Progress in Neuro-Psychopharmacology and Biological Psychiatry
Review articleCytokines and major depression
Introduction
From a psychoneuroimmunological perspective, the brain is no longer regarded as an immunopriviliged organ that is separated entirely from circulating immune cells by the blood–brain barrier (BBB) and displays reduced or altered immune responsivity. In the last decades, it has become clear that many interactions occur between neural, immune and neuroendocrine systems (Fig. 1; Plaut, 1987, Felten and Felten, 1991, Cserr and Knopf, 1992, Ader et al., 1995, McGeer and McGeer, 1995).
The concept of bidirectional communication between the immune system and the central nervous system (CNS) has led to the question whether the immune system, besides playing a role in normally occurring brain–immune interactions, is also involved in neuropathological processes (Miller et al., 1999). One of the psychiatric disorders that is assumed to be related to changes in the functional activity of the immune system, is major depression. Dysregulation of the functional activity of the immune system in depression is a phenomenon that has been demonstrated numerous times (Kronfol et al., 1983, Irwin and Gillin, 1987, Maes, 1995, Maes, 1999, Nunes et al., 2002). In 1999, Maes proposed the ‘IRS model of major depression’, which implies that major depression is related to activation of the inflammatory response system (IRS). According to this model, major depression may be considered a psychoneuroimmunological disorder, in which peripheral immune activation, through the release of proinflammatory cytokines, is responsible for the variety of behavioural, neuroendocrine and neurochemical alterations that are associated with this psychiatric condition. Besides the ‘IRS model of major depression’, this assumption has also been expressed as the ‘macrophage theory of depression’ (Smith, 1991, Leonard and Song, 1999, Leonard, 2001) and the ‘cytokine hypothesis of depression’ (Yirmiya et al., 1999). In this review, the latter expression is used.
In the present review, the nature of the interactions between cytokines, the CNS and the endocrine system, through modulation of monoaminergic neurotransmission and regulation of the activity of the hypothalamic–pituitary–adrenal (HPA) axis, is discussed. The elicitation of certain behavioural characteristics by proinflammatory cytokines (the so-called ‘sickness behaviour’) is also considered, as these behavioural features resemble the symptoms of depression. In addition, putative mechanisms and pathways for the mode of action of central cytokines in major depression are suggested. Finally, the possible implications that the present model of aetiology and pathophysiology of major depression might have for cytokine treatment in (cancer and hepatitis C) therapies and the use of antidepressants, are mentioned.
Section snippets
Cytokines and neuroimmunology
Cytokines comprise a heterogeneous group of messenger molecules that are produced by immunocompetent cells, such as lymphocytes and macrophages, in order to regulate immune responses. Although their specific biological activities may vary, two general categories of cytokines can be distinguished, i.e. proinflammatory and anti-inflammatory cytokines (Table 1). The former group consists of cytokines that are directly or indirectly involved in inflammatory processes, such as interleukin (IL)-1,
Immune activation in major depression
Although major depression has been associated with ex vivo downregulated T and B cell proliferation as well as reduced natural killer (NK) cell activity (Kronfol et al., 1983, Irwin and Gillin, 1987), in vivo systemic activation of cell-mediated immune responses has been reported (Maes, 1995). Characteristics of immune activation in depressive illness include increases in the numbers of circulating lymphocytes and phagocytic cells upregulated serum levels of indicators of activated immune cells
Cytokines and monoaminergic disorders
Major depression is characterised by disorders in NA and 5-HT neurotransmission (Schildkraut, 1965, Ressler and Nemeroff, 1999, Ressler and Nemeroff, 2000, Dursun et al., 2001). It has been hypothesised that immune activation may be causally related to these signalling disorders, as proinflammatory cytokines have been implicated in alterations in NA and 5-HT turnover in brain regions assumed to be involved in major depression, including the hypothalamus, hippocampus, amygdala and prefrontal
Antidepressants: do these drugs exert immune effects?
The cytokine hypothesis of depression suggests a key role for cytokines in the mediation of the pathophysiological characteristics of major depression. From this perspective, it is tempting to assume that the efficacy of antidepressants in the treatment of depressive disorders may, at least in part, rely on downregulation of proinflammatory cytokine synthesis. But do antidepressants indeed exert immunomodulatory effects?
Although it is well established that antidepressants are effective in
The cytokine hypothesis of depression: a critical discussion
In the present review, the ‘cytokine hypothesis of major depression’ has been elaborated. Various aspects concerning the assumed links between depressive illness and cytokine production have been discussed. Although accumulating evidence supports a role for immune activation, through the production of proinflammatory cytokines, in the aetiology and pathophysiology of depression, the cytokine hypothesis of depression is still debatable.
Conclusion
At present, despite the accumulating evidence in support of the ‘cytokine hypothesis of depression’, the exact role of cytokines in the mediation of depressive symptomatology remains to be identified. The question whether cytokines are causally involved in the aetiology of depression or represent immunological side effects of this disease, so far remains unsolved. In order to elucidate the functional role of low concentrations of cytokines on the onset and the duration of major depression, the
Acknowledgments
The authors would like to thank Brian Leonard for his critical remarks and helpful suggestions on earlier versions of this work.
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