What are the causal relationships between fatigue and depression

As noted earlier, there is considerable evidence that levels of fatigue and depression correspond in cancer patients. At least three different causal relationships can be theorized to explain this correspondence. One possibility is that the fatigue produced by cancer and its treatment may result in patients becoming depressed. A second possibility is that fatigue may develop in cancer patients as a consequence of their being depressed. Yet a third possibility is that no causal relationship exists; instead, the correspondence may reflect the presence of a third factor that is the cause of both fatigue and depression in patients with cancer. As will be shown, there is evidence to suggest the existence of each of these mechanisms.

Two lines of research provide support for the view that cancer patients can become depressed as a consequence of experiencing disease-related or treatment-related fatigue. One line of research consists of reports indicating that patients perceive disease-related or treatment-related fatigue as having adverse effects on their mood. For example, women undergoing bone marrow transplantation for breast cancer have been found to report more severe fatigue and greater interference of fatigue with their mood than a comparison group of women with no history of cancer (Hann et al. 1999). Differences between groups on these measures were evident only after the breast cancer patients had started treatment. A second line of evidence consists of research examining whether, over the course of cancer treatment, fatigue predicts subsequent depression better than depression predicts subsequent fatigue. Of particular relevance is a study in which fatigue and depression were assessed before the start of radiotherapy treatment and again 2 weeks after completion of treatment (Visser and Smets 1998). Pretreatment fatigue severity was found to account for 11% of the variability in subsequent depressed mood whereas pretreatment depressed mood accounted for only 4% of the variability in subsequent fatigue severity. Additional supportive evidence comes from a study that examined relations between psychiatric disorder (that is, mood, anxiety, and adjustment disorders) and fatigue in women previously treated with adjuvant chemotherapy for breast cancer (Broeckel et al. 1998). The presence of a psychiatric disorder prior to cancer diagnosis was not related to fatigue severity following chemotherapy treatment; in contrast, more severe fatigue following chemotherapy treatment was related to the concurrent presence of a psychiatric disorder.

The possibility that cancer patients may develop fatigue as a consequence of being depressed is intuitively obvious. Actually demonstrating this relationship represents a methodological challenge, since most cancer patients can also develop fatigue as a consequence of their disease or its treatment. There is, however, indirect evidence to support the possibility that fatigue in cancer patients may occur as a consequence of depression. Research has shown that patients with a prior history of depression are more likely to develop mood disorders following the diagnosis of cancer (Leopold et al. 1998).

Evidence indicating that these patients also experience worse fatigue than patients without mood disorders would be consistent with the possibility that fatigue can occur as a consequence of depression. Another indirect piece of evidence consists of reports indicating that reliance on specific forms of coping characteristic of depressed individuals is related to fatigue severity in cancer patients. For example, among women with breast cancer previously treated with chemotherapy, greater reliance on catastrophizing (a coping strategy characterized by negative self-statements and overly negative thoughts about the future) was found to be associated with more severe fatigue (Broeckel et al. 1998). Greater reliance on this coping strategy has also been shown to be related to higher levels of depressive symptomatology in breast cancer patients (Jacobsen et al. 1999).

There is considerable evidence to suggest that the correspondence between fatigue and depression in cancer patients may be due to their causal relationship to a third factor. Along these lines, attention has focused on certain cancers that are believed to cause depressive symptoms. Pancreatic cancer is one neoplasm that appears to display these characteristics. The prevalence of depression-related disorders among patients with pancreatic cancer is estimated to be as high as 71% (Green and Austin 1993). Moreover, numerous reports have documented the presence of depressive symptoms in patients before their pancreatic cancer was diagnosed (Joffe et al. 1986; Holland et al. 1986; Kelsen et al. 1995). Recent physiological findings provide further evidence of a causal link between pancreatic cancer and depression. Pancreatic tumours have been shown to secrete various neuropeptides and neurohormones, such as adrenocor-ticotropic hormone (ACTH) and cortisol (Raddatz et al. 1998; Drake et al. 1998). These findings are consistent with a wealth of data showing that hypercortisolaemia, as evidenced by non-suppression of cortisol after dexamethasone administration, is associated with major depressive disorder (Geffken et al. 1998). Pancreatic tumours have also been shown to secrete calcitonin. These secretions can result in hypercalcaemia (Sugimoto et al. 1998; Fleury et al. 1998), a condition characterized by prominent symptoms of lethargy and fatigue (Hutto 1998). In addition, there is evidence that pancreatic tumours also secrete growth hormone (Kawa et al. 1997; Losa and von Werder 1997), another substance known to be associated with increased depressive symptoms (Geffken et al. 1998).

Certain forms of cancer treatment may also be a direct cause of both fatigue and depression. Along these lines, attention has focused on biological response modifiers such as the interferons and the interleukins. These agents are used increasingly to treat a variety of cancers, including renal cell cancer and melanoma, and to control chronic myelogenous leukaemia. Administration of supraphysiological doses of these substances has been shown to be associated with prominent depressive symptoms, including fatigue (Valentine et al. 1998; Licinio et al. 1998; Meyers 1999). The occurrence of these psychiatric side-effects is consistent with research showing that elevated levels of both interferons and interleukins are present in psychiatric patients with major depressive disorder (Maes et al. 1995a,b; Anforth et al. 1998; Anisman et al. 1999; Licinio and Wong 1999).

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