Review
Inflammation-associated depression: From serotonin to kynurenine

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Summary

In the field of depression, inflammation-associated depression stands up as an exception since its causal factors are obvious and it is easy to mimic in an animal model. In addition, quasi-experimental studies can be carried out in patients who are treated chronically with recombinant cytokines for a medical condition since these patients can be studied longitudinally before, during and after stimulation of the immune system. These clinical studies have revealed that depression is a late phenomenon that develops over a background of early appearing sickness. Incorporation of this feature in animal models of inflammation-associated depression has allowed the demonstration that alterations of brain serotoninergic neurotransmission do not play a major role in the pathogenesis. This is in contrast to the activation of the tryptotphan degrading enzyme indoleamine 2,3-dioxygenase that generates potentially neurotoxic kynurenine metabolites such as 3-hydroxy kynurenine and quinolinic acid. Although the relative importance of peripherally versus centrally produced kynurenine and the cellular source of production of this compound remain to be determined, these findings provide new targets for the treatment of inflammation-associated depression that could be extended to other psychiatric conditions mediated by activation of neuroimmune mechanisms.

Section snippets

From depression to animal models of depression

Venturing into the field of depression is akin to an adventure into the unknown. Depression by itself is not a disease sensu stricto since its etiology and mechanisms have not yet been elucidated. In addition, depression is not associated with any characteristic structural alteration (despite the emphasis on possible hippocampal atrophy), and there is no biomarker of depression (in particular escape from the dexamethasone suppression test is not a consistent feature). Depression is therefore

Inflammation-associated depression—human studies

The possibility that depression is not just a disorder of the mind but rather a consequence of physical illness has haunted medicine for a long time. Melancholia, an extreme form of depression, was originally supposed to be caused by an imbalance in the four humors that control emotions, in this case an excess of black bile as its etymology refers to. In modern literature, black bile has been replaced by cortisol of which the brain effects are studied by a myriad of researchers throughout the

Cytokines and depression—animal studies

Because of the overwhelming evidence that treatment of patients with IFNα can cause depression in humans, the effects of this cytokine have also been studied in mice and rats. The problem is that recombinant mouse or rat IFNα has not been readily available so that most researchers have used recombinant human IFNα. However, it is well known that human IFNα is not biologically active in the mouse or rat system because it lacks a consensus sequence. As could have been expected, pegylated human

Depression and activation of the kynurenine pathway—back to the clinics

As already mentioned, the first clinical studies on the relationship between immune-mediated activation of the tryptophan degradation pathway and depression focused on the possible negative consequences of lowered tryptophan levels on brain serotoninergic neurotransmission. This hypothesis was formalized in a review paper published by the Fuch's group in 2002 (Widner et al., 2002). However, the prediction that decreased circulating tryptophan negatively impacts on brain tryptophan and serotonin

Conclusions

The use of animal models for studying inflammation-associated symptoms of depression is plagued with many difficulties, including the lack of a real animal model of depression and the huge confounding intervention of performance factors that are sensitive to sickness behavior. In addition, it should not be forgotten that depression remains a condition that is exclusively defined by a list of obligatory and facultative symptoms, and for which the causal factors remain unknown.

It might appear

Conflict of interest

Robert Dantzer has received honorarium from Astra-Zeneca, Bristol-Myers-Squibb and Lundbeck and is currently working as a consultant for Lundbeck laboratories. Keith W. Kelley has received honorarium from Astra-Zeneca.

Acknowledgements

Supported by grants from the National Institutes of Health to RD (MH 079829 and MH 71349) and KWK (MH 51569 and AG 029573).

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