  CAS  PubMed  Google Scholar 

  • Leonard BE, Song C. Changes in the immune system in rodent models of depression. Int J Neuropsychopharmacol. 2002;5:345–56.

    Google Scholar 

  • Lesser IM, Boone KB, Mehringer CM, et al. Cognitive and white matter hyperintensities in older depressed patients. Am J Psychiat. 1996;153:1280–87.

    Google Scholar 

  • Lynch J, Tang W, Wang H, et al. APOE genotype and APOEmimetic peptide modify the systemic and CNS inflammatory response. J Biol Chem. 2003;278:48529–33.

    Article  CAS  PubMed  Google Scholar 

  • Maes M. Evidence for an immune response in major depression: a review and hypothesis. Prog Neuropsychopharmacol Biol Psychiatry. 1995;19:11–38.

    Article  CAS  PubMed  Google Scholar 

  • Maes M. Major depression and the activation of the inflammatory response system. Adv Exp Med Biol. 1999;461:25–45.

    Article  CAS  PubMed  Google Scholar 

  • Maes M, Christophe A, Delanghe J, et al. Lowered omega 3 polyunsaturated fatty acids in serum phospholipid and cholesteryl esters in depressed patients. Psychiatry Res. 1999;85:275–91.

    Article  CAS  PubMed  Google Scholar 

  • Marcheselli VL, Hong S, Lukiw WJ, et al. Novel docoanoids inhibit brain ischaemia-reperfusion mediated leukocyte infiltration and proinflammatory gene expression. J Physiol Pharmacol. 2000;51:643–54.

    Google Scholar 

  • McIntyre RS, Rosenbluth M, Ramasulbbu R, et al. Managing medical and psychiatricco-morbidity in individuals with major depression and bipolar disorder. Ann Clin Psychiatry. 2012;24:163–9.

    PubMed  Google Scholar 

  • Merete C, Falcon LM, Tucker KL. Vitamin B6 is associated with depressive symptomatology in Massachusetts Elders. J Am Coll Nutr. 2008;27:421–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Moens AL, Kass DA. Therapeutic potential and tetrahydrobiopterin for treating vascular cardiac disease. J Cardiovasc Pharmacol. 2007;50:238–46.

    Article  CAS  PubMed  Google Scholar 

  • Murray CA, Lynch MA. Evidence that increased hippocampal expression of cytokine IL-1beta is a common trigger for age- and stress impairments in LTP. J Neurosci. 1998;18:2974–81.

    CAS  PubMed  Google Scholar 

  • Myint A-M, Kim Y-K. Cytokine-serotonin interaction through IDO: a neurodegeneration hypothesis of depression. Med Hypotheses. 2003;61:519–25.

    Article  CAS  PubMed  Google Scholar 

  • Myint A-M, Kim Y-K. Network beyond IDO in psychiatric disorders: revisiting the neurodegeneration hypothesis. Prog Neuropsychopharmacol Biol Psychiatry. 2014;48:304–13.

    Article  CAS  PubMed  Google Scholar 

  • Namekawa Y, Baba H, Maeshima H, et al. Heterogeneity of elderly depressives at increased risk of Alzheimer’s disease and amyloid beta protein metabolism. Prog Neuropsychopharmacol Biol Psychiatry. 2013;43:203–8.

    Article  CAS  PubMed  Google Scholar 

  • Nanri A, Pham NM, Kurotani K, Kume A, et al. Serum pyridoxal concentrations and depressive symptoms among Japanese adults: results of a prospective study. Eur J Clin Nutr. 2013;67:1060–5.

    Article  CAS  PubMed  Google Scholar 

  • Olazaran J, Trincado R, Bermyo-Pareja F. Cumulative effect of depression and dementia risk. Int J Alzheimers Dis. 2013. doi:10.1155/2013/457175.

    Google Scholar 

  • Ownby RL, Crocco E, Acevedo A, et al. Depression and risk of Alzheimer’s disease: systematic review, meta-analysis and meta-regression analysis. Arch Gen Psychiatry. 2006;63:530–8.

    Article  PubMed Central  PubMed  Google Scholar 

  • Oxenkrug GF. Interferon gamma inducible kynurenines/pteridines inflammation cascade: implications for ageing-associated psychiatric and medical disorders. J Neural Transm. 2011;118:75–85.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Oxenkrug GF. Insulin resistance and dysregulation of tryptophan-kynurenine-nicotinamide adenine dinucleotide pathways. Mol Neurobiol. 2013;48:294–301.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Park KM, Bowers WT. TNF-alpha mediated signaling in neuronal homeostasis and dysfunction. Cell Signal. 2010;22:977–83.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006;27:24–31.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Rapp MA, Sahnaider-Beeri M, Grossman HT, et al. Increased hippocampal plaques and tangles in patients with Alzheimer’s disease with a life-time history of major depression. Arch Gen Psychiatry. 2006;63:161–7.

    Article  PubMed  Google Scholar 

  • Sanchez-Villegas A, Poreste J, Schlatter J, Pla J, et al. Association between folate, vitamin B6 and vitamin B12 intake and depression in the SUN cohort study. J Hum Nutr Diet. 2009;22:122–33.

    Article  CAS  PubMed  Google Scholar 

  • Sas K, Robotka H, Toldi J, Vecsei L. Mitochondria, metabolic disturbances, oxidative stress and the kynurenine system, with a focus on neurodegenerative disorders. J Neurol Sci. 2007;257:221–39.

    Article  CAS  PubMed  Google Scholar 

  • Serhan CN, Clish CB, Brannon J, et al. Antimicroinflammatory lipid signals generated from dietary n-3 fatty acids via cyclooxygenase 2 and transcellular processing: a novel mechanism for NSAID and n-3 PUFA therapeutic actions. J Physiol Pharmacol. 2000;51:643–54.

    CAS  PubMed  Google Scholar 

  • Simopoulos AP. Importance of the ratio of omega 6/omega 3 essential fatty acids: evolutionary aspects. World Rev Nutr Diet. 2003;92:1–23.

    Article  CAS  PubMed  Google Scholar 

  • Smith RS. The macrophage theory of depression. Med Hypotheses. 1991;35:298–306.

    Article  CAS  PubMed  Google Scholar 

  • Song C, Horrobin DF. Omega-3 fatty acidethyl-eicosapentaenoic acid, but not soya bean oil, attenuates memory impairment induced by central il-1 beta administration. J Lipid Res. 2004;45:1112–21.

    Article  CAS  PubMed  Google Scholar 

  • Song C, Li X, Leonard BE, Horrobin DF. Effects of dietary n-3 or n-6 fatty acids on IL-1 beta induced anxiety, stress and inflammation responses in rats. J Lipid Res. 2003;44:1984–91.

    Article  CAS  PubMed  Google Scholar 

  • Song C, Phillips AG, Leonard BE, Horrobin DF. Ethyl-eicosapentaenoic acid ingestion prevents corticosterone – mediated memory impairment induced by central administration of IL-1 beta in rats. Mol Psychiatry. 2004;9:630–8.

    Article  CAS  PubMed  Google Scholar 

  • Song C, Zhang XY, Manku M. Increased PLA2 activity and inflammatory responses but decreased NGF expression in the olfactory bulbectomised rat model of depression: effects of chronic ethyl-eicosapentaenoic acid treatment. J Neurosci. 2009;29:14–22.

    Article  PubMed  Google Scholar 

  • Sperner-Unterweger B, Kohl C, Fuchs D. Immune changes and neurotransmitters: possible interactions in depression. Prog Neuropsychopharmacol Biol Psychiatry. 2014;48:268–76.

    Article  CAS  PubMed  Google Scholar 

  • Stewart JC. Negative emotions and 3 year progression of subclinical atherosclerosis. Arch Gen Psychiatry. 2007;64:225–33.

    Article  PubMed  Google Scholar 

  • Stone TW. Neuropharmacology of quinolinic and kynurenic acids. Pharmacol Rev. 1993;45:310–79.

    Google Scholar 

  • Sucher R, Schroecksnadel K. Neopterin, a prognostic marker in human malignancies. Cancer Lett. 2010;287:13–22.

    Article  CAS  PubMed  Google Scholar 

  • Sullivan MD, Katon WJ, Lovato LC, et al. Association of depression with accelerated cognitive decline among patients with type-2 diabetes in the ACCORD-Mind trial. JAMA Psychiatry. 2013;70:1041–7.

    Article  PubMed Central  PubMed  Google Scholar 

  • Sun X, Steffens DC, Au R, et al. Amyloid associated depression: a prodromal depression of Alzheimer’s disease? Arch Gen Psychiatry. 2008;65:542–50.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Waage A, Brandtzoeg P, Halstensen P, et al. Complex pattern of cytokines in serum of patients with meningococcal septic shock. J Exp Med. 1989;169:333–40.

    Article  CAS  PubMed  Google Scholar 

  • Warren RS, Starnes EF, Gabrilov JL, et al. The acute metabolic effects of TNF administration in humans. Arch Surg. 1987;122:1396–402.

    Article  CAS  PubMed  Google Scholar 

  • Werner-Falmayer G, Goldener G, Wernes ER. Tetrahydrobiopterin biosynthesis utilization and pharmacological effects. Curr Drug Metab. 2002;3:159–73.

    Article  Google Scholar 

  • Wilson RS, Barnes LL, Mendes de Leon CF, et al. Depressive symptoms, cognitive decline and risk of Alzheimer’s disease in older persons. Neurology. 2002;59:364–70.

    Article  PubMed  Google Scholar 

  • Wirleitner B, Neuranter G, Schroecksnadel K, et al. Interferon-gamma induced conversion of tryptophan immunologic and neuropsychiatric aspects. Curr Med Chem. 2005;10:1581–91.

    Article  Google Scholar 

  • Zhang J, Jia J, Qin W, Wang S. Combination of plasma TNF receptors signalling proteins, beta amyloid and apolipoprotein E for the detection of Alzheimer’s disease. Neurosci Lett. 2013;541:99–104.

    Article  CAS  PubMed  Google Scholar 

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Leonard, B.E. (2015). Depression, the Metabolic Syndrome and Neurodegeneration. In: Müller, N., Myint, AM., Schwarz, M. (eds) Immunology and Psychiatry. Current Topics in Neurotoxicity, vol 8. Springer, Cham. https://doi.org/10.1007/978-3-319-13602-8_11

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