Changes in hippocampal volume, 5-HT4 receptor binding, and verbal memory over the course of antidepressant treatment in major depressive disorder

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Abstract

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.
OriginalsprogEngelsk
TidsskriftJournal of Psychiatric Research
Vol/bind181
Sider (fra-til)197-205
Antal sider9
ISSN0022-3956
DOI
StatusUdgivet - 2025

Bibliografisk note

Funding Information:
Financial support for the study was granted from the Innovation Fund Denmark (4108-00004B), Lundbeck (GrantID: R279\u20132018\u20131145), Research Fund of the Mental Health Services - Capital Region of Denmark, Savv\u00E6rksejer Jeppe Juhl og hustru Ovita Juhls Mindelegat, Augustinus Foundation (GrantID: 16-0058), Research Council of Rigshospitalet (R149-A6325), the Independent Research Fund Denmark (GrantID: DFF-6120-00038).

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