Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways

The first inkling that there are phenomenological similarities between clinical depression and sickness behavior and that both conditions may share common pathways, that is, activation of the inflammatory responses system (IRS) was published in 1993 [1,2]. Sickness behavior is a behavioral complex that is typically induced by acute infections and tissue injury in many mammalian species. The characteristic behavioral pattern consists of malaise, hyperalgesia, pyrexia, listlessness and disinterest in social interactions with the environment, lethargy, behavioral inhibition, reduction of locomotor activity, exploration and grooming, reduction of reproductive performance, anhedonia, somnolence and sleepiness, anorexia and weight loss, failure to concentrate, and anxiety. There is evidence that sickness behavior is mediated through the effects of pro-inflammatory cytokines (PICs), such as IL-1, TNFα and IL-6 [3-10]. In this context, there is abundant evidence that clinical depression is an immuno-inflammatory disorder characterized by among other things increased levels of PICs and acute phase proteins, including C-reactive protein and haptoglobin [11-20].Characteristic symptoms of major depression include anorexia, weight loss, fatigue, lethargy, sleep disorders, hyperalgesia, reduction of locomotor activity, and failure to concentrate (American Psychiatric Association). Moreover, 'vegetative symptoms' of depression, such as anorexia, weight loss, and psychomotor retardation, are significantly associated with inflammatory markers in clinical depression, such as increased levels of plasma haptoglobin, an acute phase protein, synthesis of which is induced by the three abovementioned PICs [1,2].Thus, it may be concluded that there are striking behavioral and inflammatory similarities between both sickness behavior and clinical depression [1,2,11]. Therefore, some authors regard clinical depression as a form of sickness behavior and/or as a consequence of the sickness behav