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Baseline mood and psychosocial characteristics of patients developing depressive symptoms during interleukin-2 and/or interferon-alpha cancer therapy

https://doi.org/10.1016/j.bbi.2003.11.004Get rights and content

Abstract

It has been suggested that patients with subclinical mood symptoms prior to initiating cytokine treatment (as revealed by elevated baseline scores on depression rating scales) are more likely to become clinically depressed during the course of cytokine therapy. The present study was designed to identify which specific preexisting symptoms predict development of depressive symptomatology during treatment with the cytokines, interleukin-2 (IL-2) and/or interferon-alpha (IFN-α), in patients with cancer. Thirty-two patients with renal cell carcinoma or malignant melanoma eligible to receive treatment with IL-2 and/or IFN-α were enrolled in the study. At baseline and after one month of cytokine therapy (endpoint), depressive symptoms were assessed using the clinician-administered Montgomery–Asberg depression rating scale (MADRS). Illness-related coping strategies, social support, somatic complaints, quality of sleep and demographic factors were also assessed as relevant baseline predictive factors. MADRS scores significantly increased during cytokine therapy. Patients with moderate to marked depressive symptomatology at study endpoint exhibited higher baseline scores in dimensions of the MADRS scale assessing emotional (especially reported sadness), cognitive (especially pessimistic thoughts) and neurovegetative (sleep disturbances) symptoms compared to patients who remained free of depressive symptoms during cytokine therapy. Interestingly, only emotional symptoms and sleep disturbance at baseline, along with low social support, predicted severity of depressive symptoms at the end of the first month of therapy. By documenting specific behavioral vulnerability factors for cytokine-induced depressive symptoms, these findings may help identify patients at risk for mood disturbances during cytokine treatment and help target specific patient populations and specific symptoms for preventative strategies.

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.

Section snippets

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.

References (29)

  • D.E. Ford et al.

    Sleep disturbances and mood disorders: an epidemiologic perspective

    Depress Anxiety

    (2001)
  • J.F. Gumnick et al.

    Problems with currently available antidepressants

    J. Clin. Psychiatry

    (2000)
  • P. Hauser et al.

    A prospective study of the incidence and open-label treatment of interferon-induced major depressive disorder in patients with hepatitis C

    Mol. Psychiatry

    (2002)
  • U.S. Kammula et al.

    Trends in the safety of high dose bolus interleukin-2 administration in patients with metastatic cancer

    Cancer

    (1998)
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