Distinct genetic responses to fluoxetine sertraline and citalopram in mouse cortical neurons

Antidepressants are widely prescribed for treating major depressive disorder (MDD); however, their precise therapeutic mechanisms remain incompletely understood. A notable conundrum is the substantial heterogeneity in clinical efficacy among drugs targeting the same molecular pathway, such as selective serotonin reuptake inhibitors (SSRIs). We performed comparative transcriptome analyses of mouse cortical neuron cultures <i>in vitro</i>, treated with fluoxetine, sertraline, or citalopram, revealing distinct drug-specific gene expression patterns. Utilizing self-organizing map (SOM) clustering, we identified gene sets uniquely responsive to each SSRI treatment. Corresponding <i>in vivo</i> analyses also demonstrated drug-specific transcriptomic changes within mouse brains. Integrating both <i>in vitro</i> and <i>in vivo</i> datasets allowed identification of genes consistently and selectively regulated by each SSRI. These findings highlight distinct molecular actions among SSRIs despite their common target. These insights underscore the importance of exploring SSRI actions beyond serotonin pathway and may facilitate the development of more effective and personalized treatment strategies for MDD.