In recent decades, comprehensive evidence has accumulated that inflammation and microglia activation might be implied in the etiology of psychiatric disorders. The study of the activation state of microglia is based on the histological study of brains of deceased patients suffering from psychiatric disorders, leading to partial and biased data. The understanding of the role of microglia is yet crucial in order to develop innovative treatments. For example, ketamine has recently shown rapid antidepressant properties related to its activity of NDMA antagonism and its immunomodulatory properties.

In our work, we used a translational approach to find biomarkers of the activation state of microglia in psychiatric patients that can be determined during patient care.

First, in a murine model of LPS-induced depressive-like behavior, we observed that ketamine injection reversed the morphological microglial alterations and reduced microglial activation markers, such as quinolinic acid (QUIN) level in brain. Second, in 15 patients with treatment-resistant depressive episode, treated by a cycle of ketamine infusions (0.5mg/kg iv), we showed that the initial ratio of kynurenic acid (KYNA) to QUIN is a predictor of the antidepressant response (measured with the MADRS score) after ketamine infusion and at the end of the cycle (beta=0.28±0.07, P=0.0002 and beta=1.05±0.35, P=0.016 respectively). The variation in QUIN concentration after ketamine infusion is also a predictor of the change in MADRS score following this infusion (beta=0.35±0.14, P=0.015).

High concentrations of QUIN may then be a predictor of ketamine efficacy in patients with treatment-resistant depression and define a sub-group of patients who may have microglial alterations. This imbalance in kynurenine pathway may also be explored in other psychiatric disorders with inflammatory component and in patients with rare inflammatory diseases associated with psychiatric symptoms.