Scientists have discovered why common antidepressants make about half of users feel emotionally “stupid.” In a study published today, they show that the drugs have an impact on reinforcing 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 common class of antidepressant, particularly for persistent or severe cases, is selective serotonin reuptake inhibitors (SSRIs). These drugs target serotonin, a chemical that carries messages between nerve cells in the brain and is called the “pleasure chemical.” 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 ‘numbness’, where patients report feeling emotionally dull and not enjoying things as much as they used to. It is believed that 40-60% of patients taking SSRIs experience this side effect.
To date, most studies on SSRIs have only examined their short-term use, but for clinical use in depression, these drugs are taken chronically, over an extended period of time. A team led by researchers from the University of Cambridge, in collaboration with the University of Copenhagen, set out to tackle this by recruiting healthy volunteers and administering escitalopram, an SSRI known to be one of the best tolerated, over several weeks and assessing 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 and the remaining 34 a placebo. Volunteers took the drug or placebo for at least 21 days and completed a comprehensive battery of self-report questionnaires and were given a battery of tests to assess cognitive functions, including learning, inhibition, executive function, reinforcing behavior and decision-making.
The results of the study are published today (January 23, 2023) in the journal Neuropsychopharmacology.
The team found no significant group differences when it came to ‘cold’ cognition, such as attention and memory. There were no differences in most tests of “hot” cognition – cognitive functions involving our emotions.
However, the most important new finding was that there was a reduced gain sensitivity 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.
To assess gain sensitivity, the researchers used a “probabilistic reversal test.” In this task, a participant is typically presented with two stimuli, A and B. If they choose A, they receive a reward four times out of five; if they chose B, they would receive a reward only one in five times. Volunteers would not hear this rule, but would have to learn it themselves, and at some point in the experiment, the odds would change and participants would have to learn the new rule.
The team found that participants taking escitalopram were less likely to use the positive and negative feedback to guide their learning compared to participants taking placebo. This suggests that the drug affected their sensitivity to the rewards and their ability to respond accordingly.
The finding may also explain the only difference the team found in the self-reported questionnaires, that volunteers taking escitalopram had more difficulty reaching orgasm during 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 partly how they work – they take away some of the emotional pain that people with depression feel, but unfortunately it seems that they also take away some of the pleasure.From our research we can now see that this is because they become less sensitive to rewards, which are important to give feedback.”
Dr. Christelle Langley, co-first author also from the Department of Psychiatry, added: “Our findings provide important evidence for the role of serotonin in learning enhancement. We follow up this work with a study of 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 Double-Blind, Placebo-Controlled Semi-Randomized Study” By Langley, C, Armand, S, et al., January 23, 2023, Neuropsychopharmacology.
The research was funded by the Lundbeck Foundation.