title: Elevated brain serotonin turnover in patients with depression: effect of genotype and therapy.
abstract: BACKGROUND
  The biological basis for the development of major depressive disorder (MDD) remains incompletely understood.
  
  
  OBJECTIVE
  To quantify brain serotonin (5-hydroxytryptamine [5-HT]) turnover in patients with MDD.
  
  
  METHODS
  Patients with depression were studied both untreated and during administration of a selective serotonin reuptake inhibitor (SSRI) in an unblinded study of sequential design. Healthy volunteers were examined on only 1 occasion. Direct internal jugular venous blood sampling was used to directly quantify brain serotonin turnover. The effect of serotonin transporter (5-HTT) genotype on brain serotonin turnover was evaluated and the influence of SSRI therapy on serotonin turnover was investigated.
  
  
  METHODS
  Participants were recruited from the general community following media advertisement. Experimental procedures were performed in the research catheterization laboratory of a major training hospital and medical research institute.
  
  
  METHODS
  Studies were performed in 21 patients fulfilling the DSM-IV and International Statistical Classification of Diseases, 10th Revision diagnostic criteria for MDD and in 40 healthy volunteers.
  
  
  METHODS
  Treatment for patients consisted of SSRI administration for approximately 12 weeks.
  
  
  METHODS
  Brain serotonin turnover before and after SSRI therapy.
  
  
  RESULTS
  Brain serotonin turnover was significantly elevated in unmedicated patients with MDD compared with healthy subjects (mean [SD] internal jugular venoarterial 5-hydroxyindoleacetic acid plasma concentration difference, 4.4 [4.3] vs 1.6 [2.4] nmol/L, respectively; P = .003). Analysis of the influence of the 5-HTT genotype in MDD indicated that carriage of the s allele compared with the l allele was associated with greater than a 2-fold increase in brain serotonin turnover (mean [SD] internal jugular venoarterial 5-hydroxyindoleacetic acid plasma concentration difference, 6.5 [4.7] vs 2.7 [2.9] nmol/L, respectively; P = .04). Following SSRI therapy, brain serotonin turnover was substantially reduced (mean [SD] internal jugular venoarterial 5-hydroxyindoleacetic acid plasma concentration difference, 6.0 [4.0] nmol/L prior to treatment vs 2.0 [3.3] nmol/L following therapy; P = .008).
  
  
  CONCLUSIONS
  Brain serotonin turnover is elevated in unmedicated patients with MDD and is influenced by the 5-HTT genotype. The marked reduction in serotonin turnover following SSRI treatment and the accompanying improvement in symptoms suggest that high brain serotonin turnover may be a biological substrate of MDD.
authors.affiliation: Department of Psychological Medicine, Alfred Hospital, Monash University, Melbourne, Victoria, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Barton
authors.forename: Murray D
authors.initials: MD
authors.lastname: Esler
authors.forename: Tye
authors.initials: T
authors.lastname: Dawood
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Lambert
authors.forename: Deepak
authors.initials: D
authors.lastname: Haikerwal
authors.forename: Celia
authors.initials: C
authors.lastname: Brenchley
authors.forename: Florentia
authors.initials: F
authors.lastname: Socratous
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Hastings
authors.forename: Ling
authors.initials: L
authors.lastname: Guo
authors.forename: Glen
authors.initials: G
authors.lastname: Wiesner
authors.forename: David M
authors.initials: DM
authors.lastname: Kaye
authors.forename: Richard
authors.initials: R
authors.lastname: Bayles
authors.forename: Markus P
authors.initials: MP
authors.lastname: Schlaich
authors.forename: Gavin W
authors.initials: GW
authors.lastname: Lambert
mesh_terms: D000328:Adult; D001921:Brain / Q000378:metabolism*; D016022:Case-Control Studies; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012701:Serotonin / Q000235:genetics / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use
chemical_list: D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors