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

Abstract

BackgroundThe 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. MethodThirty-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. ResultsChanges 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. LimitationsSub-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. ConclusionsThe 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.

Highlights

Affective disorders including major depressive disorder and generalized anxiety disorder are common disabling conditions, associated with a high degree of burden (World Health Organization, 2008)
We investigate whether facilitation of this reappraisal neural pathway with escitalopram is modulated by 5-HTTLPR variation
For the purposes of this study, 5-HTTLPR allele loading prediction was performed in order to illustrate and determine the extent of the effect of 5-HTTLPR allele loading has on modulation of functional connectivity between the L amygdala-right interior frontal gyrus (R IFG) functional connectivity during reappraisal with escitalopram

Summary

Introduction

Affective disorders including major depressive disorder and generalized anxiety disorder are common disabling conditions, associated with a high degree of burden (World Health Organization, 2008). We observed that a single dose of escitalopram is associated with negative L amygdala-R IFG coupling during reappraisal of negative stimuli, suggesting facilitation of emotion regulation within this pathway (Outhred et al, 2015). It remains unclear whether allelic variation in 5-HTTLPR moderates this effect. Building on our previous findings (Outhred et al, 2014a) and the 5-HTT literature showing that ‘L’ carriers have better treatment outcomes than ‘S’ carriers both at the cellular and the behavioral levels, we predicted a linear relationship (doseresponse) between 5-HTTLPR and L amygdala-R IFG functional connectivity during the reappraisal of negative images after single dose escitalopram relative to placebo. Given that SSRI treatment is associated with increased dysregulation in ‘S/S’ allele homozygotes (Outhred et al, 2014a), we hypothesise that ‘S/S’ allele carriers will display more positive L amygdala-R IFG coupling than ‘L/L’ homozygotes during reappraisal of negative stimuli under escitalopram

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