Changes in dynamic and static functional connectivity in amygdala subregions in major depressive disorder treated with esketamine in and sertraline: A pilot study.

Introduction: Dysfunction in amygdala networks has been implicated in major depressive disorder (MDD). Pharmacological treatments, such as esketamine and sertraline, are believed to exert their antidepressant effects by modulating amygdalar activity. This study aimed to investigate the relationship between changes in dynamic functional connectivity (dFC) within amygdala subregions and treatment outcomes, with a focus on identifying potential neuroimaging markers.

Methods: Twenty-eight patients with MDD received six intravenous infusions of esketamine (0.25 mg/kg) combined with 2 weeks of sertraline treatment. Mood and cognitive recovery were assessed using the HAMA, HAMD, BSI, and MoCA. Seed-based dFC analysis of resting-state MRI focused on the dorsal amygdala (DA), medial amygdala (MA), and ventrolateral amygdala (VA).

Results: All patients demonstrated positive responses to treatment, with significant reductions in HAMA and HAMD scores, as well as improvements in MoCA scores and a decrease in suicidal ideation. Following treatment, static functional connectivity (sFC) was reduced between the right DA and paracentral lobule, the left VA and multiple regions (including the lentiform nucleus, thalamus, medial prefrontal cortex, inferior parietal lobule, precentral gyrus, and superior parietal lobule), and the right VA and middle frontal gyrus. Conversely, dFC was significantly increased between the right DA and cuneus/superior parietal lobule, and between the left VA and superior parietal lobule. A decrease in dFC was also observed between the left MA and superior temporal gyrus. Correlation analysis showed that dFC between the left MA and superior temporal gyrus was positively correlated with HAMA score. LIMITATION The combined use of esketamine and sertraline limits the ability to differentiate their individual effects. A significant proportion of the patients were adolescents, with only a few adults, which may influence the age-related response to treatment. The study utilized the lowest effective dose of esketamine, thereby leaving the dose-response relationships unexamined. The small sample size further restricts the statistical power of the findings, highlighting the need for larger studies to validate these results.

Conclusion: Altered resting-state and dFC in amygdala subregions may play a role in the mechanisms by which the combination of esketamine and sertraline alleviates depressive symptoms, primarily involving the sensorimotor and default mode networks. Together, the sFC and dFC analyses provide an integrated perspective on depression-related connectivity changes and offer potential targets for treatment.