Fig. 4: Inflammation effects on oral chronic escitalopram efficacy.

a Mast cell model of histamine degranulation. In (i), the schematic of the computational model is given. The main variables are depicted in red rectangular labels. The acronyms of main enzymes, transporters, and receptors are represented with blue elliptic labels. Pharmacological effects are represented in purple rectangular labels. In (ii), the modeled reaction of histamine (purple) and serotonin (red) to an inflammation trigger. b Modeling of oral chronic dosing escitalopram (5 mg pill, ~1.02 mg kg⁻¹) effects on brain escitalopram (i), serotonin (ii), and SERT surface ratio (iii) during control state and inflammation. For the inflammation simulation, mast cell and glia production and release of histamine is triggered 35 days before the first dose. Administration is then repeated every 8 h. c Modeling of extracellular histamine (i) and serotonin (ii) following 20 mg kg⁻¹ i.p. injection of (S) α-fluoromethylhistidine 1 h after the start of the simulation. d Modeling of oral chronic co-administration of FMH (2.5 mg analogous dose for mice, ~0.51 mg kg⁻¹) and escitalopram dosing effects on brain FMH (i), serotonin (ii), and SERT surface ratio (iii) during inflammation (purple) and comparison to control administration of escitalopram as described on panel B (blue). For the inflammation simulation, mast cell and glia production and release of histamine is triggered 35 days before the first dose. Administration is then repeated every 8 h. Results for the 10 mg and 20 mg human doses can be found in the Supplementary Information (Figs. S4,S5). Illustrations made with Biorender.com.