Psychosis: an autoimmune disease?

Abstract

Psychotic disorders are common and disabling. Overlaps in clinical course in addition to epidemiological and genetic associations raise the possibility that autoimmune mechanisms may underlie some psychoses, potentially offering novel therapeutic approaches. Several immune loci including the major histocompatibility complex and B-cell markers CD19 and CD20 achieve genome-wide significance in schizophrenia. Emerging evidence suggests a potential role via neurodevelopment in addition to classical immune pathways. Additionally, lymphocyte biology is increasingly investigated. Some reports note raised peripheral CD19 and reduced CD3 lymphocyte counts, with altered CD4 : CD8 ratios in acute psychosis. Also, post-mortem studies have found CD3 and CD20 lymphocyte infiltration in brain regions that are of functional relevance to psychosis. More specifically, the recent paradigm of neuronal surface antibody-mediated (NSAb) central nervous system disease provides an antigen-specific model linking adaptive autoimmunity to psychopathology. NSAbs bind extracellular epitopes of signalling molecules that are classically implicated in psychosis such as NMDA and GABA receptors. This interaction may cause circuit dysfunction leading to psychosis among other neurological features in patients with autoimmune encephalitis. The detection of these cases is crucial as autoimmune encephalitis is ameliorated by commonly available immunotherapies. Meanwhile, the prevalence and relevance of these antibodies in people with isolated psychotic disorders is an area of emerging scientific and clinical interest. Collaborative efforts to achieve larger sample sizes, comparison of assay platforms, and placebo-controlled randomized clinical trials are now needed to establish an autoimmune contribution to psychosis.

Clinically Relevant Anti-Neuronal Cell Surface Antibodies in Schizophrenia Spectrum Disorders

“…Relatedly, peripheral antibodies are theoretically not directly pathogenic, and rather must infiltrate the CSF to act on neural tissue. As such, the effects of antibodies in the serum may depend on the integrity of the blood-brain barrier in individual cases [43]; a variable not considered or studied in most of the aforementioned papers. Given the generally superior sensitivity and specificity associated with testing CSF in comparison to serum in the diagnosis of AE, we argue that the most clinically relevant studies to date are those that have included CSF data, and particularly those that have included both CSF and serum data.…”

Catatonia and the immune system: a review

“…100 NMDAR encephalitis is increasingly considered as an organic cause of psychosis, although controversy exists as to whether this idea is only relevant in the context of the classical encephalitis or also in isolated psychiatric presentations. 7,103 The association NMDAR encephalitis with catatonia seems to be even stronger than the association with psychosis. 72 Where catatonia is reported, it is often malignant catatonia and tends to cooccur with psychosis 104 and mania.…”

“…Immune dysregulation is gaining interest as a patho physiological mechanism underlying neuro psychi atric disorders as diverse as narcolepsy, some dementias, depression, and psychosis-with converging evidence from biochemical, neuroimaging, genetic, and post mortem studies. 7,8 Roles for both the innate immune system, which concerns the rapid, undirected response to pathogenassociated or injuryrelated signals, and the adaptive immune system, which functions over a longer timescale and involves the selection and maturation of antigenspecific Tcell and Bcell mediated responses, have been identified.…”

N-Methyl-D-Aspartate(NMDA) Receptor and Voltage-Gated Potassium Channel (VGKC) Antibody-Associated Encephalitides Presenting as First Episode Acute Psychosis

“…A substantial number of patients improve if properly diagnosed and treated with immunotherapy (1). Considerations for an autoimmune basis for schizophrenia and other psychiatric disorders date back to the 1960s and continue to be debated (2)(3)(4).…”