¹University of Cambridge, Psychiatry, Cambridge, United Kingdom

Background: Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed chronically to patients, including those with major depressive disorder (MDD). However, most research with SSRIs has focused on acute and sub-chronic administration, leaving the long-term cognitive effects poorly understood. ‘Hot’ and ‘cold’ cognitive processes are known to be affected in MDD¹, but it is not yet known how these are modulated by SSRIs. Serotonin has been shown to play a key role in reinforcement learning, cognitive flexibility, and affective processing by shaping sensitivity to rewards and punishments^{2,3,4,5,6,7,8,9,10,11}. However, evidence regarding the modulation of SSRIs with more chronic administration remains to be examined. To avoid confounding of the effects of MDD with those of SSRIs, we used healthy volunteers.

Aims & Objectives: We aimed to (i) quantify the effects of at least 3 weeks of escitalopram on ‘hot’ and ‘cold’ cognition, in particular reward learning; (ii) delineate neural correlates of reward-learning and emotion recognition under chronic SSRI exposure; and (iii) test whether escitalopram alters synaptic density in healthy volunteers.

Method: We synthesise findings from four complementary studies, including behavioural assessments¹², fMRI during reward learning¹³ and face processing¹⁴, and PET imaging of synaptic density using [¹¹C]UCB‑J¹⁵.
In a double-blind, placebo-controlled, semi‑randomised trial in healthy volunteers, participants received chronic escitalopram (20mg) for at least 21 days. Behavioural tasks probed ‘hot’ and ‘cold’ cognition, reinforcement learning and cognitive flexibility, including computational modelling to dissociate reward learning parameters¹². fMRI studies examined neural responses during probabilistic reward learning¹³ and emotional face processing¹⁴. PET imaging with [¹¹C]UCB‑J indexed SV2A binding as a proxy for synaptic plasticity, comparing regional and global changes over weeks of escitalopram versus placebo¹⁵.

Results: Behaviourally, chronic escitalopram produced specific alterations in reinforcement sensitivity, which may reflect the 'blunting' effect often reported by patients with MDD treated with SSRIs¹². fMRI during reward learning revealed decreased activation of the intraparietal sulcus following SSRI when compared to the placebo, suggesting altered value encoding, potentially reducing reinforcement sensitivity and learning from feedback¹³. However, this may be an advantage in MDD as it reduces the abnormal response to negative feedback. In the face processing paradigm, chronic escitalopram attenuated functional responses to emotional faces in frontal and occipital networks, consistent with dampened affective reactivity under SSRI exposure¹⁴. PET imaging demonstrated an association between duration of escitalopram and SV2A binding, indicating elevated synaptic plasticity with longer duration, providing a biological substrate for the observed changes in cognition and affect¹⁵.

Discussion & Conclusions: Chronic escitalopram in healthy volunteers yields convergent behavioural and neural effects: a selective reduction in reinforcement sensitivity and altered feedback learning, attenuation of affective reactivity to emotional stimuli, and measurable increases in synaptic plasticity. Our results suggest that sustained serotonergic modulation may recalibrate decision policies and affective processing via synaptic plasticity mechanisms, informing how SSRIs support recovery in disorders characterised by maladaptive reinforcement learning and heightened negative affect. Our studies also highlight the need for future research to examine the chronic effects of SSRI administration in ‘hot’, and ‘cold’ cognition, particularly reinforcement behaviour in patients with neuropsychiatric disorders such as MDD.