Dissociable effects of acute SSRI (escitalopram) on executive, learning and emotional functions in healthy humans

Nikolina Skandali,Julia B Deakin,Ralf Regenthal,Trevor W Robbins,Luca Passamonti,Rudolf N Cardinal,William R Bevan-Jones,James B Rowe,Francesca Cormack,Samuel R Chamberlain,Barbara J Sahakian,Valerie Voon

doi:10.1038/s41386-018-0229-z

Abstract

Serotonin is implicated in multiple executive functions including goal-directed learning, cognitive flexibility, response inhibition and emotional regulation. These functions are impaired in several psychiatric disorders, such as depression and obsessive–compulsive disorder. We tested the cognitive effects of the selective serotonin reuptake inhibitor escitalopram, using an acute and clinically relevant dose (20 mg), in 66 healthy male and female volunteers in a double-blind, placebo-controlled study. Participants performed a cognitive test battery including a probabilistic and reversal learning task, the CANTAB intra-dimensional/extra-dimensional shift test of cognitive flexibility, a response inhibition task with interleaved stop-signal and No-Go trials and tasks measuring emotional processing. We showed that acute escitalopram administration impaired learning and cognitive flexibility, but improved the ability to inhibit responses in stop-signal trials while leaving unaffected acute emotional processing. Our findings suggest a dissociation of effects of acute escitalopram on cognitive functions, possibly mediated by differential modulation of brain serotonin levels in distinct functional neural circuits.

Highlights

Serotonin (5-HT) is implicated in learning, executive and affective functions [1]
We showed contrasting detrimental and enhancing effects of acute high-dose escitalopram on cognitive functioning in human volunteers, while probabilistic learning was impaired in a manner consistent with the effects of reduced 5-HT transmission and depression
The results are relevant to understanding the clinical effects of selective serotonin reuptake inhibitors (SSRIs) at early stages of treatment, as well as the role of 5-HT in emotional and cognitive processing

Summary

Introduction

Serotonin (5-HT) is implicated in learning, executive and affective functions [1]. Much of the relevant evidence has depended on examining the effects of 5-HT loss in humans using acute dietary tryptophan depletion (ATD) [2], or in experimental animals, using 5-HT neurotoxins such as 5,7-dihydroxytryptamine (5,7-DHT) (e.g. [3]). ATD impairs visual discrimination learning and reversal [4], while selective 5-HT depletion in the amygdala has been shown to increase sensitivity to aversive feedback in probabilistic learning and reversal tasks [5] This is analogous to the effects of an acute low dose of citalopram in healthy volunteers [6] and rats [7] hypothesised to arise from inhibitory effects on 5-HT transmission [8]. Higher doses or sub-chronic treatment with citalopram improve performance in probabilistic reversal learning tasks in rats [7] These findings have clinical implications, as depressed humans show deficits in cognitive flexibility [9] and exaggerated reactions to negative feedback mediated by the prefrontal cortex (PFC) and the amygdala [10]. Selective serotonin reuptake inhibitors (SSRIs) constitute the firstline treatment for mood disorders [11]

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Conclusion