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Elevated Prefrontal Cortex -Aminobutyric Acid and Glutamate-Glutamine Levels in Schizophrenia Measured In Vivo With Proton Magnetic Resonance Spectroscopy

Lawrence S. Kegeles, MD, PhD; Xiangling Mao, MS; Arielle D. Stanford, MD; Ragy Girgis, MD; Najate Ojeil, MA; Xiaoyan Xu, PhD; Roberto Gil, MD; Mark Slifstein, PhD; Anissa Abi-Dargham, MD; Sarah H. Lisanby, MD; Dikoma C. Shungu, PhD

Arch Gen Psychiatry. Published online January 2, 2012. doi:10.1001/archgenpsychiatry.2011.1519

Context  Postmortem studies have found evidence of -aminobutyric acid (GABA) deficits in fast-spiking, parvalbumin-positive interneurons in the prefrontal cortex in schizophrenia. Magnetic resonance spectroscopy studies in unmedicated patients have reported glutamine or glutamate-glutamine (Glx) elevations in this region. Abnormalities in these transmitters are thought to play a role in cognitive impairments in the illness.

Objective  To measure GABA and Glx levels in vivo in 2 prefrontal brain regions in unmedicated and medicated patients with schizophrenia and healthy controls.

Design  Case-control study.

Setting  Inpatient psychiatric research unit and associated outpatient clinic.

Participants  Sixteen unmedicated patients with schizophrenia, 16 medicated patients, and 22 healthy controls matched for age, sex, ethnicity, parental socioeconomic status, and cigarette smoking.

Methods  Proton magnetic resonance spectroscopy with a 3-T system and the J-edited spin-echo difference method. The GABA and Glx levels were measured in the dorsolateral and medial prefrontal cortex and normalized to the simultaneously acquired water signal. Working memory performance was assessed in all subjects.

Main Outcome Measures  The GABA and Glx concentrations determined by proton magnetic resonance spectroscopy.

Results  In the medial prefrontal cortex region, 30% elevations were found in GABA (P = .02) and Glx (P = .03) levels in unmedicated patients compared with controls. There were no alterations in the medicated patients or in either group in the dorsolateral prefrontal cortex. Both regions showed correlations between GABA and Glx levels in patients and controls. No correlations with working memory performance were found.

Conclusions  To our knowledge, this study presents the first GABA concentration measurements in unmedicated patients with schizophrenia, who showed elevations in both GABA and Glx levels in the medial prefrontal cortex but not the dorsolateral prefrontal cortex. Medicated patients did not show these elevations, suggesting possible normalization of levels with antipsychotic medication. The Glx elevations agree with prior magnetic resonance spectroscopy literature, but GABA elevations were unexpected and suggest possible involvement of classes of interneurons not found to show impairments in postmortem studies.

Author Affiliations: Departments of Psychiatry (Drs Kegeles, Stanford, Girgis, Xu, Gil, Slifstein, and Abi-Dargham and Ms Ojeil) and Radiology (Drs Kegeles and Abi-Dargham), Columbia University College of Physicians and Surgeons and the New York State Psychiatric Institute, and Department of Radiology, Weill Cornell Medical College (Ms Mao and Dr Shungu), New York; and Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina (Dr Lisanby).

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