Escitalopram disrupts PDK1-Akt signaling in B cells through a structure-dependent mechanism independent of SERT.

The PI3K-Akt pathway is a central regulator of survival and growth signals across receptor systems, controlled at the membrane-proximal PDK1-Akt signaling node. Although selective serotonin reuptake inhibitors (SSRIs) primarily target the serotonin transporter (SERT), evidence suggests additional effects on intracellular signaling. Escitalopram, a widely used SSRI, was previously shown to inhibit Syk phosphorylation in platelets, raising the possibility of SERT-independent effects on kinase cascades. Here, we investigated whether escitalopram and related compounds interfere with PI3K-Akt signaling in Ramos B lymphoma cells stimulated through the B cell receptor (BCR). Escitalopram and its enantiomer R-citalopram selectively reduced phosphorylation of Akt and its downstream effector FoxO1 while sparing upstream Syk and parallel ERK and PLC-PKC pathways. To localize the site of interference, we combined analyses of PDK1-dependent targets with a PTEN-inhibition model. Escitalopram suppressed PLK1 and S6K1 phosphorylation without altering mTORC2 autophosphorylation, and it also reduced H₂O₂-induced Akt phosphorylation. These complementary results point to a downstream site of interference at the level of PDK1-Akt complex formation, beyond PI3K and PIP3 availability. By contrast, the structurally related analog N-methyl-citalopram showed no effect, reinforcing a structure-dependent mechanism of interference with PDK1-Akt signaling. Functionally, escitalopram enhanced apoptosis in BCR-stimulated cells. Similar inhibition under insulin and SDF-1 stimulation indicates a generalized, receptor-independent effect. These findings reveal a noncanonical, SERT-independent mechanism by which escitalopram disrupts PDK1-Akt activation, with potential relevance to the broader intracellular effects of SSRI treatment.