Scientists have unraveled why commonly used antidepressants cause about half of users to feel emotionally ‘blunted’. In a study published today, they show that drugs affect reinforcement learning, an important behavioral process that allows us to learn from our environment.
According to the NHS, more than 8.3 million patients in England took antidepressant medication in 2021/22. One class of antidepressants commonly used, especially for persistent or severe cases, are selective serotonin reuptake inhibitors (SSRIs). These drugs target serotonin, a chemical called the “pleasure chemical” that carries messages between nerve cells in the brain. Common SSRIs include Citalopram (Celexa), Escitalopram (Lexapro), Paroxetine (Paxil, Pexeva), Fluoxetine (Prozac), and Sertraline (Zoloft).
One of the commonly reported side effects of SSRIs is “blinding,” in which patients report feeling emotionally dull and no longer find things as pleasurable as they used to be. It is believed that 40-60% 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 have been 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 issue by recruiting healthy volunteers and administering escitalopram, an SSRI known to be one of the best tolerated, for several weeks and evaluating the effect. The drug’s performance was in a series of cognitive tests.
A total of 66 volunteers participated in the trial, 32 of whom were given escitalopram and the other 34 were given placebo. Volunteers took the drug or placebo for at least 21 days and completed a comprehensive set of self-report questionnaires and were given a series of tests to assess cognitive functions, including learning, inhibition, executive function, reinforcement behavior, and decision-making.
The results of the study were published today (January 23, 2023) in the journal. neuropsychopharmacology.
The team found no significant group differences when it comes to ‘cold’ cognition such as attention and memory. On most ‘hot’ tests of cognition – there was no difference in cognitive function involving our emotions.
However, the key new finding was reduced susceptibility to supplementation in the two tasks for the escitalopram group compared to placebo. Reinforcement learning is how we learn from our actions and feedback from our environment.
To assess supplement sensitivity, the researchers used a ‘probability reversal test’. In this task, a participant is typically shown two stimuli, A and B. If they choose A, four out of five times get a prize; If they chose B, they would only get one-fifth of the prize. Volunteers would not be told this rule, but would have to learn it themselves, and at some point in the experiment, the probabilities would change and participants would have to learn the new rule.
The team found that participants who took escitalopram were less likely to use positive and negative feedback to guide their learning of the task, compared to participants who took a placebo. This suggests that the drug affects their sensitivity to rewards and their ability to respond accordingly.
This finding may also explain the only difference the team found in self-reported surveys; Volunteers taking escitalopram have more difficulty achieving orgasm while having sex, a side effect often reported by patients.
Professor Barbara Sahakian, senior author in the Department of Psychiatry at the University of Cambridge and a Fellow at Clare Hall, said: “Emotional atrophy is a common side effect of SSRI antidepressants. In a way, they may partly work that way – they get some of the emotional pain that people with depression feel, but unfortunately, they also seem to get some of the pleasure. We can now see from our study that this is because they become less sensitive to rewards that provide important feedback.”
Also from the Department of Psychiatry, co-first author Dr. Christelle Langley added: “Our findings provide important evidence for the role of serotonin in reinforcement learning. We follow up with a study that examines neuroimaging data to understand how escitalopram affects the brain during reward learning.
Reference: “Chronic escitalopram has certain effects on supplementation sensitivity in healthy volunteers: A double-blind, placebo-controlled quasi-randomized study”, Langley, C, Armand, S, et al, 23 Jan 2023. neuropsychopharmacology.
The research was funded by the Lundbeck Foundation.