SSRIs May Boost Verbal Memory by Lowering 5-HT4 Receptor Levels in Depression, Study Reveals

"Antidepressants such as escitalopram and duloxetine have been found to enhance verbal memory in individuals with moderate to severe depression. This clinical effect is associated with alterations in serotonin 4 (5-HT4) receptor levels in the brain, as observed through PET imaging," the researchers stated. The findings indicate that specifically targeting the 5-HT4 receptor may play a key role in enhancing verbal memory in individuals with depression.

According to the authors, the study represents the largest single-site PET trial to date examining serotonergic neurotransmission in major depressive disorder throughout antidepressant treatment.

In untreated patients with Major Depressive Disorder (MDD), levels of brain serotonin 4 receptors (5-HT4R) are lower and associated with verbal memory performance. Vibe G. Frokjaer, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark, and colleagues explored the relationship between 5-HT4R, clinical outcomes, and cognitive function in patients with MDD who begin treatment with selective serotonin reuptake inhibitors (SSRIs).

For this purpose, ninety patients with moderate to severe depression underwent molecular brain imaging to assess 5-HT4R binding before starting treatment with escitalopram. The researchers evaluated pretreatment 5-HT4R binding to predict treatment outcomes at weeks 4, 8, and 12.

In a subset of 40 patients who were rescanned eight weeks after beginning treatment, changes in cerebral 5-HT4R binding were found to correlate with improvements in verbal memory and reductions in depressive symptoms, as measured by the Hamilton Depressive Rating Scale 6 (HAMD6).

The study led to the following findings:

• After eight weeks of serotonergic intervention, neostriatal 5-HT4R binding was reduced by 9%.
• Global change in 5-HT4R binding from baseline was associated with verbal memory outcomes but not overall clinical depressive symptom outcomes.
• Pretreatment 5-HT4R binding did not predict clinical recovery status at week 8, nor was it associated with a change in HAMD6.

The authors concluded that in patients with moderate to severe MDD, SSRI treatment leads to a downregulation of neostriatal 5-HT4 receptor levels, supporting the idea that these medications enhance cerebral extracellular serotonin. They found that greater reductions in global brain 5-HT4 receptor levels following SSRI treatment were associated with improved verbal memory. This underscores the potential significance of 5-HT4 receptors as a therapeutic target in MDD.

"The findings provide valuable insights into the mechanisms behind antidepressant effects and suggest new pathways for precision medicine approaches in treating MDD," they wrote.

Reference:

Dam, V. H., Köhler-Forsberg, K., Ozenne, B., Larsen, S. V., Ip, C. T., Jorgensen, A., Stenbæk, D. S., Madsen, J., Svarer, C., Jørgensen, M. B., Knudsen, G. M., & Frokjaer, V. G. (2024). Effect of antidepressant treatment on 5-HT4 receptor binding and associations with clinical outcomes and verbal memory in major depressive disorder. Biological Psychiatry. https://doi.org/10.1016/j.biopsych.2024.08.009