SCHRES-07205; No of Pages 4

Schizophrenia Research xxx (2017) xxxxxx

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Schizophrenia Research

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Seroprevalence survey of selective anti-neuronal autoantibodies in

patients with rst-episode schizophrenia and chronic schizophrenia
Chia-Hsiang Chen a,b,, Min-Chih Cheng c, Chih-Min Liu d,e, Chen-Chung Liu d, Ko-Huan Lin f, Hai-Gwo Hwu d
a
Department of Psychiatry, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
b
Department and Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan
c
Department of Psychiatry, Yuli Mental Health Research Center, Yuli Branch, Taipei Veterans General Hospital, Hualien, Taiwan
d
Department of Psychiatry, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
e
Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan
f
Department of Psychiatry, Hualien Armed Forces General Hospital, Hualien, Taiwan

a r t i c l e i n f o a b s t r a c t

Article history: Autoimmune encephalopathy caused by autoantibodies against neuronal cell-surface proteins in the brain is a
Received 8 January 2017 newly discovered disease category associated with psychiatric disorders. Correct diagnosis of this condition relies
Received in revised form 1 March 2017 on the detection of specic autoantibodies in the blood or cerebral spinal uid in addition to the clinical presen-
Accepted 5 March 2017
tations. The study aimed to understand the seroprevalence of selective anti-neuronal autoantibodies in our pa-
Available online xxxx
tients with schizophrenia. First, we screened for six anti-neuronal autoantibodies in an archived blood sample
Keywords:
collected from patients with the rst-episode schizophrenia. The six autoantibodies including antibodies against
Autoimmune encephalopathy N-methyl-D-aspartate (NMDA) receptor, -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) re-
Anti-neuronal autoantibodies ceptors 1 and 2, -butyric acid receptor type B1 (GABARB1), leucine-rich glioma inactivated-1 (LGI1) protein,
Anti-NMDA receptor encephalitis and contactin-associated protein-like 2 (CASPR2) protein. A total of 78 plasma samples (46 males and 32 fe-
First-episode schizophrenia males) were investigated; however, no positive case was identied. In this second study, we screened anti-
Chronic schizophrenia NMDA receptor autoantibodies in a blood sample of 234 patients with chronic schizophrenia (133 females and
Differential diagnosis 101 males) including 48 patients dened as treatment resistance. None of this sample was detected as positive.
The negative ndings in this study suggest that the seroprevalence of autoantibodies against neuronal surface
proteins might be low in patients diagnosed with schizophrenia.
2017 Elsevier B.V. All rights reserved.

1. Introduction Recently, several new autoantibodies against neuronal cell-surface

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 dys-
function 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 preva-
lence of multiple autoantibodies was reported in a systematic and quan-
titative review of blood autoantibodies in schizophrenia (Ezeoke et al.
2013). Together, these data suggest autoimmune diseases are associat-
ed with the pathogenesis of schizophrenia and its related disorders.
Corresponding author at: Department of Psychiatry, Chang Gung Memorial Hospital,
Linkou, No. 5 Fusing St, Kueishan District, Taoyuan City 333, Taiwan.
E-mail address: cchen3801@gmail.com (C.-H. Chen).
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 con-
dition 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 rst-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 rst-
episode schizophrenia using a commercially available indirect immuno-
uorescence assay. The six autoantibodies including antibodies against
N-methyl-D-aspartate (NMDA) receptor, -amino-3-hydroxy-5-meth-
yl-4-isoxazolepropionic acid (AMPA) receptors 1 and 2, -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 psy-
chiatric condition, anti-NMDA receptor encephalitis is the most well-
studied in recent years. It is characterized by the presence of IgG

http://dx.doi.org/10.1016/j.schres.2017.03.012
0920-9964/ 2017 Elsevier B.V. All rights reserved.

Please cite this article as: Chen, C.-H., et al., Seroprevalence survey of selective anti-neuronal autoantibodies in patients with rst-episode
schizophrenia and chronic schizophr..., Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.03.012
2 C.-H. Chen et al. / Schizophrenia Research xxx (2017) xxxxxx
antibody against the NR1 subunit of NMDA receptor in the affected pa-
tients. Several studies reported the detection of anti-NMDA receptor au-
toantibodies 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 ag-
itation, irritability, anxiety, insomnia, hallucinations, delusions, aggres-
sion, and bizarre behaviors. A wide range of neurological symptoms
may concur with or follow the appearance of psychiatric symptoms, in-
cluding movement abnormalities, autonomic dysregulation, seizure at-
tacks, 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 pri-
mary psychiatric diagnosis (Barry et al. 2015; Barry et al. 2011;
Chapman and Vause 2011). Early recognition of this condition and time-
ly 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 diag-
nosed with chronic schizophrenia or even those who were refractory
to psychopharmacotherapy might be associated with anti-NMDA recep-
tor encephalopathy. Hence, in the second study, we conducted a sero-
prevalence survey of anti-NMDA receptor autoantibodies in patients
with chronic schizophrenia, including some who were refractory to an-
tipsychotic treatment.
2. Methods
2.1. Subjects
For the rst-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 institu-
tional review board of the study hospital. All adult participants volun-
tarily provided their written informed consents and minors gave
written assent with informed consent from their parents after full ex-
planation of the study procedures to them. We recruited the patients
between 16 and 45 years old, who newly developed the rst episode
of full-blown psychosis which met the Diagnostic and Statistical Manual
of Mental Disorders, Fourth Edition (DSM-IV) criteria for schizophrenia
or schizophreniform disorder. Excluded from the study were those who
had mood episodes, current use of the psychoactive substance, a history
of central nervous system illness or traumatic brain injury, and an intel-
ligent quotient (IQ) below 70. A total of 78 patients were recruited, and
they received blood withdrawal and plasma extraction during acute
phase of illness. The plasmas were stored at the 80 C refrigerator.
There were 32 male and 46 female subjects. The mean age was
24.1 6.5 years old, and the mean age at onset was 23.2 6.8 years
old. The mean duration of illness was 1.1 1.5 years. The mean storage
years of plasma were 7.1 2.1 years.
For the chronic schizophrenia study, patients meeting the diagnostic
criteria for chronic schizophrenia according to the Diagnostic and Statis-
tical Manual of Mental Disorders, Fourth Edition, text revision (DSM-IV-
TR; American Psychiatric Association, 2000) were recruited into this
study. They were from the Department of Psychiatry, Chang Gung Me-
morial Hospital-Linkou, Taoyuan, Taiwan, the Department of Psychiatry,
Yuli Mental Health Research Center, Yuli Branch, Taipei Veterans Gener-
al Hospital Hualien, Taiwan, and the Department of Psychiatry, Hualien
Armed Forces General Hospital, Hualien, Taiwan. Patients met the pro-
posed guidelines for determining treatment resistance in schizophrenia
by Conley & Kelly were dened as treatment-resistance in this study
(Conley and Kelly 2001). The study was approved by the Institutional
Review Board of each hospital. Informed consent was obtained from
each subject and their families after the study was fully explained to
the patients and their families. A total of 234 patients with chronic
Please cite this article as: Chen, C.-H., et al., Seroprevalence survey of selective anti-neuronal autoantibodies in patients with rst-episode
schizophrenia and chronic schizophr..., Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.03.012
schizophrenia were recruited into this study, including 133 female pa-
tients (mean age: 50.3 8.4 years) and 101 male patients (mean age:
40.6 7.0 years). Among these 234 chronic patients, 48 patients met
the proposed guidance of treatment resistance. A total of 5 ml venous
blood was collected from each subject with ethylenediaminetetraacetic
acid (EDTA) as anti-coagulant. Plasma was collected and was frozen in
30 C freezer until use.
2.2. Autoantibody screening assay
For the rst-episode schizophrenia study, plasma autoantibodies
from each subject were assessed using a commercially available indirect
immunouorescence test kit, IIFT: Autoimmune Encephalitis Mosaic 1
(FA 112d-1005-1, Euroimmun AG, Lbeck, Germany). This assay
contained six wells of xed HEK293 cells transfected with cDNA of
NR1 subunit of NMDA receptor, AMPA1 and AMPA2 of AMPA receptor,
GABARB1 of GABA receptor, leucine-rich glioma inactivated-1 (LGI1),
and contactin-associated protein-like 2 (CASPR2), respectively. The ex-
perimental procedures followed the instructions from the manufacturer
with the initial 1:10 dilution of the plasma. The results were examined
under a uorescent microscope. Samples were classied as positive or
negative based on the intensity and pattern of surface immunouores-
cence of transfected cells following the recommendations from the
manufacturer.
For chronic schizophrenia study, the commercially available
anti-glutamate receptor (type NMDA) IIFT kit (FA 112d-1005-51,
Euroimmun AG, Lbeck, Germany) was used in the screening assay
to detect the plasma anti-NMDA receptor IgG autoantibodies. The
kit is an indirect immunouorescence cell-based assay containing
the xed EU 90 cells that expressed the recombinant subunit 1 of
NMDA receptor. Non-transfected cells were used as negative control.
Testing was performed following the manufacturer instructions. In
brief, slides were incubated with the plasma sample with the initial di-
lution of 1:10. Following the incubation, slides were washed and
stained with uorescein-labeled anti-human IgG antibodies and visual-
ized using a uorescence microscope. Positive or negative results were
based on the comparison of the intensity of surface immunouores-
cence between transfected cells and non-transfected cells following
the manufacturer's recommendations.
2.3. Verication assay
The immunohistochemistry on rat brain was used for verication
purpose. The assay was performed using the commercially available
indirect immunouorescence test IIFT: Neurology Mosaics (FA 111
m-3, Euroimmun AG, Lbeck, Germany) which contains rat hippo-
campus and cerebellum tissue, EU90 cell transfected with glutamate
receptor (type NMDA) and untransfected UE90 cells as negative
control. The experimental procedures followed the manufacturer's
instructions. The results were examined under a uorescent micro-
scope, and the interpretation of the results followed the manufac-
turer's recommendation.
3. Results
In the rst-episode schizophrenia study, none of the 78 patients was
positive in the screening of six neuronal autoantibodies using the indi-
rect immunouorescent cell-based assay. In the chronic schizophrenia
study, also no positive case among 234 patients was detected in the sur-
vey of anti-NMDA receptor autoantibody. Two patients with ambiguous
results in the initial screening were subjected to further verication test
using rat brain immunohistochemistry assay; however, both of them
were negative in the verication study.
 C.-H. Chen et al. / Schizophrenia Research xxx (2017) xxxxxx
4. Discussion
In the rst study, we screened for autoantibodies against six neuro-
nal cell-surface proteins in a sample of archived plasmas from 78 pa-
tients with rst-episode schizophrenia and found no positive case in
this sample. Similar study had been performed by Haussleiter and col-
leagues. They screened for the same six anti-neuronal autoantibodies
as ours in 50 chronic patients with psychotic disorders of varying sever-
ity. No positive case was detected in their sample (Haussleiter et al.
2012). Together, given the small sample sizes of both studies, the pre-
liminary data suggest that the seroprevalence of anti-neuronal autoan-
tibodies in patients with psychosis might be low. Nevertheless, the
number of neuronal cell-surface proteins or synaptic proteins as target
antigens for autoimmune encephalitis has increased recently. At least
twelve autoantibodies against neuronal cell-surface proteins were
found in patients with autoimmune encephalitis who presented psychi-
atric symptoms in addition to neurologic symptoms (Chefdeville et al.
2016). Some researchers referred them as autoimmune synaptopathy
(Crisp et al. 2016). Hence, increasing awareness of this new disease cat-
egory as a differential diagnosis is essential to guide the accurate diag-
nosis and treatment of patients manifesting psychiatric symptoms
(Briggs et al. 2015; Chang et al. 2015; Chapman and Vause 2011).
Although some studies reported the detection of anti-NMDA recep-
tor autoantibodies in patients with acute psychosis or rst episode
schizophrenia (van de Riet and Schieveld 2013; Zandi et al. 2011),
Masdeu and colleagues investigated 80 patients with the rst-episode
psychosis; they found no positive case having serum anti-NMDA recep-
tor autoantibodies in their study (Masdeu et al. 2012). More recently,
Masopust and colleagues also reported no positive serum antibodies
against NMDA receptor in 50 patients with rst-episode schizophrenia
(Masopust et al. 2015). The negative results of our studies in rst-
episode schizophrenia and chronic schizophrenia are consistent with
these studies.
The discrepant results among different studies might be attribut-
ed to several factors. First, the real incidence of anti-NMDA receptor
encephalitis among patients with schizophrenia might be very low.
According to a review paper, the estimated incidence of acute en-
cephalitis syndrome ranged from 10.513.8 per 100,000 for children,
and the minimal incidence of acute encephalitis syndrome was 2.2
per 100,000 for adults in Western industrialized countries (Jmor
et al. 2008). Acute encephalitis syndrome can be categorized as in-
fectious and non-infectious, and most of the acute encephalitis was
attributed to infectious encephalitis. The incidence of autoimmune
encephalitis is still not established (Barry et al. 2015). Gable and col-
leagues reported 32 out of 801 patients (4%) were tested positive for
anti-NMDA receptor encephalitis from California Encephalitis Project
(Gable et al. 2012). In a large study of 3000 patients with encephalitis
screened in China, 43 patients (4%) were positive for anti-NMDA recep-
tor antibody in CSF or serum (Wang et al. 2015). Lim and colleagues
screened 721 Korean patients with undetermined causes of encephalitis
and detected 40 patients (5.5%) were positive for anti-NMDA receptor
antibodies. Gresa-Arribas and colleagues reported that 100 among
1500 samples (6.7%) referred to their center were positive (Dalmau
et al. 2008; Gresa-Arribas et al. 2014). Furthermore, only 4% of patients
with anti-NMDA receptor encephalitis were estimated to present isolat-
ed psychiatric symptoms (Kayser et al. 2013). Thus, the incidence of
anti-NMDA receptor encephalitis among schizophrenia would be very
low, and the positive predictive frequency of anti-NMDA receptor auto-
antibody among schizophrenia patients would also be very low.
Second, the titer of anti-NMDA receptor antibodies may change dur-
ing different stages of the psychosis associated with anti-NMDA recep-
tor autoimmune encephalitis. High titer might be detected during the
early acute phase of the disease, while the titer of autoantibody may de-
cline and even disappear over time during the chronic phase of the dis-
ease. Also, antipsychotics treatment is known to decrease immune
response. Hence, it is likely that the anti-NMDA receptor autoantibodies
Please cite this article as: Chen, C.-H., et al., Seroprevalence survey of selective anti-neuronal autoantibodies in patients with rst-episode
schizophrenia and chronic schizophr..., Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.03.012
3
might be undetectable in patients with chronic schizophrenia associat-
ed with anti-NMDA receptor autoimmune encephalitis.
Third, the detection of anti-NMDA receptor autoantibodies relies
on the assay methods. Different immunological tests used in differ-
ent studies may result in heterogeneous ndings. It is suggested
that the detection of anti-NMDA receptor antibodies should include
the immunohistochemistry of rat brain, cultures of dissociated rat
hippocampal neurons, and cell lines that overexpress NR1 subunit
alone or in combination with NR2A or 2B subunits (cell-based
assay) (Dalmau et al. 2008). de Witte and colleagues recently report-
ed two samples that were false positive in their study. They recom-
mended that positive serum antibody results in patients with
psychosis should be conrmed by alternative test methods and as-
says using cerebrospinal uid samples (de Witte et al., 2015). In
line with this, in our study, two patients were found to have ambig-
uous results in the initial cell-based assay. They were found negative
in further verication test using rat brain immunohistochemistry
assay. Pathmanandavel and colleagues recently demonstrated the
detection of IgG autoantibodies against NR1 subunit of NMDA receptor
in 5 out of 43 children with the rst episode of psychosis using immu-
noassays with the substrates of primary mouse hippocampus cultured
neurons and a ow cytometry live cell-based assay (Pathmanandavel
et al. 2015). Their study supports the presence of a biological subgroup
of patients with the initial psychiatric diagnosis. Thus, the availability of
a battery of validated immunological tests with high sensitivity and
specicity is essential for the translation of autoimmune encephalitis
in clinical psychiatric service.
In Taiwan, patients with anti-NMDA receptor encephalitis present-
ing with behavioral or psychiatric symptoms had been reported before
(Dou et al. 2012; Guo et al. 2014; Lin et al., 2014). Hung and colleagues
reported a 14-year-old girl who was suspected to have bipolar disorder
or schizophrenia and received psychiatric treatment before she was di-
agnosed with anti-NMDA receptor encephalitis (Hung et al. 2011). Kuo
and colleagues also reported a 16-year-old girl who initially presented
psychotic mania but was nally diagnosed with anti-NMDA receptor
encephalitis (Kuo et al. 2012). These studies indicate the presence of
anti-NMDA receptor encephalitis in our population and also demon-
strate the importance of considering anti-NMDA receptor encephalitis
as a differential diagnosis in our patients with acute psychosis.
5. Concluding remarks
In this study, we did not detect autoantibodies against six neuronal
cell-surface proteins in a sample of seventy-eight patients with rst-
episode schizophrenia, nor did we detect anti-NMDA receptor autoanti-
bodies 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 worthy of special attention in clinical psychiatric
services.
Conict of interest
The authors declare no conict 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 rst-episode schizophrenia patients. Min-
Chih Cheng, Ko-Huan Lin and Chia-Hsiang Chen helped recruit chronic schizophrenia pa-
tients 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.
4 C.-H. Chen et al. / Schizophrenia Research xxx (2017) xxxxxx

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Please cite this article as: Chen, C.-H., et al., Seroprevalence survey of selective anti-neuronal autoantibodies in patients with rst-episode
schizophrenia and chronic schizophr..., Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.03.012