Maryfrances R. Porter, B.A.. Amita Manatunga, Ph.D. Feng Gao, M.P.H.. Suzanne ... Charles B. Nemeroff, M.D., Ph.D. Objective: This study investigated whether.
Article
Higher Than Normal Plasma Interleukin-6 Concentrations in Cancer Patients With Depression: Preliminary Findings Dominique L. Musselman, M.D. Andrew H. Miller, M.D. Maryfrances R. Porter, B.A. Amita Manatunga, Ph.D. Feng Gao, M.P.H. Suzanne Penna, B.A. Brad D. Pearce, Ph.D. Jacque Landry, B.S. Susan Glover, M.D. J. Stephen McDaniel, M.D. Charles B. Nemeroff, M.D., Ph.D.
Objective: This study investigated whether cancer patients with and without major depression exhibit immune system abnormalities similar to those reported in medically healthy, depressed subjects without cancer. Method: The study subjects consisted of patients diagnosed with pancreatic, esophageal, or breast cancer. Other groups consisted of subjects with major depression (without cancer) and healthy comparison subjects. Subjects’ diagnoses were made with the Structured Clinical Interview for DSM-III-R. Severity of depression was measured with the Hamilton Depression Rating Scale. Plasma concentrations of interleukin-6 (IL-6) and postdexamethasone cortisol were measured.
Results: Cancer patients with depression had markedly higher plasma concentrations of IL-6 than healthy comparison subjects and cancer patients without depression. Although significant correlations were found between Hamilton depression scale scores and plasma concentrations of postdexamethasone cortisol, no significant correlations were found between plasma IL-6 and postdexamethasone cortisol concentrations. Conclusions: Higher than normal plasma IL-6 concentrations were associated with a diagnosis of major depression in cancer patients. IL-6 may contribute to sickness behavior that has overlapping symptoms with major depression. (Am J Psychiatry 2001; 158:1252–1257)
C
ancer patients, who experience marked physiologic, economic, and psychological stressors, have long been observed to have elevated prevalence rates of major depression, compared with the general population (1). Among cancer patients, the highest prevalence rates are exhibited by patients with either oropharyngeal cancer (2–4) or pancreatic cancer (5–7). Prospective or crosssectional studies of patients with pancreatic cancer have documented a remarkable point prevalence rate of depression of 50% (5–8). Although a number of neurochemical, neuroendocrine, neuroanatomical, and neuroimmune alterations have been associated with unipolar depression, few of these psychobiologic alterations have been systematically investigated in cancer patients with depression. Increasing evidence has suggested that cytokines may play a role in the pathophysiology of mood disorders. Cytokines are intercellular signaling polypeptides produced by activated cells that regulate immune responses, the acute phase reaction, and hematopoiesis and play a central role in host defense (9, 10). Cytokines also communicate information regarding immune activity to the brain and neuroendocrine system (11). This cytokine-mediated “communication” between the immune and neuroendocrine systems (12) is exemplified by the increased pituitary and adrenocortical secretion that occurs in response to in-
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fection or inflammation. Indeed, circulating cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF) have the capacity to directly stimulate the hypothalamic-pituitary-adrenal (HPA) axis and the release of corticotropin-releasing factor (CRF) (11–13). Of relevance to mood disorders, these cytokines can also induce “sickness behavior,” which includes symptoms of fatigue, anorexia, anhedonia (loss of interest in usual activities), decreased psychomotor activity, and disappearance of body care activities (14, 15). These signs and symptoms accompany the immunologic response to infection and overlap with the symptoms of major depression. As a key regulator of the acute phase response (16, 17), IL-6 has received special attention in a number of studies that have documented higher than normal acute phase reactants in depressed patients (18, 19). Moreover, an increasing body of literature has documented the myriad neurophysiological effects of IL-6, IL-6 expression in human astrocytes and microglia (20), and the regionspecific distribution of IL-6 and IL-6 receptor mRNA in rat neurons within the medial preoptic nucleus, hippocampus, striatum, and medial hypothalamus (21–25). To our knowledge, there have been no studies measuring IL-6 and its relation to major depression and HPA axis function in patients with cancer. In an effort to understand the pathophysiology of major depression in patients Am J Psychiatry 158:8, August 2001
MUSSELMAN, MILLER, PORTER, ET AL. TABLE 1. Demographic and Clinical Characteristics of Healthy Comparison Subjects, Comparison Subjects With Major Depression, and Cancer Patients With and Without Major Depression in a Study of Immune System Abnormalities in Cancer and Depression Characteristic Gender Male Female Ethnicity Caucasian Hispanic African American Stage of cancer I II III IV Unknown Type of cancer Breast Pancreatic Esophageal
Age (years) Hamilton depression scale score Postdexamethasone cortisol plasma concentration (ng/ml) Postdexamethasone nonsuppression of cortisol Comparison subjectsa Cancer patientsb Breast cancer Pancreatic cancer Esophageal cancer Use of pain medication
Healthy Comparison Subjects (N=10) N
Depressed Comparison Subjects (N=12) N
Cancer Patients Without Major Depression (N=13) N
Cancer Patients With Major Depression (N=8) N
4 6
6 6
5 8
4 4
10 0 0
12 0 0
10 0 3
6 1 1
1 5 4 1 2
1 2 1 2 2
7 4 2
3 4 1
Mean
SD
Mean
SD
Mean
SD
42.5 0.8
9.8 0.9
53.3 24.8
12.6 8.9
51.0 11.5
11.4 8.5
57.6 20.0
13.0 9.1
1.3
0.8
3.0
3.1
2.2
1.5
12.2
13.2
N
N
0
3
0
N
1 0 1 0 4
0
Mean
SD
N
5 0 4 1 2
a Nine healthy and 11 depressed comparison subjects were tested. b Two nondepressed and three depressed breast cancer patients, four
nondepressed and four depressed pancreatic cancer patients, and two nondepressed and one depressed esophageal cancer patients were tested.
with cancer, we sought to determine whether cancer patients with comorbid major depression exhibited higher than normal plasma concentrations of the proinflammatory cytokine IL-6 and whether alterations in IL-6 were associated with perturbations of the HPA axis, i.e., a higher than normal level of cortisol in response to dexamethasone administration.
Method Subjects Study subjects were recruited among outpatients and inpatients at hospitals affiliated with Emory University and from the community by means of newspaper advertisements or word of mouth. The advertisements sought “cancer patients with and without depression” and “patients with depression.” After the study had been fully explained, 115 potential subjects gave written informed consent and were then screened by office interview for the presence of psychiatric disorders, substance abuse, medical illness, and medication intake. Subjects were excluded if they showed evidence of current alcohol or substance abuse, bipolar disorder (mania, hypomania, or cyclothymia), schizoaffective disorder, or schizophrenia. Subjects were between the ages of 18 Am J Psychiatry 158:8, August 2001
and 80, had a Mini-Mental State Examination score of at least 24 (26), and had no untreated endocrine, cardiovascular, hematologic, hepatic, renal, or neurological diseases. Subjects were not receiving any psychotropic medications for treatment of depressive or anxiety symptoms. The normal comparison subjects were without any current or past personal history of psychiatric disorder. The depressed subjects without cancer and the normal comparison subjects were without significant medical illness, on the basis of findings of a physical examination, blood and urine analyses, ECG, and chest X-ray. Of those screened, 10 healthy comparison subjects, 12 depressed subjects without cancer, and 21 cancer patients completed the study (Table 1). This study was approved by the Emory University Human Investigational Committee, and informed consent was obtained from all subjects.
Procedure All participants were interviewed with the Structured Clinical Interview for DSM-III-R (SCID) (27) and completed a series of observer-rated and self-rated scales, including dimensional measures of depressive symptoms, the 21-item Hamilton Depression Rating Scale (28), and the Carroll Rating Scale for Depression (29). Further information regarding the mood and behavior of the cancer patients was obtained from family members. Final psychiatric diagnoses were provided by consensus of the research team (a
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CANCER AND DEPRESSION FIGURE 1. Plasma Interleukin-6 (IL-6) Concentrations of Healthy Comparison Subjects, Comparison Subjects With Major Depression, and Cancer Patients With and Without Major Depressiona
Plasma IL-6 Concentrations (pg/ml)
600 500
differences on these two indices. The median IL-6 plasma concentrations and the 95% confidence interval (CI) of the median were also calculated within each group (35). Fisher’s exact test was used to determine between-group differences in postdexamethasone plasma cortisol concentrations. Spearman rankorder correlations were used to determine the relationships among Hamilton depression scale scores, plasma IL-6 concentrations, and postdexamethasone plasma cortisol concentrations.
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Results
300
Demographic and clinical characteristics of the study sample are presented in Table 1. The study groups did not differ significantly in mean age (F=2.76, df=3, 39, p=0.055). However, the cancer patients with comorbid major depression were the eldest group, and the healthy comparison subjects were the youngest group. Hamilton depression scale scores indicating moderate severity of depression were observed in the two study groups with major depression, although the cancer patients without depression exhibited some depressive symptoms. There was a significant difference in mean plasma concentrations of IL-6 between the four groups (Figure 1). Among the four study groups, the cancer patients with major depression had the highest median plasma concentration of IL-6 (median=116.4 pg/ml, 95% CI=8.6–512.5), and the cancer patients without major depression had the lowest (median=0 pg/ml, 95% CI=0.0–0.0). The median plasma IL-6 concentrations for the depressed comparison group and the healthy comparison group were 50.0 pg/ml (95% CI=11.1–296.0) and 0.1 pg/ml (95% CI=0–2.2), respectively (Figure 1). Although there were no significant differences in mean plasma cortisol concentrations after dexamethasone administration among the four groups (H=4.7, df=3, p=0.20), analysis of postdexamethasone cortisol suppressor status revealed a significant overall difference among the four groups (p=0.02, Fisher’s exact test). Cancer patients with major depression exhibited the highest rate of postdexamethasone cortisol nonsuppression, compared to the other study groups. Of the eight cancer patients with major depression, five (63%) were nonsuppressors of cortisol (plasma cortisol concentrations ≥5 ng/ml), compared to one (13%) of the eight of the cancer patients without major depression. Moreover, three (27%) of the 11 subjects with major depression without cancer were cortisol nonsuppressors, compared to none of the healthy comparison subjects. The relationships among Hamilton depression scale scores, postdexamethasone cortisol plasma concentrations, and plasma IL-6 concentrations were also explored. There was a positive correlation between Hamilton depression scale scores and postdexamethasone cortisol plasma concentrations (rs=0.35, df=30, p=0.05). The correlation between the Hamilton depression scale scores and postdexamethasone cortisol plasma concentrations was also evaluated within two subgroups: the depressed
200 100 0 Healthy Comparison Subjects (N=10)
Depressed Comparison Subjects (N=12)
Cancer Patients (N=13)
Depressed Cancer Patients (N=8)
Study Groupb a Plasma IL-6 concentrations were measured at 4:00 p.m. b Significant difference among groups (H=13.9, df=3, p=0.003).
master’s-level nurse, a research coordinator, a fourth-year psychiatry resident, and two board-certified psychiatrists) according to Spitzer’s procedure for longitudinal evaluation of all available data (30). Plasma IL-6 concentrations were obtained at 4:00 p.m. in all subjects and were measured with enzyme-linked immunosorbent assay by using sets of paired monoclonal antibodies for capture and detection, as suggested by the manufacturer’s protocol (Endogen Laboratories, Cambridge, Mass.). Samples were assayed in duplicate, and IL-6 concentrations were derived from a standard curve comprised of serial dilutions (4.1–400 pg/ml) of purified recombinant human IL-6. Assay sensitivity was
