S34 Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384

order stems from neurodevelopmental deficits that result in a disturbance

of glutamatergic neurotransmission, especially for N-methyl-D aspartate

receptor-mediated signaling. The deteriorating course of the disease maybe

partially explained by cortical neuronal toxic effects secondary to enhanced

glutamatergic exposure, and dopaminergic dysregulation may be the final

common pathway that results from altered glutamatergic neurotransmis-

sion. Recently, we and others reported the results of proton magnetic

resonance spectroscopy (1H MRS) studies that found elevated glutamate

levels in the associative striatum of subjects at ultra-high risk for psychosis

(UHR), as well as in antipsychotic-naïve subjects during their first episode of

psychosis (Cohen’s effect sizes = 0.9 and 1, respectively). Subsequently, by

longitudinally following these UHR subjects over 2 years, we demonstrated

that the subjects with higher glutamate levels at baseline later transitioned

to psychosis (Cohen’s effect size =1.39), suggesting the involvement of this

excitatory amino acid neurotransmitter in the early or prodromal phases of

schizophrenia. On the other hand, these glutamate system elevations could

be explained in terms of pyramidal cell disinhibition by impairment of

fast-spiking γ-Aminobutyric acid (GABA) interneuron function. A recent 1H

MRS study performed in a second cohort of UHR subjects found increased

levels of GABA (p<0.001, effect size=1.3) and of the combined resonance of

glutamate and glutamine – Glx (p=0.007, effect size=0.84) in the associative

striatum compared to healthy controls. These results warrant multi-site,

longitudinal studies to assess whether these neurotransmitter abnormali-

ties can serve as noninvasive biomarkers of conversion risk to psychosis, as

well as of illness progression and treatment response.

IS THE ASSOCIATIVE STRIATUM A LOCUS OF VULNERABILITY FOR

TRANSITION TO PSYCHOSIS?

Oliver Howes, Alice Egerton, Paul Allen, Chris Chaddock, Philip McGuire

Institute of Psychiatry, King’s College London

Background: The hypothesis that the dopamine dysfunction in schizophre-

nia is localized to mesolimbic pathways has been very influential despite

the lack of direct evidence from patient studies. We therefore sought to

investigate the localization of dopamine dysfunction in schizophrenia and

people at clinical risk of the disorder and the link to symptoms and cortical

function in vivo using PET and fMRI imaging.

Method: We used PET to study striatal dopamine synthesis capacity in

patients (n=36) with schizophrenia and subjects at high clinical risk of

psychosis (n=54; all meeting the CAARMS criteria for an at risk mental state

[ARMS]) who show prodromal signs of schizophrenia and matched controls

(n=41). The ARMS subjects received assessment of verbal fluency and clin-

ical follow-up to determine who developed psychosis. The striatal regions

of interest were the whole striatum (S), and its limbic (LS), associative

(AST) and sensorimotor (SMST) subdivisions. Additionally we investigated

dopamine synthesis capacity in the nigral origin of the dopaminergic pro-

jections to the dorsal striatum in schizophrenia in complementary PET and

post-mortem studies. A sub-sample of the ARMS subjects and controls also

received fMRI imaging using a task that activates the frontal cortex to

investigate fronto-striatal interactions.

Results: Striatal dopamine synthesis capacity was significantly elevated in

the associative striatum in the ARMS subjects (p<0.05), and was signif-

icantly related to symptoms and cognitive performance (p<0.05), and to

fMRI activation during the cognitive task (p<0.0.05). In contrast dopamine

synthesis capacity was not significantly elevated in the limbic striatum

(p>0.1). The elevation in dopamine synthesis capacity was specific to

the ARMS subjects who want on to develop psychosis. In schizophre-

nia dopamine synthesis capacity was significantly elevated in associative

(p=0.001), sensorimotor (p=0.001) and limbic striatum (p=0.017), although

this was relatively less marked in the limbic striatum. Furthermore the

uptake of labeled-DOPA indexed using PET in vivo and tyrosine hydroxylase

staining ex vivo were both elevated in the substantia nigra.

Conclusion: These findings indicate that i) dysfunction in associative stri-

atal dopamine function, rather than limbic dysfunction, predates the onset

of psychosis, ii) in schizophrenia dorsal striatal dysfunction is more marked

than limbic alterations; and iii) dopamine synthesis capacity is also altered

in the nigral origin of dopaminergic projections to the dorsal striatum

in schizophrenia. These findings link dorsal striatal dopamine dysfunc-

tion to the development of psychosis and do not support the mesolimbic

hypothesis.

Symposium

POTENTIAL ROLE OF NMDA-RECEPTOR ANTIBODIES IN

SCHIZOPHRENIA: OVERLAP AND DISTINCTION FROM

NMDA-RECEPTOR ENCEPHALITIS

Chairpersons: Johann Steiner and Hannelore Ehrenreich

Discussant: Souhel Najjar

Monday, 7 April 2014 4:15 PM – 6:15 PM

Overall Abstract: NMDA-receptor encephalitis has been discovered by J.

Dalmau in 2007. Many of these patients develop a multistage illness that

progresses from psychosis, memory deficits, seizures, and language dis-

integration to a state of unresponsiveness with catatonic features often

associated with abnormal movements, as well as autonomic and breath-

ing instability. It has been suggested that mild or incomplete forms of

the disorder (formes frustes) with predominant or isolated psychiatric

symptoms could occur. This symposium aims to summarize recent stud-

ies on the prevalence of NMDA-receptor antibodies in schizophrenia. In

this context, we will discuss the influence of diagnostic criteria (defi-

nition of “schizophrenia”) on the study results. Belinda Lennox (Oxford,

UK) will present data on first-onset schizophrenia, estimating that the

prevalence of NMDA-receptor antibodies in first episode psychosis is ap-

proximately 4%. She will present the clinical and cognitive characteristics

of a cohort of NMDAR receptor antibody positive patients with a pri-

mary psychotic illness, without other features of encephalitis, and their

response to treatment with immunotherapy. Takashi Kanbayashi (Akita,

Japan) detected NMDA-receptor antibodies not only in encephalitis, but

also in schizophrenia and narcolepsy with psychotic features. Notably, most

of these seropositive patients showed catatonic or disorganized features.

Johann Steiner (Magdeburg, Germany) analyzed serum from 459 acutely

ill patients admitted with the DSM-IV diagnoses of schizophrenia, major

depression (MD), and borderline personality disorder (BLPD) or matched

controls. Diverse NMDA-R antibodies were identified in subjects with

an initial diagnosis of schizophrenia (9.9%), opposed to MD (2.8%), BLPD

(0), and controls (0.4%). Retrospectively, 2 patients initially classified as

having catatonic or disorganized schizophrenia were reclassified as hav-

ing misdiagnosed NMDA-R encephalitis (presence of specific serum and

cerebrospinal fluid IgG NR1a antibodies). Hannelore Ehrenreich (Göttingen,

Germany) will report on an overall 10% seroprevalence of NMDA-R antibod-

ies in >2800 individuals, ranging from healthy to schizophrenic, affective

disorder, stroke and Parkinson patients, as well as on genetic and environ-

mental risk factors predisposing to antibody formation. Blood-brain-barrier

(BBB) integrity seems to be crucial (only those individuals with circulating

NMDA-receptor antibodies who suffer from BBB dysfunction may expe-

rience neuropsychiatric symptoms). Urs Meyer (Zurich, Switzerland) will

guide through these presentations as an international expert in the field of

psychoneuroimmunology (invited discussant).

INCREASED PREVALENCE OF DIVERSE N-METHYL-D-ASPARTATE

GLUTAMATE RECEPTOR ANTIBODIES IN PATIENTS WITH AN INITIAL

DIAGNOSIS OF SCHIZOPHRENIA

Johann Steiner1, Martin Walter2, Jolja Schiltz2, Bernhard Bogerts2,

Hans-Gert Bermstein2, Wenzel Glanz3, Stefan Vielhaber3, Zoltan Sarnyai4,

Christine Klingbiel5, Klaus-Peter Wandinger5, Winfried Stoecker5

1University of Magdeburg, Germany; 2Dept. of Psychiatry, University of

Magdeburg, Germany; 3Dept. of Neurology, University of Magdeburg,

Germany; 4Dept. of Pharmacology, University of Cambridge, UK; 5Institute for

Experimental Immunology, affiliated with Euroimmun, Lübeck, Germany

Evidence for symptomatic convergence of schizophrenia and N-methyl-D-

aspartate glutamate receptor (NMDA-R) encephalitis highlights the need

for an assessment of antibody prevalence and specificity for distinct disease

mechanisms in patients with a diagnosis of schizophrenia among gluta-

matergic pathophysiologic abnormalities in psychiatric disorders. Serum

from 459 patients admitted with acute schizophrenia, major depression

(MD), and borderline personality disorder (BLPD) or individuals serving

as matched controls was obtained from our scientific blood bank. To

explore epitope specificity and antibody subtype, IgA/IgG/IgM NMDA-R

(NR1a or NR1a/NR2b) and alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-