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Effect of Genotype and Therapy

David A. Barton, MBBS, FRANZCP; Murray D. Esler, MBBS, PhD; Tye Dawood, PhD; Elisabeth A. Lambert, PhD; Deepak Haikerwal, MBBS; Celia Brenchley, BSc; Florentia Socratous, BSc; Jacqueline Hastings, PhD; Ling Guo, MD; Glen Wiesner, PhD; David M. Kaye, MBBS, PhD; Richard Bayles, BSc(Hon); Markus P. Schlaich, MD; Gavin W. Lambert, PhD

Arch Gen Psychiatry. 2008;65(1):38-46.

Context  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.

Design  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.

Setting  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.

Participants  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.

Interventions  Treatment for patients consisted of SSRI administration for approximately 12 weeks.

Main Outcome Measures  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.

Author Affiliations: Department of Psychological Medicine, Alfred Hospital, Monash University (Dr Barton), and Human Neurotransmitters Laboratory (Drs Barton, Esler, Dawood, E. A. Lambert, Haikerwal, Hastings, Guo, Wiesner, Schlaich, and G. W. Lambert, Mss Brenchley and Socratous, and Mr Bayles) and Wynn Department of Metabolic Cardiology (Dr Kaye), Baker Heart Research Institute, Melbourne, Victoria, Australia.