A study published in Biological Psychiatry investigated the role of the 5-HT4 receptor (5-HT4R) in patients with major depressive disorder (MDD) and how changes in this receptor may relate to the effects of antidepressant treatment, particularly focusing on cognitive outcomes. The study included 90 participants, 81 of whom completed the 8-week follow-up and 78 who completed the 12-week assessment.
The results showed a significant 9% decrease in 5-HT4R binding in the neostriatum after eight weeks of antidepressant treatment. This reduction in 5-HT4R binding aligns with findings from prior studies, which showed similar effects in healthy individuals treated with SSRIs, indicating that these medications can effectively alter serotonergic neurotransmission. However, the study found no evidence that the extent of this reduction was linked to overall clinical improvements in depression symptoms, suggesting that the downregulation of 5-HT4R may not directly contribute to the therapeutic effects of Selective Serotonin Reuptake Inhibitors (SSRIs) on core symptoms of MDD.
While the reduction in 5-HT4R binding did not predict clinical response, it did correlate with cognitive outcomes, particularly verbal memory. Patients who experienced less reduction in 5-HT4R binding showed more significant improvements in verbal memory performance over the 12 weeks of treatment.
Vibeke H. Dam, PhD, from Copenhagen University Hospital, highlighted the significance of these findings, stating, "Verbal memory is often impaired in depression, and this has a lot of impact on patients' ability to work and have a normal life. That's why we're so excited about this receptor in particular. If we can find a way to activate it more directly, we're thinking this could be a way to treat this memory symptom that a lot of patients have and that currently we don't really have a treatment for."
The findings open up the possibility of using 5-HT4R agonists as an augmentation strategy to specifically address cognitive symptoms in MDD. Since SSRIs and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) are primarily designed to alleviate mood symptoms, the co-administration of drugs that target 5-HT4R might offer a new therapeutic avenue for improving memory and other cognitive functions in depressed patients.
This study contributes to our understanding of how serotonergic neurotransmission is modulated by antidepressants and underscores the importance of 5-HT4R as a target for cognitive symptoms in MDD. While current treatments reduce 5-HT4R availability, the study suggests that maintaining or even enhancing 5-HT4R signaling could improve cognitive outcomes, particularly verbal memory.
Sources: Biological Psychiatry, Medscape