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Altered Cerebral -Aminobutyric Acid Type A–Benzodiazepine Receptor Binding in Panic Disorder Determined by [¹¹C]Flumazenil Positron Emission Tomography

Gregor Hasler, MD; Allison C. Nugent, PhD; Paul J. Carlson, MD, PhD; Richard E. Carson, PhD; Marilla Geraci, MS; Wayne C. Drevets, MD

Arch Gen Psychiatry. 2008;65(10):1166-1175.

Context  The benzodiazepine (BZD) receptor system has been implicated in the pathophysiologic mechanism of panic disorder (PD) by indirect evidence from pharmacological challenge studies and by direct evidence from single-photon emission computed tomography and positron emission tomography neuroimaging studies. However, the results of previous neuroimaging studies are in disagreement, possibly because of experimental design limitations related to sample size, matching between patients and controls, and confounding medication effects.

Objective  To compare BZD receptor binding between subjects with PD and healthy control subjects.

Design  Cross-sectional study for association.

Setting  Psychiatric outpatient clinic of the National Institute of Mental Health.

Participants  Fifteen subjects with PD who were naïve to BZD drug exposure and were not receiving other drug treatment, and 18 healthy controls.

Intervention  Images of BZD receptor binding were acquired using positron emission tomography and flumazenil tagged with carbon 11.

Main Outcome Measures  The BZD receptor binding potential was assessed by a simplified reference tissue-tracer kinetic model.

Results  The BZD receptor binding potential was decreased in multiple areas of the frontal, temporal, and parietal cortices and was increased in the hippocampus/parahippocampal region in subjects with PD vs controls. The most significant decrease was located in the dorsal anterolateral prefrontal cortex (DALPFC); the most significant increase, in the hippocampus/parahippocampal gyrus. These abnormalities were not accounted for by comorbid depression. In subjects with PD, the severity of panic and anxiety symptoms correlated positively with BZD receptor binding in the DALPFC but negatively with binding in the hippocampus/parahippocampal gyrus.

Conclusions  These data provide evidence of abnormal BZD–-aminobutyric acid type A receptor binding in PD, suggesting that basal and/or compensatory changes in inhibitory neurotransmission play roles in the pathophysiologic mechanism of PD. They also provide evidence of an impairment of frontal-limbic interaction in the modulation of anxiety responses, consistent with previous functional and structural neuroimaging studies in PD.

Author Affiliations: Department of Psychiatry, University Hospital, Zurich, Switzerland (Dr Hasler); Section on Neuroimaging in Mood and Anxiety Disorders, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (Drs Nugent, Carlson, and Drevets and Ms Geraci); and Departments of Diagnostic Radiology and Biomedical Engineering, Yale University School of Medicine, New Haven, Connecticut (Dr Carson).

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