Men and women often experience different symptoms or rates of occurrence for a variety of mood disorders. Many of the symptoms of mood disorders overlap with autoimmune disorders, which also have a higher prevalence in women. There is a growing interest in exploring the immune system to provide biomarkers for diagnosis of mood disorders, along with new targets for developing treatments. This review examines known sex differences in the immune system and their relationship to mood disorders. We focus on immune alterations associated with unipolar depression, bipolar depression, and anxiety disorders. We describe work from both basic and clinical research examining potential immune mechanisms thought to contribute to stress susceptibility and associated mood disorders. We propose that sex and age are important, intertwined factors that need to be included in future experimental designs if we are going to harness the power of the immune system to develop a new wave of treatments for mood disorders.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $43.69 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Will TR, Proaño SB, Thomas AM, Kunz LM, Thompson KC, Ginnari LA, et al. Problems and progress regarding sex bias and omission in neuroscience research. Eneuro. 2017;4:ENEURO.0278-17.2017
Zucker I, Beery AK. Males still dominate animal studies. Nature. 2010;465:690.
Abdi F, Mobedi H, Mosaffa N, Dolatian M, Ramezani Tehrani F. Effects of hormone replacement therapy on immunological factors in the postmenopausal period. Climacteric. 2016;19:234.
Paganelli R, Iorio ADi, Cherubini A, Lauretani F, Mussi C, Volpato S, et al. Frailty of older age: the role of the endocrine - immune interaction. Curr Pharm Des. 2006;12:3147–59.
Giefing-Kröll C, Berger P, Lepperdinger G, Grubeck-Loebenstein B. How sex and age affect immune responses, susceptibility to infections, and response to vaccination. Aging Cell. 2015;14:309–21.
Gubbels Bupp MR. Sex, the aging immune system, and chronic disease. Cell Immunol. 2015;294:102–10.
Kessler RC. Epidemiology of women and depression. J Affect Disord. 2003;74:5–13.
Kessler RC, Demler O, Frank RG, Olfson M, Pincus HA, Walters EE, et al. Prevalence and treatment of mental disorders, 1990 to 2003. N Engl J Med. 2005;352:2515–23.
Kessler RC, McGonagle KA, Swartz M, Blazer DG, Nelson CB. Sex and depression in the National Comorbidity Survey I: lifetime prevalence, chronicity and recurrence. J Affect Disord. 1993;29:85–96.
Parker G, Brotchie H. Gender differences in depression. Int Rev Psychiatry. 2010;22:429–36.
Weissman MM, Bland R, Joyce PR, Newman S, Wells JE, Wittchen HU. Sex differences in rates of depression: cross-national perspectives. J Affect Disord. 1993;29:77–84.
Weissman MM, Klerman GL. Sex differences and the epidemiology of depression. Arch Gen Psychiatry. 1977;34:98–111.
Kornstein SG, Schatzberg AF, Thase ME, Yonkers KA, McCullough JP, Keitner GI, et al. Gender differences in chronic major and double depression. J Affect Disord. 2000;60:1–11.
Scott KM. Sex differences in the disability associated with mental disorders. Curr Opin Psychiatry. 2011;24:331–5.
Zagni E, Simoni L, Colombo D. Sex and gender differences in central nervous system-related disorders. Neurosci J. 2016;2016:1–13.
Zetin M, Sklansky GJ, Cramer M. Sex differences in inpatients with major depression. J Clin Psychiatry. 1984;45:257–9.
Marcus SM, Kerber KB, Rush AJ, Wisniewski SR, Nierenberg A, Balasubramani GK, et al. Sex differences in depression symptoms in treatment-seeking adults: confirmatory analyses from the sequenced treatment alternatives to relieve depression study. Compr Psychiatry. 2008;49:238–46.
Marcus SM, Young EA, Kerber KB, Kornstein SG, Farabaugh AH, Mitchell J, et al. Gender differences in depression: findings from the STAR*D study. J Affect Disord. 2005;87:141–50.
Frank E, Carpenter LL, Kupfer DJ. Sex differences in recurrent depression: are there any that are significant? Am J Psychiatry. 1988;145:41–45.
Halbreich U, Kahn LS. Atypical depression, somatic depression and anxious depression in women: are they gender-preferred phenotypes? J Affect Disord. 2007;102:245–58.
Kapfhammer H-P. Somatic symptoms in depression. Dialogues Clin Neurosci. 2006;8:227–39.
Diflorio A, Jones I. Is sex important? Gender differences in bipolar disorder. Int Rev Psychiatry. 2010;22:437–52.
Baldassano CF, Marangell LB, Gyulai L, Ghaemi SN, Joffe H, Kim DR, et al. Gender differences in bipolar disorder: Retrospective data from the first 500 STEP-BD participants. Bipolar Disord. 2005;7:465–70.
Schneck CD, Miklowitz DJ, Miyahara S, Araga M, Wisniewski S, Gyulai L, et al. The prospective course of rapid-cycling bipolar disorder: findings from the STEP-BD. Am J Psychiatry. 2008;165:370–7.
Cassano GB, Akiskal HS, Savino M, Musetti L, Perugi G. Proposed subtypes of bipolar II and related disorders: with hypomanic episodes (or cyclothymia) and with hyperthymic temperament. J Affect Disord. 1992;26:127–40.
Hendrick V, Altshuler LL, Gitlin MJ, Delrahim S, Hammen C, Gender and bipolar illness. J Clin Psychiatry. 2000;61:393–6.
Rasgon N, Bauer M, Grof P, Gyulai L, Elman S, Glenn T, et al. Sex-specific self-reported mood changes by patients with bipolar disorder. J Psychiatr Res. 2005;39:77–83.
Kupka RW, Luckenbaugh DA, Post RM, Leverich GS, Nolen WA. Rapid and non-rapid cycling bipolar disorder: a meta-analysis of clinical studies. J Clin Psychiatry. 2003;64:1483–94.
Leibenluft E. Women and bipolar disorder: an update. Bull Menn Clin. 2000;64:5–17.
Tondo L, Baldessarini RJ. Rapid cycling in women and men with bipolar manic-depressive disorders. Am J Psychiatry. 1998;155:1434–6.
Kawa I, Carter JD, Joyce PR, Doughty CJ, Framtpon CM, Wells JE, et al. Gender differences in bipolar disorder: age of onset, course, comorbidity, and symptom presentation. Bipolar Disord. 2005;7:119–25.
Benazzi F. The role of gender in depressive mixed state. Psychopathology. 2003;36:213–7.
Frye Ma, Altshuler LL, McElroy SL, Suppes T, Keck PE, Denicoff K, et al. Gender differences in prevalence, risk, and clinical correlates of alcoholism comorbidity in bipolar disorder. Am J Psychiatry. 2003;160:883–9.
Suominen K, Mantere O, Valtonen H, Arvilommi P, Leppämäki S, Isometsä E. Gender differences in bipolar disorder type i and II. Acta Psychiatr Scand. 2009;120:464–73.
Benedetti A, Fagiolini A, Casamassima F, Mian MS, Adamovit A, Musetti L, et al. Gender differences in bipolar disorder type 1. J Nerv Ment Dis. 2007;195:93–96.
Kennedy BL, Dhaliwal N, Pedley L, Sahner C, Greenberg R, Manshadi MS. Post-traumatic stress disorder in subjects with schizophrenia and bipolar disorder. J Ky Med Assoc. 2002;100:395–9.
Marsh WK, Templeton A, Ketter TA, Rasgon NL. Increased frequency of depressive episodes during the menopausal transition in women with bipolar disorder: Preliminary report. J Psychiatr Res. 2008;42:247–51.
Blehar MC, DePaulo JR, Gershon ES, Reich T, Simpson SG, Nurnberger JI. Women with bipolar disorder: findings from the NIMH Genetics Initiative sample. Psychopharmacol Bull. 1998;34:239–43.
Freeman MP, Smith KW, Freeman SA, McElroy SL, Kmetz GE, Wright R, et al. The impact of reproductive events on the course of bipolar disorder in women. J Clin Psychiatry. 2002;63:284–7.
Jones I, Craddock N. Bipolar disorder and childbirth: the importance of recognising risk. Br J Psychiatry. 2005;186:453–4.
Jones L, Scott J, Cooper C, Forty L, Smith KG, Sham P, et al. Cognitive style, personality and vulnerability to postnatal depression. Br J Psychiatry. 2010;196:200–5.
Munk-Olsen T, Laursen TM, Pedersen CB, Mors O, Mortensen PB. New parents and mental disorders. JAMA. 2006;296:2582.
Kessler RC, Foster CL, Saunders WB, Stang PE. Social consequences of psychiatric disorders, I: educational attainment. Am J Psychiatry. 1995;152:1026–32.
Kessler RC, Mcgonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Arch Gen Psychiatry. 1994;51:8–19.
Gater R, Tansella M, Korten A, Tiemens B, Mavreas V, Olatawura M. Sex differences in the prevalence and detection of depressive and anxiety disorders in general health care settings. Arch Gen Psychiatry. 1998;55:405–13.
Ruscio AM, Stein DJ, Chiu WT, Kessler RC. The epidemiology of obsessive-compulsive disorder in the National Comorbidity Survey Replication. Mol Psychiatry. 2010;15:53–63.
Weissman MM, Bland RC, Canino GJ, Greenwald S, Hwu HG, Lee CK, et al. The cross national epidemiology of obsessive compulsive disorder. The Cross National Collaborative Group. J Clin Psychiatry. 1994;55:5–10.
Xu Y, Schneier F, Heimberg RG, Princisvalle K, Liebowitz MR, Wang S, et al. Gender differences in social anxiety disorder: Results from the national epidemiologic sample on alcohol and related conditions. J Anxiety Disord. 2012;26:12–19.
Altemus M, Sarvaiya N, Neill Epperson C. Sex differences in anxiety and depression clinical perspectives. Front Neuroendocrinol. 2014;35:320–30.
Narrow WE, Rae DS, Robins LN, Regier DA. Revised prevalence estimates of mental disorders in the United states. Arch Gen Psychiatry. 2002;59:115.
Roberts A, Gilman S, Breslau J, Breslau N, Koenen K. Race/ethnic differences in exposure to traumatic events, development of post-traumatic stress disorder, and treatment- seeking for post-traumatic stress disorder in the United States. Psychol Med. 2011;41:71–83.
Tolin DF, Foa EB. Sex differences in trauma and posttraumatic stress disorder: a quantitative review of 25 years of research. Psychol Bull. 2006;132:959–92.
Crum-Cianflone NF, Jacobson I. Gender differences of postdeployment post-traumatic stress disorder among service members and veterans of the Iraq and Afghanistan conflicts. Epidemiol Rev. 2014;36:5–18.
Freedman SA, Gluck N, Tuval-Mashiach R, Brandes D, Peri T, Shalev AY. Gender differences in responses to traumatic events: a prospective study. J Trauma Stress. 2002;15:407–13.
De Bellis MD, Keshavan MS. Sex differences in brain maturation in maltreatment-related pediatric posttraumatic stress disorder. Neurosci Biobehav Rev. 2003;27:103–17.
Samplin E, Ikuta T, Malhotra AK, Szeszko PR, DeRosse P. Sex differences in resilience to childhood maltreatment: Effects of trauma history on hippocampal volume, general cognition and subclinical psychosis in healthy adults. J Psychiatr Res. 2013;47:1174–9.
Ressler KJ, Mercer KB, Bradley B, Jovanovic T, Mahan A, Kerley K, et al. Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor. Nature. 2011;470:492–7.
Turner MD, Nedjai B, Hurst T, Pennington DJ. Cytokines and chemokines: at the crossroads of cell signalling and inflammatory disease. Biochim Biophys Acta. 2014;1843:2563–82.
Coutinho AE, Chapman KE. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell Endocrinol. 2011;335:2–13.
Turvey SE, Broide DH. Innate immunity. J Allergy Clin Immunol. 2010;125:S24–32.
Bonilla FA, Oettgen HC. Adaptive immunity. J Allergy Clin Immunol. 2010;125:S33–40.
Hodes GE, Ménard C, Russo SJ. Integrating Interleukin-6 into depression diagnosis and treatment. Neurobiol Stress. 2016;4:15–22.
Klein SL. Immune cells have sex and so should journal articles. Endocrinology. 2012;153:2544–50.
Nalbandian G, Kovats S. Understanding sex biases in immunity: effects of estrogen on the differentiation and function of antigen-presenting cells. Immunol Res. 2005;31:91–106.
Zuk M. Disease, endocrine-immune interactions, and sexual selection. Ecology. 1996;77:1037–42.
Bouman A, Jan Heineman M, Faas MM. Sex hormones and the immune response in humans. Hum Reprod Update. 2005;11:411–23.
Bianchi I, Lleo A, Gershwin ME, Invernizzi P. The X chromosome and immune associated genes. J Autoimmun. 2012;38:J187–92.
Qin S, Rottman JB, Myers P, Kassam N, Weinblatt M, Loetscher M, et al. The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J Clin Invest. 1998;101:746–54.
Wang J, Syrett CM, Kramer MC, Basu A, Atchison ML, Anguera MC (2016). Unusual maintenance of X chromosome inactivation predisposes female lymphocytes for increased expression from the inactive X. Proc Natl Acad Sci. 2016;113:E2029–38
Libert C, Dejager L, Pinheiro I. The X chromosome in immune functions: when a chromosome makes the difference. Nat Rev Immunol. 2010;10:594–604.
Pinheiro I, Dejager L, Libert C. X-chromosome-located microRNAs in immunity: might they explain male/female differences?: the X chromosome-genomic context may affect X-located miRNAs and downstream signaling, thereby contributing to the enhanced immune response of females. BioEssays. 2011;33:791–802.
Case LK, Wall EH, Dragon JA, Saligrama N, Krementsov DN, Moussawi M, et al. The y chromosome as a regulatory element shaping immune cell transcriptomes and susceptibility to autoimmune disease. Genome Res. 2013;23:1474–85.
Arnold AP, Chen X. What does the “four core genotypes” mouse model tell us about sex differences in the brain and other tissues? Front Neuroendocrinol. 2009;30:1–9.
Palaszynski KM, Smith DL, Kamrava S, Burgoyne PS, Arnold AP, Voskuhl RR. A yin-yang effect between sex chromosome complement and sex hormones on the immune response. Endocrinology. 2005;146:3280–5.
de Kloet ER, Otte C, Kumsta R, Kok L, Hillegers MHJ, Hasselmann H et al. Stress and depression: a crucial role of the mineralocorticoid receptor. J Neuroendocrinol. 2016;28:1–12.
Keselman A, Heller N. Estrogen signaling modulates allergic inflammation and contributes to sex differences in asthma. Front Immunol. 2015;6:568.
McMurray RW, Suwannaroj S, Ndebele K, Jenkins JK. Differential effects of sex steroids on T and B cells: modulation of cell cycle phase distribution, apoptosis and bcl-2 protein levels. Pathobiology. 2001;69:44–58.
Shiau HJ, Aichelmann-Reidy ME, Reynolds MA, Influence of sex steroids on inflammation and bone metabolism. Periodontol 2000. 2014;64:81–94.
Trigunaite A, Dimo J, Jørgensen TN. Suppressive effects of androgens on the immune system. Cell Immunol. 2015;294:87–94.
Erlandsson MC, Ohlsson C, Gustafsson JÅ, Carlsten H. Role of oestrogen receptors alpha and beta in immune organ development and in oestrogen-mediated effects on thymus. Immunology. 2001;103:17–25.
Hemmi H, Akira S. TLR signalling and the function of dendritic cells. Chem Immunol Allergy. 2005;86:120–35.
Ghosh S, Klein RS. Sex drives dimorphic immune responses to viral infections. J Immunol. 2017;198:1782–90
Rainville JR, Tsyglakova M, Hodes GE, Deciphering sex differences in the immune system and depression. Front Neuroendocrinol. 2018 (In press).
Young NA, Wu LC, Burd CJ, Friedman AK, Kaffenberger BH, Rajaram MVS, et al. Estrogen modulation of endosome-associated toll-like receptor 8: an IFNα-independent mechanism of sex-bias in systemic lupus erythematosus. Clin Immunol. 2014;151:66–77.
Luster MI, Hayes HT, Korach K, Tucker AN, Dean JH, Howard MIL, et al. Estrogen immunosuppression is regulated through estrogenic responses in the thymus. J Immunol. 1984;133:110–6.
Pelekanou V, Kampa M, Kiagiadaki F, Deli A, Theodoropoulos P, Agrogiannis G, et al. Estrogen anti-inflammatory activity on human monocytes is mediated through cross-talk between estrogen receptor ERa36 and GPR30/GPER1. J Leukoc Biol. 2014;31:333–47.
Oertelt-Prigione S. Immunology and the menstrual cycle. Autoimmun Rev. 2012;11:A486–92.
Neigh GN, Nemeth CL, Rowson SA. Sex differences in immunity and inflammation: implications for brain and behavior. In: Shansky RM editor. Sex Differences in the Central Nervous System. Elsevier; 2015. p.1–26.
Furman D, Hejblum BP, Simon N, Jojic V, Dekker CL, Thiébaut R, et al. Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination. Proc Natl Acad Sci. 2014;111:869–74.
Dhabhar FS, McEwen BS. Stress-induced enhancement of antigen-specific cell-mediated immunity. J Immunol. 1996;156:2608–15.
Dhabhar FS, Miller AH, McEwen BS, Spencer RL. Effects of stress on immune cell distribution. Dynamics and hormonal mechanisms. J Immunol. 1995;154:5511–27.
Dhabhar FS, McEwen BS. Enhancing versus suppressive effects of stress hormones on skin immune function. Proc Natl Acad Sci. 1999;96:1059–64.
Dhabhar FS, McEwen BS. Acute stress enhances while chronic stress suppresses cell-mediated immunity in vivo: a potential role for leukocyte trafficking. Brain Behav Immun. 1997;11:286–306.
Ramamoorthy S, Cidlowski JA. Corticosteroids. mechanisms of action in health and disease. Rheum Dis Clin North Am. 2016;42:15–31.
Benea NC, Alcaidea P, Wortis HH, Jaffe IZ. Mineralocorticoid receptors in immune cells: emerging role in cardiovascular disease. Steroids. 2014;0:38–45.
McKim DB, Weber MD, Niraula A, Sawicki CM, Liu X, Jarrett BL et al. Microglial recruitment of IL-1β-producing monocytes to brain endothelium causes stress-induced anxiety. Mol Psychiatry. 2017; https://doi.org/10.1038/mp.2017.64.
Wohleb ES, McKim DB, Sheridan JF, Godbout JP. Monocyte trafficking to the brain with stress and inflammation: a novel axis of immune-to-brain communication that influences mood and behavior. Front Neurosci. 2015;9:1–17.
Niraula A, Wang Y, Godbout JP, Sheridan JF. Corticosterone production during repeated social defeat causes monocyte mobilization from the bone marrow, glucocorticoid resistance and neurovascular adhesion molecule expression. J Neurosci. 2018;38:2568–17.
Holsboer-Trachsler E, Stohler R, Hatzinger M. Repeated administration of the combined dexamethasone-human corticotropin releasing hormone stimulation test during treatment of depression. Psychiatry Res. 1991;38:163–71.
Baumeister D, Lightman SL, Pariante CM. The interface of stress and the HPA axis in behavioural phenotypes of mental illness. Behav Neurobiol Stress Disord. 2014;18:14–34.
Burke HM, Davis MC, Otte C, Mohr DC. Depression and cortisol responses to psychological stress: a meta-analysis. Psychoneuroendocrinology. 2005;30:846–56.
Holsen LM, Lancaster K, Klibanski A, Whitfield-Gabrieli S, Cherkerzian S, Buka S et al. HPA axis hormone modulation of stress response circuitry activity in women with remitted major depression. Neuroscience. 2013;250:732–42.
Ahrens T, Deuschle M, Krumm B, Van Der Pompe G, Den Boer JA, Lederbogen F. Pituitary-adrenal and sympathetic nervous system responses to stress in women remitted from recurrent major depression. Psychosom Med. 2008;70:461–7.
de Kloet CS, Vermetten E, Geuze E, Kavelaars A, Heijnen CJ, Westenberg HGM. Assessment of HPA-axis function in posttraumatic stress disorder: Pharmacological and non-pharmacological challenge tests, a review. J Psychiatr Res. 2006;40:550–67.
Agarwal SK, Marshall GD. Glucocorticoid-induced type 1/type 2 cytokine alterations in humans: a model for stress-related immune dysfunction. J Interf Cytokine Res. 1998;18:1059–68.
Pariante CM, Pearce BD, Pisell TL, Sanchez CI, Po C, Su C, et al. The proinflammatory cytokine, interleukin-1a, reduces glucocorticoid receptor translocation and function. Endocrinology. 1999;140:4359–66.
Kudielka BM, Kirschbaum C. Sex differences in HPA axis responses to stress: a review. Biol Psychol. 2005;69:113–32.
Kirschbaum C, Wüst S, Hellhammer D. Consistent sex differences in cortisol responses to psychological stress. Psychosom Med. 1992;54:648–57.
Rohleder N, Schommer NC, Hellhammer DH, Engel R, Kirschbaum C. Sex differences in glucocorticoid sensitivity of proinflammatory cytokine production after psychosocial stress. Psychosom Med. 2001;63:966–72.
Solomon MB, Furay AR, Jones K, Packard AEB, Packard BA, Wulsin AC, et al. Deletion of forebrain glucocorticoid receptors impairs neuroendocrine stress responses and induces depression-like behavior in males but not females. Neuroscience. 2012;203:135–43.
Solomon MB, Loftspring M, De Kloet AD, Ghosal S, Jankord R, Flak JN, et al. Neuroendocrine function after hypothalamic depletion of glucocorticoid receptors in male and female mice. Endocrinology. 2015;156:2843–53.
Bangasser D, Reyes B, Piel D, Garachh V, Zhang X-Y, Plona Z, et al. Increased vulnerability of the brain norepinephrine system of females to corticotropin-releasing factor overexpression. Mol Psychiatry. 2012;18:166–73.
Hodes GE, Kana V, Menard C, Merad M, Russo SJ. Neuroimmune mechanisms of depression. Nat Neurosci. 2015;18:1386–93.
Barnes JN. Sex specific factors regulating pressure and flow. Exp Physiol. 2017;11:1385–92.
Casey DP, Curry TB, Joyner MJ, Charkoudian N, Hart EC. Relationship between muscle sympathetic nerve activity and aortic wave reflection characteristics in young men and women. Hypertension. 2011;57:421–7.
Kneale BJ, Chowienczyk PJ, Brett SE, Coltart DJ, Ritter JM. Gender differences in sensitivity to adrenergic agonists of forearm resistance vasculature. J Am Coll Cardiol. 2000;36:1233–8.
Freedman RR, Sabharwal SC, Desai N. Sex differences in peripheral vascular adrenergic receptors. Circ Res. 1987;61:581–5.
Hart EC, Charkoudian N, Wallin BG, Curry TB, Eisenach J, Joyner MJ. Sex and ageing differences in resting arterial pressure regulation: the role of the beta-adrenergic receptors. J Physiol. 2011;589:5285–97.
Balhara YS, Verma R, Gupta C. Gender differences in stress response: role of developmental and biological determinants. Ind Psychiatry J. 2012;20:4.
Head JR, Griffin WST. Functional capacity of solid tissue transplants in the brain: evidence for immunological privilege. Proc R Soc London B Biol Sci. 1985;224:375–87.
Louveau A, Harris TH, Kipnis J. Revisiting the mechanisms of CNS immune privilege. Trends Immunol. 2015;36:569–77.
Louveau A, Kipnis J. Sex, gut, and microglia. Dev Cell. 2018;44:137–8.
Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015;523:337–41.
Wohleb ES, Powell ND, Godbout JP, Sheridan JF. Stress-induced recruitment of bone marrow-derived monocytes to the brain promotes anxiety-like behavior. J Neurosci. 2013;33:13820–33.
Pan W, Stone KP, Hsuchou H, Manda VK, Zhang Y, Kastin AJ. Cytokine signaling modulates blood-brain barrier function. Curr phar. 2011;17:3729–40.
Banks W. Blood-brain barrier transport of cytokines: a mechanism for neuropathology. Curr Pharm Des. 2005;11:973–84.
Menard C, Pfau ML, Hodes GE, Kana V, Wang VX, Bouchard S, et al. Social stress induces neurovascular pathology promoting depression. Nat Neurosci. 2017;20:1752–60.
Golden SA, Covington HE III, Berton O, Russo SJ. A standardized protocol for repeated social defeat stress in mice. Nat Protoc. 2011;6:1183–91.
Krishnan V, Han M, Graham DL, Berton O, Renthal W, Russo SJ, et al. Molecularadaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell. 2007;131:391–404.
Cheng Y, Desse S, Martinez A, Worthen RJ, Jope RS, Beurel E. TNFα disrupts blood brain barrier integrity to maintain prolonged depressive-like behavior in mice. Brain Behav Immun. 2018;69:556–67.
Ataka K, Asakawa A, Nagaishi K, Kaimoto K, Sawada A, Hayakawa Y, et al. Bone marrow-derived microglia infiltrate into the paraventricular nucleus of chronic psychological stress-loaded mice. PLoS ONE. 2013;8:1–14.
Engler H, Bailey MT, Engler A, Sheridan JF. Effects of repeated social stress on leukocyte distribution in bone marrow, peripheral blood and spleen. J Neuroimmunol. 2004;148:106–15.
Powell ND, Sloan EK, Bailey MT, Arevalo JMG, Miller GE, Chen E, et al. Social stress up-regulates inflammatory gene expression in the leukocyte transcriptome via β-adrenergic induction of myelopoiesis. Proc Natl Acad Sci. 2013;110:16574–9.
Wohleb ES, Godbout JP. Basic aspects of the immunology of neuroinflammation. Inflamm Psychiatry. 2013;28:1–19.
Wohleb ES, McKim DB, Shea DT, Powell ND, Tarr AJ, Sheridan JF, et al. Re-establishment of anxiety in stress-sensitized mice is caused by monocyte trafficking from the spleen to the brain. Biol Psychiatry. 2014;75:970–81.
Kelly JR, Kennedy PJ, Cryan JF, Dinan TG, Clarke G, Hyland NP. Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders. Front Cell Neurosci. 2015;9:392.
Doran KS, Banerjee A, Disson O, Lecuit M. Concepts and mechanisms: crossing host barriers. Cold Spring Harb Perspect Med. 2013;3:1–20.
Wiley NC, Dinan TG, Ross RP, Stanton C, Clarke G, Cryan JF. The microbiota-gut-brain axis as a key regulator of neural function and the stress response: Implications for human and animal health. J Anim Sci. 2017;95:3225–46.
Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu XN, et al. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol. 2004;558:263–75.
Fung TC, Olson CA, Hsiao EY. Interactions between the microbiota, immune and nervous systems in health and disease. Nat Neurosci. 2017;20:145–55.
Maes M, Kubera M, Leunis J-C. 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 Lett. 2008;29:117–24.
Kelly JR, Borre Y, O’ Brien C, Patterson E, Aidy SEl, Deane J, et al. Transferring the blues: Depression-associated gut microbiota induces neurobehavioural changes in the rat. J Psychiatr Res. 2016;82:109–18.
Liu R, Zhang C, Shi Y, Zhang F, Li L, Wang X, et al. Dysbiosis of gut microbiota associated with clinical parameters in polycystic ovary syndrome. Front Microbiol. 2017;8:1–12.
Macut D, Bjekić-Macut J, Rahelić D, Doknić M. Insulin and the polycystic ovary syndrome. Diabetes Res Clin Pract. 2017;130:163–70.
Evans SJ, Bassis CM, Hein R, Assari S, Flowers SA, Kelly MB, et al. The gut microbiome composition associates with bipolar disorder and illness severity. J Psychiatr Res. 2017;87:23–29.
Severance EG, Gressitt KL, Stallings CR, Katsafanas E, Schweinfurth LA, Savage CL, et al. Candida albicans exposures, sex specificity and cognitive deficits in schizophrenia and bipolar disorder. npj Schizophr. 2016;2:16018.
Jašarević E, Morrison KE, Bale TL. Sex differences in the gut microbiome–brain axis across the lifespan. Philos Trans R Soc B Biol Sci. 2016;371:20150122.
Moloney GM, O’Leary OF, Salvo-Romero E, Desbonnet L, Shanahan F, Dinan TG, et al. Microbial regulation of hippocampal miRNA expression: Implications for transcription of kynurenine pathway enzymes. Behav Brain Res. 2017;334:50–54.
Davis DJ, Hecht PM, Jasarevic E, Beversdorf DQ, Will MJ, Fritsche K, et al. Sex-specific effects of docosahexaenoic acid (DHA) on the microbiome and behavior of socially-isolated mice. Brain Behav Immun. 2017;59:38–48.
Yurkovetskiy L, Burrows M, Khan AA, Graham L, Volchkov P, Becker L, et al. Gender bias in autoimmunity is influenced by microbiota. Immunity. 2013;39:400–12.
Bonaccorso S, Marino V, Biondi M, Grimaldi F, Ippoliti F, Maes M. Depression induced by treatment with interferon-alpha in patients affected by hepatitis C virus. J Affect Disord. 2002;72:237–41.
Kim J-M, Stewart R, Kim J-W, Kang H-J, Bae K-Y, Kim S-W, et al. Changes in pro-inflammatory cytokine levels and late-life depression: a two year population based longitudinal study. Psychoneuroendocrinology. 2018;90:85–91.
Khandaker GM, Pearson RM, Zammit S, Lewis G, Jones PB. Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in Young Adult Life. JAMA Psychiatry. 2014;71:1121.
Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. Arch Gen Psychiatry. 2013;70:31–41.
Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67:446–57.
Gabay C. Interleukin-6 and chronic inflammation. Arthritis Res Ther. 2006;8:S3.
Breslau J, Gilman SE, Stein BD, Ruder T, Gmelin T, Miller E. Sex differences in recent first-onset depression in an epidemiological sample of adolescents. Transl Psychiatry. 2017;7:e1139.
Deecher D, Andree TH, Sloan D, Schechter LE. From menarche to menopause: exploring the underlying biology of depression in women experiencing hormonal changes. Psychoneuroendocrinology. 2008;33:3–17.
Lamason R, Zhao P, Rawat R, Davis A, Hall JC, Chae JJ, et al. Sexual dimorphism in immune response genes as a function of puberty. BMC Immunol. 2006;7:2.
Joinson C, Heron J, Lewis G, Croudace T, Araya R. Timing of menarche and depressive symptoms in adolescent girls from a UK cohort. Br J Psychiatry. 2011;198:17–23.
Gouon-Evans V, Lin EY, Pollard JW. Requirement of macrophages and eosinophils and their cytokines/chemokines for mammary gland development. Breast Cancer Res. 2002;4:155–64.
Shrier LA, Bowman FP, Lin M, Crowley-nowick PA. Mucosal immunity of the adolescent female genital tract. J Adolesc Heal. 2003;32:183–6.
Itman C, Mendis S, Barakat B, Loveland KL. All in the family: TGF- b family action in testis development. Reproduction. 2006;132:233–46.
Witkin SS, Jeremias J, Bongiovanni AM, Munoz MG, Immune regulation in the male genital tract. Infect Dis Obstet Gynecol. 1996;4:131–5.
Tam CS, Garnett SP, Cowell CT, Heilbronn LK, Lee JW, Wong M, et al. IL-6, IL-8 and IL-10 levels in healthy weight and overweight children. Horm Res Paediatr. 2010;73:128–34.
Martos-Moreno GÁ, Barrios V, Argente J. Normative data for adiponectin, resistin, interleukin 6 and leptin/receptor ratio in a healthy Spanish pediatric population: Relationship with sex steroids. Eur J Endocrinol. 2006;155:429–34.
Roomruangwong C, Anderson G, Berk M, Stoyanov D, Carvalho AF, Maes M (2017a). A neuro-immune, neuro-oxidative and neuro-nitrosative model of prenatal and postpartum depression. Prog Neuropsychopharmacology Biol Psychiatry. 2018;81:262–74.
Bränn E, Papadopoulos F, Fransson E, White R, Edvinsson Å, Hellgren C, et al. Inflammatory markers in late pregnancy in association with postpartum depression—a nested case-control study. Psychoneuroendocrinology. 2017;79:146–59.
Leff-Gelman P, Mancilla-Herrera I, Flores-Ramos M, Cruz-Fuentes C, Reyes-Grajeda JP, García-Cuétara Mdel P, et al. The immune system and the role of inflammation in perinatal depression. Neurosci Bull. 2016;32:398–420.
Roomruangwong C, Barbosa DS, Matsumoto AK, Nogueira A, de S, Kanchanatawan B, Sirivichayakul S, et al. Activated neuro-oxidative and neuro-nitrosative pathways at the end of term are associated with inflammation and physio-somatic and depression symptoms, while predicting outcome characteristics in mother and baby. J Affect Disord. 2017;223:49–58.
Simpson W, Steiner M, Coote M, Frey BN. Relationship between inflammatory biomarkers and depressive symptoms during late pregnancy and the early postpartum period: a longitudinal study. Rev Bras Psiquiatr. 2016;38:190–6.
Munk-Olsen T, Laursen TM, Mendelson T, Pedersen CB, Mors O, Mortensen PB. Risks and predictors of readmission for a mental disorder during the postpartum period. Arch Gen Psychiatry. 2009;66:189–95.
Munk-Olsen T, Laursen TM, Meltzer-Brody S, Mortensen PB, Jones I. Psychiatric disorders with postpartum onset: Possible early manifestations of bipolar affective disorders. Arch Gen Psychiatry. 2012;69:428–34.
Bergink V, Laursen TM, Johannsen BMW, Kushner SA, Meltzer-Brody S, Munk-Olsen T. Pre-eclampsia and first-onset postpartum psychiatric episodes: a Danish population-based cohort study. Psychol Med. 2015;45:3481–9.
Bergink V, Kushner SA, Pop V, Kuijpens H, Lambregtse-van den Berg MP, Drexhage RC, et al. Prevalence of autoimmune thyroid dysfunction in postpartum psychosis. Br J Psychiatry. 2011;198:264–8.
Kumar MM, Venkataswamy MM, Sathyanarayanan G, Thippeswamy H, Chandra PS, Mani RS. Immune system aberrations in postpartum psychosis: an immunophenotyping study from a tertiary care neuropsychiatric hospital in India. J Neuroimmunol. 2017;310:8–13.
Bergink V, Burgerhout KM, Weigelt K, Pop VJ, De Wit H, Drexhage RC, et al. Immune system dysregulation in first-onset postpartum psychosis. Biol Psychiatry. 2013;73:1000–7.
Posillico CK, Schwarz JM. An investigation into the effects of antenatal stressors on the postpartum neuroimmune profile and depressive-like behaviors. Behav Brain Res. 2016;298:218–28.
Haim A, Julian D, Albin-Brooks C, Brothers HM, Lenz KM, Leuner B. A survey of neuroimmune changes in pregnant and postpartum female rats. Brain Behav Immun. 2016;59:67–78.
O’Mahony SM, Myint A-M, van den Hove D, Desbonnet L, Steinbusch H, Leonard BE. Gestational stress leads to depressive-like behavioural and immunological changes in the rat. Neuroimmunomodulation. 2006;13:82–8.
Wharton W, Gleason CE, Olson SR, Carlsson CM, Asthana S. Neurobiological underpinnings of the estrogen – mood relationship. Curr Psychiatr Rev. 2013;8:247–56.
Hu L-Y, Shen C-C, Hung J-H, Chen P-M, Wen C-H, Chiang Y-Y, et al. Risk of psychiatric disorders following symptomatic menopausal transition. Med (Baltim). 2016;95:e2800.
Pfeilschifter J, Köditz R, Pfohl M, Schatz H. Changes in proinflammatory cytokine activity after menopause. Endocr Rev. 2002;23:90–119.
Vogels RJ, Koenders MA, van Rossum EFC, Spijker AT, Drexhage HA. T cell deficits and overexpression of hepatocyte growth factor in anti-inflammatory circulating monocytes of middle-aged patients with bipolar disorder characterized by a high prevalence of the metabolic syndrome. Front Psychiatry. 2017;8:1–11.
Seidman SN. Testosterone deficiency and mood in aging men: pathogenic and therapeutic interactions. World J Biol Psychiatry. 2003;4:14–20.
Grinspoon S, Corcoran C, Stanley T, Baaj A, Basgoz N, Klibanski A et al. (2008). Effects of hypogonadism and testosterone HIV-infected men. J Clin Endocrinol Metab. 2000;85:60–65.
Chen CY, Lee CP, Chen Y, Jiang JR, Chu CL, Chen CL. The correlation between emotional distress and aging males’ symptoms at a psychiatric outpatient clinic: Sexual dysfunction as a distinguishing characteristic between andropause and anxiety/depression in aging men. Clin Interv Aging. 2013;8:635–40.
Khosravi S, Ardebili HE, Larijani B, Nedjat S, Nikbakht Nasrabadi A, Ardebili ME, et al. Are andropause symptoms related to depression? Aging Clin Exp Res. 2015;27:813–20.
Sato Y, Tanda H, Kato S, Onishi S, Nakajima H, Nanbu A, et al. Prevalence of major depressive disorder in self-referred patients in a late onset hypogonadism clinic. Int J Impot Res. 2007;19:407–10.
Mor G, Nilsen J, Horvath T, Bechmann I, Brown S, Garcia-Segura LM, et al. Estrogen and microglia: a regulatory system that affects the brain. J Neurobiol. 1999;40:484–96.
Hanisch U-K, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci. 2007;10:1387–94.
Banati RB, Gehrmann J, Schubert P, Kreutzberg GW. Cytotoxicity of microglia. Glia. 1993;7:111–8.
Nelson LH, Lenz KM. The immune system as a novel regulator of sex differences in brain and behavioral development. J Neurosci Res. 2017;95:447–61.
Sawada M, Kondo N, Suzumura A, Marunouchi T. Production of tumor necrosis factor-alpha by microglia and astrocytes in culture. Brain Res. 1989;491:394–7.
Schnieder TP, Trencevska I, Rosoklija G, Stankov A, Mann JJ, Smiley J, et al. Microglia of pre-frontal white matter in suicide. J Neuropathol Exp Neurol. 2014;73:880–90.
Steiner J, Bielau H, Brisch R, Danos P, Ullrich O, Mawrin C, et al. Immunological aspects in the neurobiology of suicide: elevated microglial density in schizophrenia and depression is associated with suicide. J Psychiatr Res. 2008;42:151–7.
Torres-Platas SG, Cruceanu C, Chen GG, Turecki G, Mechawar N. Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides. Brain Behav Immun. 2014;42:50–59.
Hawton K, van Heeringen K. Suicide. Lancet. 2009;373:1372–81.
Gandal MJ, Haney J, Parikshak N, Leppa V, Horvath S, Geschwind DH. Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. bioRxiv. 2016;697:40022.
Sandiego CM, Gallezot J-D, Pittman B, Nabulsi N, Lim K, Lin S-F, et al. Imaging robust microglial activation after lipopolysaccharide administration in humans with PET. Proc Natl Acad Sci USA. 2015;112:12468–73.
Setiawan E, Wilson AA, Mizrahi R, Rusjan PM, Miler L, Rajkowska G, et al. Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiatry. 2015;72:268–75.
Hannestad J, DellaGioia N, Gallezot JD, Lim K, Nabulsi N, Esterlis I, et al. The neuroinflammation marker translocator protein is not elevated in individuals with mild-to-moderate depression: a [11C]PBR28 PET study. Brain Behav Immun. 2013;33:131–8.
Notter T, Meyer U. Microglia and schizophrenia: where next? Mol Psychiatry. 2017;22:788–9.
Altshuler LL, Abulseoud OA, Foland-Ross L, Bartzokis G, Chang S, Mintz J, et al. Amygdala astrocyte reduction in subjects with major depressive disorder but not bipolar disorder. Bipolar Disord. 2010;12:541–9.
Gosselin RD, Gibney S, O’Malley D, Dinan TG, Cryan JF. Region specific decrease in glial fibrillary acidic protein immunoreactivity in the brain of a rat model of depression. Neuroscience. 2009;159:915–25.
Lenz KM, Nugent BM, Haliyur R, McCarthy MM. Microglia are essential to masculinization of brain and behavior. J Neurosci. 2013;33:2761–72.
Hanamsagar R, Alter MD, Block CS, Sullivan H, Bolton JL, Bilbo SD. Generation of a microglial developmental index in mice and in humans reveals a sex difference in maturation and immune reactivity. Glia. 2017;6:1504–20.
Thion MS, Low D, Silvin A, Chen J, Grisel P, Schulte-Schrepping J, et al. Microbiome influences prenatal and adult microglia in a sex-specific manner. Cell. 2017;172:500–7.e16.
Bollinger JL, Bergeon Burns CM, Wellman CL. Differential effects of stress on microglial cell activation in male and female medial pre-frontal cortex. Brain Behav Immun. 2016;52:88–97.
Schwarz JM, Sholar PW, Bilbo SD. Sex differences in microglial colonization of the developing rat brain. J Neurochem. 2012;120:948–63.
Nemeth CL, Reddy R, Bekhbat M, Bailey J, Neigh GN. Microglial activation occurs in the absence of anxiety-like behavior following microembolic stroke in female, but not male, rats. J Neuroinflamm. 2014;11:174.
Lehmann ML, Cooper HA, Maric D, Herkenham M. Social defeat induces depressive-like states and microglial activation without involvement of peripheral macrophages. J Neuroinflamm. 2016;13:1–19.
Hodes GE, Pfau ML, Leboeuf M, Golden SA, Christoffel DJ, Bregman D, et al. Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc Natl Acad Sci. 2014;111:18799–18799.
Takahashi A, Zhang H, Zhang S, Grossman Y, Aleyasin H, Flanigan M, et al. Establishment of repeated social defeat stress model in female mice. Soc Neurosci. 2017;7:12838.
Iñiguez SD, Flores-Ramirez FJ, Riggs LM, Alipio JB, Garcia I, Hernandez MA et al. Vicarious social defeat stress induces depression-related outcomes in female mice. Biol Psychiatry. 2018;83:9–17.
Sial OK, Warren BL, Alcantara LF, Parise EM, Bola CA. Vicarious social defeat stress: bridging the gap between physical and emotional stress. J Neurosci Methods. 2016;258:94–103.
Warren BL, Vialou VF, Iñiguez SD, Alcantara LF, Wright KN, Feng J, et al. Neurobiological sequelae of witnessing stressful events in adult mice. Biol Psychiatry. 2013;73:7–14.
Finnell JE, Wood SK. Neuroinflammation at the interface of depression and cardiovascular disease: evidence from rodent models of social stress. Neurobiol Stress. 2016;4:1–14.
Giannarelli C, Rodriguez DT, Zafar MU, Christoffel D, Alique M, Villa G, et al. Susceptibility to chronic social stress increases plaque progression, vulnerability and platelet activation. Thromb Haemost. 2017;117:816–8.
Finnell JE, Lombard CM, Padi AR, Moffitt CM, Wilson LB, Wood CS, et al. Physical versus psychological social stress in male rats reveals distinct cardiovascular, inflammatory and behavioral consequences. PLoS ONE. 2017;12:1–24.
Scheinert RB, Haeri MH, Lehmann ML, Herkenham M. Therapeutic effects of stress-programmed lymphocytes transferred to chronically stressed mice. Prog Neuropsychopharmacol Biol Psychiatry. 2016;70:1–7.
Brachman RA, Lehmann ML, Maric D, Herkenham M. Lymphocytes from chronically stressed mice confer antidepressant-like effects to naive mice. J Neurosci. 2015;35:1530–8.
Wang J, Hodes GE, Zhang H, Zhang S, Zhao W, Golden SA et al. Epigenetic modulation of inflammation and synaptic plasticity promotes resilience against stress in mice. Nat Commun. 2018;9:477.
Wood SK, Wood CS, Lombard CM, Lee CS, Zhang XY, Finnell JE, et al. Inflammatory factors mediate vulnerability to a social stress-induced depressive-like phenotype in passive Coping Rats. Biol Psychiatry. 2015;78:38–48.
Howes OD, McCutcheon R. Inflammation and the neural diathesis-stress hypothesis of schizophrenia: a reconceptualization. Transl Psychiatry. 2017;7:e1024–11.
Kiraly DD, Horn SR, Van Dam NT, Costi S, Schwartz JC, Kim-Schulze S, et al. Altered peripheral immune profiles in treatment-resistant depression: response to ketamine and prediction of treatment outcome. Transl Psychiatry. 2017;7:e1065.
Munkholm K, Vinberg M, Vedel Kessing L. Cytokines in bipolar disorder: a systematic review and meta-analysis. J Affect Disord. 2013;144:16–27.
Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah I, Van de Water J. Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain Behav Immun. 2011;25:40–5.
Gilman SE, Cherkerzian S, Buka SL, Hahn J, Hornig M, Goldstein JM. Prenatal immune programming of the sex-dependent risk for major depression. Transl Psychiatry. 2016;6:e822.
Simanek AM, Parry A, Dowd JB. Differences in the association between persistent pathogens and mood disorders among young- to middle-aged women and men in the U.S. Brain Behav Immun. 2017;68:56–65.
Köhler-Forsberg O, Sylvia L, Deckersbach T, Ostacher MJ, McInnis M, Iosifescu D et al. Clinically relevant and simple immune system measure is related to symptom burden in bipolar disorder. Acta Neuropsychiatr. 2017;7:1–9.
Zheng P, Chen JJ, Zhou CJ, Zeng L, Li KW, Sun L, et al. Identification of sex-specific urinary biomarkers for major depressive disorder by combined application of NMR- and GC-MS-based metabonomics. Transl Psychiatry. 2016;6:e955.
Gordon JA,Hen R, The serotonergic system and anxiety. Neuromolecular Med. 2004;5:27–40.
Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905–17.
Baca E, Garcia-Garcia M, Porras-Chavarino A. Gender differences in treatment response to sertraline versus imipramine in patients with nonmelancholic depressive disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28:57–65.
Sramek JJ, Murphy MF, Cutler NR. Sex differences in the psychopharmacological treatment of depression. Dialogogues Clin Neurosci. 2016;18:447–57.
Quitkin FM, Stewart JW, McGrath PJ, Taylor BP, Tisminetzky MS, Petkova E, et al. Are there differences between women’s and men’s antidepressant responses? Am J Psychiatry. 2002;159:1848–54.
Morsel AM, Morrens M, Sabbe B. An overview of pharmacotherapy for bipolar I disorder. Expert Opin Pharmacother. 2018;19:203–22.
Bobo WV. The diagnosis and management of bipolar I and II disorders: clinical practice update. Mayo Clin Proc. 2017;92:1532–51.
Viguera aC, Tondo L, Baldessarini RJ. Sex differences in response to lithium treatment. Am J Psychiatry. 2000;157:1509–11.
Geddes JR, Goodwin GM, Rendell J, Morriss R, Alder N, Juszczak E, et al. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet. 2010;375:385–95.
Johnston AM, Eagles JM. Lithium-associated clinical hypothyroidism. Preval risk Factors Br J Psychiatry. 1999;175:336–9.
Saleh LA, Hamza M, El Gayar NH, Abd El-Samad AA, Nasr EA, Masoud SI. Ibuprofen suppresses depressive like behavior induced by BCG inoculation in mice: Role of nitric oxide and prostaglandin. Pharmacol Biochem Behav. 2014;125:29–39.
Warner-Schmidt JL, Vanoverb KE, Chena EY, Marshalla JJ, Greengarda P. Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans. Proc Natl Acad Sci. 2011;108:7826–31.
Köhler O, Petersen L, Mors O, Gasse C. Inflammation and depression: combined use of selective serotonin reuptake inhibitors and NSAIDs or paracetamol and psychiatric outcomes. Brain Behav. 2015;5:1–12.
Anderson GD. Gender differences in pharmacological response. Int Rev Neurobiol. 2008;83:1–10.
Miners J, Attwood J, Birkett D. Influence paracetamol. Br J Clin Pharmac. 1983;16:503–9.
Franconi F, Brunelleschi S, Steardo L, Cuomo V. Gender differences in drug responses. Pharmacol Res. 2007;55:81–95.
Li N, Lee B, Liu R-J, Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–64.
Tan S, Wang Y, Chen K, Long Z, Zou J. Ketamine alleviates depressive-like behaviors via down-regulating inflammatory cytokines induced by chronic restraint stress in mice. Biol Pharm Bull. 2017;40:1260–7.
Wang N, Yu H-Y, Shen X-F, Gao Z-Q, Yang C, Yang J-J, et al. The rapid antidepressant effect of ketamine in rats is associated with down-regulation of pro-inflammatory cytokines in the hippocampus. Ups J Med Sci. 2015;120:241–8.
Li Y, Shen R, Wen G, Ding R, Du A, Zhou J, et al. Effects of ketamine on levels of inflammatory cytokines IL-6, IL-1β, and TNF-α in the hippocampus of mice following acute or chronic administration. Front Pharmacol. 2017;8:1–14.
Yang Y, Cui Y, Sang K, Dong Y, Ni Z, Ma S, et al. Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature. 2018;554:317–22.
Cui Y, Yang Y, Ni Z, Dong Y, Cai G, Foncelle A, et al. Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression. Nature. 2018;554:323–7.
Franceschelli A, Sens J, Herchick S, Thelen C, Pitychoutis PM. Sex differences in the rapid and the sustained antidepressant-like effects of ketamine in stress-naïve and “depressed” mice exposed to chronic mild stress. Neuroscience. 2015;290:49–60.
Sarkar A, Kabbaj M. Sex differences in effects of ketamine on behavior, spine density and synaptic proteins in socially isolated rats. Biol Psychiatry. 2016;80:448–56.
Carrier N, Kabbaj M. Sex differences in the antidepressant-like effects of ketamine. Neuropharmacology. 2013;70:27–34.
Dossat AM, Wright KN, Strong CE, Kabbaj M. Behavioral and biochemical sensitivity to low doses of ketamine: Influence of estrous cycle in C57BL/6 mice. Neuropharmacology. 2018;130:30–41.
Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med. 2016;22:238–49.
Kappelmann N, Lewis G, Dantzer R, Jones PB, Khandaker GM. Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions. Mol Psychiatry. 2016;23:335–43.
Sun Y, Wang D, Salvadore G, Hsu B, Curran M, Casper C, et al. The effects of interleukin-6 neutralizing antibodies on symptoms of depressed mood and anhedonia in patients with rheumatoid arthritis and multicentric Castleman’s disease. Brain Behav Immun. 2017;66:156–64.
Miyamoto N, Mochizuki S, Fujii S, Yoshida K, Sakurai K. Adjuvant activity enhanced by cross-linked cpg-oligonucleotides in β-glucan nanogel and its antitumor effect. Bioconjug Chem. 2017;28:565–73.
Uemura Y, Naoi T, Kanai Y, Kobayashi K. The efficiency of lipid nanoparticles with an original cationic lipid as a siRNA delivery system for macrophages and dendritic cells. Pharm Dev Technol. 2018; https://doi.org/10.1080/10837450.2018.1469149.
Farina M, Alexander JF, Thekkedath U, Ferrari M, Grattoni A. Cell encapsulation: overcoming barriers in cell transplantation in diabetes and beyond. Adv Drug Deliv Rev. 2018; https://doi.org/10.1016/j.addr.2018.04.018.
Lanquillon S, Krieg J-C, Bening-Abu-Shach U, Vedder H. Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology. 2000;22:370–9.
Birur B, Amrock EM, Shelton RC, Li L. Sex differences in the peripheral immune system in patients with depression. Front Psychiatry. 2017;8:1–7.
Pallavi P, Sagar R, Mehta M, Sharma S, Subramanium A, Shamshi F, et al. Serum cytokines and anxiety in adolescent depression patients: gender effect. Psychiatry Res. 2015;229:374–80.
Maes M, Scharpé S, Meltzer HY, Bosmans E, Suy E, Calabrese J, et al. Relationships between interleukin-6 activity, acute phase proteins, and function of the hypothalamic-pituitary-adrenal axis in severe depression. Psychiatry Res. 1993;49:11–27.
Valkanova V, Ebmeier KP, Allan CL. CRP, IL-6 and depression: a systematic review and meta-analysis of longitudinal studies. J Affect Disord. 2013;150:736–44.
Himmerich H, Fulda S, Linseisen J, Seiler H, Wolfram G, Himmerich S, et al. Depression, comorbidities and the TNF-α system. Eur Psychiatry. 2008;23:421–9.
Domenici E, Wille DR, Tozzi F, Prokopenko I, Miller S, McKeown A et al. Plasma protein biomarkers for depression and schizophrenia by multi analyte profiling of case-control collections. PLoS ONE. 2010;5:e9166.
Maes M, Lambrechts J, Suy E, Vandervorst C, Bosmans E. Absolute number and percentage of circulating natural killer, non-mhc-restricted t cytotoxic, and phagocytic cells in unipolar depression. Neuropsychobiology. 1994;29:157–63.
Dickerson F, Stallings C, Origoni A, Boronow J, Yolken R. Elevated serum levels of C-reactive protein are associated with mania symptoms in outpatients with bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:952–5.
Goldstein BI, Collinger KA, Lotrich F, Marsland AL, Gill M-K, Axelson DA, et al. Preliminary findings regarding proinflammatory markers and brain-derived neurotrophic factor among adolescents with bipolar spectrum disorders. J Child Adolesc Psychopharmacol. 2011;21:479–84.
Luo Y, He H, Zhang M, Huang X, Fan N. Altered serum levels of TNF-α, IL-6 and IL-18 in manic, depressive, mixed state of bipolar disorder patients. Psychiatry Res. 2016;244:19–23.
Gill J, Vythilingam M, Page GG, Manuscript A, Cortisol L. Low cortisol, high DHEA, and high levels of stimulated TNF-alpha, and IL-6 in women with PTSD. J Trauma Inj Infect Crit Care. 2008;21:530–9.
Hoge EA, Brandstetter K, Moshier S, Pollack MH, Wong KK, Simon NM. Broad spectrum of cytokine abnormalities in Panic disorder and Posttraumatic stress disorder. Depress Anxiety. 2009;26:447–55.
Gill J, Luckenbaugh D, Charney D, Vythilingam M. Sustained elevation of serum interleukin-6 and relative insensitivity to hydrocortisone differentiates posttraumatic stress disorder with and without depression. Biol Psychiatry. 2010;68:999–1006.
We thank Mariya Tsyglakova for her assistance with editing the manuscript. This work was funded by a NARSAD Young Investigator award from the Brain and Behavior research foundation to GEH.
About this article