Effect of antidepressant treatment on 5-HT4 receptor binding and associations with clinical outcomes and verbal memory in major depressive disorder

• Published in: Biological psychiatry (1969)
• Main Authors: Dam, Vibeke H., Köhler-Forsberg, Kristin, Ozenne, Brice, Larsen, Søren V., Ip, Cheng Teng, Jorgensen, Anders, Stenbæk, Dea S., Madsen, Jacob, Svarer, Claus, Jørgensen, Martin B., Knudsen, Gitte M., Frokjaer, Vibe G.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 22.08.2024
• Subjects: Antidepressant treatment; Cognition; Depression; Positron emission tomography (PET); Serotonin 4 Receptor; Verbal Memory; Depression; Positron emission tomography (PET); Cognition; Antidepressant treatment; Verbal Memory; Serotonin 4 Receptor
• ISSN: 0006-3223; 1873-2402; 1873-2402
• DOI: 10.1016/j.biopsych.2024.08.009

Brain serotonin 4 receptor (5-HT4R) levels are lower in untreated patients with Major Depressive Disorder (MDD) and are linked to verbal memory. We here investigate the relationship between 5-HT4R, clinical outcomes, and cognitive function in patients with MDD who initiate SSRI drug treatment. Ninety moderately to severely depressed patients 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 week 4, 8 or 12. In 40 patients rescanned 8 weeks post treatment, the change in cerebral 5-HT4R binding was correlated to change in verbal memory and to change in depressive symptoms, as evaluated by the Hamilton Depressive Rating Scale 6 (HAMD6). 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, nor was it associated with change in HAMD6. In patients with moderate to severe MDD, treatment with SSRI’s downregulates neostriatal 5-HT4R levels, consistent with the notion that the drugs increase cerebral extracellular serotonin. The less global brain 5-HT4R levels are downregulated after SSRIs, the more verbal memory improves, highlighting the potential importance of 5-HT4R as a treatment target in MDD. The findings offer insights to mechanisms underlying antidepressant effects and point to new directions for precision medicine treatments for MDD.