MOODINFLAME

"Early diagnosis, treatment and prevention of mood disorders targetting the activated inflammatory response system"

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 Obiettivo del progetto (Objective)

'Partners come from 10 European countries to achieve two main objectives: A) The further exploration of 3 animal models (the OBX rat, GS rat and NOD mouse) characterized by an activated immune response system (IRS), an abnormal tryptophan catabolism and a depressive-like behaviour to study the pathogenesis of inflammation-related mood disorders and the efficacy/working mechanism of anti-inflammatory and tryptophan metabolism restoring drugs. B) The in-parallel study of mood disorder patients to validate two sets of already developed biomarker tests to identify patients and individuals at risk for a mood disorder and characterized by an activated IRS to be able to treat these patients/individuals with drugs counteracting the consequences of the activated IRS/disturbed catabolism of tryptophan. Five strategic approaches (broken down in 12 workpackages) are used: 1) Study of the animal models for depressive-like behavior and aberrancies in monocytes/ macrophages, the tryptophan metabolism and the microglia-astrocyte-neuron interaction. 2/3) The validation of a high-throughput biomarker mRNA blood monocyte signature test and a biomarker test to detect an abnormal tryptophan catabolism. 4) Correlation studies between the outcomes of these biomarker tests in patients to various clinical variables, a.o. gene polymorphisms and the brain scan. 5) The therapeutic targetting of the activated IRS/abnormal tryptophan catabolism using a PDE4 inhibitor, a COX-2 inhibitor and a KMO-inhibitor in the animal models and in a phase II intervention study in depressed patients. Novel approaches are the prospective assessment of patients/individuals to identify whether changes in the IRS have any prognostic value and that the program aims at a personalized treatment of patients on the basis of their activated IRS. We heavily rely in this on the study of the animal models, which allow us to test anti-inflammatory therapeutics and to know their mechanism of action at the brain.'

Introduzione (Teaser)

Accumulating evidence suggests that the neural and immune systems are tightly intertwined. With this mind, European researchers investigated the novel hypothesis that immune dysfunction could be the triggering event in mood disorders.

Descrizione progetto (Article)

An abnormal immune activation is emerging as central to the development of mood disorders. A chronic state of inflammation in certain brain areas involved in mood regulation could cause mood imbalance, as a result of hormonal or metabolic disturbance. For example, immune activation could impair the catabolism of tryptophan, an important precursor of the neurotransmitter serotonin.

The EU-funded http://moodinflame.eu/ (MOODINFLAME) study was designed to test the underlying hypothesis that many mood or psychiatric disorders are triggered by increased susceptibility to inflammation. Their objective was to study immune dysfunction in psychiatric patients and mouse models of disease and develop brain and blood scans for assessing immune dysfunction.

Large number of patient samples were analysed. Results linked mood disorder with increased numbers of monocytes expressing both pro- and anti-inflammatory genes as well as high levels of pro-inflammatory cytokines. All this data validated the overall immune dysfunction pattern in patients with mood disorders. Interestingly, an activated state of monocytes negatively determined the outcome of anti-depressant therapy.

Work in animal models of depressive-like behaviour further corroborated these findings. Animals exhibited activated inflammatory responses and an abnormal tryptophan metabolism. Scientists identified three major pathways that were implicated in the aberrant immune-endocrine interface. This abnormal communication led to structural and functional deficits of important brain regions.

Regarding therapeutic strategies, part of the MOODINFLAME work entailed the screening of various non-steroid anti-inflammatory drugs in the animal models. The PSYCH-AID project, which is an EU-funded continuation project of MOODINFLAME will continue the investigation of such drugs in patients with mood disorders.

Overall, the outcome of the study has the potential to change the way psychiatric disorders are treated. The generated diagnostic tools will be of enormous help down this path, facilitating the screening of patients with mood disorders for immune dysregulation.