Cytokine-induced changes in mood and behaviour: Implications for 'depression due to a general medical condition', immunotherapy and antidepressive treatment

Several lines of evidence indicate that cytokine-mediated communication pathways between the immune system and the brain are involved in the pathophysiology of depression: (1) Depression is highly prevalent in various medical conditions, including infectious, autoimmune and neurodegenerative diseases. This clinical association cannot be attributed solely to psychological distress, and it probably reflects direct activation of illness-induced physiological processes. (2) Experiments in humans and in animals demonstrate that exposure to cytokines induces depressive-like mood and behavioural alterations. (3) Cytokine immunotherapy in cancer and hepatitis patients elicits a major depressive episode in a large percentage of the patients. (4) Several types of depression that are not directly associated with a physical disease (e.g. major depression, melancholia, dysthymia) were also associated with cytokine hypersecretion. (5) Antidepressant drugs possess anti-inflammatory characteristics, which may partly account for their therapeutic effect. Congruently, antidepressants were found to reverse cytokine-induced major depression in humans and depressive-like behaviours in animals. (6) Cytokines affect brain systems that were implicated in the aetiology of depression, including the hypothalamus-pituitary-adrenal axis and monoaminergic systems. These conclusions strongly suggest that during medical conditions elevated levels of cytokines directly contribute to the induction of depression. Therefore, illness-associated depression should not be underestimated (in terms of prevalence and severity), and should be treated with antidepressant drugs, which may act on the specific physiological mechanisms of this disorder.