Elsevier

Psychoneuroendocrinology

Volume 26, Issue 8, November 2001, Pages 797-808
Psychoneuroendocrinology

Association between immune activation and early depressive symptoms in cancer patients treated with interleukin-2-based therapy

https://doi.org/10.1016/S0306-4530(01)00030-0Get rights and content

Abstract

The relationship between immune activation and the development of early depressive symptoms were studied in 33 cancer patients undergoing cytokine therapy. Patients were treated either with subcutaneous IL-2 administered alone (n=13) or in association with IFN-α (n=5), or with IFN-α alone administered subcutaneously at low doses (n=5) or intravenously at high doses (n=10). The intensity of depressive symptoms was assessed during a clinical interview carried out before the start of cytokine therapy and five days later using the Montgomery and Asberg Depression Rating Scale (MADRS). On the same days, blood samples were collected for each patient to measure serum concentrations of cytokines (IL-6, IL-10, IL-1ra) and cytokine-receptors (sIL-2R, LIF-R). Results showed that patients treated with IL-2 or IL-2+IFN-α displayed concomitant mood symptoms and increased serum cytokine levels during treatment. In these patients, the intensity of depressive symptoms at endpoint was positively correlated with the increases measured in serum levels of IL-10 between baseline and endpoint. IL-10 is an anti-inflammatory cytokine that is produced in response to the production of pro-inflammatory cytokines, and thereby reflects an inflammatory response. These results support the hypothesis of close relationship between depressive symptoms and the activation of the cytokine network.

Introduction

Cytokine immunotherapy with interleukin-2 [IL-2] and/or interferon-α [IFN-α] for the treatment of cancer is accompanied by the appearance of depressive symptoms in a large proportion of treated patients (Denicoff et al., 1987, Kirkwood et al., 1996, Valentine et al., 1998, Ravaud et al., 1999). When they become severe and detrimental to the patient's quality of life, these symptoms may be treatment-limiting and lead to the modification of the therapeutic schedule or even more to the interruption of therapy. Several mechanisms have been proposed to explain the neuropsychiatric side effects of IL-2 and IFN-α. Interleukin-2 and IFN-α, given peripherally, may directly alter brain functions by penetrating into the central nervous system at sites devoid of blood–brain barrier, such as the circumventricular organs (Bocci, 1988). Cytokines might also enter the brain via transporter systems at the level of the blood–brain barrier or activate the brain indirectly via afferent neural pathways (Banks and Kastin, 1987, Waguespack et al., 1994). In either case, since cytokines function in a network fashion, it is also possible that IL-2 and IFN-α indirectly exert their adverse effects via the production of secondary cytokines (Janssen et al., 1994, Cavaillon, 1996). It has been shown that the administration of IL-2 in cancer patients increased plasma levels of interleukin-6 [IL-6], soluble receptors of interleukin-2 [sIL-2R], IL-1 receptor antagonist [IL-1ra] and IL-10 (Meffert et al., 1994, Tilg et al., 1994, Tilg et al., 1995). Data concerning the effects of IFN-α administration on cytokine production in cancer patients are less numerous. Nevertheless, transient increases in serum levels of IL-1ra have been observed after the administration of IFN-α to healthy individuals and to patients with chronic hepatitis B (Tilg et al., 1993). In another study, IFN-α administered to healthy volunteers elevated serum levels of IL-6 and induced headache, fever, chills, and increased pulse rate (Corssmit et al., 1995). In vitro, this cytokine has been shown to stimulate the production of IL-1β and IL-2 (Taylor and Grossberg, 1998).

The hypothesis of an involvement of the activation of the cytokine network in the development of depressive symptoms is sustained by several observations. Studies in laboratory animals showed that treatments with cytokines, mainly IL-2 and IL-1, or with the endotoxin lipopolysaccharide [LPS] induced depressive-like behavioral effects (Yirmiya, 1996, Anisman and Merali, 1999). In clinical studies, increased concentrations of IL-1ra, IL-6, sIL-2R and IL-10 have been observed in the serum of depressive patients (Maes et al., 1997, Seidel et al., 1995, Sluzewska et al., 1996) together with an elevated production of IFN-γ and IL-10 in the supernatant of leukocyte cultures (Seidel et al., 1995, Maes et al., 1994). Interestingly, several weeks of treatment with the selective serotonin reuptake inhibitors (SSRIs) antidepressants fluoxetine or sertraline normalized the initially increased serum IL-6 and IL-1 concentrations in depressed patients (Sluzewska et al., 1995). Taken together, these data suggest that the activation of the cytokine network could participate to the development of depressive symptoms in patients receiving cytokine therapy (Dantzer et al., 1999).

The aims of the present study were therefore to prospectively assess the relationship between the development of depressive symptoms and cytokine responses in cancer patients treated with IL-2 and/or IFN-α. In a previous study, we reported that depressive symptoms developed as soon as the first week of treatment in patients receiving IL-2-based therapy whereas these symptoms appeared later during IFN-α therapy (Capuron and Ravaud, 1999, Capuron et al., 2000). We therefore hypothesized that in those patients who develop depressive symptoms during the first week of IL-2 treatment, the cytokine network should be more activated than in IFN-α-treated patients. The present study was carried out to test this hypothesis, using a naturalistic setting of a cancer ward in which patients with renal cell carcinoma or melanoma were treated with IL-2 and IFN-α in various combinations and modalities of treatment.

Section snippets

Patients

Thirty-three patients participated in the present study and were included in four distinct groups according to the treatment they received. The treatment regimens for the first month of therapy are described in Table 1. All patients were adults with an initial Karnofsky performance index of at least 70%.

The first group included 13 patients (10 men, 3 women. Mean age (±SD): 60 (±11) years) with metastatic renal cell carcinoma treated with subcutaneous IL-2 (IL-2 patients) according to Sleijfer's

Effects of cytokine therapies on MADRS scores

There was no difference between groups in terms of MADRS scores at baseline. As expected, MADRS scores significantly increased between baseline and day five only in patients that received IL-2 and IL-2+IFN (Simple main effects: F(1,29)=14.02, P<0.001 and F(1,29)=14.9, P<0.001, respectively). In IFN-treated patients, whatever the dose and the route of administration of the cytokine, there was no change in MADRS scores during the first week of treatment (Fig. 1a).

Baseline values

There was no significant

Discussion

The results of the present study showed differential effects for IL-2 and IFN-α treatments on mood and immune activity during the first week of therapy in cancer patients. Besides their early timing, these changes were unambiguous and particularly marked in patients who received cytokine therapy using IL-2, administered alone or in association with IFN-α.

Whereas before starting immunotherapy treatment groups were comparable for MADRS scores, IL-2 and IL-2+IFN therapies were associated with

Acknowledgements

The authors thank the patients for their participation in the study, the clinical staff for his helpful collaboration and A. Lin for her technical assistance. This study was supported by Ligue Nationale contre le Cancer, Fondation pour la Recherche Medicale, and Association pour la Recherche sur le Cancer.

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