Inflammatory and Oxidative Pathways Are New Drug Targets in Multiple Episode Schizophrenia and Leaky Gut, Klebsiella pneumoniae, and C1q Immune Complexes Are Additional Drug Targets in First Episode Schizophrenia.

Breakdown of paracellular and vascular pathways and activated neuroimmune and oxidative pathways was established in (deficit) schizophrenia. The aim of this study was to delineate (a) the differences in these pathways between stable-phase, first (FES) and multiple (MES) episode schizophrenia and (b) the pathways that determine the behavioral-cognitive-physical-psychosocial (BCPS) deterioration in FES/MES. This study included 21 FES and 58 FES patients and 40 healthy controls and measured indicants of serum C1q circulating immune complexes (CIC), leaky gut, immune activation, and oxidative stress toxicity (OSTOX). We constructed a BCPS-worsening index by extracting a latent vector from symptomatic, neurocognitive, and quality of life data. FES was associated with higher IgA CIC-C1q, IgA directed to cadherin, catenin, and plasmalemma vesicle-associated protein, and IgA/IgM to Gram-negative bacteria as compared with FES and controls. In FES patients, the BCPS-worsening score was predicted (48.7%) by IgA to Klebsiella pneumoniae and lowered paraoxonase 1 activity. In MES patients, the BCPS-worsening score was explained (42.7%) by increased tumor necrosis factor-α, OSTOX, and number of episodes. In schizophrenia, 34.0% of the variance in the BCPS-worsening score was explained by IgA to K. pneumoniae, OSTOX, and number of episodes. Increased IgA to K. pneumoniae was the single best predictor of residual psychotic symptoms in FES and MES. This study delineated different mechanistic processes in FES, including breakdown of adherens junctions, bacterial translocation, and IgA CIC-C1q formation, and MES, including immune and oxidative neurotoxic pathways. FES and MES comprise different staging subtypes, i.e., FES and MES with and without worsening.