Autoimmune neuropsychiatric disorders manifesting with psychosis
José Maria Cabrera-Maqueda, … , Mar Guasp, Josep Dalmau
José Maria Cabrera-Maqueda, … , Mar Guasp, Josep Dalmau
Published October 15, 2025
Citation Information: J Clin Invest. 2025;135(20):e196507. https://doi.org/10.1172/JCI196507.
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Review

Autoimmune neuropsychiatric disorders manifesting with psychosis

Abstract

The increasing recognition of a new category of encephalitides that occur in association with antibodies against neuronal surface proteins has prompted the use of terms like “autoimmune psychosis” and “autoimmune psychiatric disorders.” However, although psychosis and other psychiatric symptoms can occur in autoimmune encephalitides and systemic autoimmune diseases, evidence for a distinct psychiatric entity beyond these conditions is lacking. A particularly defining condition is anti-NMDA receptor encephalitis, which has been central to promoting concepts such as autoimmune psychosis and autoimmune psychiatric disorders. While anti-NMDA receptor encephalitis can resemble primary psychiatric conditions, certain clinical features often suggest the specific diagnosis. This Review traces the development of the autoimmune psychosis concept and examines the implications of framing it as a separate entity. We discuss leading theories of psychosis and the convergence of the NMDA receptor hypofunction/glutamate hypothesis with anti-NMDA receptor encephalitis mechanisms. The interest generated by such disorders has driven uncontrolled antibody testing in psychiatric populations, often neglecting pretest probability and favoring prevalence over diagnostic specificity. Finally, we highlight the main limitations of current approaches and propose directions for future research.

Authors

José Maria Cabrera-Maqueda, Jesús Planagumà, Mar Guasp, Josep Dalmau

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Figure 1

Effects of NMDAR autoantibodies on neurons and synaptic networks, microglia, and white matter.

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Effects of NMDAR autoantibodies on neurons and synaptic networks, microg...
(A) Hippocampus from the autopsy of a patient with anti-NMDAR encephalitis (top) shows markedly reduced expression of NMDARs detected using a specific biomarker (brown immunostaining), compared with a control hippocampus (bottom) (65). (B) Experimental studies demonstrate that the antibodies crosslink and internalize NMDARs (left). This disrupts long-term potentiation compared with control-IgG (right) (66, 156), associated with impairment of function of NMDAR-dependent networks (72). (C) Microglial activation is consistently observed in patient neuropathological studies, as shown with HLA-DR staining (65). (D) Experimental models demonstrate that activated microglia endocytose IgG bound to NMDARs (top), with stimulated emission depletion (STED) superresolution microscopy confirming colocalization of endosomes (CD68), IgG, and the GluN1 subunit of NMDAR (bottom) (77). Microglia may process internalized NMDARs, contributing to epitope spreading and the polyclonal antibody response, likely occurring in deep cervical lymph nodes (not shown). (E) MRI from a patient with anti-NMDAR encephalitis shows mild increase of FLAIR signal in the left parietal region. (F) Although MRI studies in patients with anti-NMDAR encephalitis are often unremarkable, experimental data from cultured oligodendrocytes show that patients’ antibodies, but not control IgG, impair NMDAR-mediated calcium currents (left), which lead to reduced surface expression of GLUT1 (right; GLUT1 shown in pink), likely contributing to white matter abnormalities frequently observed with advanced neuroimaging, such as diffusion tensor imaging (81, 82). GLUT1, glucose transporter 1. Scale bars: 1 mm (A); 20 μm (C); 100 nm (D); 10 μm (F). Images were reproduced with permission from Annals of Neurology (65) (A), Annals of Neurology (40) (C), Brain (77) (D), New England Journal of Medicine (157) (E), and Annals of Neurology (82) (F).