Several studies of the effects on cognition of selective serotonin reuptake inhibitors (SSRI), administered either acutely or sub-chronically in healthy volunteers, have found changes in learning and reinforcement outcomes. In contrast, to our knowledge, there have been no studies of chronic effects of escitalopram on cognition in healthy volunteers. This is important in view of its clinical use in major depressive disorder (MDD) and obsessive-compulsive disorder (OCD). Consequently, we aimed to investigate the chronic effect of the SSRI, escitalopram, on measures of ‘cold’ cognition (including inhibition, cognitive flexibility, memory) and ‘hot cognition’ including decision-making and particularly reinforcement learning. The study, conducted at the University of Copenhagen between May 2020 and October 2021, used a double-blind placebo-controlled design with 66 healthy volunteers, semi-randomised to receive either 20 mg of escitalopram (n = 32) or placebo (n = 34), balanced for age, sex and intelligence quotient (IQ) for at least 21 days. Questionnaires, neuropsychological tests and serum escitalopram measures were taken. We analysed group differences on the cognitive measures using linear regression models as well as innovative hierarchical Bayesian modelling of the Probabilistic Reversal Learning (PRL) task. The novel and important finding was that escitalopram reduced reinforcement sensitivity compared to placebo on both the Sequential Model-Based/Model-Free task and the PRL task. We found no other significant group differences on ‘cold’ or ‘hot’ cognition. These findings demonstrate that serotonin reuptake inhibition is involved in reinforcement learning in healthy individuals. Lower reinforcement sensitivity in response to chronic SSRI administration may reflect the ‘blunting’ effect often reported by patients with MDD treated with SSRIs. Trial Registration: NCT04239339.

Cognitive affective biases describe the tendency to process negative information or positive information over the other. These biases can be modulated by changing extracellular serotonin (5‐HT) levels in the brain, for example, by pharmacologically blocking and downregulating the 5‐HT transporter (5‐HTT), which remediates negative affective bias. This suggests that higher levels of 5‐HTT are linked to a priority of negative information over positive, but this link remains to be tested in vivo in healthy individuals. We, therefore, evaluated the association between 5‐HTT levels, as measured with [ 11 C]DASB positron emission tomography (PET), and affective biases, hypothesising that higher 5‐HTT levels are associated with a more negative bias. We included 98 healthy individuals with measures of [ 11 C]DASB binding potential (BP ND ) and affective biases using The Emotional Faces Identification Task by subtracting the per cent hit rate for happy from that of sad faces (EFIT AB ). We evaluated the association between [ 11 C]DASB BP ND and EFIT AB in a linear latent variable model, with the latent variable (5‐HTT LV ) modelled from [ 11 C]DASB BP ND in the fronto‐striatal and fronto‐limbic networks implicated in affective cognition. We observed an inverse association between 5‐HTT LV and EFIT AB ( β = −8% EFIT AB per unit 5‐HTT LV , CI = −14% to −3%, p = .002). These findings show that higher 5‐HTT levels are linked to a more negative bias in healthy individuals. High 5‐HTT supposedly leads to high clearance of 5‐HT, and thus, a negative bias could result from low extracellular 5‐HT. Future studies must reveal if a similar inverse association exists in individuals with affective disorders.

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