Elevated brain serotonin turnover in patients with depression: effect of genotype and therapy.
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.
Barton
David A
DA
Department of Psychological Medicine, Alfred Hospital, Monash University, Melbourne, Victoria, Australia.
Esler
Murray D
MD
Dawood
Tye
T
Lambert
Elisabeth A
EA
Haikerwal
Deepak
D
Brenchley
Celia
C
Socratous
Florentia
F
Hastings
Jacqueline
J
Guo
Ling
L
Wiesner
Glen
G
Kaye
David M
DM
Bayles
Richard
R
Schlaich
Markus P
MP
Lambert
Gavin W
GW
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
D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors