Psychosomatics 2014:55:37–44 & 2014 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
Review Article
Psychiatric Manifestations of Anti-NMDA Receptor
Encephalitis: Neurobiological Underpinnings and
Differential Diagnostic Implications
Eleni Maneta, M.D., Georgina Garcia, M.D.
Objective: Anti-N-methyl-D-aspartate receptor
(NMDA-R) encephalitis is a recently discovered dis-
order with prominent psychiatric manifestations that is
often misdiagnosed. The objective of this review is to
raise awareness of the disorder among psychiatrists and
to expand upon the diagnostic considerations that arise
in the context of the neurobiology and symptomatology
of this disorder. We also aim to examine the similarities
in terms of symptoms and underlying neurobiology
between anti-NMDA-R encephalitis and schizophrenia-
spectrum illnesses. Methods: The information presented
will reflect a review of the literature of the symptoma-
tology and pathophysiology of anti-NMDA-R
encephalitis and the role of the NMDA-R in both anti-
NMDA-R encephalitis and schizophrenia-spectrum
A nti-N-methyl-D-aspartate receptor (NMDA-R)
encephalitis is an autoimmune disorder with a
complex presentation that includes psychiatric symp-
toms, memory deficits, and autonomic instability
often requiring hospitalization in intensive care units.
The predominance of early psychiatric symptoms
often leads patients to initially seek psychiatric eval-
uation and treatment. As a result there is a delay in the
diagnosis of this potentially lethal disorder because of
limited knowledge among psychiatrists about anti-
NMDA-R encephalitis.
First identified in 2007 by Dalmau et al.,1 in a
series of 12 patients, the hallmark of anti-NMDA-R
encephalitis is the presence of autoantibodies that
target the NMDA-R. Since then over 400 patients with
Psychosomatics 55:1, January/February 2014
illnesses. Results: The studies reviewed highlight the role
of the NMDA-R in both anti-NMDA-R encephalitis
and schizophrenia in terms of symptom presentation and
neurobiology. Studies have also begun to identify
involvement of NMDA-R antibodies in patients diag-
nosed with schizophrenia. Conclusions: There is an
increasing need for psychiatrists to become aware of the
disorder and consider it in their differential diagnosis, as
they are often the first to be consulted on patients with
anti-NMDA-R encephalitis. The similarities identified
between anti-NMDA-R encephalitis and schizophrenia-
spectrum illnesses also raise questions about a common
underlying pathophysiology particularly in regard to the
NMDA-R.
(Psychosomatics 2014; 55:37–44)
anti-NMDA-R encephalitis have been identified,2 and
there have been numerous other case studies pointing
to this diagnosis,3–5 including patients initially mis-
diagnosed as having psychiatric disorders, such as
postpartum psychosis6 and conversion disorder.7
Highlighting the importance of accurate and rapid
diagnosis, the symptoms of anti-NMDA-R encephalitis,
Received March 19, 2013; revised May 29, 2013; accepted May 31,
2013. From Department of Psychiatry, Boston Children's Hospital,
Harvard Medical School, Boston, MA. Send correspondence and reprint
requests to Eleni Maneta, M.D., Department of Psychiatry, Boston
Children's Hospital, Harvard Medical School, 300 Longwood Avenue,
Boston, MA 02115; e-mail: eleni.maneta@childrens.harvard.edu
& 2014 The Academy of Psychosomatic Medicine. Published by
Elsevier Inc. All rights reserved.
www.psychosomaticsjournal.org 37
Psychiatric Manifestations of Anti-NMDA Receptor Encephalitis
although often severe and potentially fatal, can be
reversed in the majority of the cases with appropriate
treatment.8
Although the literature on anti-NMDA-R ence-
phalitis has increased dramatically since its discovery,
most of the studies to date focus on case presentations
and the underlying neurologic and paraneoplastic
aspects of the syndrome. At the same time, anti-
NMDA-R encephalitis has been significantly un-
derrepresented in psychiatric literature despite the
prominent psychiatric symptoms and the importance
of psychiatric involvement in the treatment.9
Our primary aim in reviewing the literature on
anti-NMDA-R encephalitis is to raise awareness
among practicing psychiatrists for the need of a broad
differential diagnosis when evaluating patients with
new onset of some forms of psychiatric symptomatol-
ogy. We support this need by examining the overlap
of symptomatology and neurobiology between anti-
NMDA-R encephalitis and manifestations, such as
catatonia and psychosis, through the potential under-
lying role of the NMDA-R, with the understanding
that available data to date are limited.
EPIDEMIOLOGY
When anti-NMDA-R encephalitis was first discovered
it was thought to be a paraneoplastic phenomenon
that was primarily associated with ovarian teratomas
and hence was seen as predominantly occurring in
women.1 Within 1 year, Eker et al.10 reported on the
first case of anti-NMDA-R encephalitis in the pres-
ence of a testicular teratoma and metastatic seminoma
raising the possibility that men may also be susceptible
to this syndrome. More recently it has been found that
anti-NMDA-R encephalitis is not necessarily a para-
neoplastic syndrome and can occur in the absence
of a tumor.2,11 Florance et al.12 reported that tumor
presence was associated with age and younger indi-
viduals with anti-NMDA-R encephalitis are less likely
to have a teratoma. Gender has also been shown to
play a role in the presence or absence of a tumor, with
women being more likely to have tumors.2
Although many patients have been diagnosed
with anti-NMDA-R encephalitis to date, the exact
prevalence of this disorder is unknown. The increas-
ing number of case reports, however, as well as
evidence from various studies looking at causes of
encephalitis has pointed to a much more frequent
38 www.psychosomaticsjournal.org
disorder than what was originally thought.2 Gable
et al.,13 in their study of 79 patients with encephalitis
through the California Encephalitis Project identified
a total of 32 patients (40%) with anti-NMDA-R
encephalitis making it the leading diagnosis of ence-
phalitis in their cohort and raising the issue of
including anti-NMDA-R encephalitis in the top of
the differential diagnosis of encephalitis. Given the
limited awareness of anti-NMDA-R encephalitis
among psychiatrists and other physicians, it is possi-
ble that many more cases exist that are not identi-
fied, particularly when it comes to differentiating
anti-NMDA-R encephalitis from other cerebrotoxi-
cities, such as catatonia or neuroleptic malignant
syndrome.
CLINICAL MANIFESTATIONS, TREATMENT,
AND OUTCOME
The clinical presentation of anti-NMDA-R encepha-
litis includes psychiatric symptoms ranging from
anxiety and insomnia2 to mania, psychosis, and even
catatonia.14 Sansing et al.,15 in their case report,
argued that psychiatric symptoms are the most fre-
quent symptoms associated with this disorder, which
can mislead treaters to focus on a primary psychiatric
cause rather than an organic cause.
Dalmau et al.2 have described the stages of anti-
NMDA-R encephalitis more extensively and describe
a prodromal flu-like phase that is seen in about 70% of
cases and presents with fever, headache, nausea,
vomiting, diarrhea, or upper respiratory tract symp-
toms. After the initial phase, psychiatric manifesta-
tions go on to develop in patients, including anxiety,
insomnia, mania, and psychosis followed by physical
decompensation involving autonomic instability, seiz-
ures, decreased responsiveness, and occasionally
short-term memory loss (Table 1).
Literature on anti-NMDA-R encephalitis to date
has shown that imaging has limited usefulness in the
diagnosis due to the fact that in 50% of cases, the
results of magnetic resonance imaging of the brain are
normal.1 Positron emission tomography has also
shown variable results in patients with anti-NMDA-
R encephalitis with some studies finding evidence of
cortical hypometabolism,16 and other studies finding
evidence of subcortical hypermetabolism,17 thereby
limiting its usefulness as a diagnostic tool. Electro-
encephalography shows nonspecific disorganized
Psychosomatics 55:1, January/February 2014

TABLE 1. Stages of Anti-NMDA-R Encephalitis
Stage Clinical presentation
Early Flu-like symptoms: headaches, fever, and nausea
Middle Psychiatric symptoms: psychosis, grandiose delusions,
anxiety, and insomnia
Late Autonomic instability, catatonia, rigidity, dystonia,
and seizures*
n
Seizures also occur at earlier stages of the disease.
activity in most patients.2 Electroencephalography
monitoring, however, is important to capture seizure
activity. Laboratory studies provide more certainty for
the diagnosis. Dalmau et al.2 report that cerebrospinal
fluid (CSF) abnormalities (e.g., lymphocytic pleocy-
tosis and CSF-specific oligoclonal bands) can be seen
in up to 80% of patients and that number increases
with disease progression. NMDA-R antibodies, the
hallmark of the disease, can be detected in either CSF
or serum of patients and titers can be used to help
follow progression and recovery. CSF titers are
indicative of intrathecal antibody production and
often correlate better with disease severity.2
Once the diagnosis of anti-NMDA-R encephalitis is
confirmed by the presence of autoantibodies, prompt
treatment is imperative. The initial phase of treatment
involves removal of a teratoma and corticosteroids,
intravenous (IV) immunoglobulins or plasma exchange,
which is followed by rituximab or cyclophosphamide in
patients who do not respond.2 Because of the prominent
psychiatric symptoms, patients have also frequently
been given antipsychotics. Caution is needed, however,
when using antipsychotics as they have been associated
with exacerbation of dystonic and catatonic symptoms
and can produce a complex clinical picture that resem-
bles neuroleptic malignant syndrome.9,18 Electrocon-
vulsive therapy (ECT) has also been used to treat
patients with anti-NMDA-R encephalitis although its
effectiveness has been variable, and some case reports
have indicated a limited response.9,19 However, Iwata
et al.20 reported on an 18-year-old male with anti-
NMDA-R encephalitis (CSF positive for antibodies)
who was treated solely with ECT and recovered.
Braakman et al.21 present yet another interesting case
of a 47-year-old male with anti-NMDA-R encephalitis
(CSF positive for antibodies) who did not respond to a
3-day course of IV methylprednisolone pulse therapy
but who subsequently responded to bilateral ECT.
Although the exact mechanism of action of ECT has
Psychosomatics 55:1, January/February 2014
Maneta and Garcia
yet to be determined,22 Watkins et al.23 studied an
animal model and found that exposure to ECT led to an
increase in the NR2A and NR2B subunits of the
NMDA-R, which is documented by increased levels
of the respective messenger ribonucleic acids. This raises
the possibility that ECT ameliorates symptoms of anti-
NMDA-R encephalitis by increasing expression of the
NMDA-R.
Although the short-term morbidity and mortality
of anti-NMDA-R encephalitis have been well docu-
mented, less is known about the long-term outcomes.
Titulaer et al.24 conducted the first long-term follow-
up of 577 patients with anti-NMDA-R encephalitis for
24 months and found that immunotherapy and tumor
removal resulted in improvement in 81% of their
sample. Predictors of good outcome included prompt
initiation of treatment with immunotherapy and no
need for intensive care treatment.24
NEUROBIOLOGY OF THE NMDA-R
The NMDA-R is an ionotropic glutamate receptor that
functions both presynaptically and postsynaptically to
regulate synaptic transmission, neuronal maturation,
and brain plasticity.25 Additionally, the NMDA-R has
been linked with excitotoxicity and neuronal death, and
has therefore been implicated in various disorders, such
as stroke and epilepsy.25,26 Upregulation and hyper-
function of NMDA-R have been associated with a
proconvulsive state and seizure activity.27 Inhibition of
the NMDA-R, however, is anticonvulsant, but is
associated with psychosis. These effects of the
NMDA-R along with the hypothesis that epilepsy is
a state of “excitation-inhibition imbalance” have been
used to explain the occurrence of postictal and interictal
psychosis,28 2 states that should also be considered in the
differential diagnosis of new onset psychosis.
Anti-NMDA-R encephalitis represents a state of
NMDA-R hypofunction caused by autoantibodies
against the NR1a subunit.2 Dalmau et al.2 have
hypothesized that the NMDA-R antibodies lead to
inactivation of gamma-aminobutyric acid (GABA)
ergic interneurons (Figure). The NMDA-R hypo-
function can explain some of the prominent psychi-
atric manifestations of anti-NMDA-R encephalitis.
Catatonia, for example, which is frequently associ-
ated with anti-NMDA-R encephalitis, had been
linked with NMDA-R dysfunction and glutamate
overexcitation, even before the discovery of the
www.psychosomaticsjournal.org 39
Psychiatric Manifestations of Anti-NMDA Receptor Encephalitis
autoantibodies.29,30 Glutamatergic overactivity can
stem from acute blockade of the NMDA-R,31,32
which could account for the presence of catatonic
symptoms in patients with anti-NMDA-R encepha-
litis. As stated earlier, NMDA-R dysfunction also
leads to GABA-ergic dysregulation,33 which has also
been implicated in the development of catatonia and
represents the therapeutic target of benzodiazepines
(GABA-α agonists).34
The psychotic symptoms present in anti-NMDA-R
encephalitis can also be explained by NMDA-R
hypofunction, particularly given the link between the
NMDA-R and schizophrenia.35–37 Although the “dop-
amine hypothesis”38 has previously been the most
widespread explanatory model of schizophrenia,
research within the past 2 decades has shed light on a
different potential mechanism—NMDA-R hypofunc-
tion with glutamate dysregulation.36,37 Evidence for the
involvement of the NMDA-R and the role of glutamate
in schizophrenia comes primarily from studies on
phencyclidine and ketamine, known antagonists of
the NMDA-R, which produce psychotic symptoms
FIGURE. Schematic of Proposed Interactions Between NMDA
Receptor on GABA Interneurons and Glutamate and
Dopamine (A) and the Effects of NMDA-Receptor
Hypofunction or Blockade by Autoantibodies (B)
40 www.psychosomaticsjournal.org
and cognitive impairment similar to that seen in
schizophrenia.37 Glutamatergic pathways in the cortex
exert both direct stimulatory and indirect inhibitory
(through GABA interneurons) control over subcortical
dopaminergic pathways,37,39 however, there is compel-
ling evidence that glutamate dysregulation in schizo-
phrenia is specifically associated with NMDA-R
hypofunction, as disturbances of other glutamatergic
pathways do not produce symptoms consistent with
schizophrenia.33 Although an extensive review of the
neurobiology of schizophrenia is beyond the scope of
this paper, some studies are highlighted to outline the
connection between schizophrenia and NMDA-R
hypofunction. For example, Stephan et al.40 have
drawn links between impaired synaptic plasticity as a
result of dopamine, serotonin and acetylcholine mod-
ulation of the NMDA-R and symptoms of schizophre-
nia. Kantrowitz and Javitt33 describe NMDA-R
dysfunction as the “final common pathway” for the
mechanisms that lead to schizophrenia and associate it
to both positive and negative symptoms. They note that
positive symptoms occur in the context of NMDA-R
dysfunction that leads to increased release of striatal
dopamine, by removing inhibitory control (GABA
interneurons), and is consistent with dopamine hyper-
activity present during psychosis (Figure 1). They also
described how NMDA-R potentiators, such as glycine,
can play a role in reversing the dopaminergic dysregu-
lation. In terms of the negative symptoms of schizo-
phrenia, Kantrowitz and Javitt33 report that although
there is less clarity around the role of the NMDA-R,
there is still compelling evidence from NMDA-R
antagonists that the resultant glutamate dysfunction
plays a central role.
When looking at the evidence for NMDA-R
dysfunction in schizophrenia, Olney et al.31 also point
to a developmental effect that is seen both in drug-
induced NMDA-R blockade and schizophrenia; psy-
chotic symptoms in both conditions occur more
commonly at later developmental stages nearing
adulthood.
Genetic studies have also supported a link between
schizophrenia and the NMDA-R particularly through
regulatory proteins.36,37 O'Tuathaigh et al.41 have
discussed the involvement of the NRG1 gene, which
expresses neuregulin-1, a growth and differentiation
factor in the regulation of the NMDA-R. They also
described findings from animal studies that indicate a
relationship between NRG1 dysfunction and negative
Psychosomatics 55:1, January/February 2014

symptoms of schizophrenia through reduced NMDA-
R expression.
The overlap between schizophrenia and anti-
NMDA-R encephalitis in regard to the NMDA-R
hypofunction and psychotic symptoms raises a question
about possible involvement of autoantibodies in the
pathogenesis of, at least some of, the schizophrenia-
spectrum illnesses. Three studies to date have inves-
tigated the presence of anti-NMDA-R antibodies in
patients with schizophrenia and have found intriguing
results. Zandi et al.42 examined 46 patients with first-
episode psychosis, and identified 3 patients with positive
anti-NMDA-R antibodies in their serum. They also
noted that 1 of the 3 patients who was unresponsive to
antipsychotics, received plasmapheresis with good
results. Tsutsui et al.43 examined 51 patients with
schizophrenia or schizoaffective disorder or both and
found that 4 had positive anti-NMDA-R antibodies in
their serum. More recently Steiner et al.44 examined
patients with schizophrenia (n ¼ 121), major depressive
disorder (n ¼ 70), and borderline personality disorder
(n ¼ 38) and found that 9.9% of the patients diagnosed
with schizophrenia had NMDA-R antibodies in their
serum compared with 2.8% of the depressed patients
and 0% of the borderline personality disorder. Interest-
ingly patients with schizophrenia, who were seropos-
itive, had immunoglobulin G antibodies not only
directed against the NR1a subunit of the NMDA-R
(seen in anti-NMDA-R encephalitis) but also against
the NR1a/NR2b subunit44 again raising the question
about what involvement the immune system might have
in the pathogenesis of some forms of schizophrenia.
The concept of an autoimmune-mediated patho-
genesis of schizophrenia dates back to the 1960s and
continues to evolve in psychiatric research. Potvin
et al.45 examined the presence of inflammatory cyto-
kines in patients with schizophrenia by conducting a
meta-analysis of 62 studies (total sample of 2298
patients) and found persistent evidence for increased
serum levels of interleukin (IL)-1RA, sIL-2R, and IL-
6, thus providing support to the hypothesis of an
immune activation and an inflammatory response in
schizophrenia. Although the effects of these cytokines
is complex and beyond the scope of this paper, it is
interesting to note that IL-6 specifically has been
associated with manifestations of autoimmune disor-
ders in the central nervous system (CNS) by enhancing
antibody production and disrupting the blood-brain
barrier.46,47 One possible hypothesis that can be
Psychosomatics 55:1, January/February 2014
Maneta and Garcia
generated therefore is that elevated levels of IL-6 in
patients with schizophrenia can disrupt the blood-
brain barrier and allow circulating autoantibodies to
enter the CNS. Interestingly, before the discovery of
anti-NMDA-R encephalitis, Jones et al.46 had alluded
to a connection between autoantibodies against the
NMDA-R and schizophrenia by drawing a parallel
with anti-deoxyribonucleic acid antibodies that cross-
react with the NR2 subunit of the NMDA-R and
cause psychosis in systemic lupus erythematosus.
The association between schizophrenia and the
immune system has also been examined from the
perspective of prenatal and perinatal exposure to
viruses that can lead to neurodevelopmental changes
in the brain.48,49 Moreno et al.50 studied an animal
model and found an association between prenatal
exposure to influenza and downregulation of the
mGlu2 receptor, a metabotropic glutamate receptor,
in offspring which leads to schizophrenia-like behav-
ioral changes. Interestingly, the mGlu2 receptor has
been associated with regulation of the NMDA-R, and
activation of the mGlu2 receptor can reverse the
effects of NMDA-R hypofunction.51
Although the role of viral infections has been
examined as a possible mechanism of pathogenesis for
anti-NMDA-R encephalitis, to date there has been no
association between the development of the disorder
and direct CNS viral infection.2 However, the possi-
bility of early infections leading to an activation of the
immune system, or concurrent infections leading to an
alteration of the blood-brain barrier have not been
fully ruled out.11 This is particularly interesting when
thought of in the context of possible blood-brain
barrier dysfunction as a result of elevated levels of
IL-6 in patients with schizophrenia,46 and raises a
question about whether there is a higher likelihood of
development of anti-NMDA-R encephalitis in indi-
viduals who have a diathesis for schizophrenia because
of autoantibodies gaining entrance into the CNS.
IS IT ON THE SAME SPECTRUM AFTER ALL?
The NMDA-R is complex; it has very diverse func-
tions and directly and indirectly affects multiple
neurotransmitters through both presynaptic and post-
synaptic neurons.25,26 Its central role in anti-NMDA-
R encephalitis, catatonia, and schizophrenia raises
questions about common underlying pathophysio-
logic links between these conditions.
www.psychosomaticsjournal.org 41
Psychiatric Manifestations of Anti-NMDA Receptor Encephalitis
The NMDA-R may represent a bridge to close the
chasm between “primary psychiatric conditions” and
“primary organic conditions.” The autoantibodies
against the NR1 and NR2 subunit of the NMDA-
R, as described by Dalmau et al.,1,2 may also play a
role in the development of some forms of schizophre-
nia, as positive titers have been identified in patients
diagnosed with the disease.42–44 One possibility could
be that in schizophrenia-spectrum illnesses these
autoantibodies are present during an earlier devel-
opmental period resulting in a more gradual and
chronic exposure to NMDA-R hypofunction.
The presence of autoantibodies to the NR1 and
NR2 subunits of the NMDA-R raise the possibility
that autoantibodies to other receptor binding sites
exist and Steiner et al.44 provide the first evidence of
epitope specificity of NMDA-R antibodies in anti-
NMDA-R encephalitis and schizophrenia. Evidence
also exists about different subunits of the NMDA-R
being more prominent at different developmental
stages,26 which again raises a possibility of autoanti-
bodies to other subunits of the NMDA-R being
blocked at earlier developmental stages and leading
to the chronic changes associated with schizophrenia.
CONCLUDING THOUGHTS, LIMITATIONS,
AND FUTURE DIRECTIONS
The role of the NMDA-R in anti-NMDA-R ence-
phalitis, and in schizophrenia-spectrum illnesses, and
the similarities in symptom presentation, point to a
different direction for future schizophrenia research:
to reexamine the role of autoimmunity. More specif-
ically, the role of the currently identified anti-NMDA-
R antibodies in schizophrenia should be further
investigated, as well as the role of autoantibodies
to different NMDA-R subunits. Although a few
studies have already found an association between
some cases of schizophrenia and anti-NMDA-R anti-
bodies, more research is needed that would include
larger sample sizes and would further investigate the
relationship between antibody titers and psychosis
(e.g., do higher titers correlate with more severe
psychosis?) Longitudinal monitoring of antibody titers
in seropositive patients with schizophrenia would
also be important. The developmental variation of
the NMDA-R subunits should also be further exam-
ined in relation to schizophrenia as the presence of
such autoantibodies may result in different effects
42 www.psychosomaticsjournal.org
depending on the stage of the developing brain. For
example, the presence of anti-NMDA-R antibodies
can be investigated in youths considered ultra-high
risk for schizophrenia, or in family members of
patients with schizophrenia.
However, research is also needed on anti-NMDA-
R encephalitis to further investigate the effects of the
antibodies on brain circuitry and to shed more light on
treatment approaches and process of recovery through
animal models. The effects of the autoantibodies on
GABA-ergic dysfunction and subsequent psychiatric
symptoms also remain to be investigated.2
From a clinical perspective, it is clear that psy-
chiatrists need to become aware of anti-NMDA-R
encephalitis and consider it in the differential diagnosis
when evaluating patients with sudden-onset catatonia
or psychosis, particularly when these are accompanied
by rapid deterioration and severe autonomic dysfunc-
tion (Table 2). Although not currently recommended,
psychiatrists may want to consider screening CSF and
serum for anti-NMDA-R antibodies in patients pre-
senting with first-episode psychosis particularly young
females also presenting with catatonia.44,52 Identifying
anti-NMDA-R antibodies could alter the treatment
rather dramatically as antipsychotics, which are the
first-line treatment for psychosis, have had equivocal
results and have sometimes been harmful in cases of
anti-NMDA-R encephalitis.9 At the same time treat-
ments such as ECT, which has been more successfully
used in both conditions, may be considered sooner
particularly in light of the morbidity and mortality
associated with anti-NMDA-R encephalitis.
Although the studies reviewed in this article point
to interesting findings about possible common under-
lying neurobiologic pathways between anti-NMDA-R
TABLE 2. Factors That Should Prompt Consideration of Anti-
NMDA-R Encephalitis in First-Episode Psychosis
Signs and symptoms
Flu-like prodrome
Rapid onset of psychotic symptoms
Rapid onset of catatonia
Female gender
Seizures or other neurological dysfunction (e.g. aphasia)
Severe autonomic dysfunction requiring ICU admission
Presence of malignancy (e.g. ovarian teratoma)
Worsening of symptoms on antipsychotics
ICU ¼ intensive care unit.
Psychosomatics 55:1, January/February 2014

encephalitis and schizophrenia, it is important to
acknowledge that there is still not enough evidence
to draw conclusions about the links between the two
conditions. It is also important to note that although a
lot of research has been conducted on the NMDA-R
and its role in schizophrenia and anti-NMDA-R ence-
phalitis, there is still a lot to be learned about its exact
role within the brain circuitry and the effects of its
modulation.
As we continue to learn more about anti-NMDA-
R encephalitis, NMDA-R antibodies, and other
autoantibodies, we will be able to use this information
in conjunction with what is already known about the
References
1. Dalmau J, Tuzun E, Wu HY, et al: Paraneoplastic anti-
N-methyl-D-aspartate receptor encephalitis associated with
ovarian teratoma. Ann Neurol 2007; 61:25–36
2. Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld
MR, Balice-Gordon R: Clinical experience and laboratory
investigations in patients with anti-NMDAR encephalitis.
Lancet Neurol 2011; 10:63–74
3. Lebas A, Husson B, Didelot A, Honnorat J, Tardieu M:
Expanding spectrum of encephalitis with NMDA receptor
antibodies in young children. J Child Neurol 2010; 25:742–745
4. Varvat J, Lafond P, Page Y, Coudrot M, Reynaud-Salard
M, Tardy B: Acute psychiatric syndrome leading young
patients to ICU: consider anti-NMDA-receptor antibodies.
Anaesth Intensive Care 2010; 38:748–750
5. Maggina P, Mavrikou M, Karagianni S, et al: Anti-N-
methyl-D-aspartate receptor encephalitis presenting with
acute psychosis in a preteenage girl: a case report. J Med
Case Rep 2012; 6:224
6. Yu AY, Moore FG: Paraneoplastic encephalitis presenting
as postpartum psychosis. Psychosomatics 2011; 52:568–570
7. Caplan JP, Binius T, Lennon VA, Pittock SJ, Rao MS:
Pseudopseudoseizures: conditions that may mimic psycho-
genic non-epileptic seizures. Psychosomatics 2011; 52:501–506
8. Wandinger K-P, Saschenbrecker S, Stoecker W, Dalmau J:
Anti-NMDA-receptor encephalitis: a severe, multistage,
treatable disorder presenting with psychosis. J Neuroim-
munol 2011; 231:86–91
9. Mann A, Machado NM, Liu N, Mazin AH, Silver K, Afzal
KI: A multidisciplinary approach to the treatment of anti-
NMDA-receptor antibody encephalitis: a case and review
of the literature. J Neuropsychiatry Clin Neurosci 2012;
24:247–254
10. Eker A, Saka E, Dalmau J, et al: Testicular teratoma and
anti-N-methyl-D-aspartate receptor-associated encephalitis.
J Neurol Neurosurg Psychiatry 2008; 79:1082–1083
11. Dalmau J, Gleichman AJ, Hughes EG, et al: Anti-NMDA-
receptor encephalitis: case series and analysis of the effects
of antibodies. Lancet Neurol 2008; 7:1091–1098Ą
Psychosomatics 55:1, January/February 2014
Maneta and Garcia
pathophysiology of psychiatric disorders, such as
schizophrenia, to enhance and affect future ap-
proaches and to catalyze both research and clinical
practice in this growing area.
We would like to acknowledge Dr. David DeMaso,
M.D. Psychiatrist-in-Chief and Chairman of the
Department of Psychiatry, Boston Children's Hospital,
and Dr. Enrico Mezzacappa, Boston Children's Hos-
pital for their encouragement and support.
Disclosure: The authors disclosed no proprietary or
commercial interest in any product mentioned or con-
cept discussed in this article.
12. Florance NR, Davis RL, Lam C, et al: Anti-N-methyl-D-
aspartate receptor (NMDAR) encephalitis in children and
adolescents. Ann Neurol 2009; 66:11–18
13. Gable MS, Sheriff H, Dalmau J, Tilley DH, Glaser CA: The
frequency of autoimmune N-methyl-D-aspartate receptor
encephalitis surpasses that of individual viral etiologies in
young individuals enrolled in the California Encephalitis
Project. Clin Infect Dis 2012; 54:899–904
14. Barry H, Hardiman O, Healy DG, et al: Anti-NMDA
receptor encephalitis: an important differential diagnosis in
psychosis. Br J Psychiatry 2011; 199:508–509
15. Sansing LH, Tuzun E, Ko MW, Baccon J, Lynch DR,
Dalmau J: A patient with encephalitis associated with
NMDA receptor antibodies. Nat Clin Pract Neurol 2007;
3:291–296
16. Pillai SC, Gill D, Webster R, Howman-Giles R, Dale RC:
Cortical hypometabolism demonstrated by PET in relaps-
ing NMDA receptor encephalitis. Pediatr Neurol 2010;
43:217–220
17. Maeder-Ingvar M, Prior JO, Irani SR, Rey V, Vincent A,
Rossetti AO: FDG-PET hyperactivity in basal ganglia corre-
lating with clinical course in anti-NDMA-R antibodies ence-
phalitis. J Neurol Neurosurg Psychiatry 2011; 82:235–236
18. Chapman MR, Vause HE: Anti-NMDA receptor encepha-
litis: diagnosis, psychiatric presentation, and treatment. Am
J Psychiatry 2011; 168:245–251
19. Lee A, Glick DB, Dinwiddie SH: Electroconvulsive therapy
in a pediatric patient with malignant catatonia and para-
neoplastic limbic encephalitis. J ECT 2006; 22:267–270
20. Iwata M, Hazama GI, Nakagome K: Depressive state due
to isolated adrenocorticotropic hormone deficiency under-
lies school refusal. Psychiatry Clin Neurosci 2012;
66:243–244
21. Braakman HMH, Moers-Hornikx VMP, Arts BMG,
Hupperts RMM, Nicolai J: Pearls & Oy-sters: Electro-
convulsive therapy in anti-NMDA receptor encephalitis.
Neurology 2010; 75:e44–e46
www.psychosomaticsjournal.org 43
Psychiatric Manifestations of Anti-NMDA Receptor Encephalitis
22. Grover S, Mattoo SK, Gupta N: Theories on mechanism of
action of electroconvulsive therapy. German J Psychiatry
2005; 8:70–84
23. Watkins CJ, Pei Q, Newberry NR: Differential effects of
electroconvulsive shock on the glutamate receptor mRNAs
for NR2A, NR2B and mGluR5b. Brain Res Mol Brain Res
1998; 61:108–113
24. Titulaer MJ, McCracken L, Gabilondo I, et al: Treatment
and prognostic factors for long-term outcome in patients
with anti-NMDA receptor encephalitis: an observational
cohort study. Lancet Neurol 2013; 12:157–165
25. Corlew R, Brasier DJ, Feldman DE, Philpot BD: Presy-
naptic NMDA receptors: newly appreciated roles in cortical
synaptic function and plasticity. Neuroscientist 2008;
14:609–625
26. Cull-Candy S, Brickley S, Farrant M: NMDA receptor
subunits: diversity, development and disease. Curr Opin
Neurobiol 2001; 11:327–335
27. Steffens M, Huppertz HJ, Zentner J, Chauzit E, Feuerstein
TJ: Unchanged glutamine synthetase activity and increased
NMDA receptor density in epileptic human neocortex:
implications for the pathophysiology of epilepsy. Neuro-
chem Int 2005; 47:379–384
28. Sachdev PS: Alternating and postictal psychoses: review
and a unifying hypothesis. Schizophr Bull 2007; 33:
1029–1037
29. Northoff G. What catatonia can tell us about “top-down
modulation”: a neuropsychiatric hypothesis. Behav Brain
Sci. 2002; 25: 555-577; [discussion 78-604].
30. Northoff G, Eckert J, Fritze J: Glutamatergic dysfunction
in catatonia? Successful treatment of three acute akinetic
catatonic patients with the NMDA antagonist amantadine
J Neurol Neurosurg Psychiatry 1997; 62:404–406
31. Olney JW, Newcomer JW, Farber NB: NMDA receptor
hypofunction model of schizophrenia. J Psychiatr Res 1999;
33:523–533
32. Moghaddam B, Adams B, Verma A, Daly D: Activation of
glutamatergic neurotransmission by ketamine: a novel step in
the pathway from NMDA receptor blockade to dopaminergic
and cognitive disruptions associated with the prefrontal
cortex. J Neurosci 1997; 17:2921–2927
33. Kantrowitz JT, Javitt DC: N-methyl-D-aspartate (NMDA)
receptor dysfunction or dysregulation: the final common
pathway on the road to schizophrenia? Brain Res Bull 2010;
83:108–121
34. Carroll BT, Goforth HW, Thomas C, et al: Review of
adjunctive glutamate antagonist therapy in the treatment of
catatonic syndromes. J Neuropsychiatry Clin Neurosci 2007;
19:406–412
35. Fumagalli F, Molteni R, Roceri M, et al: Effect of
antipsychotic drugs on brain-derived neurotrophic factor
expression under reduced N-methyl-D-aspartate receptor
activity. J Neurosci Res 2003; 72:622–628
36. Coyle JT, Tsai G: NMDA receptor function, neuroplas-
ticity, and the pathophysiology of schizophrenia. Int Rev
Neurobiol 2004; 59:491–515
44 www.psychosomaticsjournal.org
37. Javitt DC: Glutamate and schizophrenia: phencyclidine,
N-methyl-D-aspartate receptors, and dopamine-glutamate
interactions. Int Rev Neurobiol 2007; 78:69–108
38. Carlsson A, Lindqvist M: Effect of chlorpromazine or
haloperidol on formation of 3methoxytyramine and nor-
metanephrine in mouse brain. Acta Pharmacol Toxicol
1963; 20:140–144
39. Carlsson A: The neurochemical circuitry of schizophrenia.
Pharmacopsychiatry 2006; 39(1 Suppl):S10–S14
40. Stephan KE, Friston KJ, Frith CD: Dysconnection
in schizophrenia: from abnormal synaptic plasticity to
failures of self-monitoring. Schizophr Bull 2009; 35:
509–527
41. O'Tuathaigh CM, Babovic D, O'Meara G, Clifford JJ,
Croke DT, Waddington JL: Susceptibility genes for schiz-
ophrenia: characterisation of mutant mouse models at the
level of phenotypic behaviour. Neurosci Biobehav Rev
2007; 31:60–78
42. Zandi MS, Irani SR, Lang B, et al: Disease-relevant
autoantibodies in first episode schizophrenia. J Neurol
2011; 258:686–688
43. Tsutsui K, Kanbayashi T, Tanaka K, et al: Anti-NMDA-
receptor antibody detected in encephalitis, schizophrenia,
and narcolepsy with psychotic features. BMC Psychiatry
2012; 12:37
44. Steiner J, Walter M, Glanz W, et al: Increased prevalence of
diverse N-Methyl-D-aspartate glutamate receptor antibod-
ies in patients with an initial diagnosis of schizophrenia:
specific relevance of IgG NR1a antibodies for distinction
from N-Methyl-D-aspartate glutamate receptor encephalitis.
JAMA Psychiatry 2013; 70:1–8
45. Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, Kouassi E:
Inflammatory cytokine alterations in schizophrenia: a system-
atic quantitative review. Biol Psychiatry 2008; 63:801–808
46. Jones AL, Mowry BJ, Pender MP, Greer JM: Immune
dysregulation and self-reactivity in schizophrenia: do some
cases of schizophrenia have an autoimmune basis? Immunol
Cell Biol 2005; 83:9–17
47. Abbott NJ, Ronnback L, Hansson E: Astrocyte-endothelial
interactions at the blood-brain barrier. Nat Rev Neurosci
2006; 7:41–53
48. Brown AS: Prenatal infection as a risk factor for schizo-
phrenia. Schizophr Bull 2006; 32:200–202
49. Meyer U, Feldon J: Epidemiology-driven neurodevelop-
mental animal models of schizophrenia. Prog Neurobiol
2010; 90:285–326
50. Moreno JL, Kurita M, Holloway T, et al: Maternal
influenza viral infection causes schizophrenia-like altera-
tions of 5-HT(2)A and mGlu(2) receptors in the adult
offspring. J Neurosci 2011; 31:1863–1872
51. Homayoun H, Jackson ME, Moghaddam B: Activation of
metabotropic glutamate 2/3 receptors reverses the effects of
NMDA receptor hypofunction on prefrontal cortex unit
activity in awake rats. J Neurophysiol 2005; 93:1989–2001
52. Lennox BR, Coles AJ, Vincent A: Antibody-mediated
encephalitis: a treatable cause of schizophrenia. Br J
Psychiatry 2012; 200:92–94
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