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Higher hippocampal glutamate levels tied to psychosis risk

Study finding indicated that adverse clinical outcomes in patients at clinical high-risk for psychosis may be linked to higher baseline hippocampal metabolite concentrations.

“Neuroimaging studies in individuals at clinical high risk for psychosis suggest that the subsequent onset of psychosis is associated with changes in several measures of hippocampal integrity,” Matthijs G. Bossong, PhD, from the department of psychiatry, University Medical Center Utrecht in the Netherlands, and colleagues wrote. “The mechanisms underlying these changes are unclear, but experimental work in rodents suggests that these changes may be secondary to increases in hippocampal glutamate levels.”

In this cross-sectional study, the investigators examined the link between hippocampal glutamate levels in 86 individuals at clinical high risk for psychosis and 30 healthy controls and their subsequent clinical outcomes for an average follow-up of 18.5 months.

Using 3-T proton-magnetic resonance spectroscopy at the first clinical presentation, researchers measured concentrations of glutamate and other metabolites in the left hippocampus. They evaluated transition or nontransition to psychosis via the Comprehensive Assessment of the At-Risk Mental State criteria and level of overall functioning via the Global Assessment of Function scale at follow-up.

At follow up, 12 high-risk individuals developed a first episode of psychosis and 74 did not, with 19 showing good overall functioning and 38 showing a poor functional outcome.

Patients at clinical high-risk who developed psychosis showed higher hippocampal glutamate levels than those who did not develop psychosis (mean glutamate levels = 9.16 vs. 8.33; P = .048). On average, these patients who developed psychosis also had higher myo-inositol levels (7.6 vs 6.24; P = .002) and higher creatine levels (8.18 vs. 7.32; P = .01) than high-risk patients who did not develop psychosis. They also had higher myo-inositol levels than healthy controls (7.6 vs. 6.19; P = .005).

Bossong and colleagues also found that patients at high-risk for psychosis with a poor functional outcome had higher glutamate levels than patients with a good outcome on average (8.83 vs. 7.76; P = .02). In addition, data from logistic regression analyses revealed that hippocampal glutamate levels were linked to clinical outcome in terms of transition and nontransition to psychosis (OR = 1.61; 95% CI, 1-2.59) and overall functioning (OR = 1.71; 95% CI, 1.1-2.66).

“Our study suggests that clinical outcomes in patients at clinical high risk for psychosis may be associated with baseline hippocampal metabolite concentrations,” the researchers concluded. “Although the findings require replication, they raise the possibility that measuring hippocampal metabolite levels could contribute to the stratification of clinical high-risk individuals according to future clinical outcomes.”

It’s uncertain what these study findings mean in terms of treatment, Juan R. Bustillo, MD, from the departments of psychiatry and neuroscience at the University of New Mexico, Albuquerque, and colleagues wrote in an accompanying comment.

“Pharmacological treatments that engage glutamatergic targets have been generally unsuccessful for treatment of psychotic, negative and cognitive symptoms of schizophrenia,” Bustillo and colleagues wrote. “However, because schizophrenia is highly heritable and glutamatergic-associated genes are among the most involved, in vivo glutamate measurements may still assist the delineation of subgroups of patients with vulnerable disease stages.” – by Savannah Demko

Disclosure: The authors and comment authors report no relevant financial disclosures.