Hormonal and inflammatory signatures of different mood episodes in bipolar disorder: a large-scale clinical study
Tóm tắt
Bipolar disorder (BD) is characterized by intensive mood fluctuations. While hormones imbalance plays important role in the mood swings, it is unknown whether peripheral hormones profiles could differentiate the manic and depressive mood episodes in BD. In this study, we investigated the changes of various hormones and inflammatory markers across distinct mood episodes of BD in a large clinical study to provide mood episode-specific peripheral biomarkers for BD. A total of 8332 BD patients (n = 2679 depressive episode; n = 5653 manic episode) were included. All patients were in acute state of mood episodes and need hospitalization. A panel of blood tests were performed for levels of sex hormones (serum levels of testosterone, estradiol, and progesterone), stress hormones (adrenocorticotropic hormone and cortisol), and an inflammation marker (C-reactive protein, CRP). A receiver operating characteristic (ROC) curve was used to analyze the discriminatory potential of the biomarkers for mood episodes. In overall comparison between mood episodes, the BD patients expressed higher levels of testosterone, estradiol, progesterone, and CRP (P < 0.001) and lower adrenocorticotropic hormone (ACTH) level (P < 0.001) during manic episode. The episode-specific changes of testosterone, ACTH, and CRP levels remained between the two groups (P < 0.001) after correction for the confounding factors including age, sex, BMI, occupation, marital status, tobacco use, alcohol consumption, psychotic symptoms, and age at onset. Furthermore, we found a sex- and age-specific impact of combined biomarkers in mood episodes in male BD patients aged ≥ 45 years (AUC = 0.70, 95% CI, 0.634–0.747), not in females. While both hormone and inflammatory change is independently associated with mood episodes, we found that the combination of sex hormones, stress hormones and CRP could be more effective to differentiate the manic and depressive episode. The biological signatures of mood episodes in BD patients may be sex- and age-specific. Our findings not only provide mood episode-related biological markers, but also better support for targeted intervention in BD treatments.
Tài liệu tham khảo
Grande I, Berk M, Birmaher B, Vieta E, Bipolar disorder. Lancet. 2016;387(10027):1561–72. https://doi.org/10.1016/s0140-6736(15)00241-x
Alonso J, Petukhova M, Vilagut G, Chatterji S, Heeringa S, Üstün TB, et al. Days out of role due to common physical and mental conditions: results from the WHO World Mental Health surveys. Mol Psychiatry. 2011;16(12):1234–46. https://doi.org/10.1038/mp.2010.101
Meinhard N, Kessing LV, Vinberg M. The role of estrogen in bipolar disorder, a review. Nord J Psychiatry. 2014;68(2):81–7. https://doi.org/10.3109/08039488.2013.775341
Sigitova E, Fišar Z, Hroudová J, Cikánková T, Raboch J. Biological hypotheses and biomarkers of bipolar disorder. 2017; 71(2):77–103. doi: https://doi.org/10.1111/pcn.12476
Pape K, Tamouza R, Leboyer M, Zipp F. Immunoneuropsychiatry - novel perspectives on brain disorders. 2019; 15(6):317–28. doi: https://doi.org/10.1038/s41582-019-0174-4
Rowland T, Perry BI, Upthegrove R, Barnes N, Chatterjee J, Gallacher D, et al. Neurotrophins, cytokines, oxidative stress mediators and mood state in bipolar disorder: systematic review and meta-analyses. Br J Psychiatry. 2018;213(3):514–25. https://doi.org/10.1192/bjp.2018.144
Teatero ML, Mazmanian D, Sharma V. Effects of the menstrual cycle on bipolar disorder. Bipolar Disord. 2014;16(1):22–36. https://doi.org/10.1111/bdi.12138
Hwang WJ, Lee TY, Kim NS, Kwon JS. The Role of Estrogen Receptors and Their Signaling across Psychiatric Disorders. 2020; 22(1). doi: https://doi.org/10.3390/ijms22010373
Gogos A, Ney LJ, Seymour N, Van Rheenen TE, Felmingham KL. Sex differences in schizophrenia, bipolar disorder, and post-traumatic stress disorder: Are gonadal hormones the link? 2019; 176(21):4119–35. doi: https://doi.org/10.1111/bph.14584
McHenry J, Carrier N, Hull E, Kabbaj M. Sex differences in anxiety and depression: role of testosterone. Front Neuroendocrinol. 2014;35(1):42–57. https://doi.org/10.1016/j.yfrne.2013.09.001
Flores-Ramos M, Becerra-Palars C, Hernández González C, Chavira R, Bernal-Santamaría N, Martínez Mota L. Serum testosterone levels in bipolar and unipolar depressed female patients and the role of medication status. Int J Psychiatry Clin Pract. 2020;24(1):53–8. https://doi.org/10.1080/13651501.2019.1680696
Castañeda Cortés DC, Langlois VS, Fernandino JI. Crossover of the hypothalamic pituitary-adrenal/interrenal, -thyroid, and -gonadal axes in testicular development. Front Endocrinol (Lausanne). 2014;5:139. https://doi.org/10.3389/fendo.2014.00139
Juruena MF, Cleare AJ, Young AH. Neuroendocrine stress system in bipolar disorder. Curr Top Behav Neurosci. 2021;48:149–71. https://doi.org/10.1007/7854_2020_184
Belvederi Murri M, Prestia D, Mondelli V, Pariante C, Patti S, Olivieri B, et al. The HPA axis in bipolar disorder: systematic review and meta-analysis. Psychoneuroendocrinology. 2016;63:327–42. https://doi.org/10.1016/j.psyneuen.2015.10.014
Cervantes P, Gelber S, Kin FN, Nair VN, Schwartz G. Circadian secretion of cortisol in bipolar disorder. J Psychiatry Neurosci. 2001;26(5):411–6.
Feng G, Kang C, Yuan J, Zhang Y, Wei Y, Xu L, et al. Neuroendocrine abnormalities associated with untreated first episode patients with major depressive disorder and bipolar disorder. Psychoneuroendocrinology. 2019;107:119–23. https://doi.org/10.1016/j.psyneuen.2019.05.013
Juruena MF. Early-life stress and HPA axis trigger recurrent adulthood depression. Epilepsy Behav. 2014;38:148–59. https://doi.org/10.1016/j.yebeh.2013.10.020
Black S, Kushner I, Samols D, C-reactive Protein. J Biol Chem. 2004;279(47):48487–90. https://doi.org/10.1074/jbc.R400025200
Wysokiński A, Margulska A, Strzelecki D, Kłoszewska I. Levels of C-reactive protein (CRP) in patients with schizophrenia, unipolar depression and bipolar disorder. Nord J Psychiatry. 2015;69(5):346–53. https://doi.org/10.3109/08039488.2014.984755
Fernandes BS, Steiner J, Molendijk ML, Dodd S, Nardin P, Gonçalves CA, et al. C-reactive protein concentrations across the mood spectrum in bipolar disorder: a systematic review and meta-analysis. Lancet Psychiatry. 2016;3(12):1147–56. https://doi.org/10.1016/s2215-0366(16)30370-4
Brietzke E, Stertz L, Fernandes BS, Kauer-Sant’anna M, Mascarenhas M, Escosteguy Vargas A, et al. Comparison of cytokine levels in depressed, manic and euthymic patients with bipolar disorder. J Affect Disord. 2009;116(3):214–7. https://doi.org/10.1016/j.jad.2008.12.001
Bai YM, Su TP, Tsai SJ, Wen-Fei C, Li CT, Pei-Chi T, et al. Comparison of inflammatory cytokine levels among type I/type II and manic/hypomanic/euthymic/depressive states of bipolar disorder. J Affect Disord. 2014;166:187–92. https://doi.org/10.1016/j.jad.2014.05.009
Zhou J, Guo C, Ren L, Zhu D, Zhen W, Zhang S, et al. Gender differences in outpatients with dementia from a large psychiatric hospital in China. BMC Psychiatry. 2022;22(1):208. https://doi.org/10.1186/s12888-022-03852-z
Lyu N, Xing G, Yang J, Zhu X, Zhao X, Zhang L, et al. Comparison of inflammatory, nutrient, and neurohormonal indicators in patients with schizophrenia, bipolar disorder and major depressive disorder. J Psychiatr Res. 2021;137:401–8. https://doi.org/10.1016/j.jpsychires.2021.03.010
Sawyer SM, Afifi RA, Bearinger LH, Blakemore SJ, Dick B, Ezeh AC, et al. Adolescence: a foundation for future health. Lancet. 2012;379(9826):1630–40. https://doi.org/10.1016/s0140-6736(12)60072-5
Trévoux R, De Brux J, Castanier M, Nahoul K, Soule JP, Scholler R. Endometrium and plasma hormone profile in the peri-menopause and post-menopause. Maturitas. 1986;8(4):309–26. https://doi.org/10.1016/0378-5122(86)90039-3
Pisanu C, Williams MJ, Ciuculete DM, Olivo G, Del Zompo M, Squassina A, et al. Evidence that genes involved in hedgehog signaling are associated with both bipolar disorder and high BMI. Transl Psychiatry. 2019;9(1):315. https://doi.org/10.1038/s41398-019-0652-x
Bolstad I, Alakokkare AE, Bramness JG, Rognli EB, Levola J, Mustonen A, et al. The relationships between use of alcohol, tobacco and coffee in adolescence and mood disorders in adulthood. Acta Psychiatr Scand. 2022;146(6):594–603. https://doi.org/10.1111/acps.13506
Das SK, Vasudevan DM. Alcohol-induced oxidative stress. Life Sci. 2007;81(3):177–87. https://doi.org/10.1016/j.lfs.2007.05.005
Brettle H, Tran V, Drummond GR, Franks AE, Petrovski S, Vinh A, et al. Sex hormones, intestinal inflammation, and the gut microbiome: major influencers of the sexual dimorphisms in obesity. Front Immunol. 2022;13:971048. https://doi.org/10.3389/fimmu.2022.971048
Cairney J, Boyle M, Offord DR, Racine Y. Stress, social support and depression in single and married mothers. Soc Psychiatry Psychiatr Epidemiol. 2003;38(8):442–9. https://doi.org/10.1007/s00127-003-0661-0
Haarman BC, Riemersma-Van der Lek RF, Burger H, Netkova M, Drexhage RC, Bootsman F, et al. Relationship between clinical features and inflammation-related monocyte gene expression in bipolar disorder - towards a better understanding of psychoimmunological interactions. Bipolar Disord. 2014;16(2):137–50. https://doi.org/10.1111/bdi.12142
Labad J. The role of cortisol and prolactin in the pathogenesis and clinical expression of psychotic disorders. Psychoneuroendocrinology. 2019;102:24–36. https://doi.org/10.1016/j.psyneuen.2018.11.028
Huang Y, Wang Y, Wang H, Liu Z, Yu X, Yan J, et al. Prevalence of mental disorders in China: a cross-sectional epidemiological study. Lancet Psychiatry. 2019;6(3):211–24. https://doi.org/10.1016/s2215-0366(18)30511-x
Kalman JL, Olde Loohuis LM, Vreeker A, McQuillin A, Stahl EA, Ruderfer D, et al. Characterisation of age and polarity at onset in bipolar disorder. Br J Psychiatry. 2021;219(6):659–69. https://doi.org/10.1192/bjp.2021.102
Solmi M, Radua J, Olivola M, Croce E, Soardo L, Salazar de Pablo G, et al. Age at onset of mental disorders worldwide: large-scale meta-analysis of 192 epidemiological studies. Mol Psychiatry. 2022;27(1):281–95. https://doi.org/10.1038/s41380-021-01161-7
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(5):465–70. https://doi.org/10.1111/j.1399-5618.2005.00237.x
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(3):370–7. https://doi.org/10.1176/appi.ajp.2007.05081484. quiz 410.
Kessing LV. Gender differences in the phenomenology of bipolar disorder. Bipolar Disord. 2004;6(5):421–5. https://doi.org/10.1111/j.1399-5618.2004.00135.x
McIntyre RS, Berk M, Brietzke E, Goldstein BI, López-Jaramillo C, Kessing LV, et al. Bipolar disorders. Lancet. 2020;396(10265):1841–56. https://doi.org/10.1016/s0140-6736(20)31544-0
Sher L, Grunebaum MF, Sullivan GM, Burke AK, Cooper TB, Mann JJ, et al. Testosterone levels in suicide attempters with bipolar disorder. J Psychiatr Res. 2012;46(10):1267–71. https://doi.org/10.1016/j.jpsychires.2012.06.016
Pope HG Jr, Cohane GH, Kanayama G, Siegel AJ, Hudson JI. Testosterone gel supplementation for men with refractory depression: a randomized, placebo-controlled trial. Am J Psychiatry. 2003;160(1):105–11. https://doi.org/10.1176/appi.ajp.160.1.105
Keshri N, Nandeesha H, Kattimani S. Elevated interleukin-17 and reduced testosterone in bipolar disorder. Relation with suicidal behaviour. Asian J Psychiatr. 2018;36:66–8. https://doi.org/10.1016/j.ajp.2018.06.011
Mousavizadegan S, Maroufi M. Comparison of salivary testosterone levels in different phases of bipolar I disorder and control group. J Res Med Sci. 2018;23:31. https://doi.org/10.4103/jrms.JRMS_1009_17
Sher L, Sublette ME, Grunebaum MF, Mann JJ, Oquendo MA. Plasma testosterone levels and subsequent suicide attempts in males with bipolar disorder. Acta Psychiatr Scand. 2022;145(2):223–5. https://doi.org/10.1111/acps.13381
Batrinos ML. Testosterone and aggressive behavior in man. Int J Endocrinol Metab. 2012;10(3):563–8. https://doi.org/10.5812/ijem.3661
Bedgood D, Boggiano MM, Turan B. Testosterone and social evaluative stress: the moderating role of basal cortisol. Psychoneuroendocrinology. 2014;47:107–15. https://doi.org/10.1016/j.psyneuen.2014.05.007
Stanikova D, Luck T, Bae YJ, Thiery J, Ceglarek U, Engel C, et al. Increased estrogen level can be associated with depression in males. Psychoneuroendocrinology. 2018;87:196–203. https://doi.org/10.1016/j.psyneuen.2017.10.025
Orwoll E, Lambert LC, Marshall LM, Phipps K, Blank J, Barrett-Connor E, et al. Testosterone and estradiol among older men. J Clin Endocrinol Metab. 2006;91(4):1336–44. https://doi.org/10.1210/jc.2005-1830
Szeliga A, Stefanowski B, Meczekalski B, Snopek M, Kostrzak A, Smolarczyk R, et al. Menopause in women with schizophrenia, schizoaffective disorder and bipolar disorder. Maturitas. 2021;152:57–62. https://doi.org/10.1016/j.maturitas.2021.07.003
Halaris A, Sohl E, Whitham EA. Treatment-Resistant Depression Revisited: A Glimmer of Hope. 2021; 11(2). doi: https://doi.org/10.3390/jpm11020155
Choi KW, Na EJ, Fava M, Mischoulon D, Cho H, Jeon HJ. Increased adrenocorticotropic hormone (ACTH) levels predict severity of depression after six months of follow-up in outpatients with major depressive disorder. Psychiatry Res. 2018;270:246–52. https://doi.org/10.1016/j.psychres.2018.09.047
Hennings JM, Ising M, Uhr M, Holsboer F, Lucae S. Effects of weariness of life, suicide ideations and suicide attempt on HPA axis regulation in depression. Psychoneuroendocrinology. 2021;131:105286. https://doi.org/10.1016/j.psyneuen.2021.105286
Slavich GM, Sacher J. Stress, sex hormones, inflammation, and major depressive disorder: extending Social Signal Transduction Theory of Depression to account for sex differences in mood disorders. Psychopharmacology. 2019;236(10):3063–79. https://doi.org/10.1007/s00213-019-05326-9
Lloyd RB, Nemeroff CB. The role of corticotropin-releasing hormone in the pathophysiology of depression: therapeutic implications. Curr Top Med Chem. 2011;11(6):609–17. https://doi.org/10.2174/1568026611109060609
Tsai SY, Chung KH, Wu JY, Kuo CJ, Lee HC, Huang SH. Inflammatory markers and their relationships with leptin and insulin from acute mania to full remission in bipolar disorder. J Affect Disord. 2012;136(1–2):110–6. https://doi.org/10.1016/j.jad.2011.08.022
Tsai SY, Yang YY, Kuo CJ, Chen CC, Leu SJ. Effects of symptomatic severity on elevation of plasma soluble interleukin-2 receptor in bipolar mania. J Affect Disord. 2001;64(2–3):185–93. https://doi.org/10.1016/s0165-0327(00)00252-4
Liu HC, Yang YY, Chou YM, Chen KP, Shen WW, Leu SJ. Immunologic variables in acute mania of bipolar disorder. J Neuroimmunol. 2004;150(1–2):116–22. https://doi.org/10.1016/j.jneuroim.2004.01.006
Queissner R, Pilz R, Dalkner N, Birner A, Bengesser SA, Platzer M, et al. The relationship between inflammatory state and quantity of affective episodes in bipolar disorder. Psychoneuroendocrinology. 2018;90:61–7. https://doi.org/10.1016/j.psyneuen.2018.01.024
Toufexis D, Rivarola MA, Lara H, Viau V. Stress and the reproductive axis. J Neuroendocrinol. 2014;26(9):573–86. https://doi.org/10.1111/jne.12179
Le-Niculescu H, Kurian SM, Yehyawi N, Dike C, Patel SD, Edenberg HJ, et al. Identifying blood biomarkers for mood disorders using convergent functional genomics. Mol Psychiatry. 2009;14(2):156–74. https://doi.org/10.1038/mp.2008.11
Kéri S, Szabó C, Kelemen O. Blood biomarkers of depression track clinical changes during cognitive-behavioral therapy. J Affect Disord. 2014;164:118–22. https://doi.org/10.1016/j.jad.2014.04.030
Le-Niculescu H, Roseberry K, Gill SS, Levey DF, Phalen PL, Mullen J, et al. Precision medicine for mood disorders: objective assessment, risk prediction, pharmacogenomics, and repurposed drugs. Mol Psychiatry. 2021;26(7):2776–804. https://doi.org/10.1038/s41380-021-01061-w
Barbosa IG, Morato IB, Huguet RB, Rocha FL, Machado-Vieira R, Teixeira AL. Decreased plasma neurotrophin-4/5 levels in bipolar disorder patients in mania. Braz J Psychiatry. 2014;36(4):340–3. https://doi.org/10.1590/1516-4446-2014-1380
Ortiz-Domínguez A, Hernández ME, Berlanga C, Gutiérrez-Mora D, Moreno J, Heinze G, et al. Immune variations in bipolar disorder: phasic differences. Bipolar Disord. 2007;9(6):596–602. https://doi.org/10.1111/j.1399-5618.2007.00493.x
Kim YK, Jung HG, Myint AM, Kim H, Park SH. Imbalance between pro-inflammatory and anti-inflammatory cytokines in bipolar disorder. J Affect Disord. 2007;104(1–3):91–5. https://doi.org/10.1016/j.jad.2007.02.018
Kim YK, Myint AM, Lee BH, Han CS, Lee SW, Leonard BE, et al. T-helper types 1, 2, and 3 cytokine interactions in symptomatic manic patients. Psychiatry Res. 2004;129(3):267–72. https://doi.org/10.1016/j.psychres.2004.08.005
O’Brien SM, Scully P, Scott LV, Dinan TG. Cytokine profiles in bipolar affective disorder: focus on acutely ill patients. J Affect Disord. 2006;90(2–3):263–7. https://doi.org/10.1016/j.jad.2005.11.015
Hope S, Dieset I, Agartz I, Steen NE, Ueland T, Melle I, et al. Affective symptoms are associated with markers of inflammation and immune activation in bipolar disorders but not in schizophrenia. J Psychiatr Res. 2011;45(12):1608–16. https://doi.org/10.1016/j.jpsychires.2011.08.003