Brain Imaging of the Glutamatergic System in Depression

Irina Esterlis, Ph.D.

Yale University School of Medicine

Grant Program:

David Mahoney Neuroimaging Program

Funded in:

December 2011, for 3 years

Funding Amount:


Lay Summary

Brain’s glutamate system may be target for treating depression and related cognitive deficits

Investigators will use PET and MRS (magnetic resonance spectroscopy) imaging in patients with depression and healthy volunteers to determine the role that the brain’s glutamate (excitatory) neurotransmitter system plays in depression and its associated cognitive deficits.

While about 20 percent of the nation’s population will suffer from major depression or bi-polar disorder in their lifetimes, effective treatment remains a challenge. It usually takes weeks to months for current treatments to produce beneficial effects in most patients, and in others treatment does not work at all. Moreover, current therapies do not address associated cognitive deficits in attention, concentration, memory, and learning that may persist even after the major depressive episode has resolved.  Prior research has implicated possible defects in the brain’s system that enables cells to transmit and receive the excitatory neurotransmitter glutamate (the “glutamatergic” system). Research also suggests that antidepressants may work by acting on this system. Moreover, glutamate may modify associated symptoms including problems with sleep, appetite, motivation, and concentration. Lacking, though, is a clear understanding of glutamate dysfunction in depression or its involvement in the lasting, associated cognitive impairments.

The investigators hypothesize that people with depression have lower glutamate levels in the brain’s anterior cingulate cortex, and reduced availability of glutamate receptors across brain regions. Additionally, they hypothesize that the glutamate system plays a beneficial role in cognition, and therefore that people with lower glutamate levels and receptor availability will perform worse on cognitive tests. They will test these hypotheses through imaging using MRS and high resolution PET (with a tracer, called “FPEB,” that specifically identifies glutamate receptors) in 18 depressed adults and 18 healthy adult volunteers, obtaining information on both glutamate levels and glutamatergic receptors in each individual.  They will determine whether those with depression, compared to the healthy volunteers, show through PET a lower level of glutamatergic receptors, and show with MRS a compromise in glutamate neurotransmitter levels. Additionally, they will determine, though cognitive testing of participants, whether alterations in the glutamatergic system are associated with cognitive deficits in concentration, attention, and memory. If so, the research will have identified important diagnostic and treatment biomarkers in the glutamatergic system.

Significance: Experts consider this study to be a novel approach and to have substantial potential to lead to improved therapies that more effectively reduce depressive symptoms and associated cognitive deficits.