Schmack, K. | bioRxiv Science

bioRxiv2026

The antipsychotic drug clozapine suppresses autoimmunity driving psychosis-like behavior in mice

Antipsychotic drugs are the first-line treatment for psychosis yet their mechanism of action remains poorly understood, largely due to the challenge to faithfully model psychosis preclinically. Here, we focus on the emerging concept that psychosis can be caused by brain autoimmunity and present a novel mouse model of anti-N-methyl-D-aspartate-receptor (anti-NMDAR) encephalitis, a condition that manifests with psychosis and autoanti-bodies against the NMDAR. We devised a new mRNA-based approach to immunize mice against the NMDAR. Immunized mice developed psychosis-like behaviors that were caused by anti-NMDAR autoantibodies leading to phagocytosis of NMDARs by brain microglia. The antipsychotic drug clozapine rescued psychosis-like behaviors and, remarkably, reduced anti-NMDAR autoantibody levels and antibody-mediated phagocytosis of NMDARs. The immunomodulatory effects of clozapine were confirmed in a mouse model of systemic lupus erythematosus. Our results demonstrate that clozapine suppresses autoimmunity driving psychosis-like behaviors, raising the possibility that immunomodulation contributes to antipsychotic drug action. HIGHLIGHTSO_LImRNA immunization against the NMDAR induces psychosis-like behavior in mice C_LIO_LIAnti-NMDAR autoantibodies are sufficient for psychosis-like behavior C_LIO_LIMicroglial phagocytosis of NMDARs mediates psychosis-like behavior induced by anti-NMDAR autoanti-bodies. C_LIO_LIClozapine reduces anti-NMDAR autoantibodies, microglial phagocytosis and psychosis-like behavior, consistent with immunomodulation as a potential mechanism of antipsychotic drug action. C_LI

neuroscience↗

bioRxiv2018

Overly strong priors for socially meaningful visual signals in psychosis proneness

Predictive coding accounts of psychosis state that an overweighing of high-level priors relative to sensory information may lead to the misperception of meaningful signals underlying the experience of auditory hallucinations and delusions. However, it is currently unclear whether the hypothesized overweighing of priors (1) represents a pervasive alteration that also affects the visual modality, and, (2) takes already effect at early automatic processing stages.\n\nHere, we addressed these questions by studying visual perception of socially meaningful stimuli in healthy individuals with varying degrees of psychosis proneness (n=39). In a first task, we quantified participants prior for detecting faces in visual noise. In a second task, we measured participants prior for detecting direct gaze stimuli that were rendered invisible by continuous flash suppression. We found that the prior for detecting faces in noise correlated with hallucination proneness (rho=0.50, p=0.001) as well as delusion proneness (rho=0.44, p=0.005). Similarly, the prior for detecting invisible direct gaze was significantly associated with hallucination proneness (rho = 0.42, p = 0.010) and trend-wise with delusion proneness (rho = 0.29, p = 0.087). Our results provide evidence for the idea that overly strong high-level priors for automatically detecting socially meaningful stimuli might constitute a generic processing alteration in psychosis.

neuroscience↗