Scientists have explained why common antidepressants cause half of most users to feel emotionally “blunted”, their recent collaborative study showing that the drugs affect reinforcement learning, an important behavioural process allowing us to learn from our environment.
More than 8.3m patients in England received an antidepressant drug in 2021/22. A widely-used class of antidepressants, particularly for persistent or severe cases, is selective serotonin reuptake inhibitors (SSRIs), which target serotonin, the chemical that carries messages between nerve cells in the brain and has been dubbed the “pleasure chemical”.
A common side effect of SSRIs is “blunting”, where patients report feeling emotionally dull, no longer finding things as pleasurable as previously. Between 40% and 60% of patients taking SSRIs experience this side effect.
To date, most studies of SSRIs have only examined their short term use, but, for clinical use in depression these drugs are taken chronically, over a longer period of time.
A team led by researchers at the University of Cambridge, in collaboration with the University of Copenhagen, sought to address this by recruiting healthy volunteers and administering escitalopram, an SSRI known as one of the best-tolerated, over several weeks, and assessing the impact it had on their performance on a suite of cognitive tests.
In total, 66 volunteers were involved, 32 of whom were given escitalopram while the other 34 were given a placebo. Volunteers took the drug or placebo for at least 21 days and completed a comprehensive set of self-report questionnaires. They were also given tests to assess cognitive functions including learning, inhibition, executive function, reinforcement behaviour, and decision-making.
The results of the study were published in Neuropsychopharmacology.
The team found no significant group differences when it came to “cold” cognition, like attention and memory. There were also no differences in most tests of “hot” cognition – cognitive functions that involve our emotions.
However, the key novel finding was that there was reduced reinforcement sensitivity on two tasks for the escitalopram group compared with those on placebo. Reinforcement learning is how we learn from feedback from our actions and environment.
To assess reinforcement sensitivity, the researchers used a probabilistic reversal test. In this task, a participant would typically be shown two stimuli, A and B. If they chose A, then four out of five times, they would receive a reward; if they chose B, they would only receive a reward one time out of five. Volunteers would not be told this rule, but would have to learn it themselves, and at some point in the experiment, the probabilities would switch and participants would need to learn the new rule.
The team found that those taking escitalopram were less likely to use the positive and negative feedback to guide their learning of the task compared with participants on placebo. This suggests the drug affected their sensitivity to the rewards and their ability to respond accordingly.
The finding may also explain the one difference the team found in the self-reported questionnaires: that volunteers taking escitalopram had more trouble reaching orgasm when having sex, a side effect often reported by patients.
Professor Barbara Sahakian, senior author, from the Department of Psychiatry at the University of Cambridge and a Fellow at Clare Hall, said: “Emotional blunting is a common side effect of SSRI antidepressants. In a way, this may be in part how they work – they take away some of the emotional pain felt by people with depression, but unfortunately, it seems they also remove some of the enjoyment. From our study, we can now see that this is because they become less sensitive to rewards, which provides important feedback.”
Study details
Chronic escitalopram in healthy volunteers has specific effects on reinforcement sensitivity: a double-blind, placebo-controlled semi-randomised study.
Christelle Langley, Sophia Armand, Qiang Luo, George Savulich, Tina Segerberg, Anna Søndergaard, Elisabeth B. Pedersen, Nanna Svart, Oliver Overgaard-Hansen, Annette Johansen, Camilla Borgsted, Rudolf N. Cardinal, Trevor W. Robbins, Dea S. Stenbæk, Gitte M. Knudsen, Barbara J. Sahakian.
Published in Nature’s Neuropsychopharmacology on 23 January 2023
Abstract
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.
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