Impact of 5-HTTLPR on SSRI serotonin transporter blockade during emotion regulation: A preliminary fMRI study

Tim Outhred; Pritha Das; Carol Dobson-Stone; Kim L Felmingham; Richard A Bryant; Pradeep J Nathan; Gin S Malhi; Andrew H Kemp

doi:10.1016/j.jad.2016.02.019

Impact of 5-HTTLPR on SSRI serotonin transporter blockade during emotion regulation: A preliminary fMRI study

J Affect Disord. 2016 May 15:196:11-9. doi: 10.1016/j.jad.2016.02.019. Epub 2016 Feb 10.

Authors

Tim Outhred¹, Pritha Das², Carol Dobson-Stone³, Kim L Felmingham⁴, Richard A Bryant⁵, Pradeep J Nathan⁶, Gin S Malhi², Andrew H Kemp⁷

Affiliations

¹ Academic Department of Psychiatry, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW 2065, Australia; Sydney Medical School Northern, University of Sydney, NSW 2006, Australia.
² Academic Department of Psychiatry, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW 2065, Australia; Sydney Medical School Northern, University of Sydney, NSW 2006, Australia; CADE Clinic, Royal North Shore Hospital, Northern Sydney Local Health District, St Leonards, NSW 2065, Australia; Advanced Research and Clinical Highfield Imaging (ARCHI), University of Sydney, Royal North Shore Hospital, NSW 2065, Australia.
³ Neuroscience Research Australia, Randwick, NSW 2031, Australia; School of Medical Sciences, University of New South Wales, Kensington, NSW 2033, Australia.
⁴ School of Psychology, University of Tasmania, Hobart, TAS 7001, Australia.
⁵ School of Psychology, University of New South Wales, Kensington, NSW 2033, Australia.
⁶ Department of Psychiatry, University of Cambridge, Cambridge CB2 1QB, United Kingdom; School of Psychology and Psychiatry, Monash University, VIC 3800, Australia.
⁷ Academic Department of Psychiatry, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW 2065, Australia; Sydney Medical School Northern, University of Sydney, NSW 2006, Australia; CADE Clinic, Royal North Shore Hospital, Northern Sydney Local Health District, St Leonards, NSW 2065, Australia; Advanced Research and Clinical Highfield Imaging (ARCHI), University of Sydney, Royal North Shore Hospital, NSW 2065, Australia; Department of Psychology, College of Human and Health Sciences, Swansea University, Vivian Tower, Singleton Park, SWANSEA SA2 8PP, United Kingdom. Electronic address: A.H.Kemp@swansea.ac.uk.

PMID: 26896742
DOI: 10.1016/j.jad.2016.02.019

Abstract

Background: The short ('S') allele of the serotonin transporter (5-HTT)-linked polymorphic region (5-HTTLPR) is associated with increased negative emotion processing bias, and this polymorphism moderates acute effects of selective serotonin reuptake inhibitor (SSRI) treatment. In this preliminary study, we explore the moderating effect of 5-HTTLPR on the impact of the SSRI, escitalopram during emotion regulation of negative emotional stimuli.

Method: Thirty-six healthy Caucasian, female participants underwent two fMRI scanning sessions following single dose escitalopram and placebo administration separated by a seven-day washout period according to a double-blind, randomized, placebo-controlled crossover design. Functional connectivity analysis was employed with a left (L) amygdala seed and a right interior frontal gyrus (R IFG) target.

Results: Changes in functional connectivity with emotion regulation and treatment were linearly related to 5-HTTLPR 'L' allele load such that negative R IFG-L amygdala connectivity was increased with an increasing number of 'L' alleles. Therefore, escitalopram may facilitate the effects of reappraisal by enhancing negative functional connectivity, a finding that is greatest in participants homozygous for the 'L' allele and least in those homozygous for the 'S' allele.

Limitations: Sub-samples of the homozygote 'S/S' and 'L/L' 5-HTTLPR groupings were small. However, the within-subjects nature of the experiment and observing changes at the individual subject level increases our confidence in the findings of the present study.

Conclusions: The present study elucidates a potential neural mechanism by which antidepressant treatment produces differential treatment outcomes dependent on the 5-HTTLPR polymorphism, providing new and important leads for models of antidepressant action.

Keywords: 5-HTTLPR; Antidepressant; Emotion; Pharmacogenetics; Serotonin; fMRI.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Alleles
Amygdala / drug effects
Antidepressive Agents, Second-Generation / pharmacology*
Citalopram / pharmacology*
Cross-Over Studies
Double-Blind Method
Emotions / drug effects*
Emotions / physiology
Female
Genotype
Healthy Volunteers
Humans
Magnetic Resonance Imaging
Middle Aged
Pharmacogenetics
Polymorphism, Genetic
Prefrontal Cortex / drug effects
Selective Serotonin Reuptake Inhibitors / pharmacology*
Serotonin Plasma Membrane Transport Proteins / metabolism*
Young Adult

Substances

Antidepressive Agents, Second-Generation
SLC6A4 protein, human
Serotonin Plasma Membrane Transport Proteins
Serotonin Uptake Inhibitors
Citalopram