Seroprevalence survey of selective anti-neuronal autoantibodies in patients with first-episode schizophrenia and chronic schizophrenia
Introduction
Schizophrenia is a devastating chronic mental disorder that affects approximately 1% of the general population. It is also a complex disorder with high clinical and etiological heterogeneity. Immune system dysfunction is an important factor associated with the pathogenesis of schizophrenia. Several epidemiological studies have demonstrated that patients with autoimmune diseases had increased the risk of schizophrenia and other psychiatric diagnoses, and patients with schizophrenia had a higher prevalence of autoimmune diseases (Benros et al., 2014, Chen et al., 2012). Furthermore, increased prevalence of multiple autoantibodies was reported in a systematic and quantitative review of blood autoantibodies in schizophrenia (Ezeoke et al. 2013). Together, these data suggest autoimmune diseases are associated with the pathogenesis of schizophrenia and its related disorders.
Recently, several new autoantibodies against neuronal cell-surface proteins and synaptic proteins were detected in patients presenting with a range of acute neuropsychiatric features, representing a new type of autoimmune encephalitis associated with psychiatric disorders (Lancaster, 2016, Linnoila et al., 2014). The correct diagnosis of this condition relies on the serological tests to detect the autoantibodies against neuronal surface proteins, which are only available recently. We were interested to know whether some of our first-episode schizophrenia might be due to this condition. Hence, we conducted a serological screening of autoantibodies against six neuronal cell-surface proteins in a sample of archived plasma from 78 patients diagnosed with first-episode schizophrenia using a commercially available indirect immunofluorescence assay. The six autoantibodies including antibodies against N-methyl-d-aspartate (NMDA) receptor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors 1 and 2, γ-butyric acid receptor type B1 (GABARB1), leucine-rich glioma inactivated-1 (LGI1) protein, and contactin-associated protein-like 2 (CASPR2) protein.
Among these autoimmune encephalopathies associated with psychiatric condition, anti-NMDA receptor encephalitis is the most well-studied in recent years. It is characterized by the presence of IgG antibody against the NR1 subunit of NMDA receptor in the affected patients. Several studies reported the detection of anti-NMDA receptor autoantibodies in patients with acute psychosis and schizophrenia-related diagnoses (Wandinger et al. 2011). The disease can occur in patients of all ages, and more predominantly in female patients. Patients with anti-NMDA receptor encephalitis usually have prodromal symptoms of a headache or fever, followed by the quick development of consciousness level change and a wide spectrum of psychiatric symptoms such as agitation, irritability, anxiety, insomnia, hallucinations, delusions, aggression, and bizarre behaviors. A wide range of neurological symptoms may concur with or follow the appearance of psychiatric symptoms, including movement abnormalities, autonomic dysregulation, seizure attacks, and loss of consciousness (Dalmau et al., 2011, Leypoldt et al., 2015). It is suggested that anti-NMDA receptor encephalitis should be considered as an important differential diagnosis of patients with a primary psychiatric diagnosis (Barry et al., 2015, Barry et al., 2011, Chapman and Vause, 2011). Early recognition of this condition and timely treatment with immunotherapy will have a better outcome and even recovery in affected patients (Titulaer et al. 2013).
We were interested to know whether some of the patients diagnosed with chronic schizophrenia or even those who were refractory to psychopharmacotherapy might be associated with anti-NMDA receptor encephalopathy. Hence, in the second study, we conducted a seroprevalence survey of anti-NMDA receptor autoantibodies in patients with chronic schizophrenia, including some who were refractory to antipsychotic treatment.
Section snippets
Subjects
For the first-episode schizophrenia study, the patients came from two research projects of the early course of schizophrenia (Liu et al., 2013, Liu et al., 2011). Both projects have been approved by the institutional review board of the study hospital. All adult participants voluntarily provided their written informed consents and minors gave written assent with informed consent from their parents after full explanation of the study procedures to them. We recruited the patients between 16 and 45
Results
In the first-episode schizophrenia study, none of the 78 patients was positive in the screening of six neuronal autoantibodies using the indirect immunofluorescent cell-based assay. In the chronic schizophrenia study, also no positive case among 234 patients was detected in the survey of anti-NMDA receptor autoantibody. Two patients with ambiguous results in the initial screening were subjected to further verification test using rat brain immunohistochemistry assay; however, both of them were
Discussion
In the first study, we screened for autoantibodies against six neuronal cell-surface proteins in a sample of archived plasmas from 78 patients with first-episode schizophrenia and found no positive case in this sample. Similar study had been performed by Haussleiter and colleagues. They screened for the same six anti-neuronal autoantibodies as ours in 50 chronic patients with psychotic disorders of varying severity. No positive case was detected in their sample (Haussleiter et al. 2012).
Concluding remarks
In this study, we did not detect autoantibodies against six neuronal cell-surface proteins in a sample of seventy-eight patients with first-episode schizophrenia, nor did we detect anti-NMDA receptor autoantibodies in a sample of 234 patients with schizophrenia. Our data indicate that the seroprevalence of neuronal antibodies among schizophrenia patients might be low. However, autoimmune encephalopathy is still considered as a new emerging condition associated with psychiatric symptoms that are
Conflict of interest
The authors declare no conflict of interest.
Contributors
Chia-Hsiang Chen designed and conducted the study. Chih-Min Liu, Chen-Chung Liu, and Hai-Gwo Hwu recruited and evaluated the first-episode schizophrenia patients. Min-Chih Cheng, Ko-Huan Lin and Chia-Hsiang Chen helped recruit chronic schizophrenia patients and conducted the experiments. Chia-Hsiang Chen wrote the manuscript and all the authors reviewed and approved the manuscript.
Role of the funding source
The funding source has no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Acknowledgements
The study was supported by grants CMRPG3C1771, CMRPG3C1772, CMRPG3E0631, CMRPG3E0632 and CMRPG3E0633 from Chang Gung Memorial Hospital, Likou, Taoyuan, Taiwan. We also thank Mr. Synn-Yu Wu and Mr. Chun-Long Cheng for their technical assistance in carrying out the experimental works.
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