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Reduced parahippocampal and lateral temporal GABAA-[11C]flumazenil binding in major depression: preliminary results

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Major depressive disorder (MDD) has been related to both a dysfunctional γ-amino butyric acid (GABA) system and to hyperactivity of the hypothalamic-pituitary-adrenal axis (HPA). Although GABA has been suggested to inhibit HPA axis activity, their relationship has never been studied at the level of the central GABAA-benzodiazepine receptor in depressed patients or in relation to antidepressant treatment.

Methods

Eleven depressed outpatients were compared, before and after treatment with citalopram, with nine age-matched healthy controls. The subjects were scanned using the positron emission tomography (PET) tracer [11C]flumazenil ([11C]FMZ). Parametric voxel-by-voxel Logan plots were compared with methods based on regions of interest (ROI), to provide volume of distribution (VT) and binding potential (BPND) values. Plasma GABA levels were determined and a dexamethasone-corticotropin releasing hormone (DEX-CRH) test was performed.

Results

In MDD, parametric voxel-by-voxel Logan plots showed bilateral reduced [11C]FMZ binding in the parahippocampal gyrus and right lateral superior temporal gyrus (p uncorrected ≤0.001). In the temporal area, [11C]FMZ binding showed a strong inverse correlation with HPA axis activity. Plasma GABA did not discriminate MDD from controls, but correlated inversely with [11C]FMZ binding in the right insula. Following treatment with citalopram, voxel-based analysis revealed reduced binding in the right lateral temporal gyrus and dorsolateral prefrontal cortex.

Conclusion

The bilateral reduction in limbic parahippocampal and right temporal [11C]FMZ binding found in MDD indicates decreased GABAA-benzodiazepine receptor complex affinity and/or number. The inverse relationship between GABAA binding in the temporal lobe and HPA axis activity, suggests that HPA axis hyperactivity is partly due to reduced GABA-ergic inhibition.

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Acknowledgments

We thank Dr. Jakobs and his neuroendocrinology laboratory for measurements of plasma GABA, neuroradiology staff for interpretation of MRI scans, and the staff of the Department of Nuclear Medicine & PET Research for tracer production, technical assistance and data acquisition. We would also like to thank Ferring Pharmaceuticals Ltd. for generously providing human CRH. This work was supported in part by ZONMW, The Netherlands (Dutch Organization for Health Research and Development), grant no. 907-00-012.

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Authors and Affiliations

  1. Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands

    Ursula M. H. Klumpers, Dick J. Veltman, Gerben Meynen & Witte J. G. Hoogendijk

  2. Department of Endocrinology, VU University Medical Center, Amsterdam, The Netherlands

    Madeleine L. Drent

  3. Department of Nuclear Medicine & PET Research, VU University Medical Center, Amsterdam, The Netherlands

    Ronald Boellaard, Emile F. I. Comans & Adriaan A. Lammertsma

  4. Center for Neurogenomics and Cognitive Research, VU University Medical Center, Amsterdam, The Netherlands

    Witte J. G. Hoogendijk

  5. Department of Psychiatry, GGZ inGeest, partner of VUmc, C/o AJ Ernststraat 887, 1081 HL, Amsterdam, The Netherlands

    Ursula M. H. Klumpers

  6. Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands

    Ursula M. H. Klumpers, Dick J. Veltman, Ronald Boellaard, Adriaan A. Lammertsma & Witte J. G. Hoogendijk

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  1. Ursula M. H. Klumpers
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Klumpers, U.M.H., Veltman, D.J., Drent, M.L. et al. Reduced parahippocampal and lateral temporal GABAA-[11C]flumazenil binding in major depression: preliminary results. Eur J Nucl Med Mol Imaging 37, 565–574 (2010). https://doi.org/10.1007/s00259-009-1292-9

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