The glutamate system as a therapeutic target and impact of genes on suicidality

Excerpt

Based on the fact that antagonists at the glutamatergic N-methyl-d-aspartate (NMDA) receptor cause psychosis, a dysfunction of the glutamate system has been proposed to play a role in schizophrenia and major depression. In a detailed review, Hashimoto et al. [1] compared schizophrenia add-on treatments with glycine, d-serine, d-alanine, d-cycloserine, d-amino acid oxidase inhibitors and recently glycine transporter inhibitors as well as modulators of group II metabotropic glutamate receptors, which have shown to improve function of the NMDA receptor and exert effects on negative symptoms and cognition. In depression, an overactive glutamate system has been suggested due to magnetic resonance spectroscopy (MRS) studies reporting increased levels of glutamine/glutamate in the frontal and occipital cortex. Concordantly, NMDA receptor antagonists, partial antagonists at the glycine site of the receptor, metabotropic glutamate receptor (mGluR) 2/3 and mGluR5 allosteric modulators have been proven to be effective in animal models and first clinical trials. In the need of innovative treatment approaches in major psychiatric disorders, such investigations should be encouraged and may lead to new add-on therapeutic strategies. A dysregulation of the glutamate system has been implicated in autism as well. In a MRS study at 4 Tesla measuring glutamate levels more accurately, Joshi et al. [2] compared patients suffering from autistic disorder to healthy controls. They found higher glutamate levels in the anterior cingulate cortex and a similar trend in the right medial temporal lobe in autism, indicating higher glutamate activity in these patients. Since many risk genes are targeting the glutamate system, in larger study effects of polymorphisms should be investigated. …