Letter to the Editor
Immunotherapy for patients with acute psychosis and serum N-Methyl d-Aspartate receptor (NMDAR) antibodies: A description of a treated case series

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Study approval

AV has approval from Oxfordshire REC A (07/Q1604/28 Immune factors in neurological diseases) for the study of any patients whose samples have been referred for testing. This work is classified as Service Evaluation rather than research according to NHS Health Research Authority guidance, and accordingly review by a Research Ethics Committee was not required (http://www.nres.nhs.uk/applications/is-your-project-research/). The work described has been carried out in accordance with The Code of

Role of funding source

The study was supported by the NIHR Biomedical Research Centres in Cambridge and Oxford.

Contributors

MSZ, JB, CB, AJC, PBJ, AV and BRL designed the study and treatment protocols. MSZ, JB, KM, CB, LS, ALC, AJC and BRL assessed the patients and collected data. LJ carried out and interpreted the NMDAR cell based assays. MSZ and AV undertook the statistical analysis. MSZ, JBD, AV and BRL wrote the first and revised drafts of the manuscript, which was reviewed and edited by all authors. All authors contributed to and have approved the final manuscript. BRL holds responsibility for all of the data.

Conflict of interest

AV and the University of Oxford hold patents and receive royalties from Athena Diagnostics and Euroimmun AG. Alasdair Coles reports receiving consulting and lecture fees from Genzyme, lecture fees from Merck Serono, and research support paid to his institution from Genzyme. The other authors have no conflicts of interest.

Acknowledgements

None.

References (16)

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    However, neither plasmapheresis nor hemodialysis produced benefit in patients with schizophrenia thereby reducing the likelihood that a serum antibody or other circulating factor is responsible [11,12], although the presence of serum antibodies against human brain tissue [13] in schizophrenia patients has been reported. Anti-NMDA receptor (NMDAR) encephalitis, a related encephalitis illness that can present with psychosis and can be associated with ovarian tumors, has been attributed to circulating antibodies against NMDAR and often responds to immune therapy [14,15]; however, this is considered a separate entity from schizophrenia. An alternate paradigm suggests that disease-associated B cells and the pathological antibodies they produce are located within the central nervous system (and may not be present peripherally).

  • The search for an autoimmune origin of psychotic disorders: Prevalence of autoantibodies against hippocampus antigens, glutamic acid decarboxylase and nuclear antigens

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    One of the proteins targeted is the N-methyl-d-aspartate receptor (NMDAR) causing patients to develop characteristic neurologic and psychiatric symptoms (Dalmau et al., 2011). It is clinically important that these diseases respond very well to immunosuppressive treatment indicating that any neuronal damage might be largely reversible (Graus et al., 2016; Varley et al., 2017; Zandi et al., 2014). Whether NSAbs can occur in purely psychotic patients, however, is less clear; their prevalence varies between 0 and 11% (Bergink et al., 2015; Endres et al., 2015; Lennox et al., 2017), possibly due to differences in the methodology of antibody detection and patient cohorts (Jezequel et al., 2017; Leypoldt et al., 2017; Pathmanandavel et al., 2015).

  • Autoantibody-associated psychiatric symptoms and syndromes in adults: A narrative review and proposed diagnostic approach

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    However, the evidence level is moderate to high for autoimmune encephalitis and autoimmune psychosis, as two randomized placebo-controlled trials with small cohorts exist for LG1-positive encephalitis (Dubey et al., 2020) with an immunoglobulin effect in 75% of patients and involving antibody-positive psychosis [study of immunotherapy in antibody-positive psychosis: feasibility and acceptability (SINAPPS1)] with a relevant reduction of psychotic symptoms (Lennox et al., 2017). Observational, retrospective studies indicate that immunotherapy is beneficial in NMDAR-positive psychosis in 43–80% (Zandi et al., 2014; Scott et al., 2018) or in autoimmune dementia in 64% of patients (Flanagan et al., 2010). A recent systematic review supports these results described an immunotherapeutic effect in 94% of 145 patients with autoantibody-associated psychiatric syndromes (Endres et al., 2020c).

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    This identified that immunoglobulin G antibodies from NMDAR-Ab seropositive cases of first episode psychosis destabilised hippocampal neurons in contrast with purified immunoglobulin G antibodies from healthy seronegative donors and akin to patients with NMDAR-Ab encephalitis (Bard and Groc, 2011; Mikasova et al., 2012). The literature has several reports of patients with isolated psychotic symptoms seropositive for NMDAR-Ab who respond to treatment with immunotherapy (Zandi et al., 2014; Kuppuswamy et al., 2014). However NMDAR-Ab has also been reported in a range of non-autoimmune neuropsychiatric disorders (Zandi et al., 2015) and immunotherapy treatment such as plasmapheresis is not without its side effects.

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1

These authors contributed equally to this work.

2

Present address: Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Brazil.

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