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

Abstract

Schizophrenia is a phenotypically heterogeneous and poorly understood disorder. While its etiology is likely multifactorial, immune system dysfunction has increasingly been implicated in its development. As hallucinations and delusions occur frequently and prominently in autoimmune encephalitis (AE), numerous studies have sought to determine whether a small subset of individuals diagnosed with schizophrenia possess anti-neuronal antibodies implicated in AE. Exploring this possibility is of clinical relevance, as identifying individuals with AE who have been misdiagnosed as having a primary psychotic disorder may allow for the implementation of appropriate immune-related therapies as early as possible in the course of the illness, in order to optimize outcomes, reduce illness chronicity, and minimize adverse events. This qualitative review serves to provide an overview of the existing literature on this topic, as well as to update previously published reviews. Although there is some evidence to suggest that in rare cases AE may be misdiagnosed as a primary psychotic disorder, particularly early in the course of the illness, numerous methodological differences between studies likely account for the highly variable findings, and interpretation of the results is particularly limited by a paucity of cerebrospinal fluid data. Moreover, the prevalence of misdiagnosis in chronic and treatment-resistant populations remains understudied. This is particularly problematic, as treatment resistance may represent an enriched population with respect to the presence of anti-neuronal antibodies, and given that such patients have few evidence-based treatment options available to them beyond clozapine.

Exploring autoantibody signatures in brain tissue from patients with severe mental illness

“…The results showed a statistically significant difference between the patient and control groups, where 9.9% of the patients showed increased prevalence of different types of NMDAR antibodies while only 0.4% of controls were seropositive 45 . The percentages are similar to the findings in our study and are higher compared to other studies in serum samples, usually the frequency of patients showing autoantibody reactivity is around ≤5%, as reviewed previously 46 . For the majority of the samples in our study, the highest reactivity was measured in the processed tissue pellet which might indicate that reactive autoantibodies are bound to targets located in the brain tissue rather than bound to targets in residual blood components that might have diffused into the brain after death.…”

Clozapine-associated secondary antibody deficiency

“…Early diagnosis directs treatments to remove autoantibodies and halt production to induce remission (55). It has been suggested TRS may represent an enriched patient cohort with respect to the presence of anti-neuronal antibodies (56). A smaller study identified anti-NMDA-R antibodies in 3 of 43 patients (7%) with chronic treatment-resistance psychosis (57).…”

Immunological investigations of the cerebrospinal fluid in patients with recent onset psychotic disorders: A study protocol

“…However, antineuronal autoantibodies need to reach the brain to be pathogenic, and currently the prevalence of antineuronal autoantibodies in the CSF of patients with psychotic disorders compared to healthy controls is unknown. A handful of studies has screened the CSF of patients with psychotic disorders for antineuronal autoantibodies [ 24 ], with a recently published German study [ 25 ] including 456 patients with non-affective psychotic disorders, where they found autoantibodies against surface antigens in the CSF of 0.6%. However, none of them have compared the findings hereof with the CSF of healthy controls, limiting the interpretation of the clinical relevance of the prior findings.…”