Imaging-Based Biomarker May Find Schizophrenia Patients Most Likely to Benefit from Glutamate-Targeted Drugs
A functional MRI response could identify patients with altered glutamate metabolism.
Glutamate, the most important neurotransmitter for brain function, has been a target for treatments of schizophrenia for more than two decades. The approach is based on the hypothesis that glutamate abnormalities could disturb brain function and induce the psychotic symptoms seen in the disease.
Despite significant evidence supporting this model, clinical trials of several glutamate-based treatments in patients produced disappointing results. One reason for the failure may be that different patients in the study population exhibited different forms of the disease. With this challenge in mind, a new study published in November by JAMA Psychiatry explored whether imaging-based biomarkers could identify patients who are likely to benefit from glutamate-targeted drugs.
The authors evaluated the utility of three biomarkers. They studied 65 healthy volunteers, some of whom had been given the drug ketamine to induce symptoms that resemble those found in schizophrenia by blocking N-methyl-D-aspartate receptors for glutamate. Subjects received either ketamine or placebo infusions while in an MRI scanner.
Out of the three biomarkers—ketamine-evoked changes in the functional MRI (fMRI) blood oxygen level-dependent response (pharmacoBOLD), glutamate proton magnetic resonance spectroscopy (MRS), and task-based fMRI—only pharmacoBOLD successfully detected a large, consistent response. Glutamate proton MRS showed a small but significant change, while task-based fMRI showed no change.
Although further experiments are needed, the pharmacoBOLD biomarker shows promise as a screening tool to select patients with altered glutamate metabolism for future clinical trials of glutamate-based treatments.