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MILAN, September 23, 2024 – A groundbreaking study has revealed that antidepressants, specifically escitalopram and duloxetine, significantly improve verbal memory in individuals with moderate to severe depression. This clinical effect has been linked to changes in serotonin 4 (5-HT4) receptor levels in the brain, as detected through PET scans. These findings were presented at the 37th European College of Neuropsychopharmacology (ECNP) Congress and published in Biological Psychiatry.
The research, led by Dr. Vibeke H. Dam of Copenhagen University Hospital, suggests that targeting the 5-HT4 receptor may offer a new approach to treating memory impairments commonly experienced by depression patients. “Verbal memory is often impaired in depression, impacting patients’ ability to work and lead normal lives. We’re excited about this receptor’s potential,” Dr. Dam shared.
Dr. Dam emphasized the importance of these findings, as current treatments for depression-related memory problems are limited. “If we can find a way to activate the 5-HT4 receptor more directly, we may be able to address this challenging symptom.”
Largest Trial of Its Kind
The study is the largest single-site PET trial to explore serotonergic neurotransmission during antidepressant treatment in major depressive disorder. It included 90 patients who underwent cognitive testing and brain scans before starting escitalopram, a selective serotonin reuptake inhibitor (SSRI). Those who did not respond after four weeks (n=14) were switched to duloxetine, a serotonin-norepinephrine reuptake inhibitor (SNRI).
Both medications influence serotonin 4 receptor activity. Escitalopram primarily increases serotonin levels, while duloxetine affects both serotonin and norepinephrine. The study’s primary focus was on verbal memory changes, while secondary outcomes included working memory, reaction time, and emotional recognition.
After eight weeks, a subset of 40 patients underwent repeat PET scans, and all patients completed follow-up cognitive tests after 12 weeks. Matching neuroimaging and cognitive data were available for 88 patients at baseline and 39 patients at follow-up.
The study showed a reduction in 5-HT4 receptor levels following antidepressant treatment, indicating a physiological response to increased serotonin availability. However, there was no direct correlation between 5-HT4 receptor levels and depressive symptoms, as measured by the Hamilton Depression Rating Scale (HAMD6).
Verbal Memory Gains Observed
Interestingly, while most patients showed improvements in both depressive symptoms and verbal memory, these two outcomes were not correlated. Dr. Dam noted that verbal memory improvements were linked to changes in 5-HT4 receptor activity, suggesting that this receptor plays a key role in cognitive function, regardless of mood improvements.
“Even though there is a downregulation of the receptor, there is still significant activation, and we believe this is the important factor for memory improvement,” Dr. Dam explained.
Potential for Future Treatments
The study’s findings have sparked interest in the potential to repurpose existing drugs that target the 5-HT4 receptor. Dr. Dam highlighted that prucalopride, a medication currently used for treating gastroparesis, has been shown to enhance memory and learning in healthy volunteers by activating the 5-HT4 receptor. Researchers are now seeking funding to explore its use in treating cognitive symptoms in depression, as well as in other conditions such as concussion and diabetes.
Dr. Vibe G. Frokjaer, a co-investigator, emphasized the importance of further research to understand the broader implications of these findings. “Poor cognitive function is difficult to treat, and may require separate interventions beyond the treatment of core depressive symptoms,” Dr. Frokjaer said.
Expert Commentary
Commenting on the study, Dr. Philip Cowen, a professor of psychopharmacology at the University of Oxford, noted the significance of the findings in the context of ongoing debates about the role of serotonin in depression. “The PET studies by the Copenhagen Group provide clear evidence that 5-HT4 receptors are decreased in unmedicated depressed patients and play a key role in cognitive function,” he said.
Dr. Cowen highlighted recent research from Oxford demonstrating that prucalopride, used for constipation, improves memory in both healthy individuals and those at risk of depression, reinforcing the potential for targeting the 5-HT4 receptor in future treatments.
Funding and Support
The study was funded by several organizations, including the Innovation Fund Denmark, the Research Fund of the Mental Health Services – Capital Region of Denmark, and the Lundbeck Foundation.
As research continues, these findings may pave the way for new treatments that address the cognitive symptoms of depression, offering hope to patients struggling with memory impairments alongside their mood disorders.
