Abstract
Background
Amitriptyline, mirtazapine, and escitalopram are effective antidepressants for treating major depressive disorder (MDD). Our study aimed to use computational biology to understand the mechanisms for the similarities and differences in efficacies and side effects of these drugs.
Methods
Potential targets for MDD and the three drugs were obtained using public databases. Venn diagrams and protein–protein interaction (PPI) networks were constructed. Drug‐target‐pathway (D‐T‐P) networks were built using Cytoscape, and core targets were filtered using CytoNCA and CytoHubba plugins. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted using the Database for Annotation, Visualization, and Integrated Discovery. Ligand compounds and receptor proteins were processed with PyMOL and AutoDock. The binding of amitriptyline, mirtazapine, and escitalopram with core targets was predicted by molecular docking using AutoDock Vina. The results were visualized using PyMOL and protein–ligand interaction profiler (PLIP).
Results
Forty‐eight overlapping targets and 66, 50, and 30 individual targets for MDD treatment were identified for amitriptyline, mirtazapine, and escitalopram, respectively. Critical pathways included “Neuroactive ligand–receptor interaction,” “Calcium signaling pathway,” and “Serotonergic synapse.” Key targets, indicating a wide range of effects on cellular activities and signaling mechanisms, included D(2) dopamine receptor (DRD2), CYP2D6, monoamine oxidase type B (MAOB), solute carrier family 6 member 3 (SLC6A3), solute carrier family 6 member 4 (SLC6A4), 5‐hydroxytryptamine receptor 2C (HTR2C), and CHRNA4. MAOB had the highest binding affinity with amitriptyline, followed by SLC6A4 and DRD2. Binding stability was enhanced by salt bridges and π‐stacking interactions. Mirtazapine formed strong binding affinities with HTR2C, SLC6A4, and CHRNA4 through hydrogen bonds and π‐stacking interactions. Escitalopram exhibited the highest affinity for SLC6A3, followed by HTR2C.
Conclusion
All three drugs regulated serotonin, norepinephrine (NE), and dopamine, but target specificity, pathways, and binding patterns differed. Amitriptyline exhibited stronger antidepressant effects and broader mechanisms but a higher risk of side effects. Mirtazapine’s dual mechanism regulates broad targets with reliable efficacy and fewer side effects. Escitalopram selectively acts on serotonin‐related targets, with narrow actions and potentially fewer side effects. These findings align with the clinical profiles of the antidepressant efficacy and side effects.