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Moderation of antidepressant response by the serotonin transporter gene

  • Patricia Huezo-Diaz (a1), Rudolf Uher (a1), Rebecca Smith (a1), Marcella Rietschel (a2), Neven Henigsberg (a3), Andrej Marušiˇ (a4), Ole Mors (a5), Wolfgang Maier (a6), Joanna Hauser (a7), Daniel Souery (a8), Anna Placentino (a9), Astrid Zobel (a6), Erik Roj Larsen (a10), Piotr M. Czerski (a7), Bhanu Gupta (a1), Farzana Hoda (a1), Nader Perroud (a1), Anne Farmer (a1), Ian Craig (a1), Katherine J. Aitchison (a1) and Peter McGuffin (a1)...
Abstract
Background

There have been conflicting reports on whether the length polymorphism in the promoter of the serotonin transporter gene (5-HTTLPR) moderates the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs). We hypothesised that the pharmacogenetic effect of 5-HTTLPR is modulated by gender, age and other variants in the serotonin transporter gene.

Aims

To test the hypothesis that the 5-HTTLPR differently influences response to escitalopram (an SSRI) compared with nortriptyline (a noradrenaline reuptake inhibitor).

Method

The 5-HTTLPR and 13 additional markers across the serotonin transporter gene were genotyped in 795 adults with moderate-to-severe depression treated with escitalopram or nortriptyline in the Genome Based Therapeutic Drugs for Depression (GENDEP) project.

Results

The 5-HTTLPR moderated the response to escitalopram, with long-allele carriers improving more than short-allele homozygotes. A significant three-way interaction between 5-HTTLPR, drug and gender indicated that the effect was concentrated in males treated with escitalopram. The single-nucleotide polymorphism rs2020933 also influenced outcome.

Conclusions

The effect of 5-HTTLPR on antidepressant response is SSRI specific conditional on gender and modulated by another polymorphism at the 5' end of the serotonin transporter gene.

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Copyright
Corresponding author
Rudolf Uher, P080, Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, 16 De Crespigny Park, London SE5 8AF UK. Email: rudolf.uher@iop.kcl.ac.uk
Footnotes
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These authors contributed equally to the work.

The GENDEP study was funded by a European Commission Framework 6 grant, EC Contract Ref.: LSHB-CT-2003-503428. Lundbeck provided both nortriptyline and escitalopram free of charge for the GENDEP study. GlaxoSmithKline contributed by funding an add-on project in the London centre. The sponsors had no role in the design and conduct of the study, in data collection, analysis, interpretation or writing the report.

Declaration of interest

N.H. participated in clinical trials sponsored by pharmaceutical companies including GlaxoSmithKline and Lundbeck. A.F, P.M. and K.J.A have received consultancy fees and honoraria for participating in expert panels from pharmaceutical companies, including Lundbeck and GlaxoSmithKline.

Footnotes
References
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Moderation of antidepressant response by the serotonin transporter gene

  • Patricia Huezo-Diaz (a1), Rudolf Uher (a1), Rebecca Smith (a1), Marcella Rietschel (a2), Neven Henigsberg (a3), Andrej Marušiˇ (a4), Ole Mors (a5), Wolfgang Maier (a6), Joanna Hauser (a7), Daniel Souery (a8), Anna Placentino (a9), Astrid Zobel (a6), Erik Roj Larsen (a10), Piotr M. Czerski (a7), Bhanu Gupta (a1), Farzana Hoda (a1), Nader Perroud (a1), Anne Farmer (a1), Ian Craig (a1), Katherine J. Aitchison (a1) and Peter McGuffin (a1)...
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