Computational Insights into Cognitive Trajectories Across Antidepressant Mechanisms in Bipolar Disorder

Background: Bipolar disorder features recurrent mood episodes alongside persistent cognitive impairments—particularly in executive flexibility, attention, and sensory integration—that endure into euthymia and drive functional disability more than residual symptoms. The kindling hypothesis links episode recurrence to progressive sensitization and potential cognitive deterioration via neuroprogressive mechanisms. Computational modeling enables mechanistic dissection, yet few studies integrate recurrent dynamics with multi-domain cognitive probes to track treatment-induced vulnerabilities. Methods: A GRU-based recurrent neural network simulated vulnerable circuitry (pruned baseline with early scarring). Three antidepressant mechanisms were compared: ketamine-like (rapid regrowth/excitation), SSRI-like (gradual monoaminergic tuning), and neurosteroid-like (GABAergic inhibition). An iso-dose pipeline equated intervention intensity via L1 weight-change norms. A comprehensive cognitive battery probed flexibility (45° rotation), visuospatial processing (1.5× scaling), perceptual acuity (fine discrimination), distraction resistance (high noise), and sensory integration (conflicting blends at 25–75%). Outcomes spanned acute recovery, manic risk, kindling (six cycles with scarring), and domain-specific cognitive trajectories. Results: Treatments restored core performance acutely, with iso-dose equivalence and SSRI-like efficiency standout. Neurosteroid-like best resisted kindling (minimal scarring, partial autonomy). Cognitively, all induced profound flexibility deficits (45–57% drops from baseline) that crystallized post-recovery—remaining stable without progression through recurrent episodes or scarring—mirroring trait-like executive impairments. Attentional/perceptual domains showed milder, non-progressive costs with relative resilience (e.g., ~87–93% preserved acuity even under damage); integration tolerated moderate conflict (~56%). Neurosteroid effects reversed sharply off-medication. Conclusions: Treatment recovery imposes stable, trait-like cognitive rigidity—predominantly executive—independent of further kindling, while sparing attentional resilience. Neurosteroid modulation uniquely preserves cognition amid progression, supporting targeted remediation for flexibility deficits and mechanism-personalized strategies in bipolar disorder.