Reinforcement Sensitivity Eased with Chronic Escitalopram in Healthy Volunteers

In healthy volunteers, chronic escitalopram reduces reinforcement sensitivity without significantly affecting cold cognition.

Reinforcement sensitivity is reduced with chronic escitalopram compared with placebo in healthy volunteers with no significant effects on cold cognitive measures. These study findings were published in Neuropsychopharmacology.

Researchers sought to evaluate the chronic effect of escitalopram (a selective serotonin reuptake inhibitor [SSRI]) on inhibition, cognitive flexibility, and memory (cold cognition), and on decision-making and reinforcement learning (hot cognition) in healthy volunteers. They hypothesized SSRI treatment would affect reinforcement-related behavior, probabilistic reversal learning, and response inhibition.

They conducted a double-blind placebo-controlled study ( Identifier:      NCT04239339) between May 2020 and October 2021 at the University of Copenhagen, Copenhagen, Denmark. They included 66 healthy volunteers recruited from an established database at the Neurobiology Research Unit at the university and balanced for sex, age (between 18 and 45 years), and intelligence quotient (average >110).

Participants were semi-randomly assigned to receive 20 mg escitalopram (n=32) or placebo (n=34) for at least 21 days (mean treatment 26 days escitalopram and placebo). Linear regression models and hierarchical Bayesian modelling of the Probabilistic Reversal Learning (PRL) task were used to analyze differences on the cognitive measures (questionnaires, neuropsychologic tests, serum escitalopram measures).

In contrast with previous reports on the acute effects of SSRI administration, we did not find any significant effects on ‘cold’ cognitive measures after more chronic administration.

Biochemical analysis was used to confirm self-administration of medication in the -escitalopram group was strictly adhered to.

Self-report questionnaires assessing depressive symptoms, anxiety, impulsivity, compulsivity, and personality traits were completed at baseline, at 21 days or more during treatment (cognitive visit), and 1 week later but after medication had stopped. During the cognitive visit, participants completed extensive neuropsychologic tests assessing cold and hot cognition and reinforcement learning (PRL Task, the Interleaved Stop-Signal Go/No-Go Task, the Three-Dimensional Intra-Extra Dimensional [3D-IED] Set Shifting Task, Cambridge Neuropsychological Test Automated Battery [CANTAB] Paired Associates Learning, CANTAB Spatial Working Memory, CANTAB Rapid Visual Information Processing, EMOTICOM Moral Judgement Task, EMOTICOM Intensity Morphing Task, EMOTICOM Emotion Recognition [Eyes] Task, EMOTICOM Ultimatum Game, EMOTICOM Cambridge Gambling Task, and the Sequential Model-Based Model-Free Task [MBMF]).

After correction, there were no significant between-group differences on baseline questionnaires. Differences between the change scores between baseline and cognitive visit questionnaires showed the escitalopram group had significantly lower scores on the Changes in Sexual Functioning questionnaire, with higher dysfunction on orgasm/ejaculation and orgasm/completion (all P =.01). They found no between-group differences on any of the follow-up questionnaires.

They noted no between-group differences in analysis for the standard PRL measures. They noted both groups performed the MBMF task in an equivalently model-based way.

They found escitalopram reduced reinforcement sensitivity vs placebo on the Sequential Model-Based/Model-Free task and the PRL task (in Hierarchical Bayesian modelling). There were no other significant group differences on cold or hot cognition. In measures of cold cognition, the current study showed no effect of escitalopram on response inhibition or on performance of the 3D-IED task. In measures of hot cognition in the current study, affective bias was not significantly affected by escitalopram, and they found no effects on moral judgements.

Study limitations include the possibility neuroplasticity effects may be greater with longer duration of escitalopram, varying approaches for induction of changes in serotonin, escitalopram effects less discernible in healthy cognitively high-performing volunteers than in patients with MDD, and a significant difference in guessing group allocation (53% [chance level] of the escitalopram group guessed correctly).

Researchers concluded, “In contrast with previous reports on the acute effects of SSRI administration, we did not find any significant effects on ‘cold’ cognitive measures after more chronic administration (mean 26 days).” They wrote, “Using an innovative computational modelling approach, we did find significant effects specific to reinforcement learning; chronic escitalopram reduced reinforcement sensitivity compared to placebo.” They believe their findings represent strong evidence for a key role of serotonin in reinforcement learning, and may reflect the blunting effect patients with neuropsychiatric disorders often report when receiving chronic SSRI treatment.

Disclosure: Some [or 1] study author(s) declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Langley C, Armand S, Luo Q, et al. Chronic escitalopram in healthy volunteers has specific effects on reinforcement sensitivity: a double-blind, placebo-controlled semi-randomized study. Neuropsychopharmacology. Published online January 23, 2023. doi:10.1038/s41386-022-01523-x