Regulating Glutamate May Help Early Detection of Schizophrenia, Study Finds

May 20, 2013

In a recent study conducted at Columbia University Medical Center and published in the journal Neuron, researchers followed a group of 25 young people who were at risk for schizophrenia to see what happens to their brains as they develop the disorder. They also used a mouse model to look at the effects of glutamate on the brain during acute psychosis. Their findings suggest that an excess level of the brain neurotransmitter glutamate may be what triggers the transition to psychosis.

According to senior author Scott Small, M.D., previous research has shown that in schizophrenia and related disorders, the two prominent changes that occur in patient’s brain are hypermetabolism (abnormally increased activity) and atrophy (a decrease in size) of the hippocampus. However, the relation between the two changes had not been studied.

Schizophrenia is a progressive disease characterized by a gradual onset, beginning with a prodromal stage then progressing to psychotic symptoms.  Previous studies (Fusar-Poli et al., 2012) have shown that approximately 30 percent of patients with prodromal symptoms progress to psychosis.

In 2009, the authors of this study had previously shown that an increase in hippocampal metabolism was a good predictor of development of psychosis. In the current study, the authors used brain imaging tools in both human and mouse models to examine the temporal sequence of events during disease progression.

Twenty-five human subjects experiencing prodromal symptoms of psychosis (thus putting them at “clinical high risk” for progression to schizophrenia) underwent neuroimaging of the hippocampus, were followed for an average of 2.4 years, and then reimaged.

Of the 25 subjects, a total of 10 progressed to psychosis, while 15 did not develop a psychotic disorder. In those who did progress to schizophrenia, a pattern of  increase in hippocampal metabolism, followed by atrophy of the hippocampus was seen.

The researchers then turned to a mouse model to further look at the effects of glutamate on the brain.  They used male mice in an age range analogous to young adulthood in humans, a time where the risk of psychosis rises sharply.

The drug ketamine was used to model acute psychosis in mice.  Ketamine is known to mimic symptoms of schizophrenia in humans, as well as cause an increase in glutamate levels in the brain. Following acute ketamine administration in mice, researchers saw a significant increase in glutamate, followed by the human pattern of hypermetabolism and atrophy of the hippocampus.

The researchers conducted parallel experiments in mice using an experimental drug that reduces glutamate release in neurons. When mice were pre-treated with this drug, it prevented ketamine-induced increases in glutamate, as well as hypermetabolism and atrophy of the hippocampus.

These mouse studies suggest that preventing excess glutamate could prevent atrophy of the brain. While glutamate has been associated with schizophrenia since the 1980s, its precise mechanism has not been determined, and no medications targeting the glutamate receptor have been successfully developed.

The results of this study have potentially significant implications in the prevention and treatment of schizophrenia. The study established that hypermetabolism occurs before atrophy of the hippocampus.  Neuroimaging could theoretically be used as a diagnostic tool for identification of individuals who are at risk or in the early stages of the disease. Early detection before loss of brain tissue could be key in preventing or reversing early functional defects.

For those in the early stages of the disease, treatment with glutamate-reducing drugs may help protect the hippocampus and prevent progression to psychosis. According to the authors, glutamate-reducing drugs include approved drugs such as lamotrigine or gabapentin, as well as the experimental compound they used in the mouse studies. 

Continued research in this glutamatergic model of schizophrenia, including clinical studies using glutamate-reducing drugs, will help further reveal the mechanisms of schizophrenia. This study provides hope that one day we will be able to prevent and treat schizophrenia and other related disorders.