Abstract
Background
Brain serotonin 4 receptor (5-HT4R) levels are lower in untreated patients with major depressive disorder (MDD) and are linked to verbal memory. Here, we investigated the relationship between 5-HT4R levels, clinical outcomes, and cognitive function in patients with MDD who initiated selective serotonin reuptake inhibitor drug treatment.
Methods
Ninety patients with moderate to severe depression underwent molecular brain imaging to measure 5-HT4R binding prior to antidepressant treatment with escitalopram. Pretreatment 5-HT4R binding was assessed for its ability to predict treatment outcome at weeks 4, 8, or 12. In 40 patients who were rescanned 8 weeks posttreatment, change in cerebral 5-HT4R binding was correlated with change in verbal memory and with change in depressive symptoms, as evaluated by the 6-item Hamilton Depression Rating Scale.
Results
After 8 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 with overall clinical depressive symptom outcomes. Pretreatment 5-HT4R binding did not predict clinical recovery status at week 8 and was not associated with change in the 6-item Hamilton Depression Rating Scale scores.
Conclusions
In patients with moderate to severe MDD, treatment with selective serotonin reuptake inhibitors downregulated neostriatal 5-HT4R levels, which is consistent with the notion that the drugs increase cerebral extracellular serotonin. The less global brain 5-HT4R levels were downregulated after selective serotonin reuptake inhibitors, the more verbal memory improved, highlighting the potential importance of 5-HT4R as a treatment target in MDD. The findings offer insights into mechanisms that underlie antidepressant effects and point to new directions for precision medicine treatments for MDD.
Brain serotonin 4 receptor (5-HT4R) levels are lower in untreated patients with major depressive disorder (MDD) and are linked to verbal memory. Here, we investigated the relationship between 5-HT4R levels, clinical outcomes, and cognitive function in patients with MDD who initiated selective serotonin reuptake inhibitor drug treatment.
Methods
Ninety patients with moderate to severe depression underwent molecular brain imaging to measure 5-HT4R binding prior to antidepressant treatment with escitalopram. Pretreatment 5-HT4R binding was assessed for its ability to predict treatment outcome at weeks 4, 8, or 12. In 40 patients who were rescanned 8 weeks posttreatment, change in cerebral 5-HT4R binding was correlated with change in verbal memory and with change in depressive symptoms, as evaluated by the 6-item Hamilton Depression Rating Scale.
Results
After 8 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 with overall clinical depressive symptom outcomes. Pretreatment 5-HT4R binding did not predict clinical recovery status at week 8 and was not associated with change in the 6-item Hamilton Depression Rating Scale scores.
Conclusions
In patients with moderate to severe MDD, treatment with selective serotonin reuptake inhibitors downregulated neostriatal 5-HT4R levels, which is consistent with the notion that the drugs increase cerebral extracellular serotonin. The less global brain 5-HT4R levels were downregulated after selective serotonin reuptake inhibitors, the more verbal memory improved, highlighting the potential importance of 5-HT4R as a treatment target in MDD. The findings offer insights into mechanisms that underlie antidepressant effects and point to new directions for precision medicine treatments for MDD.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Biological Psychiatry |
| Vol/bind | 97 |
| Udgave nummer | 3 |
| Sider (fra-til) | 261-268 |
| Antal sider | 8 |
| ISSN | 0006-3223 |
| DOI | |
| Status | Udgivet - 2025 |
Bibliografisk note
Funding Information:We thank all participants for taking part in this study. We gratefully acknowledge all investigators involved, collaborating general practitioners, the Center for Referral and Diagnostics, Mental Health Services, Capital Region of Copenhagen and other collaborators who helped throughout the study. We especially thank Lone Ibsgaard Freyr, Bente Dall, Gerda Thomsen, Svitlana Olsen, Agnete Dyssegaard, Arafat Nasser, Ida Marie Brandt, Anna Maria Florescu, Asbj\u00F8rn Poulsen and Mads Heidemann for their excellent clinical, laboratory and technical assistance. Economic support was granted from the Innovation Fund Denmark, Research Fund of the Mental Health Services - Capital Region of Denmark, Independent Research Fund Denmark, G.J. Foundation, Research Council of Rigshospitalet, Augustinus Foundation, Savv\u00E6rksejer Jeppe Juhl og hustru Ovita Juhls Mindelegat, Lundbeck Foundation and the H. Lundbeck A/S. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
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© 2024 Society of Biological Psychiatry