Elevated Glutamate Levels May Be Biomarker For Severe Schizophrenia

Patients with worse schizophrenia symptoms have higher brain glutamate (Glu) levels, a new so-called mega-analysis of proton magnetic resonance spectroscopy (1H-MRS) studies suggest.

"Higher brain Glu levels may act as a biomarker of illness severity in schizophrenia," Dr. Kate Merritt of University College London and colleagues write in JAMA Psychiatry.

"These findings are consistent with previous research that glutamate levels are higher in treatment-resistant patients compared to treatment responders," she told Reuters Health by email. "This indicates that medications targeting glutamate may be beneficial in the subpopulation."

Meanwhile, lower-than-normal levels of glutamate seen in some patients "may be due to the effects of antipsychotic medication (as shown by our study), and/or they may be due to compensatory processes in the brain, both of which may be associated with better functional outcomes," Dr. Merritt added.

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She and her colleagues searched MEDLINE for studies published between 1980 and 2020 for terms that related to age, symptom severity, ability to function, and antipsychotic treatment with brain glutamatergic metabolites.

After collecting data from studies that measured glutamate levels in individual patients with schizophrenia, the authors analyzed 42 1H-MRS studies involving 1,251 participants who averaged around 30 years of age and 1,197 healthy volunteers with a mean age of 28 years.

The authors used linear mixed models to investigate links between glutamate, glutamate-plus-glutamine (Glx), or total creatine plus phosphocreatine levels, and age, symptom severity, antipsychotic medication dose, and functioning.

Glutamate levels (P=0.04) and Glx (P=0.02) levels in the medial frontal cortex were lower in patients than in healthy volunteers. Creatine levels appeared lower in patients, but not significantly so.

In patients and healthy volunteers, medial frontal cortex glutamate levels decreased similarly with age. Medial frontal cortex creatine also increased in both groups with age; among patients, this change over time was not linked with symptom severity or antipsychotic-medication dose.

Among patients, antipsychotic-medication dose was negatively linked with medial frontal cortex glutamate levels (SE, 0.03) and Glx (SE, 0.04).

Also among patients, the glutamate-to-creatine ratio in the medial frontal cortex was positively linked with total system severity (SE, 0.005). Medial temporal lobe Glx-to-creatine ratio was positively linked with total symptom severity (SE, 0.03).

Dr. Merritt noted that the study results are consistent with existing literature. "However," she added, "a shift in the field is the finding of lower glutamate levels in patients who are not treatment resistant."

"Although the literature contains a wealth of glutamate studies in schizophrenia, the results have appeared inconsistent, with some studies finding higher levels in patients and some finding lower levels," she explained. "Our study helps clarify this discrepancy, as the differing results are due to the impact of symptom severity (high Glu) and antipsychotic medication (low Glu)."

These findings may help doctors predict patient prognosis and enroll them in appropriate clinical trials of new drugs, she said. "For example, only patients with higher glutamate should receive a drug that tries to lower glutamate."

Dr. Carrie Bearden, a clinical psychologist at the University of California, Los Angeles, welcomed the study.

"What is really valuable about this study is that, as a mega-analysis, it combines individual subject data from lots of different small studies," she told Reuters Health by email. "So the conclusions are much more reliable than those from any individual study."

"This is, to my knowledge, the first mega-analysis of proton magnetic resonance spectroscopy studies," said Dr. Bearden, who was not involved in the study. "Results from individual studies are notoriously heterogeneous (i.e., messy), so it is very important to get a better sense of what the actual patterns are in patients with schizophrenia."

The study has limitations, according to Dr. Bearden. "Because it is a mega-analysis, this study is limited by the quality of the studies that are included. The data go back to 1980, and the methods in those earlier studies were much less advanced. Also, it is important to keep in mind that 1H-MRS does not directly measure glutamate, but glutamatergic metabolites in the brain, which are affected by many different things and are not very stable over time."

"The conclusion that higher brain glutamate may be a biomarker of illness severity only means that it is related to current symptom severity, not that it could be used predictively," she added.

In future research, Dr. Merritt would like to explore whether low glutamate levels confer good outcomes, or, if too low, they can be detrimental.

The study did not receive commercial support. Several of Dr. Merritt's coauthors report ties to drugmakers. Dr. Bearden stated that she has no conflicts of interest with the study.

—Lorraine L. Janeczko

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