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

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. We here investigate the relationship between 5-HT₄R, clinical outcomes, and cognitive function in patients with MDD who initiate SSRI drug treatment.

Methods: 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).

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, nor was it associated with change in HAMD₆.

Conclusions: 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.