Researchers have uncovered that SSRIs, specifically escitalopram, not only improve mood in depressed patients but also enhance cognitive functions such as verbal memory.
This improvement is linked to a reduction in the brain’s 5HT4 serotonin receptors. Further studies aim to investigate drugs targeting these receptors to potentially treat cognitive deficits in depression, affirming the critical role of serotonin in both mood and cognitive functions.
SSRI Antidepressants and Cognitive Enhancement
Antidepressants have the potential to improve certain cognitive functions, such as verbal memory, according to new research on SSRI (Selective Serotonin Reuptake Inhibitors). The scientists measured brain function in patients before and after taking the SSRI escitalopram and correlated this to a drop in the level of one of the serotonin receptors in the brain and to cognitive improvements during treatment. This work is presented for the first time at the ECNP Conference in Milan, after recent publication in the journal Biological Psychiatry.
Serotonin’s Role in Well-being and Depression
Serotonin is often described as a ‘feel good’ chemical, and higher levels of serotonin circulating in the brain contribute to a sense of well-being, and can ease clinical depression in most sufferers. There are several serotonin receptors in the brain, and all will serve to regulate well-being by regulating circulating serotonin’s interaction with the brain. However, this work concentrated on only one serotonin receptor, the 5HT4 receptor.
The researchers began by scanning the brains of 90 depressed patients, to measure the quantity of 5HT4 receptor to which serotonin binds. At the same time, patients were given a series of tests to measure mood and cognitive abilities.
Linking Cognitive Gains to SSRI Treatment
Patients were given daily doses of escitalopram, and at the end of an 8-week period, 40 patients were rescanned to measure the quantity of 5HT4 receptors in the brain. The mood of the patients had improved, but the team also found that the levels of 5HT4 receptor had dropped by around 9% possibly due to adaptations to increased levels of serotonin. When they asked these patients to undertake more cognitive tests, they found that their performance had improved, so that the less the 5HT4 receptor had changed the better the cognitive outcome. This phenomenon was particularly prominent for the ability to recall words.
Potential Implications and Future Research
“This is potentially significant” said researcher Vibeke Dam (Copenhagen University Hospital, Rigshospitalet, Denmark), “It seems that the SSRI medication contributes to an improvement on cognitive function, at the same time as helping improve mood. Our work ties the improvement in cognitive function to the specific 5HT4 receptor and suggest that direct serotonin 4 receptor stimulation may be in important pro-cognitive target to consider in optimizing outcomes of antidepressant treatment. It also reinforces the idea that serotonin is crucial to mood improvement.
Co-researcher Vibe Froekjaer (Copenhagen University Hospital, Rigshospitalet, Denmark), added, “This is a first result, so we need to do a lot more work to look at the implications. Poor cognitive function is very hard to treat efficiently and may require extra treatment. This work points to the possibility of stimulating this specific receptor so that we can treat cognitive problems, even aside from whether or not the patient is has overcome the core symptoms of depression.”
The researchers note that this was a real-world study, so there is no placebo control.
The team’s next step is to treat patients with drugs that specifically stimulate the 5HT4 receptor to see the effect on cognitive function; interestingly, serotonin is also found in the gut, and there are drugs available to treat irritable bowel syndrome that specifically bind to and stimulate 5HT4 , which the team may repurpose in these trials.
Expert Perspectives on Serotonin and Cognitive Functions
Commenting, Professor Philip Cowen, Professor of Psychopharmacology at the University of Oxford said:
“In the context of recent controversies about the role of brain serotonin in clinical depression, it is noteworthy that the PET studies of the Copenhagen Group provide unequivocal evidence that brain 5-HT4 receptors are decreased in unmedicated depressed patients. Their work also demonstrates the intimate role of brain 5-HT4 receptors in cognitive function. This confirms recent work from Oxford showing that the 5-HT4 receptor stimulant, prucalopride – a drug licensed for the treatment of constipation- improves memory in both healthy participants and people at risk of depression.”
This is an independent comment, Professor Cowen was not involved in this work.
Reference: “Effect of antidepressant treatment on 5-HT4 receptor binding and associations with clinical outcomes and verbal memory in major depressive disorder” by Vibeke H. Dam, Kristin Köhler-Forsberg, Brice Ozenne, Søren V. Larsen, Cheng Teng Ip, Anders Jorgensen, Dea S. Stenbæk, Jacob Madsen, Claus Svarer, Martin B. Jørgensen, Gitte M. Knudsen and Vibe G. Frokjaer, 22 August 2024, Biological Psychiatry.
DOI: 10.1016/j.biopsych.2024.08.009