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Objectives: This study aimed to assess whether race modifies irritability and immunological inflammation, and their interaction to worsen depression during chemotherapy. Methods: 25 African American and 19 White nonmetastasized breast cancer patients were assessed on irritability, inflammation biomarker (hsCRP and IL-6), and depression at baseline (T 1 ) and after 3 months of chemotherapy (T 2 ). Wilcoxon rank sum test was performed to compare racial groups on these study variables. Generalized estimating equations (GEE) regression models for repeated measures were computed, using the severity of depression as the dependent variable, race, an inflammation biomarker (hsCRP or IL-6), irritability, interactions of these variables, and time as independent variables, controlling for age, baseline depression severity level and its racial difference. Results: The African American cancer patients had significantly higher levels of hsCRP (p = .040) and IL-6 (p = .018) than the White patients at T 2, without a significant baseline difference. In both regression models, the African American patients experiencing greater irritability reported significantly more severe depression at T 2 (p = .0002; .0048). In the regression model containing hsCRP, a negative interaction between irritability and hsCRP level was significantly associated with more severe depression at T 2 (p < .0001). In the regression model containing IL- 6, the African American patients (p = .03), most of whom had higher IL-6 (p < .0001), reported significantly more severe depression at T 2 , while White patients who had higher IL-6 levels also had more severe depression at T 2 (p = .016). Conclusion: Association between irritability and depression was significantly stronger for the African American patients than the White patients in this study, and the level of hsCRP influenced irritability and its association with depression. Identification of contributors to irritability, particularly for African Americans, is important for reducing irritability and depression in cancer patients undergoing chemotherapy. Moreover, the White cancer patients in the study who experienced higher IL-6 levels during chemotherapy were also at a higher risk of worsening depression and required medical attention.
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2. Brown C, Abe-Kim C, Barrio C. Depression in ethnically diverse women: Implications for treatment in primary care settings. Professional Psychology: Research and Practice. 2003; 34(1):303-314.
3. Gary FA, Yarandi HN. Depression among southern rural African American women: a factor analysis of the Beck Depression Inventory-II. Nurs Res. 2004;53(4):251-259.
4. Green CR, Baker TA, Sato Y, Washington TL, Smith EM. Race and chronic pain: A comparative study of young black and white Americans presenting for management. Journal of Pain. 2003;4(4):176-183.
5. Zhang AY, Gary F, Zhu H. Exploration of depressive symptoms in African American cancer patients. J Ment Health. 2015; 24(6):351-6. doi: 10.3109/09638237.2014. 998806.
6. Barnes DM, Bates LM. Testing a somatization hypothesis to explain the Black-White depression paradox. Soc Psychiatry Psychiatr Epidemiol. 2019; 54(10):1255-1263. doi: 10.1007/s00127-019-01707-9.
7. Pasquini M, Biondi M. Depression in cancer patients: A critical review. Clin Pract Epidemiol Mental Health. 2007; 3:2. doi: 10.1186/1745-0179-3-2.
8. Onitilo AA, Nietert PJ, Egede LE. Effect of depression on all-cause mortality in adults with cancer and differential effects by cancer site. Gen Hosp Psychiatry. 2006; 28(5):396-402.
9. Pinquart D. Depression and cancer mortality: a meta-analysis. National Institutes of Health Psychology Medicine. 2010; 40(11): 1797–1810.
10. Satin JR, Linden W, Phillips MJ. Depression as a predictor of disease progression and mortality in cancer patients: a meta-analysis. Cancer. 2009;115(22):5349-5361.
11. Kissane DW, Maj M, Sartorius N (eds.). Depression and Cancer. UK: Chichester, West Sussex, Wiley; 2008.
12. Lutgendorf SK, DeGeest K, Dahmoush L, Farley D, Penedo F, Bender D, Goodheart M, Buekers TE, Mendez L, Krueger G, Clevenger L, Lubaroff DM, Sood AK, Cole SW. Social isolation is associated with elevated tumor norepinephrine in ovarian carcinoma patients. Brain Behav Immun. 2011;25(2):250-255. doi: 10.1016/j.bbi.2010.10.012.
13. Lutgendorf SK, DeGeest K, Sung CY, Arevalo JM, Penedo F, Lucci J, 3rd, Goodheart M, Lubaroff D, Farley DM, Sood AK, Cole SW. Depression, social support, and beta-adrenergic transcription control in human ovarian cancer. Brain Behav Immun. 2009;23(2):176-183.
14. Thaker PH, Han LY, Kamat AA, Arevalo JM, Takahashi R, Lu C, Jennings NB, Armaiz-Pena G, Bankson JA, Ravoori M, Merritt WM, Lin YG, Mangala LS, Kim TJ, Coleman RL, Landen CN, Li Y, Felix E, Sanguino AM, Newman RA, Lloyd M, Gershenson DM, Kundra V, Lopez-Berestein G, Lutgendorf SK, Cole SW, Sood AK.Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nature medicine. 2006; 12(8):939-944. doi: 10.1038/ nm1447.
15. American Cancer Society. Cancer Facts & Figures for African American/Black People 2022-2024. Atlanta: American Cancer Society, 2022.
16. Kelly KM, Smith JA, Mezuk B. Depression and interleukin-6 signaling: A Mendelian Randomization study. Brain Behav Immun. 2021; 95: 106-114. doi:10.1016/j.bbi.2021. 02.019.
17. Carroll JF, Fulda KG, Chiapa AL, Rodriquez M, Phelps DR, Cardarelli KM, Vishwanatha JK, Cardarelli R. Impact of race/ethnicity on the relationship between visceral fat and inflammatory biomarkers. Obesity. 2009; 17(7):1420-1427.
18. Saban KL, Mathews HL, DeVon HA, Janusek LW. Epigenetics and social context: implications for disparity in cardiovascular disease. Aging and disease. 2014; 5(5):346-355.
19. Paalani M, Lee JW, Haddad E, Tonstad S. Determinants of inflammatory markers in a bi-ethnic population. Ethn Dis. 2011;21(2):142-149.
20. Ness RB, Haggerty C, Harger G, Ferrell R. Differential distribution of allelic variants in cytokine genes among African Americans and White Americans. American Journal of Epidemiology. 2004;160(11):1033-1038.
21. Amend K, Hicks D, Ambrosone CB. Breast cancer in African-American women: differences in tumor biology from European-American women. Cancer Res. 2006; 66(17): 8327-8330.
22. Martin DN, Boersma BJ, Yi M, Reimers M, Howe TM, Yfantis HG, Tsai YC, Williams EH, Lee DH, Stephens RM, Weissman AM, Ambs S. Differences in the tumor microenvironment between African-American and European-American breast cancer patients. PLoS One. 2009; 4(2):e4531.
23. Wallace TA, Martin DN, Ambs S. Interactions among genes, tumor biology and the environment in cancer health disparities: examining the evidence on a national and global scale. Carcinogenesis. 2011;32(8): 1107-1121.
24. Wallace TA, Prueitt RL, Yi M, Howe TM, Gillespie JW, Yfantis HG, Stephens RM, Caporaso NE, Loffredo CA, Ambs S. Tumor immunobiological differences in prostate cancer between African-American and European-American men. Cancer Res. 2008; 68(3):927-936.
25. Wang S, Dorsey TH, Terunuma A, Kittles RA, Ambs S, Kwabi-Addo B. Relationship between tumor DNA methylation status and patient characteristics in African-American and European-American women with breast cancer. PLoS One. 2012; 7(5):e37928.
26. Carpenter LL, Gawuga CE, Tyrka AR, Lee JK, Anderson GM, Price LH. Association between plasma IL-6 response to acute stress and early-life adversity in healthy adults. Neuropsychopharmacology. 2010; 35(13): 2617-2623.
27. Kiecolt-Glaser JK, Preacher KJ, MacCallum RC, Atkinson C, Malarkey WB, Glaser R. Chronic stress and age-related increases in the proinflammatory cytokine IL-6. Proceedings of the National Academy of Sciences of the United States of America. 2003;100(15):9090-9095.
28. Shelton RC, Miller AH. Eating ourselves to death (and despair): The contribution of adiposity and inflammation to depression. Progress in Neurobiology. 2010; 91(4):275-299.
29. Irwin M, Miller C. Decreased natural killer cell responses and altered interleukin-6 and interleukin-10 production in alcoholism: an interaction between alcohol dependence and African-American ethnicity. Alcohol Clin Exp Res. 2000; 24(4):560-569.
30. Jackson JS, Knight KM, Rafferty JA. Race and unhealthy behaviors: chronic stress, the HPA axis, and physical and mental health disparities over the life course. American Journal of Public Health. 2010;100(5):933-939.
31. McEwen BS. Protection and damage from acute and chronic stress: allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders. Annals of the New York Academy of Sciences. 2004;1032:1-7.
32. Liu L, Mills PJ, Rissling M, Fiorentino L, Natarajan L, Dimsdale JE, Sadler GR, Parker BA, Ancoli-Israel S. Fatigue and sleep quality are associated with changes in inflammatory markers in breast cancer patients undergoing chemotherapy. Brain, behavior, and immunity. 2012; 26(5):706-713.
33. Tsavaris N, Kosmas C, Vadiaka M, Kanelopoulos P, Boulamatsis D. Immune changes in patients with advanced breast cancer undergoing chemotherapy with taxanes. British journal of cancer. 2002; 87(1): 21-27.
34. Lazarus RS, Folkman S. Stress, Appraisal, and Coping. New York: Springer Publishing Company, 1984.
35. Franzen PL, Buysse DJ, Rabinovitz M, Pollock BG, Lotrich FE. Poor sleep quality predicts onset of either major depression or subsyndromal depression with irritability during interferon-alpha treatment. Psychiatry Res. 2010; 177(1-2):240-245.
36. Maddock C, Baita A, Orru MG, Sitzia R, Costa A, Muntoni E, Farci MG, Carpiniello B, Pariante CM. Psychopharmacological treatment of depression, anxiety, irritability and insomnia in patients receiving interferon-alpha: a prospective case series and a discussion of biological mechanisms. J Psychopharmacol. 2004;18(1):41-46.
37. Russo S, Kema IP, Haagsma EB, Boon JC, Willemse PH, den Boer JA, de Vries EG, Korf J. Irritability rather than depression during interferon treatment is linked to increased tryptophan catabolism. Psychosom Med. 2005; 67(5):773-777.
38. Shub D, Bass DM, Morgan RO, Judge KS, Snow AL, Wilson NL, Walder A, Murry B, Kunik ME. Irritability and social isolation in dementia patients with and without depression. J Geriatr Psychiatry Neurol. 2011; 24(4):229-234.
39. Zhang A, Ganocy S, Owusu C, Gao K. Associations among irritability, high-sensitivity C-reactive protein /interleukin-6, and depression in patients with early-stage breast cancer undergoing chemotherapy: A prospective study. Journal of the Academy of Consultation-Liaison Psychiatry. 2021; 63(3), 260-267. doi.org/10.1016/j.jaclp.2021.08.012.
40. Wichers M, Maes M. The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans. The international journal of neuropsychopharmacology. 2002; 5(4):375-388.
41. Szelenyi J. Cytokines and the central nervous system. Brain research bulletin. 2001; 54(4):329-338.
42. Zhang J, Zhou Y, Feng Z, Xu Y, Zeng G. Longitudinal Trends in Anxiety, Depression, and Quality of Life During Different Intermittent Periods of Adjuvant Breast Cancer Chemotherapy. Cancer Nurs. 2018; 41(1):62-68. doi: 10.1097/NCC. 0000000000000451.
43. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960; 23(1):56-62. doi: 10.1136/jnnp.23.1.56.
44. Kearns NP, Cruickshank CA, McGuigan KJ, Riley SA, Shaw SP, Snaith RP. A comparison of depression rating scales. Br J Psychiatry. 1982; 141: 45-9.
45. Zhang AY, Ganocy SJ. Measurement of irritability in cancer patients. Nursing Research. 2020; 69: 91–99.
46. Lenz ER, Pugh LC, Milligan RA, Gift A, Suppe F. The middle-range theory of unpleasant symptoms: An update. ANS Adv Nurs Sci. 1997;19(3):14-27.
47. Giudice MD, Gangestad SW. Rethinking IL-6 and CRP: Why they are more than inflammatory biomarkers, and why it matters, Brain, Behavior, and Immunity. 2018; 70: 61-75. doi.org/10.1016/j.bbi.2018.02.013.
48. Pepys MB, Hirschfield GM. C-reactive protein: a critical update. The Journal of Clinical Investigation. 2003; 111(12): 1805–1812. doi:10.1172/JCI18921.
49. 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(3):736-744.
50. Haapakoski R, Mathieu J, Ebmeier KP, Alenius H, Kivimaki M. Cumulative meta-analysis of interleukins 6 and 1beta, tumour necrosis factor alpha and C-reactive protein in patients with major depressive disorder. Brain Behav Immun. 2015; 49: 206-215.
51. Ma Y, Chiriboga DE, Pagoto SL, Rosal MC, Li W, Merriam PA, Hébert JR, Whited MC, Ockene IS. Association between depression and C-reactive protein. Cardiol Res Pract. 2011;286509. doi: 10.4061/2011/ 286509.
52. Ford DE, Erlinger TP. Depression and C-reactive protein in US adults: data from the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2004; 164(9):1010-4. doi: 10.1001/archinte.164.9. 1010.