Although fatigue has been the focus of a substantial amount of research, it generally remains an elusive concept to grasp. However, one of the most consistent findings in research on fatigue has been the strong relationship it has with common psychiatric symptoms, and depression in particular. ^{Reference Afari and Buchwald1,Reference Skapinakis, Lewis and Mavreas2} The association between fatigue and depression holds across different healthcare settings and populations, from community samples to those in specialist care. ^{Reference Skapinakis, Lewis and Meltzer3} In this issue of the Journal, Ball et al ^{Reference Ball, Sumathipala, Siribaddana, Kovas, Glozier and McGuffin4} report on a population-based twin study conducted in Sri Lanka which aimed to assess the prevalence and aetiology of fatigue and its overlap with depression. Before considering their interesting results, I will touch upon some issues relating to fatigue and its relationship with depression.

Co-occurrence and impairment

An important reason to try to understand and disentangle the relationship between fatigue and depression concerns the functional impairment that is associated with their co-occurrence. Chronic fatigue and chronic fatigue syndrome (CFS) are associated with considerable functional impairment and disability be it in a social, physical or occupational sense. ^{Reference Ross, Estok, Frame, Stone, Ludensky and Levine5,Reference Cairns and Hotopf6} However, the co-occurrence of chronic fatigue or CFS with psychiatric symptoms such as depression is associated with greater functional impairment than when it occurs alone. The presence of psychiatric symptoms in individuals with chronic fatigue or CFS has also been found to be predictive of a poor outcome in terms of fatigue complaints as well as impairment. ^{Reference Cairns and Hotopf6}

Relationship between fatigue and depression

Fatigue, in the same way as depression, can be defined in broad or narrow terms according to severity, duration and additional criteria (e.g. somatic symptoms, disability). The narrowest definitions being those for the syndromes or illnesses related to these symptoms: CFS and major depressive disorder respectively. Different studies use different definitions and it is sometimes argued that the use of stricter definitions for fatigue will reduce the overlap between fatigue and depression. However, empirical evidence suggests that the association between fatigue and depression becomes larger when a narrower, more exclusive definition for fatigue is used as opposed to a broader definition. ^{Reference Skapinakis, Lewis and Mavreas2}

The overlap in occurrence and symptoms between chronic fatigue/CFS and depression has led some to suggest that they are merely a form of depression. Research on CFS suggests that these conditions can be distinguished from each other in several ways. Importantly, they do not always co-occur. Despite the overlap in some symptoms there are also differences. Typically, central features of depression such as issues of guilt and self-esteem do not fit the phenomenology of CFS. ^{Reference Afari and Buchwald1} Moreover, some biological differences have been observed, most notably the (reversed) regulation of the hypothalamic–pituitary–adrenal (HPA) axis associated with these conditions: a down-regulation of the HPA axis has been noted in CFS, whereas an up-regulation of the HPA axis has been noted in depression. ^{Reference Parker, Wessely and Cleare7} Twin studies have shown that fatigue seems to have genetic and environmental risk factors that are independent from psychiatric symptoms. ^{Reference Hickie, Kirk and Martin8} Additionally, a recent cohort study found different and specific risk factors for fatigue with psychiatric comorbidity (e.g. family history of psychiatric disorder) and fatigue without psychiatric comorbidity (e.g. having excessive energy as a child). ^{Reference Harvey, Wessely, Kuh and Hotopf9}

So what comes first: fatigue or depression? Unfortunately the results are equivocal. There is evidence to suggest that depression may predispose individuals to subsequent fatigue. ^{Reference Harvey, Wadsworth, Wessely and Hotopf10} On the other hand, fatigue and depression have been found to predict and influence each other in time. ^{Reference Huibers, Leone, van Amelsvoort, Kant and Knottnerus11,Reference Skapinakis, Lewis and Mavreas12} It has also been suggested that their association could partly be due to some common risk factors that give rise to both. ^{Reference Skapinakis, Lewis and Mavreas12} For some, fatigue will come first; for others, depression will come first, but for most it will probably be unclear. As mood and fatigue seem to be so intertwined and the underlying mechanism remains relatively unknown, it will be difficult to identify what comes first until we understand how fatigue and mood are related to each other.

Conclusions

Fatigue is a complex concept that continues to challenge researchers and practitioners alike. Its relationship with depression and functional impairment is a complex one, but an important one to untangle nonetheless. Moreover, Ball et al's study ^{Reference Ball, Sumathipala, Siribaddana, Kovas, Glozier and McGuffin4} is an example of the emerging evidence that chronic fatigue and its association with functional impairment – especially when it co-occurs with depression – is not merely a ‘Western’ problem, but rather a global one.

In their review, Ross et al ask the question whether patients with CFS may be served better by focusing less on the medical mystery and more on the functional consequences. ^{Reference Ross, Estok, Frame, Stone, Ludensky and Levine5} Preventing and treating the primary problem of chronic fatigue is naturally an important objective and it follows that unravelling the mystery of how fatigue develops and how it becomes associated with depression remains an important focus of research. However, because of the level of disability associated with chronic fatigue (with and without depression), focusing on the nature, identification and treatment of functional impairment at different stages in the course of fatigue could possibly help to reduce the impact that chronic fatigue has on the lives of those suffering from it.