title: Reduced parahippocampal and lateral temporal GABAA-[11C]flumazenil binding in major depression: preliminary results.
abstract: OBJECTIVE
  Major depressive disorder (MDD) has been related to both a dysfunctional gamma-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 GABA(A)-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 [(11)C]flumazenil ([(11)C]FMZ). Parametric voxel-by-voxel Logan plots were compared with methods based on regions of interest (ROI), to provide volume of distribution (V(T)) and binding potential (BP(ND)) 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 [(11)C]FMZ binding in the parahippocampal gyrus and right lateral superior temporal gyrus (p uncorrected < or =0.001). In the temporal area, [(11)C]FMZ binding showed a strong inverse correlation with HPA axis activity. Plasma GABA did not discriminate MDD from controls, but correlated inversely with [(11)C]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.
  
  
  CONCLUSIONS
  The bilateral reduction in limbic parahippocampal and right temporal [(11)C]FMZ binding found in MDD indicates decreased GABA(A)-benzodiazepine receptor complex affinity and/or number. The inverse relationship between GABA(A) binding in the temporal lobe and HPA axis activity, suggests that HPA axis hyperactivity is partly due to reduced GABA-ergic inhibition.
authors.affiliation: Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands. u.klumpers@vumc.nl
authors.forename: Ursula M H
authors.initials: UM
authors.lastname: Klumpers
authors.forename: Dick J
authors.initials: DJ
authors.lastname: Veltman
authors.forename: Madeleine L
authors.initials: ML
authors.lastname: Drent
authors.forename: Ronald
authors.initials: R
authors.lastname: Boellaard
authors.forename: Emile F I
authors.initials: EF
authors.lastname: Comans
authors.forename: Gerben
authors.initials: G
authors.lastname: Meynen
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Lammertsma
authors.forename: Witte J G
authors.initials: WJ
authors.lastname: Hoogendijk
mesh_terms: D000328:Adult; D000928:Antidepressive Agents / Q000627:therapeutic use; D002250:Carbon Radioisotopes / Q000737:chemistry; D016022:Case-Control Studies; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000378:metabolism* / Q000628:therapy; D003907:Dexamethasone / Q000378:metabolism; D005260:Female; D005442:Flumazenil / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008297:Male; D009490:Neurosecretory Systems / Q000378:metabolism; D020534:Parahippocampal Gyrus / Q000378:metabolism*; D011485:Protein Binding; D011963:Receptors, GABA-A / Q000378:metabolism*; D016896:Treatment Outcome; D005680:gamma-Aminobutyric Acid / Q000097:blood / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D002250:Carbon Radioisotopes; D011963:Receptors, GABA-A; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; D003907:Dexamethasone; D003346:Corticotropin-Releasing Hormone