Dual-target mechanisms of olanzapine in bipolar disorder: a network pharmacology and molecular docking study revealing phase-specific regulation of longevity and PI3K-Akt pathways.

BACKGROUND: Bipolar disorder (BD) remains a therapeutic challenge due to its clinical heterogeneity and bidirectional mood episodes. While olanzapine is clinically effective in managing BD, its mechanisms in regulating depressive and manic phases remain unclear. This study employs network pharmacology, molecular docking and molecular dynamics (MD) simulation to systematically investigate olanzapine’s polypharmacological mechanisms in BD. METHODS: Potential targets of olanzapine were retrieved from GeneCards, SwissTargetPrediction, and PharmMapper. BD-related targets for depression and mania were collected from DisGeNET and GeneCards. Protein-protein interaction (PPI) networks were constructed using STRING and analyzed via Cytoscape. Hub genes were identified using CytoHubba. Functional enrichment (Gene Ontology, GO) and pathway analyses (KEGG) were performed using ClusterProfiler. Molecular docking validated binding affinities between olanzapine and core targets. RESULTS: A total of 187 and 116 overlapping targets were identified for olanzapine in bipolar depression and mania, respectively. PPI analysis revealed core targets including INS, IGF1, CREB1, PPARG, and PRKACA for bipolar depression, and EGFR, BDNF, GSK3B, IL6, and NTRK1 for mania. KEGG analysis highlighted the longevity regulating pathway (bipolar depression) and PI3K-Akt signaling pathway (mania) as central mechanisms. Molecular docking and MD simulation confirmed strong binding affinities between olanzapine and key targets, mediated by hydrophobic, hydrogen-bond, and π-interactions. CONCLUSION: This study reveals distinct molecular mechanisms underlying olanzapine’s bidirectional regulation of BD phases. Its antidepressant effects involve neuroplasticity and metabolic modulation via longevity-associated pathways, while anti-manic actions target synaptic and inflammatory signaling through PI3K-Akt cascades. These findings provide a foundation for optimizing BD therapeutics and highlight network pharmacology as a robust tool for dissecting complex drug-disease interactions. CLINICAL TRIAL NUMBER: Not applicable.