ReviewInflammation-associated depression: From serotonin to kynurenine
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 In modern literature, black bile has been replaced by cortisol of which the brain effects are studied by a myriad of researchers throughout the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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