Clinical Psychologist, Vol. 9, No. 2, November 2005, pp. 59 – 63.
Chronic stress, depression and immunity in spouses of metastatic breast cancer patients
JANE S. BLAKE MORTIMER1,2 SANDRA E. SEPHTON1, RACHEL KIMERLING1,3 LISA BUTLER1,3, AARON S. BERNSTEIN1, & DAVID SPIEGEL1 1
Stanford University School of Medicine, Department of Psychiatry, Stanford, Caifornia, USA, 2University of Adelaide, Department of Psychology, Adelaide, South Australia, Australia, and 3University of California School of Medicine, San Francisco General Hospital, San Francisco, California, USA
Abstract Objective: The objective of this study was to examine how the chronicity of stress affects psychological stress-responses, depressive symptoms, and in vivo immunocompetence in spouses of women with metastatic breast cancer. Methods: Participants were 34 spouses of breast cancer patients. Their wives had been living with a diagnosis of recurrence metastatic breast cancer for a mean of 2.3 (SD = 3.6) years. Stress chronicity was defined as the length of time since the partner’s diagnosis with metastatic breast cancer. Self-reports of psychological stress responses (IES) and depression (CESD) were taken, and in vivo immunocompetence was assessed by delayed type hypersensitivity (DTH) responses to skin test antigens. Results: Clinically significant levels of depressive symptoms (CES-D 4 16) were reported in 15% of participants. Suppression of the DTH response was greater in men who had been living longer with an ill spouse (Spearman r = 70.39, p = 0.011), those who reported more psychological stress (r = 0.37, p = 0.16), and those who had more severe depressive symptoms (r = 70.28, p = 0.054). There was no association between the duration of disease and spouse’s depression, however, those who had been living longer with an ill partner reported less psychological stress. Conclusions: This study substantiates a relationship between depression and cell-mediated immunity in spouses with a seriously ill partner. Further, these results suggest that the duration of stress is an important factor of stress-induced immunosuppression. They also highlight the potential importance of interventions to alleviate depression among family members of cancer patients. Keywords: Immunity, spouse, breast cancer, chronic stress.
Introduction There is growing evidence that chronic stress can affect various health outcomes (Kiecolt-Glaser & Glaser, 1995; Boscarino, 1997; Haley, 1997; Lesserman, Zhiming, Yuming, & Drossman, 1998; McEwen, 1998). Chronic stress has been associated with alterations in immunity. For example, giving long-term care to Alzheimer’s disease patients (Kiecolt-Glaser, Glaser, Shuttleworth, Dyer, Ogrocki, & Speicher, 1987; Kiecolt-Glaser, Dura, Speicher, Trask & Glaser, 1991; Mills et al., 1997), environmental stressors such as residing in the area of the damaged Three Mile Island nuclear power plant (McKinnon, Weisse, Reynolds, Bowles, & Baum, 1989), exposure to the aftermath of natural disasters
such as the Northridge Earthquake (Solomon, Segerstrom, Grohr, Kemeny & Fahey, 1997), Hurricane Andrew (Ironson et al., 1997), and bereavement (Bartrop, Lazarus, Luckhurst, Kiloh, & Penny, 1977; Schleifer, Keller, Camerino, Thornton, & Stein, 1983; Houldin, 1993) have been associated with decreases in the proliferative and functional responses of the cellular immune system. Bereavement is one of the most profound of life events, with psychological sequelae of extreme duration and magnitude (Houldin, 1993). Less research has been conducted, however, on individuals anticipating the loss of a loved one during the period preceding bereavement. Anticipating the loss of a spouse may constitute a significant source of psychological stress. The majority of studies report
Correspondence: Jane S. Blake Mortimer, Department of Psychology, University of Adelaide, North Terrace, Adelaide, SA 5005, Australia. Email:
[email protected] ISSN 1328-4207 print/ISSN 1742-9552 online ª The Australian Psychological Society Ltd Published by Taylor & Francis DOI: 10.1080/13284200500221094
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that 20 to 30% of spouses anticipating the possible loss of their wives suffer from psychological distress and increased morbidity (Blanchard & Ruckdeschel, 1997). Furthermore, many studies suggest that spouses may be as distressed as patients at the time of diagnosis (Baidler, & Kaplan De-Nour, 1984, 1988; Baidler, Cooper & Kaplan De-Nour, 1996). For example, among men anticipating the loss of a spouse due to illness, 58% had significant psychological distress as assessed by the Brief Symptom Inventory (BSI; Siegel, 1996). Moreover, there is evidence that this distress may remain unresolved for a year or more. For example, in a longitudinal study of couples’ adjustment to breast cancer, those who reported high distress and uncertainty regarding role definitions at diagnosis remain distressed one year later. Also the degree of psychological distress among husbands of women undergoing a mastectomy remained significantly above normal eighteen months post-operation, as assessed by the BSI (Northouse, 1989). Oberst and James (1985) point out that such prolonged stress may reduce the spouse’s capacity to respond to the emotional needs of the patient. This reflects the exhausting nature of prolonged caregiving stress, which can be both emotionally and physically burdensome. It is notable that studies examining caregiving stress have shown stress-induced alterations in lymphocyte subsets (Kiecolt-Glaser et al., 1987; Pariante et al., 1997); lymphocyte proliferative responses to mitogens (Kiecolt-Glaser et al., 1987) and reduced natural killer cell activity (Irwin, Brown, Patterson, Gauger, Mascovich, & Grant, 1991; Esterling, Kiecolt-Glaser, Bodnar, & Glaser, 1994). In cases where the patient’s metastatic disease is of a prolonged nature, stress on the spouse may become chronic. Here we examine relationships between the chronicity of stress (i.e., the duration of time spent with a partner who has cancer), depressive symptoms and in vivo immunocompetence in 34 male spouses of metastatic breast cancer patients. First, we hypothesized that men who had been living for a longer time with a spouse who has cancer would show evidence of greater psychological stress as measured by depressive symptoms. Second, we hypothesized that both objective stress measures (i.e., duration of partner’s disease) and subjective stress measures (i.e., depression, intrusion, avoidance) would be associated with in vivo immunosuppression.
Methods Subjects Thirty-four men participated in the current study. These were drawn from a larger sample of 51 men
who were recruited along with their female partners in a randomized, prospective study of Supportive/ Expressive group psychotherapy and cancer survival designed to replicate and extend our earlier finding of enhanced survival with group support (Spiegel, Bloom, Kraemer, & Gottheil, 1989). Men participating in the larger study were excluded from this analysis if they: (i) were not living with their partner (n = 3), (ii) did not complete the skin test for measurement of cell-mediated immunity (n = 10), or (iii) were anergic (non-responsive) to all of the skin test antigens (n = 4). Anergic subjects did not differ from the rest of the sample on the psychological stress measure, symptoms of depression, or the length of time they had been living with a partner with metastatic breast cancer. Thirty-three of the 34 couples in this analysis were married, and all were currently living with their partner. The mean age of the men was 58.6 (SD = 9.6) years, range 35 to 78, with only two subjects over the age of 70. Two of the couples were Asian and the rest were Caucasian-Americans. They reported an average of 16.7 years education (SD = 2.6), and a median annual household income between $60,000 and $80,000 dollars. All of the breast cancer patients had a physician’s Karnofsky rating of at least 70% (median rating = 90%), indicating their relatively high ability to care for themselves. In 31 of the 34 participants, immune competence was tested prior to randomization of the female partner in the larger study to a group psychotherapy or control condition, and the other three were tested within six weeks of randomization. Measures Chronicity. The chronicity, or duration, of participant’s stress was defined as the number of days from physician diagnosis of metastatic spread of breast cancer in the spouse to the date of participant’s assessment. Date of the diagnosis of recurrence was obtained by a trained Registered Nurse (RN) based upon medical record review. Separate measures of chronicity were calculated in reference to assessment of immunological data and psychological data, which often occurred on different testing occasions immunological and psychosocial data were collected an average of 13 days apart (SD = 30 days). Depression. Symptoms of Depression were measured at the time of study entry using the Center for Epidemiologic Studies Depression Scale (CES-D; Radloff, 1977). Cronbach’s alpha was 0.92 for the CES-D in the current sample. In this study, depression was theorized to reflect one component
Stress and immunity in spouses of cancer patients of the psychological response to coping with stress over an extended time. Stress response symptoms. General symptoms of the stress response were measured by the Impact of Event Scale (IES; Horowitz, Wilner, & Alvarez, 1979). The IES is a 15-item measure designed to assess symptoms of subjective distress due to a specific stressor. In this case, participants were instructed to respond to IES items regarding their wife’s illness. The IES contains two subscales assessing Intrusion and Avoidance symptoms, which were used separately in the analyses. Subjects indicate on a four-point scale the extent to which they experience intrusive thoughts about the stressor, or use avoidant coping mechanisms. This measure has been demonstrated to have adequate reliability and validity (Horowitz, Field, & Classen, 1993). Cronbach’s alpha in the current sample was 0.86 for the Intrusion subscale, and 0.70 for the Avoidance subscale. Metastatic breast cancer presents a partner with a series of ongoing stressors, which include supporting one’s partner through arduous treatments, receiving new evidence of disease progression, and the threat of losing one’s partner to death. Intrusion and avoidance were conceptualized to reflect traumatic responses to the current, ongoing stresses of the partners’ disease. Immune measures Antigen-Specific Cell-Mediated Immunity (CMI). Cutaneous Delayed Type Hypersensitivity (DTH) responses to commonly encountered antigens were tested using the Multitest CMI (Pasteur Merieux Connaught, Swiftwater, PA). The CMI measures responses to each of seven antigens: tuberculin, tetanus, diptheria, Streptococcus, Candida, Trichophyton, and Proteus. The panel of antigens was administered on the volar surface of the forearm through epidermal injection. Patients who failed to respond to any of the test antigens were identified as anergic. A positive response to a particular antigen was indicated by an increase in induration at the site of administration. Indurations greater than 2 mm at 48 h were considered a positive reaction. Responses were scored to indicate the number of positive responses, the average induration size (with each induration measured across two diameters at right angles, and the mean of the two measurements used), and the sum of the average induration scores (total induration score). Procedure A research associate contacted the participants and mailed the two self-report instruments (CES-D and
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IES) to them for completion immediately after recruitment into the study. The associate also scheduled times at the convenience of the participant for administration and reading of the DTH skin test by a trained R.N. in the laboratory. The average time between administration of the DTH test and the selfreport measures was 20 days (SD = 26). Data analysis One-tailed Spearman rank correlations were used to assess all bivariate relationships of interest. These relationships included: chronicity of stress and DTH response; chronicity of stress and depressive symptoms; chronicity of stress and stress response symptoms; depressive symptoms and DTH response; stress response symptoms and DTH response. Results Chronicity was highly variable: participants had been living with their partner’s diagnosis for an average of 2.3 (SD = 3.6) years, with duration ranging from 7 weeks to 17 years. Scores on the CES-D ranged from 0 to 38, with a mean of 9.5 (SD = 9.1). Scores on the Intrusion Subscale of the IES ranged from 0 to 33 with a mean of 15.1 (SD = 7.9), and scores on the Avoidance Subscale ranged from 1 to 29 with a mean of 11.2 (SD = 6.6). Results of correlations used to test the hypothesized relationships between stress and immunosuppression are displayed in Table I: Chronicity was significantly associated with the magnitude of the DTH response (average induration size), indicating that living for a longer time with an ill spouse may engender suppression of this measure of cellmediated immunity. In addition, having more intrusive thoughts was associated with suppression of the DTH response as measured by both induration size and number of positive responses. Depressive symptoms were also associated with suppression of the DTH response. However, no association was found between the duration of partner’s disease and depressive symptoms. Discussion These findings replicate those of previous studies that have assessed immune system correlates of individuals whose partners suffer from chronic illness (Kiecolt-Glaser et al., 1987) and extend such studies by directly examining the relationship between the chronicity of the stressor and cell mediated immunity in vivo. The current study reported cross-sectional relationships of both objective (stressor chronicity) and subjective (intrusive thoughts, depression) stress
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Table I. Spearman Rank Order relationships among stressor duration, psychological variables and DTH responses (N = 34)
Duration of partner’s disease Depression Intrusion Avoidance
Average induration size
Total induration score
No. positive antigens
70.39** 70.21 0.04 0.08
70.09 70.28* 70.29* 0.01
0.13 70.22 70.37** 70.06
Note. **p 5 0.02, *p 5 0.05.
measures with cellular immunity in 34 men living with partners diagnosed with metastatic breast cancer. Both the duration of the stressor and the magnitude of the psychological stress response varied widely in this sample. The absence of association between depression and the duration of the stressor may be partly explained by adaptation to the psychological demands of the partner’s illness as time progresses (Northouse, 1992). Furthermore, the men may have experienced only moderate stress associated with the physical demands of caring for the patient: although all patients had mestastases, their high Physician’s Karnofsky ratings indicated that the patients were functioning at a relatively high level, and were capable of attending to their own physical needs. Association of stressor duration with intrusion and avoidance were not examined since these measures were thought to reflect traumatic responses to the current, ongoing stressor, rather than psychological exhaustion due to coping with stress over an extended time. Although stress of longer duration was not associated with greater depression in spouses, it was associated with poorer cellular immune function. Our findings contrast with those of studies indicating that an objective stressful event such as bereavement or caring for relatives with Alzheimer’s disease was not associated with immunological changes unless this event was also associated with depression (Irwin, Daniels, Bloom, Smith, & Weiner, 1994; Zisook, Schuchter, Irwin, Carko, Sledge, & Resovsky, 1994). The current findings suggest that depression is not necessarily an etiological factor in stress-induced suppression of DTH responses. Indeed, clinically significant levels of depressive symptoms were indicated in only 15% of our subjects (CES-D 4 16). Thus, in a group of men with rather mild, depressive symptoms, these symptoms were associated with a poorer cellular immune response in male partners of cancer patients. In contrast, Pariante et al. (1997) reported no differences in CMI in depressed female caregivers of handicapped people compared to a non-depressed control group. Among subjects who are caregivers or who are anticipating the loss of a spouse to illness, relationships between depression and in vivo cell-mediated
immunity may vary by aspects of the sample such as sex, occupation, or living situation. Hickie and colleagues found reduced DTH responses in patients with melancholic versus non-melancholic depression (Hickie, Hickie, Lloyd, Silvone, & Wakefield, 1993; Hickie, Hickie et al., 1995), suggesting that only certain subtypes of depression are associated with suppression of DTH responses. In light of this, it is interesting that the CES-D, an instrument designed to screen for depression by being somewhat overinclusive, was correlated with immunosuppression in this sample. Our finding may be explained partly by the homogeneity, chronicity, and severity of the stressor in this sample, especially since the severity of depression was mild. Interestingly, while chronicity was associated with decrements in the magnitude of the antigenic response, psychological stress responses (depression, intrusive thoughts) were more strongly associated with decrements in the number of positive responses out of seven test antigens. Differential history of antigen exposure may account for some of the variance in the number of positive responses. These results may also indicate differential effects of stressor duration and psychological responses on immune capabilities. For example, mechanisms of antigen recognition may suffer as the duration of stress increases, while psychological upset may have more of an effect on the ability to mount a response once an antigen is recognized. Intrusive thoughts about the stressor were associated with a poorer cellular immune response, but avoidant coping mechanisms were not. It is not known how these two types of traumatic response may activate differential pathways of neuroendocrine effects on immune function. It is noteworthy that we observed suppression of an in vivo measure of cellular immunity, in contrast to the majority of studies performed with people undergoing stressful events that have examined in vitro measures. In vivo techniques while being less precise, have the advantage of providing a more specific test of actual somatic function (Hickie, 1990). In summary, chronic stress has been associated with significant immunosuppression, and similar impairments of immune function may occur in spouses of breast cancer patients. There is persuasive
Stress and immunity in spouses of cancer patients evidence that the physiological demands of chronic stress may affect health status (McEwen, 1998). These results highlight the need for interventions intended to alleviate psychological distress in partners of chronically and terminally ill individuals. Acknowledgements This study was funded by grant MH47226 from NIMH, NIMH grant 1HSA-410 and NCI, the John D. and Catherine T. MacArthur Foundation, and the Fetzer Institute. References Baidler, L., Cooper, C., & Kaplan De-Nour, A. (1996). Cancer and the Family. ?, New York: John Wiley & Sons. Baidler, L., & Kaplan De-Nour, A. (1984). Couples’ reactions and adjustment to mastectomy: A preliminary report. International Journal of Psychiatry Medicine, 14, 265 – 276. Baidler, L., & Kaplan De-Nour, A. (1988). Adjustment to cancer: Who is the patient — the husband or the wife? Israel Journal of Medical Science, 24, 631 – 636. Bartrop, R., Lazarus, L., Luckhurst, E., Kiloh, L., & Penny, R. (1977). Depressed lymphocyte function after bereavement. Lancet, 1, 834 – 836. Blanchard, C. A. T., & Ruckdeschel, J. (1997). The crisis of cancer: Psychological impact on family caregivers. Oncology, 11, 189 – 194. Boscarino, J. (1997). Diseases among men 20 years after exposure to severe stress: Implications for clinical research and medical care. Psychosomatic Medicine, 59, 605 – 614. Esterling, B., Kiecolt-Glaser, J., Bodnar, J., & Glaser, R. (1994). Chronic stress, social support, and persistent alterations in the natural killer cell response to cytokines in older adults. Health Psychology, 13, 291 – 298. Haley, W. (1997). The family caregiver’s role in Alzheimer’s disease. Neurology, 48, 25 – 29. Hickie, I. (1990). Is there immune dysfunction in depressive disorders. Psychological Medicine, 20, 755 – 761. Hickie, I., Hickie, C., Bennett, B., Wakefield, D., Silove, D., Mitchell, P., & Lloyd, A. (1995). Biochemical correlates of in vivo cell-mediated immune dysfunction in patients with depression: A preliminary report. International Journal of Immunopharmacology, 17, 685 – 690. Hickie, I., Hickie, C., Lloyd, A., Silvone, D., & Wakefield, D. (1993). Impaired in vivo responses in patients with melancholia. British Journal of Psychiatry, 162, 651 – 657. Horowitz, M., Field, N., & Classen, C. (1993). Stress response syndromes and their treatment. In B. S. Goldberger L. (Ed.). Stress: Theoretical and clinical aspects (pp. 757 – 773). New York: Fress Press. Horowitz, M., Wilner, N., & Alvarez, W. (1979). Impact of event scale: A measure of subjective stress. Psychosomatic Medicine, 41, 209 – 218. Houldin, A. (1993). Relaxation training psychoimmunological status of bereaved spouses. A pilot study. Cancer Nursing, 16, 47 – 52. Ironson, G., Wynings, C., Schneiderman, N., Baum, A., Rodriguez, M., Greenwood, D., Benight, C., Antoni, M., LaPerriere, A., Huang, H., Klimas, N., & Fletcher, M. (1997). Posttraumatic stress symptoms, intrusive thoughts, loss, and immune function after Hurricane Andrew. Psychosomatic Medicine, 59, 128 – 141.
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Irwin, M., Brown, M., Patterson, T., Gauger, R., & Mascovich, A. (1991). Neuropeptide Y and natural killer cell activity: Findings in depression and Alzheimer caregiver stress. FASEB Journal, 5, 3100 – 3107. Irwin, M., Daniels, M., Bloom, E., Smith, T., & Weiner, H. (1994). Life events, depressive symptoms, and immune function. Psychiatry Research, 52, 1 – 10. Kiecolt-Glaser, J., Dura, J., Speicher, C., Trask, O., & Glaser, R. (1991). Spousal caregivers of dementia victims: Longitudinal changes in immunity and health. Psychosomatic Medicine, 53, 345 – 362. Kiecolt-Glaser, J., & Glaser, R. (1995). Psychoneuroimmunology and health consequences: Data and shared mechanisms. Psychosomatic Medicine, 49, 523 – 535. Kiecolt-Glaser, J., Glaser, R., Shuttleworth, E., Dyer, C, Ogrocki, P., & Speicher, C. (1987). Chronic stress and immunity in family caregivers of Alzheimer’s disease victims. Psychosomatic Medicine, 49, 523 – 535. Lesserman, J., Zhiming, L., Yuming, J., & Drossman, D. (1998). How multiple types of stressors impact on health. Psychosomatic Medicine, 60, 175 – 181. McEwen, B. (1998). Protective and damaging effects of stress mediators: Allostasis and allostatic load. New England Journal of Medicine, 338, 171 – 179. McKinnon, W., Weisse, C., Reynolds, C., Bowles, C., & Baum, A. (1989). Chronic stress, leukocyte subpopulations and humoral responses to latent viruses. Health Psychology, 8, 389 – 402. Mills, P., Zeigler, M., Patterson, T., Dimsdale, J., Hauger, R., Irwin, M., & Grant, I. (1997). Plasma catecholamine and lymphocyte beta 2-adrenergic receptor alterations in elderly Alzheimer caregivers under stress. Psychosomatic Medicine, 59, 251 – 256. Northouse, L. (1989). A longitudinal study of the adjustment of patients and husbands to breast cancer. Oncology Nursing Forum, 16, 511 – 516. Northouse, L. (1992). Psychological impact of the diagnosis of breast cancer on the patient and her family. Journal American Medical Women’s Association, 47, 161 – 164. Oberst, M., & James, R. (1985). Going home: Patient and spouse adjustment following surgery. Topics Clinical Nursing, 7, 46 – 57. Pariante, C., Carpiniello, B., Orru, G., Farci, M., Del Giacco, G., Piludo, G., & Miller, A. (1997). Chronic caregiving stress alters peripheral blood immune parameters: The role of age and severity of stress. Psychotherapy and Psychosomatic Medicine, 66, 199 – 207. Radloff, L. (1977). The CES-D scale: A self-report depression scale for research in the general population. APMEDC, 1, 385 – 401. Schleifer, S., Keller, S. Camerino, M., Thronton, J., & Stein, M. (1983). Suppression of lymphocyte stimulation following bereavement. Journal of the American Medical Association, 250, 374 – 377. Siegel, K. (1996). Depressive distress among the spouses of terminally ill cancer patients. Cancer Practice, 4, 25 – 30. Solomon, G., Segerstrom, S., Grohr, P., Kemeny, M., & Fahey, J. (1997). Shaking up immunity: Psychological and immunological changes after a natural disaster. Psychosomatic Medicine, 59, 114 – 127. Spiegel, D., J. Bloom, J., Kraemer, H., & Gottheil, E. (1989). Effect of psychosocial treatment on survival of patients with metastatic breast cancer. Lancet, 14, 888 – 891. Zisook, S., Schuchter, S., Irwin, M., Carko, D., Sledge, P., & Resovsky, K. (1994). Bereavement, depression and immune function. Psychiatry Research, 52, 1 – 10.
