Depression pathogenesis and treatment: what can we learn from blood mRNA expression?

BMC Medicine

Carmine M Pariante¹  Patricia A Zunszain¹  Annamaria Cattaneo¹  Nilay Hepgul¹ 

[1] Sections of Perinatal Psychiatry & Stress, Psychiatry and Immunology, Department of Psychological Medicine, Institute of Psychiatry, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK

关键词: transcriptomics;    peripheral blood;    neuroplasticity;    mRNA;    microarray;    inflammation;    glucocorticoid receptor;    gene expression;    depression;   

Others  :  857204
DOI  :  10.1186/1741-7015-11-28

 received in 2012-11-15, accepted in 2013-02-05,  发布年份 2013

【 摘 要 】

Alterations in several biological systems, including the neuroendocrine and immune systems, have been consistently demonstrated in patients with major depressive disorder. These alterations have been predominantly studied using easily accessible systems such as blood and saliva. In recent years there has been an increasing body of evidence supporting the use of peripheral blood gene expression to investigate the pathogenesis of depression, and to identify relevant biomarkers. In this paper we review the current literature on gene expression alterations in depression, focusing in particular on three important and interlinked biological domains: inflammation, glucocorticoid receptor functionality and neuroplasticity. We also briefly review the few existing transcriptomics studies. Our review summarizes data showing that patients with major depressive disorder exhibit an altered pattern of expression in several genes belonging to these three biological domains when compared with healthy controls. In particular, we show evidence for a pattern of 'state-related' gene expression changes that are normalized either by remission or by antidepressant treatment. Taken together, these findings highlight the use of peripheral blood gene expression as a clinically relevant biomarker approach.

【 授权许可】

   
2013 Hepgul et al; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctot KL: A meta-analysis of cytokines in major depression. Biol Psychiatry 2010, 67:446-457.
• [2]Howren MB, Lamkin DM, Suls J: Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med 2009, 71:171-186.
• [3]Pariante CM, Lightman SL: The HPA axis in major depression: classical theories and new developments. Trends Neurosci 2008, 31:464-468.
• [4]Pittenger C, Duman RS: Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology 2008, 33:88-109.
• [5]Maes M, Galecki P, Chang YS, Berk M: A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness. Prog Neuropsychopharmacol Biol Psychiatry 2011, 35:676-692.
• [6]Moylan S, Maes M, Wray NR, Berk M: The neuroprogressive nature of major depressive disorder: pathways to disease evolution and resistance, and therapeutic implications. Mol Psychiatry 2012. [Epub ahead of print]
• [7]Sunde RA: mRNA transcripts as molecular biomarkers in medicine and nutrition. J Nutr Biochem 2010, 21:665-670.
• [8]Liew CC, Ma J, Tang HC, Zheng R, Dempsey AA: The peripheral blood transcriptome dynamically reflects system wide biology: a potential diagnostic tool. J Lab Clin Med 2006, 147:126-132.
• [9]Sullivan PF, Fan C, Perou CM: Evaluating the comparability of gene expression in blood and brain. Am J Med Genet B Neuropsychiatr Genet 2006, 141B:261-268.
• [10]Danese A, Moffitt TE, Pariante CM, Ambler A, Poulton R, Caspi A: Elevated inflammation levels in depressed adults with a history of childhood maltreatment. ArchGenPsychiatry 2008, 65:409-415.
• [11]Heim C, Newport DJ, Mletzko T, Miller AH, Nemeroff CB: The link between childhood trauma and depression: insights from HPA axis studies in humans. Psychoneuroendocrinology 2008, 33:693-710.
• [12]Mazure CM, Bruce ML, Maciejewski PK, Jacobs SC: Adverse life events and cognitive-personality characteristics in the prediction of major depression and antidepressant response. Am J Psychiatry 2000, 157:896-903.
• [13]Zunszain PA, Anacker C, Cattaneo A, Carvalho LA, Pariante CM: Glucocorticoids, cytokines and brain abnormalities in depression. Prog Neuropsychopharmacol Biol Psychiatry 2011, 35:722-729.
• [14]Zunszain PA, Hepgul N, Pariante CM: Inflammation and depression. Curr Top Behav Neurosci 2012. [Epub ahead of print]
• [15]Smith RS: The macrophage theory of depression. Med Hypotheses 1991, 35:298-306.
• [16]Maes M: Evidence for an immune response in major depression: a review and hypothesis. Prog Neuropsychopharmacol Biol Psychiatry 1995, 19:11-38.
• [17]Maes M, Bosmans E, Suy E, Vandervorst C, De Jonckheere C, Raus J: Immune disturbances during major depression: upregulated expression of interleukin-2 receptors. Neuropsychobiology 1990, 24:115-120.
• [18]Wise MG, Taylor SE: Anxiety and mood disorders in medically ill patients. J Clin Psychiatry 1990, 51(Suppl):27-32.
• [19]Pollak Y, Yirmiya R: Cytokine-induced changes in mood and behaviour: implications for 'depression due to a general medical condition', immunotherapy and antidepressive treatment. Int J Neuropsychopharmacol 2002, 5:389-399.
• [20]Maes M: Cytokines in major depression. Biol Psychiatry 1994, 36:498-499.
• [21]Shelton RC, Claiborne J, Sidoryk-Wegrzynowicz M, Reddy R, Aschner M, Lewis DA, Mirnics K: Altered expression of genes involved in inflammation and apoptosis in frontal cortex in major depression. Mol Psychiatry 2011, 16:751-762.
• [22]Tsao CW, Lin YS, Chen CC, Bai CH, Wu SR: Cytokines and serotonin transporter in patients with major depression. Prog Neuropsychopharmacol Biol Psychiatry 2006, 30:899-905.
• [23]Cattaneo A, Gennarelli M, Uher R, Breen G, Farmer A, Aitchison KJ, Craig IW, Anacker C, Zunsztain PA, McGuffin P, Pariante CM: Candidate genes expression profile associated with antidepressants response in the GENDEP study: differentiating between baseline 'predictors' and longitudinal 'targets'. Neuropsychopharmacology 2013, 38(2):376.
• [24]Zhang HL, Wu J, Zhu J: The role of apolipoprotein E in Guillain-Barre syndrome and experimental autoimmune neuritis. J Biomed Biotechnol 2010, 2010:357412.
• [25]Suzuki K, Iwata Y, Matsuzaki H, Anitha A, Suda S, Iwata K, Shinmura C, Kameno Y, Tsuchiya KJ, Nakamura K, Takei N, Mori N: Reduced expression of apolipoprotein E receptor type 2 in peripheral blood lymphocytes from patients with major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2010, 34:1007-1010.
• [26]Herz J, Chen Y: Reelin, lipoprotein receptors and synaptic plasticity. Nat Rev Neurosci 2006, 7:850-859.
• [27]Fatemi SH, Kroll JL, Stary JM: Altered levels of reelin and its isoforms in schizophrenia and mood disorders. Neuroreport 2001, 12:3209-3215.
• [28]Su KP, Huang SY, Peng CY, Lai HC, Huang CL, Chen YC, Aitchison KJ, Pariante CM: Phospholipase A2 and cyclooxygenase 2 genes influence the risk of interferon-alpha-induced depression by regulating polyunsaturated fatty acids levels. Biol Psychiatry 2010, 67:550-557.
• [29]Galecki P, Maes M, Florkowski A, Lewinski A, Galecka E, Bienkiewicz M, Szemraj J: An inducible nitric oxide synthase polymorphism is associated with the risk of recurrent depressive disorder. Neurosci Lett 2010, 486:184-187.
• [30]Vaccarino V, Brennan ML, Miller AH, Bremner JD, Ritchie JC, Linclau F, Veleclar E, Su SY, Murrah NV, Jones L, Jawed F, Dai J, Goldberg J, Hazen SL: Association of major depressive disorder with serum myeloperoxidase and other markers of inflammation: a twin study. Biol Psychiatry 2008, 64:476-483.
• [31]Herken H, Gurel A, Selek S, Armutcu F, Ozen ME, Bulut M, Kap O, Yumru M, Savas HA, Akyol O: Adenosine deaminase, nitric oxide, superoxide dismutase, and xanthine oxidase in patients with major depression: impact of antidepressant treatment. Arch Med Res 2007, 38:247-252.
• [32]Galecki P, Galecka E, Maes M, Chamielec M, Orzechowska A, Bobinska K, Lewinski A, Szemraj J: The expression of genes encoding for COX-2, MPO, iNOS, and sPLA2-IIA in patients with recurrent depressive disorder. J Affect Disord 2012, 138:360-366.
• [33]Weigelt K, Carvalho LA, Drexhage RC, Wijkhuijs A, de Wit H, van Beveren NJ, Birkenhager TK, Bergink V, Drexhage HA: TREM-1 and DAP12 expression in monocytes of patients with severe psychiatric disorders. EGR3, ATF3 and PU.1 as important transcription factors. Brain Behav Immun 2011, 25:1162-1169.
• [34]Pariante CM, Miller AH: Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment. Biol Psychiatry 2001, 49:391-404.
• [35]Katz ER, Stowe ZN, Newport DJ, Kelley ME, Pace TW, Cubells JF, Binder EB: Regulation of mRNA expression encoding chaperone and co-chaperone proteins of the glucocorticoid receptor in peripheral blood: association with depressive symptoms during pregnancy. Psychol Med 2012, 42:943-956.
• [36]Matsubara T, Funato H, Kobayashi A, Nobumoto M, Watanabe Y: Reduced glucocorticoid receptor alpha expression in mood disorder patients and first-degree relatives. Biol Psychiatry 2006, 59:689-695.
• [37]Fujimoto M, Uchida S, Watanuki T, Wakabayashi Y, Otsuki K, Matsubara T, Suetsugi M, Funato H, Watanabe Y: Reduced expression of glyoxalase-1 mRNA in mood disorder patients. Neurosci Lett 2008, 438:196-199.
• [38]Ranganathan S, Ciaccio PJ, Walsh ES, Tew KD: Genomic sequence of human glyoxalase-I: analysis of promoter activity and its regulation. Gene 1999, 240:149-155.
• [39]Pariante CM, Papadopoulos AS, Poon L, Cleare AJ, Checkley SA, English J, Kerwin RW, Lightman S: Four days of citalopram increase suppression of cortisol secretion by prednisolone in healthy volunteers. Psychopharmacology (Berl) 2004, 177:200-206.
• [40]Pariante CM, Alhaj HA, Arulnathan VE, Gallagher P, Hanson A, Massey E, McAllister-Williams RH: Central glucocorticoid receptor-mediated effects of the antidepressant, citalopram, in humans: a study using EEG and cognitive testing. Psychoneuroendocrinology 2012, 37:618-628.
• [41]Juruena MF, Pariante CM, Papadopoulos AS, Poon L, Lightman S, Cleare AJ: Prednisolone suppression test in depression: prospective study of the role of HPA axis dysfunction in treatment resistance. Br J Psychiatry 2009, 194:342-349.
• [42]Juruena MF, Cleare AJ, Papadopoulos AS, Poon L, Lightman S, Pariante CM: The prednisolone suppression test in depression: dose-response and changes with antidepressant treatment. Psychoneuroendocrinology 2010, 35:1486-1491.
• [43]Anacker C, Zunszain PA, Cattaneo A, Carvalho LA, Garabedian MJ, Thuret S, Price J, Pariante CM: Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor. Mol Psychiatry 2011, 16:738-750.
• [44]Pariante CM, Hye A, Williamson R, Makoff A, Lovestone S, Kerwin RW: The antidepressant clomipramine regulates cortisol intracellular concentrations and glucocorticoid receptor expression in fibroblasts and rat primary neurones. Neuropsychopharmacology 2003, 28:1553-1561.
• [45]Pandey GN, Dwivedi Y, Rizavi HS, Ren X, Zhang H, Pavuluri MN: Brain-derived neurotrophic factor gene and protein expression in pediatric and adult depressed subjects. Prog Neuropsychopharmacol Biol Psychiatry 2010, 34:645-651.
• [46]Cattaneo A, Bocchio-Chiavetto L, Zanardini R, Milanesi E, Placentino A, Gennarelli M: Reduced peripheral brain-derived neurotrophic factor mRNA levels are normalized by antidepressant treatment. Int J Neuropsychopharmacol 2010, 13:103-108.
• [47]Alder J, Thakker-Varia S, Bangasser DA, Kuroiwa M, Plummer MR, Shors TJ, Black IB: Brain-derived neurotrophic factor-induced gene expression reveals novel actions of VGF in hippocampal synaptic plasticity. J Neurosci 2003, 23:10800-10808.
• [48]Cattaneo A, Sesta A, Calabrese F, Nielsen G, Riva MA, Gennarelli M: The expression of VGF is reduced in leukocytes of depressed patients and it is restored by effective antidepressant treatment. Neuropsychopharmacology 2010, 35:1423-1428.
• [49]Otsuki K, Uchida S, Watanuki T, Wakabayashi Y, Fujimoto M, Matsubara T, Funato H, Watanabe Y: Altered expression of neurotrophic factors in patients with major depression. J Psychiatr Res 2008, 42:1145-1153.
• [50]Smith MA, Makino S, Kvetnansky R, Post RM: Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci 1995, 15:1768-1777.
• [51]Dwivedi Y, Mondal AC, Rizavi HS, Conley RR: Suicide brain is associated with decreased expression of neurotrophins. Biol Psychiatry 2005, 58:315-324.
• [52]Gerke V, Weber K: The regulatory chain in the p36-kd substrate complex of viral tyrosine-specific protein kinases is related in sequence to the S-100 protein of glial cells. EMBO J 1985, 4:2917-2920.
• [53]Svenningsson P, Chergui K, Rachleff I, Flajolet M, Zhang X, El Yacoubi M, Vaugeois JM, Nomikos GG, Greengard P: Alterations in 5-HT1B receptor function by p11 in depression-like states. Science 2006, 311:77-80.
• [54]Su TP, Zhang L, Chung MY, Chen YS, Bi YM, Chou YH, Barker JL, Barrett JE, Maric D, Li XX, Li H, Webster MJ, Benedek D, Carlton JR, Ursano R: Levels of the potential biomarker p11 in peripheral blood cells distinguish patients with PTSD from those with other major psychiatric disorders. J Psychiatr Res 2009, 43:1078-1085.
• [55]Zhang L, Su TP, Choi K, Maree W, Li CT, Chung MY, Chen YS, Bai YM, Chou YH, Barker JL, Barrett JE, Li XX, Li H, Benedek DM, Ursano R: P11 (S100A10) as a potential biomarker of psychiatric patients at risk of suicide. J Psychiatr Res 2011, 45:435-441.
• [56]Panutsopulos D, Zafiropoulos A, Krambovitis E, Kochiadakis GE, Igoumenidis NE, Spandidos DA: Peripheral monocytes from diabetic patients with coronary artery disease display increased bFGF and VEGF mRNA expression. J Transl Med 2003, 1:6. BioMed Central Full Text
• [57]Iga J, Ueno S, Yamauchi K, Numata S, Tayoshi-Shibuya S, Kinouchi S, Nakataki M, Song H, Hokoishi K, Tanabe H, Sano A, Ohmori T: Gene expression and association analysis of vascular endothelial growth factor in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2007, 31:658-663.
• [58]Dome P, Teleki Z, Rihmer Z, Peter L, Dobos J, Kenessey I, Tovari J, Timar J, Paku S, Kovacs G, Dome B: Circulating endothelial progenitor cells and depression: a possible novel link between heart and soul. Mol Psychiatry 2009, 14:523-531.
• [59]Anitha A, Nakamura K, Yamada K, Iwayama Y, Toyota T, Takei N, Iwata Y, Suzuki K, Sekine Y, Matsuzaki H, Kawai M, Miyoshi K, Katayama T, Matsuzaki S, Baba K, Honda A, Hattori T, Shimizu S, Kumamoto N, Tohyama M, Yoshikawa T, Mori N: Gene and expression analyses reveal enhanced expression of pericentrin 2 (PCNT2) in bipolar disorder. Biol Psychiatry 2008, 63:678-685.
• [60]Nakataki M, Iga J, Numata S, Yoshimoto E, Kodera K, Watanabe SY, Song H, Ueno S, Ohmori T: Gene expression and association analysis of the epithelial membrane protein 1 gene in major depressive disorder in the Japanese population. Neurosci Lett 2011, 489:126-130.
• [61]Sandi C: Stress, cognitive impairment and cell adhesion molecules. Nat Rev Neurosci 2004, 5:917-930.
• [62]Vawter MP, Hemperly JJ, Hyde TM, Bachus SE, VanderPutten DM, Howard AL, Cannon-Spoor HE, McCoy MT, Webster MJ, Kleinman JE, Freed WJ: VASE-containing N-CAM isoforms are increased in the hippocampus in bipolar disorder but not schizophrenia. Exp Neurol 1998, 154:1-11.
• [63]Poltorak M, Frye MA, Wright R, Hemperly JJ, George MS, Pazzaglia PJ, Jerrels SA, Post RM, Freed WJ: Increased neural cell adhesion molecule in the CSF of patients with mood disorder. J Neurochem 1996, 66:1532-1538.
• [64]Wakabayashi Y, Uchida S, Funato H, Matsubara T, Watanuki T, Otsuki K, Fujimoto M, Nishida A, Watanabe Y: State-dependent changes in the expression levels of NCAM-140 and L1 in the peripheral blood cells of bipolar disorders, but not in the major depressive disorders. Prog Neuropsychopharmacol Biol Psychiatry 2008, 32:1199-1205.
• [65]Schoenherr CJ, Anderson DJ: The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes. Science 1995, 267:1360-1363.
• [66]Somekawa S, Imagawa K, Naya N, Takemoto Y, Onoue K, Okayama S, Takeda Y, Kawata H, Horii M, Nakajima T, Uemura S, Mochizuki N, Saito Y: Regulation of aldosterone and cortisol production by the transcriptional repressor neuron restrictive silencer factor. Endocrinology 2009, 150:3110-3117.
• [67]Westbrook TF, Hu G, Ang XL, Mulligan P, Pavlova NN, Liang A, Leng Y, Maehr R, Shi Y, Harper JW, Elledge SJ: SCFbeta-TRCP controls oncogenic transformation and neural differentiation through REST degradation. Nature 2008, 452:370-374.
• [68]Otsuki K, Uchida S, Wakabayashi Y, Matsubara T, Hobara T, Funato H, Watanabe Y: Aberrant REST-mediated transcriptional regulation in major depressive disorder. J Psychiatr Res 2010, 44:378-384.
• [69]Beech RD, Lowthert L, Leffert JJ, Mason PN, Taylor MM, Umlauf S, Lin A, Lee JY, Maloney K, Muralidharan A, Lorberg B, Zhao H, Newton SS, Mane S, Epperson CN, Sinha R, Blumberg H, Bhagwagar Z: Increased peripheral blood expression of electron transport chain genes in bipolar depression. Bipolar Disord 2010, 12:813-824.
• [70]Pace TW, Mletzko TC, Alagbe O, Musselman DL, Nemeroff CB, Miller AH, Heim CM: Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. Am J Psychiatry 2006, 163:1630-1633.
• [71]Segman RH, Goltser-Dubner T, Weiner I, Canetti L, Galili-Weisstub E, Milwidsky A, Pablov V, Friedman N, Hochner-Celnikier D: Blood mononuclear cell gene expression signature of postpartum depression. Mol Psychiatry 2010, 15:93-100. 102
• [72]Anacker C, Pariante CM: Can adult neurogenesis buffer stress responses and depressive behaviour? Mol Psychiatry 2012, 17:9-10.
• [73]Kalman J, Palotas A, Juhasz A, Rimanoczy A, Hugyecz M, Kovacs Z, Galsi G, Szabo Z, Pakaski M, Feher LZ, Janka Z, Puskas LG: Impact of venlafaxine on gene expression profile in lymphocytes of the elderly with major depression--evolution of antidepressants and the role of the 'neuro-immune' system. Neurochem Res 2005, 30:1429-1438.
• [74]Yi Z, Li Z, Yu S, Yuan C, Hong W, Wang Z, Cui J, Shi T, Fang Y: Blood-based gene expression profiles models for classification of subsyndromal symptomatic depression and major depressive disorder. PLoS One 2012, 7:e31283.
• [75]Duman CH, Schlesinger L, Kodama M, Russell DS, Duman RS: A role for MAP kinase signaling in behavioral models of depression and antidepressant treatment. Biol Psychiatry 2007, 61:661-670.
• [76]Voleti B, Duman RS: The roles of neurotrophic factor and Wnt signaling in depression. Clin Pharmacol Ther 2012, 91:333-338.
• [77]Anacker C, Cattaneo A, Luoni A, Musaelyan K, Zunszain PA, Milanesi E, Rybka J, Berry A, Cirulli F, Thuret S, Price J, Riva MA, Gennarelli M, Pariante CM: Glucocorticoid-Related Molecular Signaling Pathways Regulating Hippocampal Neurogenesis. Neuropsychopharmacology 2013, in press.
• [78]Miller GE, Chen E, Fok AK, Walker H, Lim A, Nicholls EF, Cole S, Kobor MS: Low early-life social class leaves a biological residue manifested by decreased glucocorticoid and increased proinflammatory signaling. Proc Natl Acad Sci USA 2009, 106:14716-14721.
• [79]Bull SJ, Huezo-Diaz P, Binder EB, Cubells JF, Ranjith G, Maddock C, Miyazaki C, Alexander N, Hotopf M, Cleare AJ, Norris S, Cassidy E, Aitchison KJ, Miller AH, Pariante CM: Functional polymorphisms in the interleukin-6 and serotonin transporter genes, and depression and fatigue induced by interferon-alpha and ribavirin treatment. Molecular Psychiatry 2009, 14:1095-1104.
• [80]Leonard B, Maes M: Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neurosci Biobehav Rev 2012, 36:764-785.