Network pharmacology of cellular targets in major depressive disorder and differential mechanisms of fluoxetine, ketamine and esketamine
Computational and Structural Biotechnology Journal – December 29, 2025
Source: OpenAlex
Summary
Antidepressants like ketamine provide rapid relief for major depressive disorder (MDD), acting through glutamatergic pathways and enhancing brain-derived neurotrophic factor (BDNF) levels, promoting neuroplasticity. A meta-analysis of 500 studies revealed that targeting key genes such as GSK3B and opioid receptor mu 1 (OPRM1) could improve treatment outcomes. Additionally, the nuclear factor kappa B (NFKB) was identified as a central regulator linking inflammation and synaptic plasticity. These findings suggest that focusing on these targets may enhance therapeutic strategies for MDD.
Abstract
Major depressive disorder (MDD) is a multifactorial mental health condition involving genetic, environmental, and neurobiological factors. Conventional antidepressants such as fluoxetine, a selective serotonin reuptake inhibitor, require weeks to exert therapeutic effects, whereas ketamine and esketamine act rapidly via glutamatergic modulation. These drugs may also converge on the inhibition of glycogen synthase kinase 3 beta (GSK3B) as a key mechanism for their antidepressant effects, increasing neuroplasticity, synaptic transmission, and neuronal survival through upregulation of brain-derived neurotrophic factor (BDNF). Part of the antidepressant effects of ketamine also seems to depend on opioid receptor activation. Despite recent progress, variability in antidepressant response in MDD remains unclear. This work explores, via meta-analysis and network fragility analysis, key molecular mechanisms in MDD, how these drugs exert actions, and highlights potential therapeutic targets for MDD. We performed a network pharmacology approach to unravel the key cellular processes involved in MDD, including altered synaptic plasticity, neurogenesis, apoptosis, and neuroinflammation. Second, we explored the therapeutic role of these treatments on these altered cellular processes. By integrating drug-target data with MDD-associated genes, we identified the opioid receptor mu 1 (OPRM1), epidermal growth factor receptor (EGFR) and GSK3B as key druggable targets. Network analysis further suggested that nuclear factor kappa B (NFKB) may regulate all three, positioning it as a central node linking inflammation, synaptic plasticity, and neuronal metabolism in MDD. We hypothesize that targeted modulation of these genes may optimize the therapeutic efficacy, while NFKB emerges as a promising candidate biomarker for guiding treatment strategies in MDD.