Psychosomatics 49:64-66, January-February 2008
doi: 10.1176/appi.psy.49.1.64
© 2008 Academy of Psychosomatic Medicine
Depression and IL-6 Blood Plasma Concentrations in Advanced Cancer Patients
Colleen M. Jacobson, Ph.D.,
Barry Rosenfeld, Ph.D.,
Hayley Pessin, Ph.D., and
William Breitbart, M.D.
Received June 22, 2006; revised September 28, 2006; accepted October 3, 2006. From Columbia University, NY State Psychiatric Institute; Fordham University; Memorial Sloan-Kettering Cancer Center. Send correspondence and reprint requests to Colleen Jacobson, Ph.D., Dept. of Child and Adolescent Psychiatry, Columbia University/NYSPI, 1051 Riverside Dr., New York, NY 10032. e-mail: jacobsoc{at}childpsych.columbia.edu
© 2008 The Academy of Psychosomatic Medicine
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ABSTRACT
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The authors explored the relationship between depression and interleukin-6 (IL-6) blood plasma concentrations among advanced-stage cancer patients. Seventy-three patients with advanced cancer were rated on depression with the Hamilton Rating Scale for Depression and gave blood to be assayed for blood plasma concentration of IL-6. Initial results found no correlation between depression and IL-6. Subsequent analyses found that among those whose blood was drawn within 48 hours of interview completion, depression and IL-6 were highly correlated. Future studies focusing on the relationship between immune functioning and depression must be particularly vigilant regarding methodological issues.
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INTRODUCTION
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Interest in the mind–body connection has grown among psychiatric researchers over the past several years, beginning with the coining of the term psychoneuroimmunology (PNI) in 1964 by the late George Solomon. A number of PNI studies have demonstrated a link between psychological functioning and immune functioning, typically focusing on the detrimental aspects of depression and overall psychological "stress."1,2 For example, Kiecolt-Glaser et al.3 found that immune-system response to a toxin (Hepatitis B vaccine) was affected by even mild stress. Furthermore, research on the effects of more long-term stressors, such as caring for a sick spouse or family member, has demonstrated that prolonged periods of stress result in a dysregulation of immune functioning, vaccine response, and slower recovery from wounds.4,5
Recently, interest has grown in exploring the connection between proinflammatory cytokines, considered indicators of gross immune functioning and overall health, and psychological stress.6 Two previous investigations, one among a sample of 1,686 elderly people,7 and one among a group of cancer patients (N=21) and healthy-control subjects (N=22),2 found higher interleukin-6 (IL-6) concentrations, indicating compromised immune functioning, to be associated with increased levels of depression.
The current study sought to determine whether depression, measured as a continuous variable, was associated with IL-6 blood plasma concentrations among a group of terminally-ill cancer patients. This was the first attempt to demonstrate a connection between psychological and physical health among such a severely-ill group of patients. We expected that higher levels of depression would be linked to elevated IL-6 concentrations.
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METHOD
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Subjects (N=73; 65.5% women; 76.7% white) were recruited from an inpatient palliative-care hospital in New York. Participants’ ages ranged from 23 to 90 years (mean: 67.0; standard deviation [SD]: 14.37). All patients admitted to the hospital had a diagnosis of cancer and a life expectancy of  6 months. Eligibility for study participation included a score of  20 on the Mini-Mental State Exam8 (conducted routinely on all newly admitted patients who are alert and able to participate), are English-speaking, age 21, and with no acute psychotic disorder. After study goals and procedures were explained, interested participants signed informed consent, participated in the study interview, and, during their next scheduled blood-drawing, provided an additional tube of blood for the study assay. All study blood draws occurred between 7:00 A.M. and 8:30 A.M., but were scheduled when the patient required blood-testing for clinical reasons. Because of practical and ethical concerns, the blood draws could not be standardized to take place on the same day as the study interview. Because previous research has indicated stability of IL-6 over a 30-day period,9 it was not expected that the lack of standardization would skew study results. The study procedures were approved by the Institutional Review Board of each participating institution.
Demographic and medical information, including age, gender, ethnicity, religion, marital status, education, cancer diagnosis, cancer treatment history, smoking status, menopausal status, height, and weight, were collected through chart review and during the interview process. Severity of depressive symptoms was assessed with the Hamilton Rating Scale for Depression (Ham-D).10 Immune functioning was assessed by the concentration of IL-6 plasma in the blood, identified by the implementation of enzyme-linked immunosorbent assay (ELISA) techniques. Interleukin-6 values are typically nondetectable among young, healthy individuals, and an IL-6 value of >5 pg/ml is taken to indicate "elevated" IL-6.
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RESULTS
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The mean IL-6 value (pg/ml) was 53.39 (SD: 62.65), with a range of 0.31 to 300.61. Because these values were non-normally distributed, the log10 of the values was used in all analyses. The length between interview completion and blood-draw ranged from 0 to 85 days, with a median of 9 days. The most common cancer diagnoses among the participants were lung (N=15), colon (N=7), breast (N=7), pancreatic (N=5), and prostate (N=5). The participants had undergone a variety of cancer treatments, including chemotherapy (N=44) and radiation (N=31). The mean body mass index (BMI) was 23.56 (SD: 6.98), and 15.1% of the sample had smoked within the past month. Finally, 23.3% of the participants were taking selective serotonin reuptake inhibitors (SSRIs) at the time of the study, and, of the 48 women, 75% were postmenopausal. Overall, the participants were experiencing relatively low levels of depression; the mean Ham-D score for the entire sample was 9.93 (SD: 4.85), with a range of 2 to 22.
Bivariate correlations, t-tests, and one-way analyses of variance (ANOVAs) were used to determine the association between IL-6 and certain possibly confounding medical variables, such as cancer diagnosis and treatment history. Patients with liver cancer had significantly higher concentrations of IL-6 than those with other cancer diagnoses (F[6, 40]=2.98; p=0.02). A concurrent diagnosis of hepatitis C was also related to higher concentrations of IL-6. The four people with hepatitis C and/or liver cancer were excluded from correlational analyses because of their extreme elevation of IL-6. IL-6 values were not significantly related to any other medical or health variables: age, BMI, gender, menopausal status, antidepressant medication, or treatment history.
As indicated in Table 1, the correlation between IL-6 and depression for the entire sample was not significant. In response to this failure to find a significant association, we conducted exploratory analyses to determine whether the time between interview completion and blood-draw affected the associations between IL-6 and depression. As indicated in Table 1, the correlations between IL-6 and Ham-D scores were calculated separately for four groups: those who had blood drawn within 48 hours of the study interview; those who had blood drawn within 4 days of the interview; those who had blood drawn within 1 week of the interview; and the whole sample. There was a positive, significant correlation between depression and IL-6 for those who had blood drawn within 48 hours: r=0.68; p<0.05; and the strength of the correlation decreased as time between interview and blood-draw increased.
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DISCUSSION
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The current study sought to replicate previous findings demonstrating an association between depression and IL-62,7 among advanced-stage cancer patients. However, contrary to expectations, this association proved to be somewhat more complex than anticipated. Although previous reports have suggested that IL-6 concentrations are relatively stable over a 30-day period in elderly samples,9 we found that the length of time between our assessments of depression and IL-6 significantly affected the association between these variables. We observed a strong negative association between depression and IL-6 concentration among the subgroup of participants who had blood drawn within close proximity to interview completion. However, as the length of time between assessments increased, the magnitude of this correlation decreased. Thus, studies focusing on the relationship between immune functioning and other indicators of overall physical health and depression must be particularly vigilant to methodological issues such as assessment timing, particularly in the context of severe or terminal illness.
Because the current study was cross-sectional, it is impossible to identify the exact causes of the diminished relationship between depression and IL-6 over time. It is possible that the relationship between depression and IL-6 eroded because of changes in IL-6 linked to changes in physical health. However, it is also possible that the changes in IL-6 may have been accompanied by changes in the levels of depression. Also, the current study did not indicate whether increased depression preceded increased IL-6 or vice versa. Longitudinal research is needed to address these questions.
Despite its limitations, the present study did identify a strong association between higher levels of depression and elevated IL-6 among a small group of advanced-cancer patients. Further research, with a larger sample size and the ability to standardize the timing of the blood-draw to the collection of psychosocial data, is needed to replicate this finding. Clinical implications of an association between depression and immune functioning speak to the importance of assisting patients in maintaining a positive, hopeful disposition, either through psychotherapy or antidepressants, in the face of severe physical illness.
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ACKNOWLEDGMENTS
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We thank the following colleagues who participated in data collection and management of the study: Anne Kosinski, Brooke Sorger, Jennifer Abbey, Megan Olden, James Cimino, Robert Brescia, Maryann Santaserio, David Rosenstreich, Sharif Abtoga, Lawrence Berg, and Mildred Colon. We also thank those who participated in the study, allowing us to advance our knowledge of the mind–body connection.
This research was supported by grant F31 AT00169-01, Colleen M. Jacobson, P.I., from the National Center of Complementary and Alternative Medicine (received by C. Jacobson while in graduate school at Fordham University) and grant R01 NR05183-01, to W. Breitbart, P.I.
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REFERENCES
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- Kiecolt-Glaser J, Glaser R: Psychoneuroimmunology: can psychological interventions modulate immunity? J Consult Clin Psychol 1989; 60:569–575
- Musselman D, Miller A, Porter M, et al: Higher-than-normal plasma interleukin-6 concentrations in cancer patients with depression: preliminary findings. Am J Psychiatry 2001; 158:1252–1256[Abstract/Free Full Text]
- Kielcolt-Glaser J, McGuire L, Robles T, et al: Psychoneuroimmunology: psychological influences on immune function and health. J Consult Clin Psychol 2002; 70:537–547[CrossRef][Medline]
- Castle S, Wilkins S, Heck E, et al: Depression in caregivers of demented patients is associated with altered immunity, impaired proliferative capacity, increased CD8+, and a decline in lymphocytes with surface signal transduction molecules (CD38) and a cytotoxicity marker (CD56+ CD8+). Clin Exp Immunol 1995; 101:487–493[Medline]
- Esterling BA, Kiecolt-Glaser JK, Bodnar J, et al: Chronic stress, social support, and persistent alterations in the natural killer-cell response to cytokines in older adults. Health Psychol 1994; 13:291–299[CrossRef][Medline]
- Bianchi M, Sacerdote P, Locatelli L, et al: Corticotropin-releasing hormone, interleukin-1 alpha, and tumor necrosis factor share characteristics of stress mediators. Brain Res 1991; 546:139–142[CrossRef][Medline]
- Dentino AN, Pieper CF, Rao MK, et al: Association of interleukin-6 and other biologic variables with depression in older people living in the community. J Am Geriatr Soc 1999; 47:6–11[Medline]
- Folstein M, Folstein S, McHugh P: "Mini-Mental State:" a practical method of grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 1:189–198
- Koenig HG, Cohen H, George L, et al: Attendance at religious services, interleukin-6, and other biological parameters of immune function in older adults. Int J Psychiatry Med 1997; 27:233–250[Medline]
- Hamilton M: A rating scale for depression. J Neurol Neurosurgery Psychiatry 1960; 23:56–61[Free Full Text]
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ABSTRACT
INTRODUCTION
