¹Kyushu University, Department of Neuropsychiatry, Graduate School of Medical Sciences, Fukuoka, Japan, ²Asahikawa Medical University, Department of Functional Anatomy and Neuroscience, Asahikawa, Japan, ³Hokkaido University, Department of Psychiatry, Graduate School of Medicine, Sapporo, Japan

Background: Previous research on mental disorders, including depression, has mainly been based on the hypothesis that nerves and synapses are related to mental disorders. However, recent studies have highlighted inflammation as an important disease-modifying factor in mental disorders. Animal studies have reported that antidepressants, previously thought to act on neural synapses, also have anti-inflammatory effects on microglia, which are immune cells in the brain. However, analyzing live human-derived microglia at the cellular level is technically and ethically difficult, and reports on this topic are limited. Our laboratory has developed induced microglia-like cells (iMG cells) derived from peripheral blood as a tool to explore the dynamics of microglia in the human brain and has published research reports at the human level (Ohgidani, M., Kato, TA. et al. Scientific Reports 2014). In this study, we focused on escitalopram, a representative antidepressant, and evaluated its effects on microglia using iMG cells.

Aims & Objectives: This study aimed to evaluate the effects of escitalopram on microglia and to gain insights into human subjects using iMG cells.

Method: iMG cells were generated from three healthy subjects, and the effect of escitalopram on microglia activation by Poly I:C stimulation was analyzed. Inflammatory cytokine gene expression was evaluated by qPCR, and comprehensive gene expression changes in iMG cells from one participant were examined by 3' RNA-seq.

Results: The cell morphology of induced iMG cells varied among individuals. qPCR analysis showed that low-dose escitalopram suppressed TNF expression in iMG cells from all three healthy individuals, suggesting that escitalopram may exert anti-inflammatory effects. 3'RNA-seq results demonstrated that treatment with high-dose escitalopram alone increased the expression of pathways related to microtubules, indicating escitalopram may be involved in microtubule organization. Furthermore, a group of genes showed reduced expression in the presence of Escitalopram following Poly I:C stimulation. These genes were associated with pathways regulating cellular responses to various metabolic processes and cellular response to oxidative stress conditions, as well as apoptotic cell clearance.

Discussion & Conclusions: Escitalopram, which has been reported to have anti-inflammatory effects in animal models (Su F et.al. Neuroscience 2015), was also suggested to have anti-inflammatory effects in humans. Although there were individual differences in the morphology of induced iMG cells and the anti-inflammatory effects of escitalopram, these individual differences are considered useful for personalized healthcare, such as for screening drug responsiveness in individual patients. This study is valuable in that reverse translational research using iMG cells can evaluate individual differences in a heterogeneous human population. Based on reports that microtubules dynamically change in response to stimulation (Maria Rosito. et al. Cell Report 2023), it is conceivable that high-dose escitalopram may affect microtubule organization in some individuals by causing microglia to undergo amoeboid morphological changes. To validate these findings, further research is necessary, including expanding the sample size for both healthy individuals and patients and performing differential expression analysis. Obtaining more reliable results is expected to clarify the association between Escitalopram and inflammation in human specimens.