Abstract / Summary
Treatment-resistant depression (TRD) affects approximately one-third of patients with major depressive disorder (MDD). A substantial body of evidence implicates interleukin-6 (IL-6) in its pathogenesis, yet clinical trials of global IL-6 blockade have produced paradoxical psychiatric worsening. We argue that this is not a target failure but a resolution failure since prior interventions operated at the wrong level of the IL-6 system. The biologically relevant variable is the stoichiometric balance between the pathogenic IL-6/sIL-6R trans-signaling complex and the endogenous soluble gp130 (sgp130) buffer that neutralizes it. In inflammatory-endotype TRD, chronic psychosocial stress drives ADAM10/ADAM17-mediated sIL-6R shedding that overwhelms sgp130 neutralization capacity, generating sustained unconstrained trans-signaling in neural and cerebrovascular tissues. This pathway-specific excess drives a neurobiological cascade including claudin-5 downregulation with blood-brain barrier breach, microglial-astrocytic apoptotic cross-talk, IDO-1-mediated kynurenine pathway diversion, SERT hyperphosphorylation, dopaminergic suppression, and glucocorticoid receptor downregulation. We derive four testable predictions from this proposal, synthesize converging preclinical, genetic, and clinical evidence, and propose a Trans-signaling Risk Index (TSRI) as the operative stratification biomarker. This framework positions sgp130Fc as a precision pharmacological test and provides a roadmap for precision immunopsychiatry in TRD.