Scientists have discovered why common antidepressants cause about half of users to feel emotionally “dulled”. 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 received an antidepressant in 2021/22. A widely used class of antidepressants, especially for persistent or severe cases, is the selective serotonin reuptake inhibitors (SSRIs). These drugs target serotonin, a chemical that carries messages between nerve cells in the brain and has been dubbed the “pleasure chemical.” Common SSRIs include citalopram (Celexa), escitalopram (Lexapro), paroxetine (Paxil, Pexeva), fluoxetine (Prozac), and sertraline (Zoloft).
One of the widely reported side effects of SSRIs is “dullness,” where patients report feeling emotionally dull and no longer find things as enjoyable as they once were. It is thought that between 40 and 60% of patients taking SSRIs experience this side effect.
To date, most studies of SSRIs have only looked at 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 from the University of Cambridge, in collaboration with the University of Copenhagen, sought to solve this problem by recruiting healthy volunteers and administering escitalopram, an SSRI known to be one of the better tolerated, over several weeks and by evaluating the impact. the drug had on their performance on a series of cognitive tests.
A total of 66 volunteers took part in the experiment, 32 of whom received escitalopram while the other 34 received a placebo. Volunteers took the drug or placebo for at least 21 days and completed a comprehensive set of self-report questionnaires and received a series of tests to assess cognitive functions, including learning, inhibition, executive function, reinforcement behavior and decision making.
The results of the study are published today (January 23, 2023) in the journal Neuropsychopharmacology.
The team found no significant differences between the groups when it came to ‘cold’ cognition, such as attention and memory. There was no difference in most “hot” cognition tests – the cognitive functions that involve our emotions.
However, the key new finding was that there was reduced sensitivity to reinforcement on two tasks for the escitalopram group compared to those on placebo. Reinforcement learning is how we learn from feedback from our actions and environment.
In order to assess the sensitivity of the reinforcement, the researchers used a “probabilistic inversion test”. In this task, a participant would typically see 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 out of five times. The volunteers would not be told about this rule, but would have to learn it themselves, and at some point in the experiment the probabilities would change and the participants would have to learn the new rule.
The team found that participants taking escitalopram were less likely to use positive and negative feedback to guide their learning of the task compared to participants taking placebo. This suggests that the drug affected their sensitivity to rewards and their ability to respond accordingly.
The finding may also explain the only difference the team found in self-reported questionnaires, which was that volunteers taking escitalopram had more difficulty reaching orgasm during sex, a side effect often reported by women. patients.
Professor Barbara Sahakian, lead author from the University of Cambridge Department of Psychiatry and Clare Hall Fellow, said: “Emotional blunting is a common side effect of SSRI antidepressants. In a way, that may be part of how they work – they take away some of the emotional pain that people who suffer from depression feel, but, unfortunately, they seem to take away some of the fun, too. From our study, we can now see that this is because they become less responsive to rewards, which provide important feedback.
Dr Christelle Langley, co-lead author also from the Department of Psychiatry, added: “Our results provide important evidence for the role of serotonin in reinforcement learning. We are following this work with a study examining neuroimaging data to understand how escitalopram affects the brain during reward learning.
Reference: “Chronic Escitalopram in Healthy Volunteers Has Specific Effects on Reinforcement Sensitivity: A Semi-Randomized, Double-Blind, Placebo-Controlled Study” by Langley, C, Armand, S, et al., January 23, 2023 , Neuropsychopharmacology.
The research was funded by the Lundbeck Foundation.