Modeling Antidepressant-Induced Manic Switch and Longitudinal Relapse: A Unified Pruning Framework Highlights Glutamatergics' Disease-Modifying Potential
Zenodo (CERN European Organization for Nuclear Research) – January 19, 2026
Source: OpenAlex
Summary
Ketamine-like treatments offer remarkable resilience against extreme stress, achieving a 76.8% tolerance rate and zero manic relapse after discontinuation. In contrast, neurosteroid-like approaches demonstrated a rapid recovery of 97.6%, but with an 88.3% chance of relapse when off-drug. SSRI-like treatments lagged significantly, showing only 49.9% resilience under stress and a staggering 95.0% relapse risk post-treatment. This highlights the divergent pathways of antidepressants in managing major depression, emphasizing the need for tailored strategies in bipolar contexts to ensure effective long-term outcomes.
Abstract
Background: Major depressive disorder involves impaired neural plasticity, yet antidepressants targeting glutamatergic (ketamine), monoaminergic (SSRIs), and GABAergic (neurosteroids) pathways differ markedly in onset speed, durability, and risk of treatment-emergent mania—particularly in bipolar contexts. Clinical comparisons are confounded by heterogeneity; computational models enable controlled mechanistic dissection, but few integrate manic liability and post-discontinuation stability across classes. Methods: We extended a magnitude-based pruning model (95% sparsity) of depression in feed-forward networks classifying Gaussian blobs. From identical pruned baselines, three interventions were simulated: ketamine-like gradient-guided synaptic regrowth (50% reinstatement) with consolidation; SSRI-like prolonged low-rate refinement with tapering noise and escalating excitability gain; neurosteroid-like global tonic inhibition (0.7× damping, tanh activations, reduced gain). Efficacy assessed classification accuracy under clean, noisy, and combined stress; resilience via graded noise tolerance; acute relapse after further pruning; manic risk through biased positive perturbation and activation magnitude. Longitudinal relapse modeled chronic maintenance (with mood stabilizer protection) followed by discontinuation, using treatment-specific lingering decay rates. Metrics averaged across 10 seeds. Results: All treatments restored near-ceiling performance acutely, but ketamine-like regrowth yielded superior extreme-stress resilience (76.8%) and zero post-discontinuation manic relapse, reducing sparsity to 47.5%. Neurosteroid-like modulation matched rapid recovery (97.6%) but showed state-dependence and 88.3% relapse probability off-drug. SSRI-like refinement lagged in resilience (49.9% extreme) with highest manic proxies (biased accuracy 47.2%, gain 1.60) and 95.0% relapse post-cessation. Longer maintenance conferred negligible added protection for reversible mechanisms. Conclusions: Antidepressants operate via divergent plasticity routes—durable structural rebuilding (ketamine-like, low long-term risk), rapid reversible stabilization (neurosteroid-like), and vulnerable gradual optimization (SSRI-like)—reproducing clinical trade-offs in speed, persistence, and bipolar safety. These findings support mechanism-guided selection, positioning synaptogenic agents for recurrent or high-risk cases pursuing remission beyond treatment.