In the context of immunopsychiatry it is important to know whether the association between psychiatric disorders and the immune system that is reported in more and more scientific publications is a real one or just another manifestation of the many comorbid physical conditions that are affecting psychiatric patients. In the case this association is real, the next question is whether the reported alterations in immunity are causal to the psychiatric disorder or just one of its consequences, in the form for instance of the impact of unhealthy lifestyles on the microbiota. Causality, when it exists, provides a unique opportunity to identify new mechanistic targets for drug development. The observation of consistent immune alterations in psychiatric patients also leads to the important interrogation of their functional outcome on the organism resistance to infection or the progression of somatic diseases such as cancer and autoimmunity.

The possibility that inflammation plays a major role in the symptoms of sickness and depression experienced by cancer patients was initially proposed by a group of investigators led by Charles Cleeland, one of the editors of this book. The authors' reasoning was based on analogies. Laboratory animals injected with proinflammatory cytokines, or with cytokine inducers such as lipopolysaccharide, develop striking signs of sickness characterized by pain, wasting, cognitive impairment, anxiety, and fatigue. The same symptoms are observed in many patients with cancer and are exacerbated during inflammation-inducing cancer treatments, such as chemotherapy and radiotherapy. In addition, cancer patients subjected to long-term immunotherapy with interferon (IFN)-α and/or interleukin (IL)-2 for the treatment of metastatic kidney cancer or metastatic melanoma rapidly develop symptoms of sickness that can culminate in true depressive disorders. Since Cleeland's seminal paper was published, many studies have confirmed that nonspecific symptoms such as fatigue, even in long-term cancer survivors, are associated with inflammatory biomarkers and cannot be explained away solely as psychological difficulties related to coping with a diagnosis of cancer or living with the disease. A recent review paper confirmed the plausibility of the relationship between inflammation and the behavioral comorbidities experienced by patients with cancer and pointed to the pivotal role of neuroendocrine-immune mechanisms in this relationship.

The objective of this chapter is to discuss the neuroimmune mechanisms that are likely to be responsible for the development of symptoms of sickness and depression in patients with cancer.

I feel sick. What is usually meant by this deceptively simple statement? The non-specific symptoms of infectious diseases include profound behavioral and psychological changes. Sick individuals are febrile, hypersomnia depressed and lethargic. In addition, they experience malaise, generalized aches and pains, an inability to concentrate, loss of appetite, and a lack of interest in usual activities, including social contacts and sex. This constellation of non-specific symptoms is collectively referred to as 'sickness behavior’ (Hart, 1988; Kent et al., 1992a). Regardless of, or perhaps more precisely, because of their commonality, they are frequently ignored by physicians because they contribute little in facilitating a diagnosis. In fact, they are more often considered as an uncomfortable, but generally banal, part of the pathogen-induced debilitative process. Their commonality and their evolutionary conservation, however, suggest other reasons for their presence.

Fever, for example, is not merely a symptom but is an adaptive response that enables a host to defend itself against, and survive, infection by a pathogen. It is an evolutionary response that has now been demonstrated in fish, reptiles, and even invertebrates, such as mollusks and insects (for a review, see Kluger, 1991). The medical dogma of the twentieth century has suggested that fever should be prevented; however, strong evidence now suggests otherwise. Preventing the manifestation of fever in poikilothermic animals by placing them in a cool environment, or in homeostatic animals by the administration of prostaglandin (PG) synthesis inhibitors, is detrimental to their survival (for a review, see Kluger, 1991). Although, for the most part, experimental evidence is lacking, arguments can also be made for the contribution of sickness behavior to the survival of infected organisms (Hart, 1988). Recent evidence is that these non-specific symptoms are induced and controlled by the proinflammatory cytokines released by an activated immune system, and that they play a role in the recuperative process. This review focuses on the role of the central nervous system in regulating sickness behavior.

Communication between the immune and central nervous systems The cells of the immune system release a plethora of soluble factors in response to infection, tissue injury, neoplastic growth, or immunological disorders. The principal proinflammatory compounds are the cytokines, interleukin (IL)-l, IL-6, tumor necrosis factor alpha (TNF-a), and the interferons (IFN).