CENTER ON BEHAVIORAL MEDICINE

MIND-BODY CONNECTION

PSYCHOIMMUNOLOGY

Negative Emotions:  Research Article

Psychoimmunology Menu

Pathways Linking Major Depression and Immunity in Ambulatory Female Patients

CITATION:  Miller, E., Cohen, S., Herbert. T.B. (1999)  Pathways Linking Major Depression and Immunity in Ambulatory Female Patients.  Psychosomatic Medicine 61:850860.

ABSTRACT:  Objectives: The goals of this study were to investigate whether depression is associated with cellular immunity in ambulatory patients and to identify neuroendocrine and behavioral pathways that might account for this relation-ship. Methods: We studied 32 women who met Diagnostic and Statistical Manual of Mental Disorder, fourth edition, criteria for major depressive disorder and 32 healthy female control subjects. The groups were matched for age and ethnicity. None were taking medication, and all were free of disease involving the immune system. Results: Depressed subjects had reduced proliferative responses to the mitogens concanavalin A and phytohemagglutinin compared with control subjects. Natural killer cell activity was reduced among older depressed subjects but enhanced among younger depressed subjects. Although depression was associated with elevated circulating levels of norepinephrine and estradiol, these hormones could not account for the immunologic differences between depressed and control subjects. Depression was also associated with greater tobacco and caffeine consumption, less physical activity, and poorer sleep quality. Mediational analyses were consistent with physical activity acting as a pathway through which depression was associated with reduced lymphocyte proliferation. Conclusions: Ambulatory patients with mild to moderately severe depression exhibit reduced mitogen-stimulated lymphocyte proliferative responses and altered natural killer cell cytotoxicity. The relationship between depression and proliferative responses may be mediated by physical activity. 

References

1. Herbert TB, Cohen S. Depression and immunity: a meta-analytic review. Psychol Bull 1993;13:472–86.

2. Evans DL, Folds JD, Petitto JM, Golden RN, Pederson CA, Corrigan M, Gilmore JH, Silva SG, Quade D, Ozer H. Circulating natural killer cell phenotypes in men and women with major depression. Arch Gen Psychiatry 1992;49:388–95.

3. Irwin M, Caldwell C, Smith TL, Brown SA, Schuckit MA, Gillin JC. Major depressive disorder, alcoholism, and reduced natural killer cell cytotoxicity. Arch Gen Psychiatry 1990;47:713–9.

4. Schleifer SJ, Keller SE, Bond RN, Cohen J, Stein M. Major depressive disorder and immunity: role of age, sex, severity, and hospitalization. Arch Gen Psychiatry 1989;46:81–7.

5. Hickie I, Hickie C, Lloyd A, Silove D, Wakefield D. Impaired in vivo immune responses in patients with melancholia. Br J Psychiatry 1993;162:651–7.

6. Weissman MM, Bryce ML, Leaf PJ, Florio LP, Holzer C. Affective disorders. In: Robins LN, Regier DA, editors. Psychiatric disorders in America: the Epidemiologic Catchment Area Study. New York: Free Press; 1991. p. 67–92.

7. Weiss CS. Depression and immunocompetence: a review of the literature. Psychol Bull 1992;111 :475–89.

8. Schleifer SJ, Keller SE, Bartlett JA, Eckholdt HM, Delaney BR. Immunity in young adults with major depressive disorder. Am J Psychiatry 1996;153:477–82.

9. Syvalahti E, Eskola J, Ruuskanen O, Laine T. Nonsuppression of cortisol in depression and immune function. Prog Neuropsychopharmacol Biol Psychiatry 1985;9:13–22.

10. Andreoli A, Keller SE, Rabaeus M, Zaugg L, Garrone G, Taban C. Immunity, major depression, and panic disorder comorbidity. Biol Psychiatry 1992;31:896–908.

11. Ravindran AV, Griffiths J, Merali Z, Anisman H. Circulating lymphocyte subsets in major depression and dysthymia with typical or atypical features. Psychosom Med 1998;60:283–9.

12. Ravindran AV, Griffiths J, Merali Z, Anisman H. Lymphocyte subsets associated with major depression and dysthymia: modification by antidepressant treatment. Psychosom Med 1995;57: 555–63.

13. Andreoli A, Keller SE, Rabaeus M, Marin P, Bartlett JA, Taban C. Depression and immunity: age, severity, and clinical course. Brain Behav Immun 1993;7:279–92.

14. Schleifer SJ, Keller SE, Siris SG, Davis KL, Stein M. Depression and immunity: lymphocyte function in ambulatory depressed patients, hospitalized schizophrenic patients, and patients hospitalized for herniorrhaphy. Arch Gen Psychiatry 1985;42: 129 –33.

15. Akil H, Haskett RF, Young EA, Grunhaus L, Kotun J, Weinberg V, Greden J, Watson SJ. Multiple HPA profiles in endogenous depression: effect of age and sex on cortisol and beta-endorphin. Biol Psychiatry 1993;33:73–85.

16. Maes M, Minner B, Suy E, D’Hondt P, Jacobs MP, Raus J. Cortisol escape from suppression by dexamethasone during depression is strongly predicted by basal cortisol hypersecretion and in-creasing age combined. Psychoneuroendocrinology 1991; 16: 29 5–3 10.

17. von Bardeleben U, Holsboer F. Effect of age on the cortisol response to human corticotropin-releasing hormone in de-pressed patients pretreated with dexamethasone. Biol Psychiatry 1991;29:1042–50.

18. Gold PW, Goodwin FK, Chrousos GP. Clinical and biochemical manifestations of depression: relationship to the neurobiology of stress, part 2. N Engl J Med 1988;319:413–20.

19. Chrousos GP, Torpy DJ, Gold PW. Interactions between the hypothalamic-pituitary-adrenal axis and the female reproductive system: clinical implications. Ann Intern Med 1998;129:229–40. Blalock JE. The syntax of neuroendocrine-immune communication. Immunol Today 1994;15:504–11.

20. Munck A, Guyre PM. Glucocorticoids and immune function. In: Ader R, Felten DL, Cohen N, editors. Psychoneuroimmunology. 2nd ed. San Diego (CA): Academic Press; 1991. p. 447–74. Rabin BS, Kusnecov A, Shurin M, Zhou D, Rasnick S. Mechanistic aspects of stressor-induced immune alteration. In: Glaser R,  Kiecolt-Glaser JK, editors. Handbook of human stress and immunity. San Diego (CA): Academic Press; 1995. p. 23–51. 

21. Breslau N, Kilbey MM, Andreski P. Nicotine dependence and major depression: new evidence from a prospective investigation. Arch Gen Psychiatry 1993;50:31–5.

22. Newman AB, Enright PL, Manolio TA, Haponik EF, Wahl PW. Sleep disturbance, psychosocial correlates, and cardiovascular disease in 5201 older adults: the Cardiovascular Health Study. J Am Geriatric Soc 1997;45:1–7.

23. Irwin M, Mascovich A, Gillin JC, Willoughby R, Pike J, Smith TL. Partial sleep deprivation reduces natural killer cell activity in humans. Psychosom Med 1994;56:493–8.

23. Kiecolt-Glaser JK, Glaser R. Methodological issues in behavioral immunology research with humans. Brain Behav Immun 1988; 2:67–78.

24. Parry H, Cohen S, Schlarb JE, Tyrrell DA, Fisher A, Russell MAH, Jarvis MJ. Smoking, alcohol consumption, and leukocyte counts. Am J Clin Pathol 1997;107:64–7.

25. Simon HB. Exercise and the immune system. In: Ader R, Felten D, Cohen N, editors. Psychoneuroimmunology. 2nd ed. San Diego (CA): Academic Press; 1991. p. 869–95.

26. Maes M, Meltzer HY, Stevens W, Cosyns P, Blockx P. Multiple reciprocal relationships between in vivo cellular immunity and hypothalamic-pituitary-adrenal axis in depression. Psychol Med 1991;24:1671–7.

27. Maes M. Evidence for an immune response in major depression: a review and hypothesis. Prog Neuropsychopharmacol Biol Psychiatry 1995;19:11–38.

28. Kronfol Z, House JD, Silva J, Greden J, Carroll BJ. Depression, urinary free cortisol secretion, and lymphocyte function. Br J Psychiatry 1986;148:70–3.

29. Irwin M, Smith TL, Gillin JC. Electroencephalographic sleep and natural killer cell cytotoxicity in depressed patients and control subjects. Psychosom Med 1992;54:10–21.

30. Dishman RK, Warren JM, Youngstedt SD, Yoo H, Bunnell BN, Mougey EH, Meyerhoff JL, Jaso-Friedman L, Evans DL. Activity-wheel running attenuates suppression of natural killer cell activity after footshock. J Appl Physiol 1995;78:1547–54.

31. G. E. MILLER et al.34.First MB, Spitzer RL, Gibbon M, Williams JBW. Structured Clin ioral medicine. Hillsdale (NJ): Lawrence Erlbaum Associates;ical Interview for Axis I DSM-IV Psychiatric Disorders–Patient1992. p. 55–71.Edition. New York: New York State Psychiatric Institute Biometrics Research; 1994.45.

32. Schleifer SJ, Keller SE, Meyerson AT, Raskin MJ, Davis KL, Stein M. Lymphocyte function in major depressive disorder.35.Spitzer RL, Endicott J. Schedule for Affective Disorders andArch Gen Psychiatry 1984;41:484–6.

33. Schizophrenia–Lifetime Version. New York: New York State Psychiatric Institute Biometrics Research; 1978.46.

34. Darko DF, Irwin MR, Risch SC, Gillin JC. Plasma beta-endorphin and natural killer cell activity in major depression: a prelimi 36.Hamilton M. A rating scale for depression. J Neurol Neurosurgnary study. Psychiatry Res  1992;43:111–9.Psychiatry 1960;23:56–62.47.

35. Cover H, Irwin M. Immunity and depression: insomnia, retarda 37.Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inven tion, and reduction of natural killer cell activity. J Behav Medtory for measuring depression. Arch Gen Psychiatry 1961;5:1994;17:217–23.462–7.48.

36. Maier SF, Watkins LR. Cytokines for psychologists: implications38.McNair DM, Lorr M, Droppleman LF. Profile of mood states. San Diego (CA): Educational and Industrial Testing Service; 1971.of bidirectional immune-to-brain communication for under standing behavior, mood, and cognition. Psychol Rev 1998;105:39.

37. Cohen S, Doyle WJ, Skoner DP, Rabin BS, Gwaltney JM. Socialties and susceptibility to the common cold. JAMA 1997;277:83–107.49.

38. Bruce ML, Leaf PJ, Rozal GP, Florio L, Hoff RA. Psychiatric1940 –4.status and nine-year mortality data in the New Haven Epidemi 40.Cohen S, Tyrell DAJ, Russell MAH, Jarvis MJ, Smith AP. Smoking, alcohol consumption, and susceptibility to the commonologic Catchment Area Study. Am J Psychiatry 1994;151:cold. Am J Public Health 1993;83:1277–83.716–21.41.

39. Buysse DJ, Reynolds CR, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index. Psychiatry Res 1989;28:50.Frasure-Smith N, Lesperance F, Talajic M. Depression and 18 month prognosis after myocardial infarction. Circulation 1995;193–213.91:999–1005.42.

40. Herbert TB, Coriell M, Cohen S. Analysis of lymphocyte proliferation data: do different approaches yield the same results?51.Frasure-Smith N, Lesperance F, Talajic M. Depression following myocardial infarction: impact on 6-month survival. JAMA 1993;Brain Behav Immun 1994;8:153–62.270:1819–25.43.

41. Fletcher MA, Baron GC, Ashman MR, Fischl MA, Klimas NG. Use of whole blood methods in assessment of immune parameters in immunodeficiency. Diagn Clin Immunol 1987;5:68–91.52.

42. Herrmann C, Brand-Driehorst S, Kaminsky B, Leibing E, Staats, Ruger U. Diagnostic groups and depressed mood as predictors of 22-month mortality in medical conditions. Psychosom Med44.

43. Stone AA. Selected methodological concepts: mediation and1998;60:570–7.moderation, individual differences, aggregation strategies, and variability of replicates. In: Schneiderman N, McCabe P, Baum A, editors. Stress and disease processes: perspectives in behav 53.

44. Zheng D, Macera CA, Croft JB, Giles WH, Davis D, Scott, WK.  Major depression and all-cause mortality among white adults.  Ann Epidemiol 1997;7:213–8.