Certain antidepressants may improve brain function, study finds

Researchers have found that SSRI (selective serotonin reuptake inhibitor) antidepressants have the potential to improve certain cognitive functions, such as verbal memory. They 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 was presented for the first time at the ECNP Conference in Milan, after publication in the journal Biological Psychiatry.

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 5-HT₄ receptor.

The researchers began by scanning the brains of 90 depressed patients, to measure the quantity of 5-HT₄ receptor which serotonin binds to. At the same time, patients were given a series of tests to measure mood and cognitive abilities.

Patients were given daily doses of escitalopram, and at the end of an eight-week period, 40 patients were rescanned to measure the quantity of 5-HT₄ receptor in the brain. The mood of the patients had improved, but the team also found that the levels of 5-HT₄ 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.

“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 5-HT₄ receptor and suggests that direct serotonin 4 receptor stimulation may be an 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 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 which specifically stimulate the 5-HT₄ 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 which specifically bind to and stimulate 5-HT₄ , which the team may repurpose in these trials.

Professor Philip Cowen, Professor of Psychopharmacology at the University of Oxford, who was not involved in this work, 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.”