Depression is consistently moderately associated with CRF. Anxiety is also an important correlate, though at a somewhat lower magnitude than depression. Taking into account the complex and multifactorial nature of fatigue, even moderate associations are impressive. These findings support the conclusions of previous reviews of psychological correlates of CRF(15
). Moreover, our systematic review included 59 studies which is nearly double that of the largest previous review of 30 studies (18
). The heterogeneity of the 59 studies, however, precludes specific conclusions about the directionality or mechanisms underlying the relationships among fatigue, depression, and anxiety. Furthermore, data on these constructs are inherently subjective and subject to recall bias, further limiting the potential for conclusive findings.
The consistent correlation between depression and CRF has raised questions about a common etiology. Jacobsen and Weitzner (15
) discuss three possible causal relationships: that fatigue causes the cancer patient to become depressed; that cancer patients may become fatigued because they are depressed; or a third factor may cause both depression and fatigue. Although the authors cited some supporting evidence for each of these possibilities, their findings were inconclusive. Depression is a predisposing factor for the development of chronic fatigue syndrome (78
), but CRF may have different mechanisms. Some studies suggest that fatigue and depression are independent conditions in cancer patients with patterns that differ over the disease course (72
). The subset of longitudinal studies in this review assessing fatigue, depression and/or anxiety at several time points provides additional support for an interdependence among these symptoms, though the mixed findings still do not provide definitive evidence for whether fatigue is a consequence of these psychological factors, a cause, or the product of a common pathway. The development of CRF may involve several physiological, biochemical, and psychological systems (79
) which in turn may vary by type of cancer, stage of disease, and type of treatment.
Further research with robust measures administered at multiple time points and more sophisticated statistical analyses such as times series or structural equation modeling might be informative. Also, translational research examining biological or physiological measures (e.g., cytokines, neuroimaging, etc.) might disclose both shared as well as disparate mechanisms underlying fatigue, depression, and anxiety. Control groups of noncancer populations (including healthy individuals), of individuals with fatigue or depression/anxiety only, or of patients with comorbid medical illnesses might further enrich our understanding of the fatigue-depression-anxiety relationship.
Intervention studies aimed at improving outcome variables that are correlated with CRF may also be helpful in teasing apart the interrelationships (7
). For example, an intervention that improves cancer-related depression could be evaluated in terms of its concomitant effect on fatigue. Conversely, interventions targeting fatigue could be analyzed for effects on depression and anxiety. Along those lines, Tchekmedyian and colleagues (2003)
found that improvements in fatigue in 250 lung cancer patients receiving darbepoetin alfa for treatment of anemia were associated with parallel reductions in depression and anxiety. In this type of research, it is critical to include elevated fatigue levels as an inclusion criterion.
Fewer studies have explored the relationship between anxiety and CRF and have often done so as an adjunct to investigating depression’s associations with CRF. In many studies that included both variables, depression and anxiety scores were reported as if operating as a cluster. A few studies found CRF associations that were specific to anxiety, however, such as the correlation of trait anxiety with CRF and the effects of baseline anxiety on later fatigue, depression or anxiety (38
). Moreover, our pooled results suggest anxiety is consistently associated with CRF. Thus, anxiety warrants inclusion as an important psychological variable in future CRF research.
The measurement challenges already described demand careful attention in future studies. The wide variety of measures that have been used to measure fatigue has been problematic. Research in this domain will benefit if the field of fatigue instruments is narrowed to a few that have been well-validated to accurately assess CRF and distinguish it from depression. Latent variable path analysis may be particularly useful in future research. In longitudinal studies, this structural equation modeling technique can support or disconfirm a priori
hypotheses about directionality of causal effects The procedure may reduce effects of measurement error by assessing multiple indicators of study constructs within a single analysis (80
In conclusion, cancer-related fatigue is an important and highly prevalent symptom that negatively affects cancer patient’s quality of life and therefore should be a high priority for treatment. Depression and anxiety are prominent among the correlates of CRF; however, the nature and direction of causality among these variables remains uncertain, despite a recent increase in research interest in this area. More longitudinal and/or intervention studies would be desirable, as well as a more uniform use of measures across multiple studies. Meanwhile, clinicians should screen for and treat the comorbid depression and anxiety that commonly accompany cancer-related fatigue.