Serotonin reuptake inhibitors have been reported to increase hippocampal volume and improve memory function in patients with Major depressive disorder (MDD). The postsynaptic 5-HT4 receptor (5-HT4R) is involved in hippocampal development, familial risk for depression and depressive pathology. In an open-label trial with 91 patients (72% female, mean 27.2 years) with MDD, we investigated the relation between changes in hippocampal volume, 5-HT4R, and verbal memory during 12 weeks treatment with 10-20 mg escitalopram. Depression severity, verbal memory, MRI-determined hippocampus volume and PET-determined 5-HT4R were measured pretreatment. Forty-three patients were rescanned at week 8. HAMD17 was reassessed at week 8 and together with verbal memory at week 12. We used mixed-effects models and linear regressions. We estimated a 27 mm3 (p = 0.086) reduction in mean hippocampus volume over the course of eight weeks. In patients clinically responding to treatment, we estimated a 45 mm3 reduction (p = 0.019), 8 mm3 increase in non-responders (p = 0.78), and a 52 mm3 group difference (p = 0.12). Hippocampal 5-HT4 receptor binding before treatment and at week eight was negatively associated with hippocampal volume in females, regardless of treatment response (p-values≤0.006). However, no clear evidence for an association in males or sex interaction could be established (p-values≥0.16). Although the hippocampus volume did not increase with treatment, we found a decrease in clinically responsive patients. Our findings suggest an association between 5-HT4R signalling and changes in hippocampal volume in females with MDD during antidepressant treatment, highlighting the need for further investigation into the role of serotonergic mechanisms in hippocampal plasticity.
Keywords: Escitalopram; Hippocampus; Hippocampus volume; Major depressive disorder; SSRI; Verbal memory.
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