Schizophrenic hippocampal abnormalities blamed on glutamate

By Eleanor McDermid, Senior medwireNews Reporter

Elevated glutamate levels correlate with reduced tissue volume in the hippocampus of patients with schizophrenia, a study shows.

The researchers found that, in mentally healthy people, glutamate levels were associated with the ratio of N-acetylaspartate (NAA) to creatine (Cr), which is a marker of neuronal integrity. But this association was absent in schizophrenia patients, suggesting an altered role for glutamate.

Researchers Adrienne Lahti (University of Alabama at Birmingham, USA) and colleagues previously found this effect in patients on stable medication, but the current study involved 27 patients who were not currently taking antipsychotics.

“The replication of this finding in unmedicated patients is important because it shows that it is not purely a phenomenon related to antipsychotic medications,” writes the team in JAMA Psychiatry. “It also confirms that it is not merely a reflection of illness severity because we found it in both stable and acutely ill patients.”

Five patients had first-episode psychosis, while the other 22 had an average illness duration of over 10 years; 11, in all, were treatment-naïve and the remainder had not taken antipsychotics for an average of 25 months. The researchers assessed the patients with magnetic resonance spectroscopy, measuring levels of glutamate plus glutamine (Glx) using a method that they say optimizes the glutamate signal and reduces the contribution of glutamine.

The patients had significantly increased hippocampal levels of glutamate, expressed as the ratio of Glx to Cr, relative to the controls. The ratio of NAA to Cr did not differ in patients and controls, but in the patients the Glx to Cr ratio was elevated relative to the NAA to Cr ratio.

In controls, the Glx to Cr ratio correlated with the NAA to Cr ratio, implying that glutamate is involved in healthy neuronal function. But this association was not present in the patients: instead, the Glx to Cr ratio rose with decreasing hippocampal volume. Overall, hippocampal volume (measured with structural magnetic resonance imaging) was significantly reduced in patients versus controls, as has been found in previous studies. It was most pronounced in the dentate gyrus.

Lahti et al say that elevated glutamate levels are thought to result in increased blood flow in the hippocampus, which has itself been linked to psychosis.

But they say: “Assuming elevated Glx/Cr to be excitotoxic, it is unclear why progressive hippocampal volume loss is not more pronounced over the course of the illness or to what extent antipsychotic medications may counteract the progression of volume loss.”

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