Association of fatigue and depression with circulating levels of proinflammatory cytokines and epidermal growth factor receptor ligands: a correlative study of a placebo-controlled fatigue trial

Abstract

Context: The biology of fatigue and depression in cancer patients is poorly understood. Hypotheses regarding cytokines and growth factors related to sickness behavior and disruption of circadian signaling have been proposed.

Objectives: We prospectively examined proinflammatory cytokines (e.g., sickness behavior model) and epidermal growth factor receptor (EGFR) ligands (e.g., circadian disruption model) in the serum of cancer patients enrolled in a clinical trial testing levocarnitine for fatigue.

Methods: Serum samples were collected at baseline and week 4. Cytokine/growth factor analyses were performed with a Luminex analyzer. The Brief Fatigue Index and the Center for Epidemiologic Studies Depression Index were used to measure fatigue and depression severity. The association between cytokine and symptoms was examined using logistic models.

Results: Among 101 analyzable patients, all ten cytokines/growth factors examined were highly elevated at baseline and all significantly decreased at week 4 (p<0.001) regardless of treatment intervention. At baseline, the odds of severe fatigue significantly increased for patients with higher level of interleukin-1 receptor antagonist (IL-1Ra), whereas patients with higher levels of IL-1Ra, tumor necrosis factor-α, interleukin (IL)-6, IL-8, interferon-γ, transforming growth factor α, and vascular endothelial growth factor had higher odds of severe depression. At week 4, fatigue (p=0.023) and depression (p=0.007) responders had less decrease in IL-1 level than the corresponding non-responders.

Conclusion: In this correlative analysis of a fatigue clinical trial, levels of fatigue were significantly associated with levels of IL-1 and IL-1Ra. Circadian-signaling pathways related to EGFR signaling were correlated with depression as were other cytokines. A major placebo effect was associated with a global decrease in cytokine and growth factors. These data provide further basis for testing hypotheses regarding the mechanisms of fatigue and depression in cancer patients.

Keywords: cancer; circadian-signaling pathways; depression; fatigue; placebo effect; proinflammatory cytokine.

Figure 1

CONSORT diagram.

Figure 2

Mean fatigue and depression levels at baseline and week 4. Notes: (A) Mean BFI scores for patients included in or excluded from the cytokine study. (B) Mean BFI scores by treatment arm in patients included in the cytokine study. (C) Mean CES-D scores for patients included in or excluded from the cytokine study. (D) Mean CES-D scores by treatment arm in patients included in the cytokine study. lb, Lower bound of 95% confidence interval; ub, upper bound of 95% confidence interval. Abbreviations: BFI, Brief Fatigue Inventory; CES-D, Center for Epidemiologic Studies Depression Scale.