Expectancy effects on serotonin and dopamine transporters during SSRI treatment of social anxiety disorder: a randomized clinical trial

Olof R Hjorth,Tomas Furmark,Iman Alaie,Mark Lubberink,My Jonasson,Margareta Reis,Malin Gingnell,Sara Hultberg,Kurt Wahlstedt,Andreas Frick,Kristoffer N T Månsson,Mats Fredrikson,Johanna M Hoppe,Gunnar Antoni,Jörgen Rosén,Vanda Faria

doi:10.1038/s41398-021-01682-3

Abstract

It has been extensively debated whether selective serotonin reuptake inhibitors (SSRIs) are more efficacious than placebo in affective disorders, and it is not fully understood how SSRIs exert their beneficial effects. Along with serotonin transporter blockade, altered dopamine signaling and psychological factors may contribute. In this randomized clinical trial of participants with social anxiety disorder (SAD) we investigated how manipulation of verbally-induced expectancies, vital for placebo response, affect brain monoamine transporters and symptom improvement during SSRI treatment. Twenty-seven participants with SAD (17 men, 10 women), were randomized, to 9 weeks of overt or covert treatment with escitalopram 20 mg. The overt group received correct treatment information whereas the covert group was treated deceptively with escitalopram, described as an active placebo in a cover story. Before and after treatment, patients underwent positron emission tomography (PET) assessments with the [11C]DASB and [11C]PE2I radiotracers, probing brain serotonin (SERT) and dopamine (DAT) transporters. SAD symptoms were measured by the Liebowitz Social Anxiety Scale. Overt was superior to covert SSRI treatment, resulting in almost a fourfold higher rate of responders. PET results showed that SERT occupancy after treatment was unrelated to anxiety reduction and equally high in both groups. In contrast, DAT binding decreased in the right putamen, pallidum, and the left thalamus with overt SSRI treatment, and increased with covert treatment, resulting in significant group differences. DAT binding potential changes in these regions correlated negatively with symptom improvement. Findings support that the anxiolytic effects of SSRIs involve psychological factors contingent on dopaminergic neurotransmission while serotonin transporter blockade alone is insufficient for clinical response.

Highlights

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for depression and anxiety but it has been widely debated to what extent SSRI efficacy can be attributed to expectancies of improvement—a key mechanism of placebo effects [1,2,3,4,5,6]
We previously demonstrated enhanced anti-anxiety effects of overt as compared to covert SSRI treatment with escitalopram in patients with social anxiety disorder (SAD) [9]
The SSRIs are held to exert their therapeutic effects by blocking serotonin uptake via the serotonin transporter (SERT) [19] and clinical doses typically result in 76–85% SERT occupancy in the expected (Fig. 1B) [9]

Summary

INTRODUCTION

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for depression and anxiety but it has been widely debated to what extent SSRI efficacy can be attributed to expectancies of improvement—a key mechanism of placebo effects [1,2,3,4,5,6]. The SSRIs are held to exert their therapeutic effects by blocking serotonin uptake via the serotonin transporter (SERT) [19] and clinical doses typically result in 76–85% SERT occupancy in the expected (Fig. 1B) [9] Both groups were treated with 20 mg escitalopram per day, starting with 10 mg the first week. In a subsample of our previous SSRI deception study of SAD [9], we examined if giving correct or incorrect information about the drug affects serotonergic and dopaminergic neurotransmission as assessed with positron emission tomography (PET) and the highly selective radioligands [11C]DASB and [11C] PE2I, probing SERTs and DATs respectively. A 10 min transmission scan for attenuation correction was performed using three retractable germanium (68Ge) rotating line sources

Participants

RESULTS

DISCUSSION