Hippocampal N-methyl-D-aspartate receptor hypofunction in first-episode psychosis pathophysiology

Lower N-methyl-D-aspartate receptor availability in the hippocampus compared with other brain regions in patients with first-episode psychosis supports a role for N-methyl-D-aspartate receptor hypofunction in the pathophysiology of psychosis and indicates that the hippocampus is a key location. These were the findings of an imaging study presented at EPA 2022.

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.

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.

  1. Beck K, McCutcheon R, Stephenson L, et al. Prevalence of treatment-resistant psychoses in the community: A naturalistic study. J Psychopharmacol. 2019;33(10):1248–53.
  2. Merritt K, Egerton A, Kempton MJ, Taylor MJ, McGuire PK. Nature of glutamate alterations in schizophrenia. JAMA Psychiatry. 2016;73:665–74.
  3. Nakahara T, Tsugawa S, Noda Y, et al. Glutamatergic and GABAergic metabolite levels in schizophrenia-spectrum disorders: a meta-analysis of 1H-magnetic resonance spectroscopy studies. Mol Psychiatry. 2022;27(1):744–57.
  4. Ripke S, Walters J, O’Donovan M. Mapping genomic loci prioritises genes and implicates synaptic biology in schizophrenia. medRxiv 2020.09.12.20192922; doi: https://doi.org/10.1101/2020.09.12.20192922
  5. Rubio MD, Drummond JB, Meador-Woodruff JH. Glutamate receptor abnormalities in schizophrenia: implications for innovative treatments. Biomol Ther. 2012;20:1–18.
  6. Pilowsky LS, Bressan RA, Stone JM, et al. First in vivo evidence of an NMDA receptor deficit in medication-free schizophrenic patients. Mol Psychiatry. 2006;11:118–19.
  7. Beck K, Hindley G, Borgan F, et al. Association of ketamine with psychiatric symptoms and implications for its therapeutic use and for understanding schizophrenia: a systematic review and meta-analysis. JAMA Netw Open. 2020;3(5):e204693.
  8. Egerton A, Grace AA, Stone J, et al. Glutamate in schizophrenia: Neurodevelopmental perspectives and drug development. Schizophr Res. 2020;223:59–70.
  9. Beck K, Arumuham A, Veronese M, et al. N-methyl-D-aspartate receptor availability in first-episode psychosis: a PET-MR brain imaging study. Transl Psychiatry. 2021;11(1):425.
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