Glutamate Could Play Pivotal Role in Schizophrenia

Could the neurotransmitter glutamate, not dopamine, be the major neurotransmitter culprit in schizophrenia? In other words, might glutamate damage the brain and then involve the neurotransmitter dopamine, which has been strongly implicated in schizophrenia?

Quite possibly, a study reported in the June American Journal of Psychiatry suggests. Glutamate levels were found to be significantly higher in the brains of teens at high genetic risk for schizophrenia than in the brains of teens not at such risk.

The study was headed by Philip Tibbo, M.D., an assistant professor of psychiatry at the University of Alberta in Edmonton, Canada.

Tibbo and his coworkers used a technique called 3-T proton magnetic resonance spectroscopy (H-MRS) to measure glutamate levels in the brains of 20 adolescents at high genetic risk for schizophrenia because they had a parent with schizophrenia, as well as in the brains of 22 teens without such genetic risk. The region of the brain chosen for glutamate assessment was the medial prefrontal cortex, because it receives glutamate inputs from the thalamus, as well as from other brain regions that have shown structural abnormalities in schizophrenia.

Glutamate levels were found to be significantly higher in the medial prefrontal cortex of the teens at high genetic risk for schizophrenia than in the teens not at such risk.

The finding supports the hypothesis that “glutamate system dysfunction may play a role in neuroarchitectural abnormalities seen in schizophrenia...,” Tibbo and his team concluded.

These results do not have practical implications for clinical psychiatrists at this time, Tibbo told Psychiatric News. In other words, psychiatrists cannot put teens at genetic risk for schizophrenia in an H-MRS scanner to see whether they have abnormally high levels of glutamate in their brains. However, it may eventually be possible to do so “if techniques improve and [glutamate] correlations are made with cognitive tests,” Tibbo said.

In fact, he added, “I am currently writing a manuscript that has results from this same group two years later.... It indicates that changes in glutamate over time correlate with results on cognitive testing.”

Still other evidence beside that of Tibbo and his colleagues has been building for the hypothesis that glutamate plays a notable role in schizophrenia. For instance, three proteins are used for reuptake of glutamate by brain neurons. Greater genetic expression for two out of three of the proteins has been found in postmortem thalamus tissue taken from schizophrenia patients than in postmortem thalamus tissue taken from healthy control subjects (Psychiatric News, September 21, 2001).

The study was funded by the National Alliance for Research on Schizophrenia and Affective Disorders.

The study, “3-T Proton MRS Investigation of Glutamate and Glutamine in Adolescents at High Genetic Risk for Schizophrenia,” is posted online at<http://ajp.psychiatryonline.org/cgi/content/abstract/161/6/1116>.▪

Am J Psychiatry 2004 161 1116