CNS Drug Discovery and Therapy (Track)

In vivo cerebral glutamate monitoring in schizophrenia: Glutamate normalization in response to NMDA-receptor antagonist

J Gallinat
Charité University Medicine, St. Hedwig-Krankenhaus, Department of Psychiatry and Psychotherapy, Große Hamburger Strasse 5-11, 10115 Berlin, Germany

Abstract:

Introduction: A dysfunctional cerebral glutamate system in schizophrenia is a current hot spot of neurobiological research [1] and several glutamate modulating therapeutics are in phase I and II trials. Improved proton magnetic resonance spectroscopy (H-MRS) with increasing field strength [2] allows the assessment of biological effect of glutamate modulating agents during therapy.

Methods: In a RCT, 17 acute and 13 chronic schizophrenic patients (DSM-IV) on stable risperidone therapy were measured with H-MRS at baseline and after 6 weeks (T2) of add-on of memantine or placebo. Absolute glutamate concentrations [3] were measured (left hippocampus, cingulate).

Results: At baseline, patients showed increased hippocampal glutamate concentrations (11.9mmol/l vs 10.7mmol/l in healthy controls, p=0.007; Figure). After therapy glutamate decreased in acute schizophrenics (p=0.023), but remained unchanged in chronic patients (p=0.45). The differential effect of memantine/placebo will be presented at the conference after unblinding.

Discussion: The study shows abnormal glutamate concentrations in a key region of schizophrenia pathophysiology. The normalization of glutamate during add on therapy may rely on modulation of the NMDA-receptors in response to memantine. The results indicate a different pathobiology between acute and chronic patients and favor H-MRS as an interesting in-vivo tool for biological monitoring of glutamate functions.