Hypermetabolism of the neurotransmitter glutamate may trigger schizophrenia — a finding that may have significant implications for early diagnosis and more effective treatment for schizophrenia and other psychotic disorders in at-risk individuals, new research suggests.
In a unique parallel clinical and animal imaging study, investigators at Columbia Medical Center in New York City found that hypermetabolism in the CA1 subregion of the hippocampus at baseline in humans predicted hippocampal atrophy, which occurred during progression to psychosis.
Using ketamine to model acute psychosis in mice, the researchers found a similar regional pattern of hypermetabolism and hippocampal atrophy.
"Taken together, these studies suggest that in schizophrenia and related psychotic disorders, hypermetabolism occurs before atrophy, that they are mechanistically linked, and...that the common mechanism is increases in extracellular glutamate," principal investigator Scott A. Small, MD, said in a video statement.
The study is published in the April issue of Neuron.
Spreading Pattern of Dysfunction
According to investigators, previous research has shown that schizophrenia and related psychotic disorders are characterized by 2 distinct characteristics in the brain — abnormal hippocampal hypermetabolism and atrophy.
Specifically, the researchers note that recent neuroimaging studies show the CA1 and subiculum regions of the hippocampus "are differentially affected in schizophrenia, as reflected by volume, shape, and metabolic measures."
However, said Dr. Small, what is not known is whether hippocampal atrophy and hypermetabolism are linked and, if so, by what common mechanism.
To address these questions, the investigators used functional magnetic resonance imaging to examine cerebral blood volume (fMRI-CBV) to map patterns of metabolism and structural MRI to map atrophy in the hippocampi of both humans and mice.
The clinical portion of the study included 25 patients who were at clinical high risk for progression to schizophrenia. All patients underwent imaging of the anterior hippocampus using enhanced MRI while experiencing prodromal psychotic symptoms and were then followed and reimaged at an average of 2.4 years. According to investigators, previous studies have shown that about 30% of patients with prodromal symptoms progress to psychosis.
Of the original 25 patients, 80% (20) underwent reimaging at clinical follow-up. During the follow-up period, 1 patient in the progressor group and 4 patients in the nonprogressor group were lost to brain imaging follow-up. However, the researchers report that none were lost to clinical follow-up.
A total of 10 patients progressed to psychosis, and 15 did not develop a psychotic disorder during the follow-up period. The researchers report there were no significant baseline differences between the 2 study groups with respect to age, education level, or follow-up interval.
The investigators found that patients who progressed to psychosis had focal hypermetabolism in the CA1 region of the hippocampus at baseline that spread to the subiculum and that these 2 abnormalities predicted hippocampal atrophy that occurred during progression to psychosis.
In an attempt to pinpoint the mechanism driving hypermetabolism and hippocampal atrophy, the investigators used the drug ketamine to model conditions of acute psychosis in mice to determine whether it would increase glutamate and drive hypermetabolism and hippocampal atrophy.
Ketamine, explained study investigator Holly Moore, PhD, is known to cause psychosis in humans, and it has also been shown to increase glutamate levels in the brain.
However, she said, it was not known what the drug would do to the hippocampus.
The researchers found that when glutamate activity was increased in the mouse model via administration of ketamine, it created the same pattern that was observed in humans — the hippocampus became hypermetabolic, and if the glutamate level was raised repeatedly, hippocampal atrophy occurred.
"What the mouse model showed us was that there is clearly a link between an excess of extracellular glutamate and hypermetabolism in the hippocampus, particularly in CA1 and subiculum, which are the areas that were most affected in schizophrenia.... It also showed that if you prevented excess glutamate...that you could prevent atrophy," Dr. Moore added.
Regulating glutamate through glutamate-reducing drugs such as gabapentin, lamotrigine, or the experimental compound LY404309 in high-risk individuals or those in the early stages of the disease may offer an effective treatment strategy, the authors note.
Theoretically, it may be possible to identify dysregulation of glutamate and hypermetabolism by imaging high-risk individuals or those in the early stages of the disease. Reducing glutamate in individuals with schizophrenia has been attempted in the past, but only in patients with advanced disease.
"Targeting glutamate may be more useful in high-risk people or in those with early signs of the disorder. Early intervention may prevent the debilitating effects of schizophrenia, increasing recovery in one of humankind's most costly mental disorders," study author Jeffrey Lieberman, MD, said in a release.
In an accompanying editorial, Bita Moghaddam, PhD, professor of neuroscience at the University of Pittsburgh, in Pennsylvania, agreed and noted that although reducing glutamate may not be helpful in chronically ill patients, it may be "a useful approach as a prevention strategy in individuals at high risk for schizophrenia."
The authors and Dr. Moghaddam report no relevant financial relationships.
Neuron. 2013;78:81-93. Full article, Editorial
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Cite this: Excess Glutamate May Trigger Schizophrenia - Medscape - Apr 24, 2013.