Network pharmacology of cellular targets in major depressive disorder and differential mechanisms of fluoxetine, ketamine and esketamine
Silvia Tapia-Gonzalez, Josue G. Yagüe, George E. Barreto
Computational and Structural Biotechnology Journal December 29, 2025 DOI: 10.1016/j.csbj.2025.12.023 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Meta-analysis and network fragility analysis Peer reviewed |
|---|---|
| Topics | Depression Ketamine Esketamine |
| Keywords | Antidepressant Neurotrophic factors Gsk-3 Brain-derived neurotrophic factor Mechanism biology Venlafaxine Neurotransmitter receptor Pharmacology Bioinformatics Glutamate receptor Glutamatergic Drug discovery |
| Key findings | Network analysis identified OPRM1, EGFR, and GSK3B as key druggable targets in MDD, with NFKB potentially regulating all three as a central node linking inflammation, synaptic plasticity, and neuronal metabolism. |
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.
Comparable studies
Other systematic reviews and meta-analyses on esketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis Adults with unipolar or bipolar major depression | 2020 | Systematic review and meta-analysis | n = 1,877 |
| The acute antisuicidal effects of single-dose intravenous ketamine and intranasal esketamine in individuals with major depression and bipolar disorders: A systematic review and meta-analysis. Participants in randomized controlled trials of ketamine for suicidal ideation | 2020 | Systematic review and meta-analysis | n = 197 |
| Efficacy of Esketamine Augmentation in Major Depressive Disorder Patients with major depressive disorder who are treatment-resistant or acutely suicidal | 2020 | Systematic review and meta-analysis | n = 774 |
| Esketamine Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis. Patients with treatment-resistant major depressive disorder | 2025 | Systematic review and meta-analysis | |
| EFFICACY AND SAFETY OF RACEMIC KETAMINE AND ESKETAMINE FOR DEPRESSION: A SYSTEMATIC REVIEW AND META-ANALYSIS Adults with unipolar or bipolar major depression | 2022 | Systematic review and meta-analysis | n = 2,903 |