New investigator awardBaseline mood and psychosocial characteristics of patients developing depressive symptoms during interleukin-2 and/or interferon-alpha cancer therapy
Introduction
Cytokine therapy in the form of chronic administration of interleukin-2 (IL-2) and/or interferon-alpha (IFN-α) is commonly used for the treatment of cancers and chronic viral infections. Despite their clinical efficacy, cytokine therapies are associated with the occurrence of significant depressive symptoms in 30–50% of patients, depending on the dose and treatment modality (Denicoff et al., 1987; Buter et al., 1993; Miyaoka et al., 1999; Musselman et al., 2001; Capuron et al., 2002). Of note, mood symptoms have also been reported in healthy volunteers acutely administered cytokines or cytokine inducers including IFN-β and endotoxin (Reichenberg et al., 2001; Exton et al., 2002). Often described as unpredictable (Kammula et al., 1998), depressive symptoms occurring during cytokine therapy have a significant impact on the patient’s quality of life and compliance to treatment and represent a major cause of treatment discontinuation (Musselman et al., 2001). Recently, antidepressants, notably serotonin reuptake inhibitors (SRIs), have been shown to reduce the incidence of cytokine-induced depressive symptoms (Musselman et al., 2001; Hauser et al., 2002), and therefore, patients eligible for cytokine therapy are frequently offered prophylactic antidepressant treatment before starting cytokine therapy. Nevertheless, this strategy raises several important concerns. As noted above, not all patients treated with cytokines develop major depression during the course of cytokine treatment. In addition, treatment with antidepressants may induce significant side events including nausea, insomnia, visual and cardiac symptoms and sexual dysfunction (Gumnick and Nemeroff, 2000). Finally, the influence of antidepressants on the efficacy of cytokine therapy (and the related immune response) has yet to be determined. In view of these issues, identification of which patients are vulnerable to cytokine-induced depression and thus might benefit most from preventative strategies is essential for limiting the potential disadvantages and maximizing the potential benefit of routine psychiatric pretreatment approaches.
Previous data have shown that patients with higher depression scores on a variety of rating scales including the Montgomery–Asberg depression rating scale (MADRS) and the Hamilton depression scale (HAMD) before the initiation of cytokine therapy are more likely to develop significant depressive symptomatology during the course of cytokine treatment than patients with low initial depression scores (Capuron and Ravaud, 1999; Miyaoka et al., 1999; Musselman et al., 2001). Since those studies excluded patients with a diagnosis of major depression at baseline, these findings suggest that preexisting subclinical mood symptoms before initiating cytokine therapy, as reflected by relatively elevated depressing ratings at baseline, may represent risk factors for the subsequent development of cytokine-induced depression. However, which specific subclinical mood symptoms are associated with the vulnerability for depression during cytokine therapy have yet to be elucidated. In a recent study, we reported that hyper-reactivity of the hypothalamic–pituitary–adrenal (HPA) axis to the first injection of IFN-α in cancer patients was closely associated with the development of major depression at later stages of IFN-α therapy (Capuron et al., 2003). Interestingly, the HPA axis hyper-responsiveness to the initial administration of IFN-α correlated positively with depressive ratings before starting IFN-α therapy, suggesting that stress reactivity, and its biological and behavioral correlates (e.g., depressive ratings at baseline), are relevant to the vulnerability to cytokine-induced depression.
The objective of the present study was to identify the specific preexisting subclinical symptoms that predict the development of depressive symptomatology during IL-2 and/or IFN-α cancer therapy. In addition, we considered other potential contributing factors, known to influence behavioral outcomes, including social support and coping.
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Patients
Thirty-two patients (mean age (SD): 47 (13) years; 19 men, 13 women) with metastatic renal cell carcinoma or advanced melanoma eligible to receive cytokine therapy with IL-2 and/or IFN-α were recruited from the Comprehensive Cancer Center of Bordeaux, France. Patients were enrolled in the study for the first four weeks of cytokine therapy. All patients had an initial Karnofsky performance index of at least 70% (i.e., patient able to care for self). Patients with a history of mood disorder or
Effects of cytokine therapy on the development of depressive symptoms
Analysis of variance revealed that total MADRS scores increased during cytokine therapy in comparison with baseline in all treatment groups. Both at baseline and endpoint, there was no significant difference in the magnitude of total MADRS scores between treatment groups [baseline: F(2,36)=0.13, p=.87; endpoint: F(2,36)=1.10, p=.34)], even though patients treated with the two cytokines exhibited slightly higher total MADRS scores compared with other treatment groups at endpoint (Fig. 1).
Discussion
Although cytokine therapy is notorious for causing depressive symptoms in a significant proportion of patients, strategies to detect patients at risk for cytokine-induced depressive symptoms are of primary importance. Recent advances have been made in the identification of those risk factors likely to predispose certain patients to develop depressive syndrome in the context of cytokine therapy. At the biological level, it has been shown that patients with sensitized stress response pathways, as
Acknowledgements
This study was supported by Ligue Nationale contre le Cancer, Fondation pour la Recherche Médicale, and Association pour la Recherche sur le Cancer.
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