Top

Published in:

01-03-2009 | Original Paper

The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression

Authors: Michael Maes, Raz Yirmyia, Jens Noraberg, Stefan Brene, Joe Hibbeln, Giulia Perini, Marta Kubera, Petr Bob, Bernard Lerer, Mario Maj

Published in: Metabolic Brain Disease | Issue 1/2009

Abstract

Despite extensive research, the current theories on serotonergic dysfunctions and cortisol hypersecretion do not provide sufficient explanations for the nature of depression. Rational treatments aimed at causal factors of depression are not available yet. With the currently available antidepressant drugs, which mainly target serotonin, less than two thirds of depressed patients achieve remission. There is now evidence that inflammatory and neurodegenerative (I&ND) processes play an important role in depression and that enhanced neurodegeneration in depression may–at least partly–be caused by inflammatory processes. Multiple inflammatory-cytokines, oxygen radical damage, tryptophan catabolites–and neurodegenerative biomarkers have been established in patients with depression and these findings are corroborated by animal models of depression. A number of vulnerability factors may predispose towards depression by enhancing inflammatory reactions, e.g. lower peptidase activities (dipeptidyl-peptidase IV, DPP IV), lower omega-3 polyunsaturated levels and an increased gut permeability (leaky gut). The cytokine hypothesis considers that external, e.g. psychosocial stressors, and internal stressors, e.g. organic inflammatory disorders or conditions, such as the postpartum period, may trigger depression via inflammatory processes. Most if not all antidepressants have specific anti-inflammatory effects, while restoration of decreased neurogenesis, which may be induced by inflammatory processes, may be related to the therapeutic efficacy of antidepressant treatments. Future research to disentangle the complex etiology of depression calls for a powerful paradigm shift, i.e. by means of a high throughput-high quality screening, including functional genetics and genotyping microarrays; established and novel animal and ex vivo–in vitro models for depression, such as new transgenic mouse models and endophenotype-based animal models, specific cell lines, in vivo and ex vivo electroporation, and organotypic brain slice culture models. This screening will allow to: 1) discover new I&ND biomarkers, both at the level of gene expression and the phenotype; and elucidate the underlying molecular I&ND pathways causing depression; and 2) identify new therapeutic targets in the I&ND pathways; develop new anti-I&ND drugs for these targets; select existing anti-I&ND drugs or substances that could augment the efficacy of antidepressants; and predict therapeutic response by genetic I&ND profiles.

Amodio P, De Toni EN, Cavalletto L, Mapelli D, Bernardinello E, Del Piccolo F, Bergamelli C, Costanzo R, Bergamaschi F, Poma SZ, Chemello L, Gatta A, Perini G (2005) Mood, cognition and EEG changes during interferon (αIFN) treatment for chronic hepatitis C. J. Affect. Disord. 84(1):93–98PubMed

Angelucci F, Brene S, Mathe AA (2005) BDNF in schizophrenia, depression and corresponding animal models. Mol. Psychiatry 10(4):345–352PubMed

Anisman H, Kokkinidis L, Merali Z (2002) Further evidence for the depressive effects of cytokines: anhedonia and neurochemical changes. Brain Beh. Immun. 16(5):544–556 Review

Anisman H, Merali Z, Poulter MO, Hayley S (2005) Cytokines as a precipitant of depressive illness: animal and human studies. Curr. Pharm. Design 11(8):963–972

Anisman H, Poulter MO, Gandhi R, Merali Z, Hayley S (2007) Interferon-alpha effects are exaggerated when administered on a psychosocial stressor backdrop: cytokine, corticosterone and brain monoamine variations. J. Neuroimmunol. 186(1–2):45–53PubMed

Anttila S, Huuhka K, Huuhka M, Rontu R, Hurme M, Leinonen E, Lehtimaki T (2007) Interaction between 5-HT1A and BDNF genotypes increases the risk of treatment-resistant depression. J. Neural. Transm. 114(8):1065–1068PubMed

Babcock TA, Carlin JM (2000) Transcriptional activation of indoleamine dioxygenase by interleukin 1 and tumor necrosis factor alpha in interferon-treated epithelial cells. Cytokine 12(6):588–594PubMed

Banerjee A, Jain G, Grover S, Singh J (2007) Mania associated with interferon. J. Postgraduate Med. 53(2):150

Bazan NG, Marcheselli VL, Cole-Edwards K (2005) Brain response to injury and neurodegeneration: endogenous neuroprotective signaling. Ann. NY Acad. Sci. 1053:137–147 ReviewPubMed

Beck RD Jr., Wasserfull C, Ha GK, Cushman JD, Huang Z, Atkinson MA, Petitto JM (2005) Changes in hippocampal IL-15, related cytokines, and neurogenesis in IL-2 deficient mice. Brain Res. 1041:223–230PubMed

Beltz BS, Sandeman DC (2003) Regulation of life-long neurogenesis in the decapod crustacean brain. Arth. Struct. Dev. 32:39–60

Beltz BS, Tlusty MF, Benton JL, Sandeman DC (2007) Omega-3 fatty acids upregulate adult neurogenesis. Neurosci. Lett. 145(2):154–158

Benazzi F (2007a) Bipolar II Disorder : Epidemiology, Diagnosis and Management. CNS Drugs. 21(9):727–740PubMed

Benazzi F (2007b) Is there a continuity between bipolar and depressive disorders? Psychoth. Psychosom. 76(2):70–76

Berlim MT, Turecki G (2007) Definition, assessment, and staging of treatment-resistant refractory major depression: a review of current concepts and methods. Can. J. Psychiatry 52(1):46–54PubMed

Bjornebekk A, Mathe AA, Brene S (2005) The antidepressant effect of running is associated with increased hippocampal cell proliferation. Int. J. Neuropsychopharmacol. 8(3):357–368PubMed

Bjørnebekk A, Mathé AA, Gruber SH, Brené S (2007) Social isolation increases number of newly proliferated cells in hippocampus in female flinders sensitive line rats. Hippocampus. 17(12):1193–1120PubMed

Bjørnebekk A, Mathé AA, Gruber SH, Brené S (2008) Housing conditions modulate escitalopram effects on antidepressive-like behaviour and brain neurochemistry. Int. J. Neuropsychopharmacol. 23:1–13

Bonaccorso S, Puzella A, Marino V, Pasquini M, Biondi M, Artini M, Almerighi C, Levrero M, Egyed B, Bosmans E, Meltzer HY, Maes M (2001) Immunotherapy with interferon-alpha in patients affected by chronic hepatitis C induces an intercorrelated stimulation of the cytokine network and an increase in depressive and anxiety symptoms. Psychiatry Res. 105(1–2):45–55PubMed

Bonaccorso S, Marino V, Biondi M, Grimaldi F, Ippoliti F, Maes M (2002a) Depression induced by treatment with interferon-alpha in patients affected by hepatitis C virus. J. Affect. Disord. 72(3):237–241PubMed

Bonaccorso S, Marino V, Puzella A, Pasquini M, Biondi M, Artini M, Almerighi C, Verkerk R, Meltzer H, Maes M (2002b) Increased depressive ratings in patients with hepatitis C receiving interferon-alpha-based immunotherapy are related to interferon-alpha-induced changes in the serotonergic system. J. Clin. Psychopharmacol. 22(1):86–90PubMed

Bremner JD, Narayan M (1998) The effects of stress on memory and the hippocampus throughout the life cycle: implications for childhood development and aging. Developm. Psychopathol. 10(4):871–885

Brown ES, Rush AJ, McEwen BS (1999) Hippocampal remodeling and damage by corticosteroids: implications for mood disorders. Neuropsychopharmacol. 21(4):474–484

Brown ES, J Woolston D, Frol A, Bobadilla L, Khan DA, Hanczyc M, Rush AJ, Fleckenstein J, Babcock E, Cullum CM (2004) Hippocampal volume, spectroscopy, cognition, and mood in patients receiving corticosteroid therapy. Biol. Psychiatry 55(5):538–545PubMed

Bukalo O, Fentrop N, Lee AY, Salmen B, Law JW, Wotjak CT, Schweizer M, Dityatev A, Schachner M (2004) Conditional ablation of the neural cell adhesion molecule reduces precision of spatial learning, long-term potentiation, and depression in the CA1 subfield of mouse hippocampus. J. Neurosci. 24:1565–1577PubMed

Campbell S, MacQueen G (2006) An update on regional brain volume differences associated with mood disorders. Curr. Opin. Psychiatry 19(1):25–33PubMed

Capuron L, Neurauter G, Musselman DL, Lawson DH, Nemeroff CB, Fuchs D, Miller AH (2003) Interferon-alpha-induced changes in tryptophan metabolism. relationship to depression and paroxetine treatment. Biol. Psychiatry 54(9):906–914PubMed

Carter CJ (2007) Multiple genes and factors associated with bipolar disorder converge on growth factor and stress activated kinase pathways controlling translation initiation: implications for oligodendrocyte viability. Neurochem. Int. 50(3):461–490PubMed

Castanon N, Bluthé RM, Dantzer R (2001) Chronic treatment with the atypical antidepressant tianeptine attenuates sickness behavior induced by peripheral but not central lipopolysaccharide and interleukin-1beta in the rat. Psychopharmacol. 154(1):50–60

Chavez AM, Menconi MJ, Hodin RA, Fink MP (1999) Cytokine-induced intestinal epithelial hyperpermeability: role of nitric oxide. Crit. Care Med. 27(10):2246–2251PubMed

Checa N, Canals JM, Alberch J (2000) Developmental regulation of BDNF and NT-3 expression by quinolinic acid in the striatum and its main connections. Exp. Neurology 165(1):118–124

Chung KK, Dawson TM, Dawson VL (2005) Nitric oxide, S-nitrosylation and neurodegeneration. Cell Mol. Biol. (Noisy-le-grand) 51(3):247–254 Review

Clark E, Hoare C, Tanianis-Hughes J, Carlson GL, Warhurst G (2005) Interferon gamma induces translocation of commensal Escherichia coli across gut epithelial cells via a lipid raft-mediated process. Gastroenterol. 128(5):1258–1267

Contestabile A (2001) Oxidative stress in neurodegeneration: mechanisms and therapeutic perspectives. Curr. Topics Med. Chemistry 1(6):553–568 Review

Coti Bertrand P, O'Kusky JR, Innis SM (2006) Maternal dietary (n-3) fatty acid deficiency alters neurogenesis in the embryonic rat brain. J. Nutr. 136(6):1570–1575PubMed

Cowen PJ (2002) Cortisol, serotonin and depression: all stressed out? Brit. J. Psychiatry 180:99–100

de Jonge WJ, van der Zanden EP, The FO, Bijlsma MF, van Westerloo DJ, Bennink RJ, Berthoud HR, Uematsu S, Akira S, van den Wijngaard RM, Boeckxstaens GE (2005) Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway. Nature Immunol 6(8):844–851

Dinan T (2001) Novel approaches to the treatment of depression by modulating the hypothalamic—pituitary—adrenal axis. Hum. Psychopharmacol. 16(1):89–93PubMed

Duman RS (2002) Pathophysiology of depression: the concept of synaptic plasticity. Eur. Psychiatry 17(Suppl 3):306–310PubMed

Duman RS (2004) Depression: a case of neuronal life and death? Biol. Psychiatry 56(3):140–145PubMed

Ehninger D, Kempermann G (2006) Paradoxical effects of learning the Morris water maze on adult hippocampal neurogenesis in mice may be explained by a combination of stress and physical activity. Genes Brain Beh. 5(1):29–39

Ekdahl CT, Claasen JH, Bonde S, Kokaia Z, Lindvall O (2003) Inflammation is detrimental for neurogenesis in adult brain. Proc. Nat. Acad. Sci. USA. 100(23):13632–13637PubMed

el-Defrawy SR, Boegman RJ, Jhamandas K, Beninger RJ (1986) The neurotoxic actions of quinolinic acid in the central nervous system. Can. J. Physiol. Pharmacol. 64(3):369–375PubMed

Fitzgerald P, O'Brien SM, Scully P, Rijkers K, Scott LV, Dinan TG (2006) Cutaneous glucocorticoid receptor sensitivity and pro-inflammatory cytokine levels in antidepressant-resistant depression. Psychol. Med. 36(1):37–43PubMed

Forlenza MJ, Miller GE (2006) Increased serum levels of 8-hydroxy-2'-deoxyguanosine in clinical depression. Psychosomatic Med. 68(1):1–7

Fuchs E, Czeh B, Kole MH, Michaelis T, Lucassen PJ (2004) Alterations of neuroplasticity in depression: the hippocampus and beyond. Eur. Neuropsychopharmacol. 5(14 Suppl):S481–490

Garthwaite G, Garthwaite J (1987) Quinolinate mimics neurotoxic actions of N-methyl-D-aspartate in rat cerebellar slices. Neurosci. Lett. 79(1–2):35–39PubMed

Gould E, McEwen BS, Tanapat P, Galea LA, Fuchs E (1997) Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation.J. Neurosci. 17(7):2492–2498

Guillemin GJ, Smith DG, Kerr SJ, Smythe GA, Kapoor V, Armati PJ, Brew BJ (2000) Characterisation of kynurenine pathway metabolism in human astrocytes and implications in neuropathogenesis. Redox Report 5(2–3):108–111PubMed

Goshen I, Kreisel T, Ben-Menachem-Zidon O, Licht T, Weidenfeld J, Ben-Hur T, Yirmiya R (2008) Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression. Mol Psychiatry 13(7):717–728PubMed

Groves JO (2007) Is it time to reassess the BDNF hypothesis of depression? Mol. Psychiatry 12:1079–1088PubMed

Halliwell B (2006) Oxidative stress and neurodegeneration: where are we now? J. Neurochem. 97(6):1634–1658 ReviewPubMed

Hand R, Bortone D, Mattar P, Nguyen L, Heng JI, Guerrier S, Boutt E, Peters E, Barnes AP, Parras C, Schuurmans C, Guillemot F, Polleux F (2005) Phosphorylation of neurogenin2 specifies the migration properties and the dendritic morphology of pyramidal neurons in the neocortex. Neuron 48(1):45–62PubMed

Henn FA, Vollmayr B (2004) Neurogenesis and depression: etiology or epiphenomenon? Biol. Psychiatry 56(3):146–150PubMed

Heyes MP, Saito K, Crowley JS, Davis LE, Demitrack MA, Der M, Dilling LA, Elia J, Kruesi MJ, Lackner A et al (1992) Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease. Brain 115(Pt 5):1249–1273PubMed

Hibbeln JR (1998) Fish consumption and major depression. Lancet 351(9110):1213PubMed

Hibbeln JR (2002) Seafood consumption, the DHA content of mothers' milk and prevalence rates of postpartum depression: a cross-national, ecological analysis. J. Affect. Disord. 69(1–3):15–29PubMed

Horrobin DF (2001) Phospholipid metabolism and depression: the possible roles of phospholipase A2 and coenzyme A-independent transacylase. Hum. Psychopharmacol. 16(1):45–52PubMed

Huang SY, Yang HT, Chiu CC, Pariante CM, Su KP (2006) Omega-3 fatty acids on the forced-swimming test. J. Psychiatr. Res. 42(1):58–63PubMed

Ishikawa I, Kitamura H, Kimura K, Saito M (2001) Brain interleukin-1 is involved in blood interleukin-6 response to immobilization stress in rats. Jap. J. Veterinary Res. 49(1):19–25

Kawakita E, Hashimoto M, Shido O (2006) Docosahexaenoic acid promotes neurogenesis in vitro and in vivo. Neurosci. 139(3):991–997

Kempermann G, Neumann H (2003) Microglia: the enemy within? Science 302:1689–1690PubMed

Kempermann G, Kuhn HG, Gage FH (1997) More hippocampal neurons in adult mice living in an enriched environment. Nature 386(6624):493–495PubMed

Kenis G, Maes M (2002) Effects of antidepressants on the production of cytokines. Int. J. Neuropsychopharmacol. 5(4):401–412 ReviewPubMed

Kent S, Bluthé RM, Kelley KW, Dantzer R (1992) Sickness behavior as a new target for drug development. Trends Pharmacol. Sci. 13(1):24–28PubMed

Kerr SJ, Armati PJ, Guillemin GJ, Brew BJ (1998) Chronic exposure of human neurons to quinolinic acid results in neuronal changes consistent with AIDS dementia complex. AIDS 12(4):355–363PubMed

Khaspekov L, Kida E, Victorov I, Mossakowski MJ (1989) Neurotoxic effect induced by quinolinic acid in dissociated cell culture of mouse hippocampus. J. Neurosci. Res. 22(2):150–157PubMed

Kim YK, Myint AM, Lee BH, Han CS, Lee SW, Leonard BE, Steinbusch HW (2004) T-helper types 1, 2, and 3 cytokine interactions in symptomatic manic patients. Psychiatr. Res. 129(3):267–272

Kim YK, Jung HG, Myint AM, Kim H, Park SH (2007) Imbalance between pro-inflammatory and anti-inflammatory cytokines in bipolar disorder. J. Affect. Disord. 104(1–3):91–95PubMed

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT (2008) Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS. Medicine 5(2):e45PubMed

Koo JW Duman RS (2008) IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc. Nat. Acad. Sci. USA 105:751–756

Kubera M, Symbirtsev A, Basta-Kaim A, Borycz J, Roman A, Papp M, Claesson M (1996) Effect of chronic treatment with imipramine on interleukin 1 and interleukin 2 production by splenocytes obtained from rats subjected to a chronic mild stress model of depression. Pol. J. Pharmacol. 48:503–506PubMed

Kubera M, Van Bockstaele D, Maes M (1999) Leukocyte subsets in treatment-resistant major depression. Pol. J. Pharmacol. 51(6):547–549PubMed

Kubera M, Lin AH, Kenis G, Bosmans E, van Bockstaele D, Maes M (2001a) Anti-Inflammatory effects of antidepressants through suppression of the interferon-gamma/interleukin-10 production ratio. J. Clin. Psychopharmacol. 21(2):199–206PubMed

Kubera M, Maes M, Holan V, Basta-Kaim A, Roman A, Shani J (2001b) Prolonged desipramine treatment increases the production of interleukin-10, an anti-inflammatory cytokine, in C57BL/6 mice subjected to the chronic mild stress model of depression. J. Affect. Disord. 63(1–3):171–178PubMed

Kwidzinski E, Bunse J, Aktas O, Richter D, Mutlu L, Zipp F, Nitsch R, Bechmann I (2005) Indolamine 2,3-dioxygenase is expressed in the CNS and down-regulates autoimmune inflammation. FASEB J. 19(10):1347–1349PubMed

Lacosta S, Merali Z, Anisman H (1999) Behavioral and neurochemical consequences of lipopolysaccharide in mice: anxiogenic-like effects. Brain Res. 818(2):291–303PubMed

Lapin IP (2003) Neurokynurenines (NEKY) as common neurochemical links of stress and anxiety. Adv. Exp. Med. Biol. 527:121–125PubMed

Lestage J, Verrier D, Palin K, Dantzer R (2002) The enzyme indoleamine 2,3-dioxygenase is induced in the mouse brain in response to peripheral administration of lipopolysaccharide and superantigen. Brain Behav. Immun. 16(5):596–601PubMed

Levivier M, Przedborski S (1998) Quinolinic acid-induced lesions of the rat striatum: quantitative autoradiographic binding assessment. Neurol. Res. 20(1):46–56PubMed

Lin A, Song C, Kenis G, Bosmans E, De Jongh R, Scharpe S, Maes M (2000) The in vitro immunosuppressive effects of moclobemide in healthy volunteers. J. Affect. Disord. 58(1):69–74PubMed

Lin PY, Su KP (2007) A meta-analytic review of double-blind, placebo-controlled trials of antidepressant efficacy of omega-3 fatty acids. J. Clin. Psychiatr. 68(7):1056–1061

Machado-Vieira R, Dietrich MO, Leke R, Cereser VH, Zanatto V, Kapczinski F, Souza DO, Portela LV, Gentil V (2007a) Decreased plasma brain derived neurotrophic factor levels in unmedicated bipolar patients during manic episode. Biol. Psychiatry 61(2):142–144PubMed

Machado-Vieira R, Andreazza AC, Viale CI, Zanatto V, Cereser V Jr, da Silva Vargas R, Kapczinski F, Portela LV, Souza DO, Salvador M, Gentil V (2007b) Oxidative stress parameters in unmedicated and treated bipolar subjects during initial manic episode: a possible role for lithium antioxidant effects. Neurosci. Lett. 421(1):33–36PubMed

Maes M (1993) A review on the acute phase response in major depression. Rev. Neurosci. 4(4):407–416 ReviewPubMed

Maes M (1995) Evidence for an immune response in major depression: a review and hypothesis. Progr. Neuropsychopharmacol. Biol. Psychiatry 19(1):11–38 Review

Maes M (1999) Major depression and activation of the inflammatory response system. Adv. Exp. Med. Biol. 461:25–46 ReviewPubMed

Maes M, Meltzer HY (1995) The Serotonin Hypothesis of major depression. Psychopharmacology, The Fourth Generation of Progress. In: Bloom F, Kupfer D (Ed) Raven Press, pp 933–944

Maes M, Smith RS (1998) Fatty acids, cytokines, and major depression. Biol. Psychiatr. 43(5):313–314

Maes M, De Ruyter M, Claes R, Bosma G, Suy E (1987) The cortisol responses to 5-hydroxytryptophan, orally, in depressive inpatients. J. Affect. Disord. 13(1):23–30PubMed

Maes M, De Ruyter M, Claes R, Suy E (1988) Sex-related differences in the relationships between self-rated depression and biological markers. J. Affect. Disord. 15(2):119–125PubMed

Maes M, Bosmans E, Suy E, Vandervorst C, De Jonckheere C, Raus J (1990) Immune disturbances during major depression: upregulated expression of interleukin-2 receptors. Neuropsychobiol. 24(3):115–120

Maes M, De Meester I, Vanhoof G, Scharpe S, Bosmans E, Vandervorst C, Verkerk R, Minner B, Suy E, Raus J (1991) Decreased serum dipeptidyl peptidase IV activity in major depression. Biol. Psychiatry 30(6):577–586PubMed

Maes M, Bosmans E, Meltzer HY, Scharpe S, Suy E (1993a) Interleukin-1 beta: a putative mediator of HPA axis hyperactivity in major depression? Am. J. Psychiatry 150(8):1189–1193PubMed

Maes M, Meltzer HY, Scharpe S, Bosmans E, Suy E, De Meester I, Calabrese J, Cosyns P (1993b) Relationships between lower plasma L-tryptophan levels and immune-inflammatory variables in depression. Psychiatr. Res. 49(2):151–165

Maes M, Meltzer HY, Scharpé S, Cooreman W, Uyttenbroeck W, Suy E, Vandervorst C, Calabrese J, Raus J, Cosyns P (1993c) Psychomotor retardation, anorexia, weight loss, sleep disturbances, and loss of energy: psychopathological correlates of hyperhaptoglobinemia during major depression. Psychiatr. Res. 47(3):229–241

Maes M, Scharpe S, Meltzer HY, Cosyns P (1993d) Relationships between increased haptoglobin plasma levels and activation of cell-mediated immunity in depression. Biol. Psychiatry 34(10):690–701PubMed

Maes M, Scharpe S, Meltzer HY, Bosmans E, Suy E, Calabrese J, Cosyns P (1993e) Relationships between interleukin-6 activity, acute phase proteins, and function of the hypothalamic-pituitary-drenal axis in severe depression. Psychiatr. Res. 49(1):11–27

Maes M, Scharpe S, Meltzer H, Okayli G, D'Hondt P, Cosyns P (1994) Increased neopterin and interferon gamma secretion and lower L-tryptophan levels in major depression: further evidence for immune activation in severe depression. Psychiatr. Res. 54:143–160

Maes M, Bosmans E, Calabrese J, Smith R, Meltzer HY (1995a) Interleukin-2 and interleukin-6 in schizophrenia and mania: effects of neuroleptics and mood stabilizers. J. Psychiatry Res. 29(2):141–152

Maes M, Smith R, Scharpe S (1995b) The monocyte-T-lymphocyte hypothesis of major depression. Psychoneuroendocrinol. 20(2):111–116

Maes M, Smith R, Christophe A, Cosyns P, Desnyder R, Meltzer H (1996a) Fatty acid composition in major depression: decreased omega 3 fractions in cholesteryl esters and increased C20: 4 omega 6/C20:5 omega 3 ratio in cholesteryl esters and phospholipids. J. Affect. Disord. 38(1):35–46PubMed

Maes M, Wauters A, Verkerk R, Demedts P, Neels H, Van Gastel A, Cosyns P, Scharpe S, Desnyder R (1996b) Lower serum L-tryptophan availability in depression as a marker of a more generalized disorder in protein metabolism. Neuropsychopharmacol. 15(3):243–251

Maes M, Bosmans E, De Jongh R, Kenis G, Vandoolaeghe E, Neels H (1997a) Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine 9(11):853–858PubMed

Maes M, Calabrese J, Jayathilake K, Meltzer HY (1997b) Effects of subchronic treatment with valproate on L-5-HTP-induced cortisol responses in mania: evidence for increased central serotonergic neurotransmission. Psychiatr. Res. 71(2):67–76

Maes M, Delange J, Ranjan R, Meltzer HY, Desnyder R, Cooremans W, Scharpe S (1997c) Acute phase proteins in schizophrenia, mania and major depression: modulation by psychotropic drugs. Psychiatr. Res. 66(1):1–11

Maes M, Vandoolaeghe E, Neels H, Demedts P, Wauters A, Meltzer HY, Altamura C, Desnyder R (1997d) Lower serum zinc in major depression is a sensitive marker of treatment resistance and of the immune/inflammatory response in that illness. Biol. Psychiatry 42(5):349–358PubMed

Maes M, Song C, Lin A, De Jongh R, Van Gastel A, Kenis G, Bosmans E, De Meester I, Benoy I, Neels H, Demedts P, Janca A, Scharpe S, Smith RS (1998a) The effects of psychological stress on humans: increased production of pro-inflammatory cytokines and a Th1-like response in stress-induced anxiety. Cytokine 10(4):313–318PubMed

Maes M, Song C, Lin A, DeJong R, Van Gastel A, Kenis G, Bosmans E, DeMeester I, Neels H, Janca A, Scharpe S, Smith RS (1998b) Immune and clinical correlates of psychological stress-induced production of interferon-( and IL-10 in humans. In: Plotnikoff NP, Faith RE, Murgo AJ, Good RA (eds) Cytokines, Stress and Immunity, pp 39–50

Maes M, Christophe A, Delanghe J, Altamura C, Neels H, Meltzer HY (1999a) Lowered omega3 polyunsaturated fatty acids in serum phospholipids and cholesteryl esters of depressed patients. Psychiatr. Res. 85(3):275–291

Maes M, Libbrecht I, van Hunsel F, Campens D, Meltzer HY (1999b) Pindolol and mianserin augment the antidepressant activity of fluoxetine in hospitalized major depressed patients, including those with treatment resistance. J. Clin. Psychopharmacol. 19(2):177–182PubMed

Maes M, Song C, Lin AH, Bonaccorso S, Kenis G, De Jongh R, Bosmans E, Scharpe S (1999c) Negative immunoregulatory effects of antidepressants: inhibition of interferon-gamma and stimulation of interleukin-10 secretion. Neuropsychopharmacol. 20(4):370–379

Maes M, Song C, Lin AH, Pioli R, Kenis G, Kubera M, Bosmans E (1999d) In vitro immunoregulatory effects of lithium in healthy volunteers. Psychopharmacol. (Berl) 143(4):401–407

Maes M, Van Bockstaele DR, Gastel A, Song C, Schotte C, Neels H, DeMeester I, Scharpe S, Janca A (1999e) The effects of psychological stress on leukocyte subset distribution in humans: evidence of immune activation. Neuropsychobiol. 39(1):1–9

Maes M, Christophe A, Bosmans E, Lin A, Neels H (2000) In humans, serum polyunsaturated fatty acid levels predict the response of proinflammatory cytokines to psychologic stress. Biol. Psychiatr. 47(10):910–920

Maes M, Capuron L, Ravaud A, Gualde N, Bosmans E, Egyed B, Dantzer R, Neveu PJ (2001a) Lowered serum dipeptidyl peptidase IV activity is associated with depressive symptoms and cytokine production in cancer patients receiving interleukin-2-based immunotherapy. Neuropsychopharmacol. 24(2):130–140

Maes M, Ombelet W, De Jongh R, Kenis G, Bosmans E (2001b) The inflammatory response following delivery is amplified in women who previously suffered from major depression, suggesting that major depression is accompanied by a sensitization of the inflammatory response system. J. Affect. Disord. 63(1–3):85–92PubMed

Maes M, Ombelet W, Verkerk R, Bosmans E, Scharpe S (2001c) Effects of pregnancy and delivery on the availability of plasma tryptophan to the brain: relationships to delivery-induced immune activation and early post-partum anxiety and depression. Psychol. Med. 31(5):847–858PubMed

Maes M, Verkerk R, Bonaccorso S, Ombelet W, Bosmans E, Scharpe S (2002) Depressive and anxiety symptoms in the early puerperium are related to increased degradation of tryptophan into kynurenine, a phenomenon which is related to immune activation. Life Sci. 71(16):1837–1848PubMed

Maes M, Mihaylova I, Bosmans E (2007a) Not in the mind of neurasthenic lazybones but in the cell nucleus: patients with chronic fatigue syndrome have increased production of nuclear factor kappa beta. Neuro Endocrinol. Lett. 28(4):456–462PubMed

Maes M, Mihaylova I, DeRuyter MD, Kubera M, Bosmans E (2007b) The immune effects of TRYCATs (tryptophan catabolites along the IDO pathway): relevance for depression–and other conditions characterized by tryptophan depletion induced by inflammation. Neuro Endocrinol. Lett. 28(6):826–831PubMed

Maes M, Mihaylova I, Kubera M, Bosmans E (2007c) Not in the mind but in the cell: increased production of cyclo-oxygenase-2 and inducible NO synthase in chronic fatigue syndrome. Neuro Endocrinol. Lett. 28(4):463–469PubMed

Maes M, Mihaylova I, Leunis JC (2007d) Increased serum IgM antibodies directed against phosphatidyl inositol (Pi) in chronic fatigue syndrome (CFS) and major depression: evidence that an IgM-mediated immune response against Pi is one factor underpinning the comorbidity between both CFS and depression. Neuro Endocrinol. Lett. 28(6):861–867PubMed

Maes M, Mihaylova I, Ategis J-C (2008a) Evidence for an IgM-mediated immune response directed against nitro-bovine serum albumin (BSA) in chronic fatigue syndrome (CFS) and major depression (MDD): evidence that the immune response to nitrosative stress-induced damage of BSA is more pronounced in CFS than in MDD. Neuro Endocrinol. Lett. 2008, In press

Maes M, Kubera M, Leunis JC (2008b) The gut-brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuro Endocrinol. Letters. 29(1):117–124

Malberg JE, Eisch AJ, Nestler EJ, Duman RS (2000) Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J. Neurosci. 20(24):9104–9110PubMed

Mamalakis G, Kalogeropoulos N, Andrikopoulos N, Hatzis C, Kromhout D, Moschandreas J, Kafatos A (2006) Depression and long chain n-3 fatty acids in adipose tissue in adults from Crete. Eur. J. Clin. Nutr. 60(7):882–888PubMed

Mancuso M, Coppede F, Migliore L, Siciliano G, Murri L (2006) Mitochondrial dysfunction, oxidative stress and neurodegeneration. J. Alzheimer’s Dis. 10(1):59–73 Review

Marcus SM, Young EA, Kerber KB, Kornstein S, Farabaugh AH, Mitchell J, Wisniewski SR, Balasubramani GK, Trivedi MH, Rush AJ (2005) Gender differences in depression: findings from the STAR*D study. J. Affect. Disord. 87(2–3):141–150PubMed

Miller CL, Llenos IC, Dulay JR, Weis S (2006) Upregulation of the initiating step of the kynurenine pathway in postmortem anterior cingulate cortex from individuals with schizophrenia and bipolar disorder. Brain Res. 1073–1074:25–37PubMed

Mohr DC, Goodkin DE, Islar J, Hauser SL, Genain CP (2001) Treatment of depression is associated with suppression of nonspecific and antigen-specific T(H)1 responses in multiple sclerosis. Arch. Neurol. 58(7):1081–1086PubMed

Moncada S, Bolanos JP (2006) Nitric oxide, cell bioenergetics and neurodegeneration. J. Neurochem. 97(6):1676–1689 ReviewPubMed

Monje ML, Toda H, Palmer TD (2003) Inflammatory blockade restores adult hippocampal neurogenesis. Science 302:1760–1765PubMed

Monteggia LM, Luikart B, Barrot M, Theobold D, Malkovska I, Nef S, Parada LF, Nestler EJ (2007) Brain-derived neurotrophic factor conditional knockouts show gender differences in depression-related behaviors. Biol. Psychiatr. 61(2):187–197

Muller N, Schwarz MJ, Dehning S, Douhe A, Cerovecki A, Goldstein-Muller B, Spellmann I, Hetzel G, Maino K, Kleindienst N, Moller HJ, Arolt V, Riedel M (2006) The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol. Psychiatr. 11(7):680–684

Musselman DL, Lawson DH, Gumnick JF, Manatunga AK, Penna S, Goodkin RS, Greiner K, Nemeroff CB, Miller AH (2001) Paroxetine for the prevention of depression induced by high-dose interferon alfa. New Engl. J. Med. 344(13):961–966PubMed

Myint AM, Kim YK, Verkerk R, Park SH, Scharpe S, Steinbusch HW, Leonard BE (2007) Tryptophan breakdown pathway in bipolar mania. J. Affect. Disord. 102(1–3):65–72PubMed

Ngai LY, Herbert J (2005) Glucocorticoid enhances the neurotoxic actions of quinolinic acid in the striatum in a cell-specific manner. J. Neuroendocrinol. 17(7):424–434PubMed

Nguyen KT, Deak T, Owens SM, Kohno T, Fleshner M, Watkins LR, Maier SF (1998) Exposure to acute stress induces brain interleukin-1beta protein in the rat. J. Neurosci. 18:2239–2246PubMed

Noraberg J, Poulsen FR, Blaabjerg M, Kristensen BW, Bonde C, Montero M, Meyer M, Gramsbergen JB, Zimmer J (2005) Organotypic hippocampal slice cultures for studies of brain damage, neuroprotection and neurorepair. Curr. Drug Targets. CNS Neurol. Disord. 4(4):435–452 ReviewPubMed

Noraberg J, Jensen CV, Bonde C, Montero M, Nielsen JV, Jensen NA, Zimmer J (2007) Developmental expression of fluorescent proteins in organotypic hippocampal slice cultures from transgenic mice with example of excitotoxic neurodegeneration. ATLA. 35(1):61–70 ReviewPubMed

O'Brien SM, Scully P, Fitzgerald P, Scott LV, Dinan TG (2007) Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy. J. Psychiatr. Res. 41(3–4):326–331PubMed

O'Connor JC, Lawson MA, André C, Moreau M, Lestage J, Castanon N, Kelley KW, Dantzer R (2008) Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol. Psychiatry. [Epub ahead of print]

Overstreet DH, Friedman E, Mathé AA, Yadid G (2005) The Flinders Sensitive Line rat: a selectively bred putative animal model of depression. Neurosci. Biobeh. Rev. 29(4–5):739–759

Pariante CM, Miller AH (2001) Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment. Biol. Psychiatr. 49(5):391–404

Patel HC, Ross FM, Heenan LE, Davies RE, Rothwell NJ, Allan SM (2006) Neurodegenerative actions of interleukin-1 in the rat brain are mediated through increases in seizure activity. J. Neurosci. Res. 83(3):385–391PubMed

Peet M, Murphy B, Shay J, Horrobin D (1998) Depletion of omega-3 fatty acid levels in red blood cell membranes of depressive patients. Biol. Psychiatr. 43(5):315–319

Pemberton LA, Kerr SJ, Smythe G, Brew BJ (1997) Quinolinic acid production by macrophages stimulated with IFNγ, TNF-alpha, and IFNα. J. Interf. Cytokine Res. 17(10):589–595CrossRef

Periyasamy S, Sanchez ER (2002) Antagonism of glucocorticoid receptor transactivity and cell growth inhibition by transforming growth factor-beta through AP-1-mediated transcriptional repression. Int. J. Biochem. Cell Biol. 34(12):1571–1585PubMed

Pettit JW, Lewinsohn PM, Joiner TE Jr (2006) Propagation of major depressive disorder: relationship between first episode symptoms and recurrence. Psychiatr. Res. 141(3):271–278

Pláteník J, Stopka P, Vejrazka M, Stípek S (2001) Quinolinic acid-iron(ii) complexes: slow autoxidation, but enhanced hydroxyl radical production in the Fenton reaction. Free Radical Res. 34(5):445–459

Polleux F, Ghosh A (2002) The slice overlay assay: a versatile tool to study the influence of extracellular signals on neuronal development. Science STKE 136(19):1–11

Pong K (2003) Oxidative stress in neurodegenerative diseases: therapeutic implications for superoxide dismutase mimetics. Exp. Opin. Biol. Therap. 3(1):127–139 Review

Post RM (1992) Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. Am. J. Psychiatry 149(8):999–1010PubMed

Post RM (2007) Kindling and sensitization as models for affective episode recurrence, cyclicity, and tolerance phenomena. Neurosci. Biobehav. Rev 31(6):858–873PubMed

Potashkin JA, Meredith GE (2006) The role of oxidative stress in the dysregulation of gene expression and protein metabolism in neurodegenerative disease. Antioxidant Redox Sign. 8(1–2):144–151 Review

Qian L, Hong JS, Flood PM (2006) Role of microglia in inflammation-mediated degeneration of dopaminergic neurons: neuroprotective effect of interleukin 10. J. Neural Transm. Suppl. 70:367–371PubMed

Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, Knapp DJ, Crews FT (2007) Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55(5):453–462PubMed

Rao JS, Lee HJ, Rapoport SI, Bazinet RP (2008) Mode of action of mood stabilizers: is the arachidonic acid cascade a common target? Mol. Psychiatr. 13(6):585–596

Rios C, Santamaria A (1991) Quinolinic acid is a potent lipid peroxidant in rat brain homogenates. Neurochem. Res. 16(10):1139–1143PubMed

Sakic B, Szechtman H, Braciak T, Richards C, Gauldie J, Denburg JA (1997) Reduced preference for sucrose in autoimmune mice: a possible role of interleukin-6. Brain Res. Bull. 44(2):155–165PubMed

Sakic B, Gauldie J, Denburg JA, Szechtman H (2001) Behavioral effects of infection with IL-6 adenovector. Brain Beh Immun. 15(1):25–42

Sandi C (2004) Stress, cognitive impairment and cell adhesion molecules. Nature Reviews Neuroscience 5:917–930PubMed

Sandi C, Bisaz R (2007) A model for the involvement of neural cell adhesion molecules in stress-related mood disorders. Neuroendocrinol. 85(3):158–176

Sapolsky RM (2004) Is impaired neurogenesis relevant to the affective symptoms of depression? Biol. Psychiatry 56(3):137–139PubMed

Sarandol A, Sarandol E, Eker SS, Erdinc S, Vatansever E, Kirli S (2007) Major depressive disorder is accompanied with oxidative stress: short-term antidepressant treatment does not alter oxidative-antioxidative systems. Hum. Psychopharmacol. 22(2):67–73PubMed

Schiepers OJ, Wichers MC, Maes M (2005) Cytokines and major depression. Prog Neuropsychopharmacol. Biol. Psychiatr. 29(2):201–217

Schmidt HD, Duman RS (2007) The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive-like behavior. Beh. Pharmacol. 18(5–6):391–418

Schulte-Herbruggen O, Nassenstein C, Lommatzsch M, Quarcoo D, Renz H, Braun A (2005) Tumor necrosis factor-alpha and interleukin-6 regulate secretion of brain-derived neurotrophic factor in human monocytes. J. Neuroimmunol. 160(1–2):204–209PubMed

Schwarcz R, Köhler C (1983) Differential vulnerability of central neurons of the rat to quinolinic acid. Neurosci. Lett. 38(1):85–90PubMed

Shapira-Lichter I, Beilin B, Ofek K, Bessler H, Gruberger M, Shavit Y, Seror D, Grinevich G, Posner E, Reichenberg A, Soreq H, Yirmiya R (2008) Cytokines and cholinergic signals co-modulate surgical stress-induced changes in mood and memory. Brain Beh. Immun. 22:388–398

Smith MA, Makino S, Kvetnansky R, Post RM (1995) Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J. Neurosci. 15:1768–1777PubMed

Sobocki P, Jonsson B, Angst J, Rehnberg C (2006) Cost of depression in Europe. J. Ment. Health Policy Econ. 9(2):87–98PubMed

Sobczak S, Honig A, Christophe A, Maes M, Helsdingen RW, De Vriese SA, Riedel WJ (2004) Lower high-density lipoprotein cholesterol and increased omega-6 polyunsaturated fatty acids in first-degree relatives of bipolar patients. Psychol. Med 34(1):103–112PubMed

Song C, Leonard BE (1995) Interleukin-2-induced changes in behavioural, neurotransmitter, and immunological parameters in the olfactory bulbectomized rat. Neuroimmunomodulation. 2(5):263–273PubMed

Song C, Leonard BE, Horrobin DF (2004) Dietary ethyl-eicosapentaenoic acid but not soybean oil reverses central interleukin-1-induced changes in behavior, corticosterone and immune response in rats. Stress 7(1):43–54PubMedCrossRef

Song C, Li X, Kang Z, Kadotomi Y (2007) Omega-3 fatty acid ethyl-eicosapentaenoate attenuates IL-1beta-induced changes in dopamine and metabolites in the shell of the nucleus accumbens: involved with PLA2 activity and corticosterone secretion. Neuropsychopharmacol. 32(3):736–744

Steptoe A, Hamer M, Chida Y (2007) The effects of acute psychological stress on circulating inflammatory factors in humans: a review and meta-analysis. Brain Beh. Immun. 21:901–912

Stockmeier CA, Mahajan GJ, Konick LC, Overholser JC, Jurjus GJ, Meltzer HY, Uylings HB, Friedman L, Rajkowska G (2004) Cellular changes in the postmortem hippocampus in major depression. Biol. Psychiatr. 56(9):640–650

Stone TW, Behan WM (2007) Interleukin-1beta but not tumor necrosis factor-alpha potentiates neuronal damage by quinolinic acid: protection by an adenosine A2A receptor antagonist. J. Neurosci. Res. 85(5):1077–1085PubMed

Stork O, Welzl H, Wotjak CT, Hoyer D, Delling M, Cremer H, Schachner M (1999) Anxiety and increased 5-HT1A receptor response in NCAM null mutant mice. J. Neurobiol. 40:343–355PubMed

Turner CA, Akil H, Watson SJ, Evans SJ (2006) The fibroblast growth factor system and mood disorders. Biol. Psychiatr. 59(12):1128–1135

Ueda S, Sakakibara S, Yoshimoto K (2005) Effect of long-lasting serotonin depletion on environmental enrichment-induced neurogenesis in adult rat hippocampus and spatial learning. Neurosci. 135:395–402

Vaidya VA, Duman RS (2001) Depression-emerging insights from neurobiology. Brit. Med. Bull. 57:61–79PubMed

van Praag H, Kempermann G, Gage FH (1999) Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nature Neurosci. 2(3):266–270PubMed

Viviani B, Gardoni F, Bartesaghi S, Corsini E, Facchi A, Galli CL, Di Luca M, Marinovich M (2006) Interleukin-1 beta released by gp120 drives neural death through tyrosine phosphorylation and trafficking of NMDA receptors. J. Biol. Chem. 281(40):30212–3022PubMed

Wadee AA, Kuschke RH, Wood LA, Berk M, Ichim L, Maes M (2002) Serological observations in patients suffering from acute manic episodes. Human Psychopharmacol. 17(4):175–179

Walz JC, Frey BN, Andreazza AC, Cereser KM, Cacilhas AA, Valvassori SS, Quevedo J, Kapczinski F (2007) Effects of lithium and valproate on serum and hippocampal neurotrophin-3 levels in an animal model of mania. J. Psychiatr. Res. 42(5):416–421PubMed

Wang JY, Wen LL, Huang YN, Chen YT, Ku MC (2006) Dual effects of antioxidants in neurodegeneration: direct neuroprotection against oxidative stress and indirect protection via suppression of glia-mediated inflammation. Curr. Pharmac. Design 12(27):3521–3533 Review

Wichers MC, Maes M (2004) The role of indoleamine 2, 3-dioxygenase (IDO) in the pathophysiology of interferon-alpha-induced depression. J. Psychiatr. Neurosci. 29(1):11–17

Wichers MC, Koek GH, Robaeys G, Verkerk R, Scharpe S, Maes M (2005) IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity. Mol. Psychiatr. 10(6):538–544

Wichers MC, Kenis G, Koek GH, Robaeys G, Nicolson NA, Maes M (2007) Interferon-alpha-induced depressive symptoms are related to changes in the cytokine network but not to cortisol. J. Psychosom. Res. 62(2):207–214PubMed

Wu A, Ying Z, Gomez-Pinilla F (2004) Dietary omega-3 fatty acids normalize BDNF levels, reduce oxidative damage, and counteract learning disability after traumatic brain injury in rats. J. Neurotrauma. 21:1457–1467PubMed

Xia Z, DePierre JW, Nassberger L (1996) Tricyclic antidepressants inhibit IL-6, IL-1 beta and TNF-alpha release in human blood monocytes and IL-2 and interferon-gamma in T cells. Immunopharmacol. 34(1):27–37

Xu Y, Ku B, Cui L, Li X, Barish PA, Foster TC, Ogle WO (2007) Curcumin reverses impaired hippocampal neurogenesis and increases serotonin receptor 1A mRNA and brain-derived neurotrophic factor expression in chronically stressed rats. Brain Res. 1162:9–18PubMed

Yang R, Han X, Uchiyama T, Watkins SK, Yaguchi A, Delude RL, Fink MP (2003) IL-6 is essential for development of gut barrier dysfunction after hemorrhagic shock and resuscitation in mice. Am. J. Physiol. Gastrointestinal Liver Physiol. 285(3):G621–629

Yirmiya R (1996) Endotoxin produces a depressive-like episode in rats. Brain Res. 711(1–2):163–74PubMed

Yirmiya R (1997) Behavioral and psychological effects of immune activation: implications for ‘depression due to a general medical condition’. Curr. Opin. Psychiatr. 10:470–476

Yirmiya R, Weidenfeld J, Pollak Y, Morag M, Morag A, Avitsur R, Barak O, Reichenberg A, Cohen E, Shavit Y, Ovadia H (1999) Cytokines, "depression due to a general medical condition," and antidepressant drugs. Adv. Exp. Med. Biol. 461:283–316PubMed

Yirmiya R, Pollak Y, Barak O, Avitsur R, Ovadia H, Bette M, Weihe E, Weidenfeld J (2001) Effects of antidepressant drugs on the behavioral and physiological responses to lipopolysaccharide (LPS) in rodents. Neuropsychopharmacol. 24(5):531–544

Zhu SW, Pham TM, Aberg E, Brene S, Winblad B, Mohammed AH, Baumans V (2006) Neurotrophin levels and behaviour in BALB/c mice: impact of intermittent exposure to individual housing and wheel running. Beh. Brain Res. 167(1):1–8

Zou JY, Crews FT (2005) TNF alpha potentiates glutamate neurotoxicity by inhibiting glutamate uptake in organotypic brain slice cultures: neuroprotection by NF kappa B inhibition. Brain Res. 1034(1–2):11–24PubMed

Title: The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression
Authors: Michael Maes
Raz Yirmyia
Jens Noraberg
Stefan Brene
Joe Hibbeln
Giulia Perini
Marta Kubera
Petr Bob
Bernard Lerer
Mario Maj
Publication date: 01-03-2009
Publisher: Springer US
Published in: Metabolic Brain Disease / Issue 1/2009
Print ISSN: 0885-7490
Electronic ISSN: 1573-7365
DOI: https://doi.org/10.1007/s11011-008-9118-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2009

The liver, the brain and nitrogen metabolism

Liver transplantation and neurological side effects

Interorgan ammonia trafficking in liver disease

Role of artificial liver support in hepatic encephalopathy

Identifying the direct effects of ammonia on the brain

Gut ammonia production and its modulation