One-third of patients with schizophrenia do not respond to standard dopamine targeting drugs, so dopamine is clearly not the only neurochemical involved in the pathophysiology of psychosis,1 said Dr Katherine Beck, Kings College London, UK.
It is hypothesized that N-methyl-D-aspartate receptor hypofunction plays a role in psychosis
A role for glutamate
A role for glutamate in the pathophysiology of psychosis is supported by altered brain glutamate levels2,3 and genetic, postmortem, and imaging evidence of N-methyl-D-aspartate (NMDA) receptor hypofunction,4–6 explained Dr Beck.
Furthermore, a systematic review and meta-analysis has shown that transient psychotic symptoms are induced across all Positive and Negative Syndrome Scale (PANSS) domains by the NMDA receptor antagonist, ketamine.7
Is there a link between N-methyl-D-aspartate receptor hypofunction and increased glutamate levels?
There therefore seems to be a link between NMDA receptor hypofunction and increases in glutamate levels, said Dr Beck, and one psychosis model proposes that striatal dopaminergic hyperfunction is driven by the hippocampus and that glutamate is critical in this process.8
N-methyl-D-aspartate receptor availability in first-episode psychosis
Dr Beck and her colleagues investigated the availability of NMDA receptors in 21 patients with first-episode psychosis (FEP) and 19 matched healthy controls.
Hippocampal distribution volume ratio of the ligand was significantly lower in patients with first-episode psychosis than in healthy controls
They used [18F] positron emission tomography–magnetic resonance (PET-MR) imaging with an NMDA receptor selective ligand that binds to the ketamine binding site and evaluated its distribution volume ratio (DVR) and volume of distribution (VT).
The results revealed that hippocampal DVR of the NMDA receptor selective ligand, but not VT, was:
- Significantly lower in patients with FEP than in healthy controls
- Negatively associated with total, depressive and general symptom severity.
The results support a role for hippocampal N-methyl-D-aspartate receptor hypofunction in psychosis pathophysiology
No significant differences were found in other brain regions, said Dr Beck.
These results support the NMDA receptor hypofunction hypothesis in the pathophysiology of psychosis and indicate that the hippocampus is a key location for NMDA receptor hypofunction.