cheungngo/Divergent-Mechanisms-of-Antidepressant-Efficacy: Divergent Mechanisms of Antidepressant Efficacy

Background: Major depressive disorder is increasingly viewed as a disorder of impaired neural plasticity, yet the mechanisms underlying diverse antidepressant classes—glutamatergic (e.g., ketamine), monoaminergic (e.g., SSRIs), and GABAergic (e.g., neurosteroids)—remain incompletely integrated. Computational models offer a controlled means to compare these pathways, but prior work has typically examined single mechanisms. Methods: We extended a pruning-plasticity model of depression by applying 95% magnitude-based synaptic elimination to overparameterized feed-forward networks trained on a four-class Gaussian classification task. From identical pruned states, three interventions were tested: ketamine-like gradient-guided regrowth (50% reinstatement) with consolidation; SSRI-like prolonged low-learning-rate training with gradual internal noise reduction; and neurosteroid-like global tonic inhibition (30% damping plus tanh activations) with brief consolidation. Outcomes included baseline accuracy, resilience to graded internal activation noise (up to σ = 2.5) plus input perturbation, and relapse vulnerability after additional 40% pruning. Results: All treatments restored near-ceiling performance on unchallenged inputs. Ketamine-like synaptogenesis uniquely reduced sparsity (to ~47%) and conferred superior stress resilience (extreme noise accuracy 84.5%) with near-zero relapse drop (−0.2%). SSRI-like refinement improved combined stress accuracy to 83.5% but showed limited extreme noise tolerance (44.0%) and substantial relapse vulnerability (10.8% drop). Neurosteroid-like inhibition achieved rapid combined stress recovery (97.5%) while active but was state-dependent (decline upon removal) with poor extreme noise buffering (42.5%) and moderate relapse drop (4.1%). Conclusions: These simulations demonstrate that antidepressants operate through mechanistically distinct routes—structural rebuilding (ketamine), gradual optimization of existing connectivity (SSRIs), or reversible dynamic stabilization (neurosteroids)—yielding trade-offs in onset speed, durability, and stress resilience. The findings support a multifaceted plasticity framework for depression and provide computational rationale for mechanism-based treatment selection and combination strategies.