ABSTRACTS - World Psychiatric Association

elease in hippocampus. We now report that acute stress (footshock)
induces a marked increase of glutamate release in prefrontal/frontal
cortex, while antidepressants completely abolish this stress-induced
increase. We suggest that this is a component of the therapeutic
action of these drugs, particularly the anxiolytic effect. Schizophrenia
is also characterized by marked alterations in glutamate system. Further
support came recently from genetic studies showing a link
between this system and several susceptibility genes. Although mainly
affecting D2 and other monoamine receptors, it has been shown
that antipsychotic drugs may regulate the expression and synaptic
localization of NMDA/AMPAR. Glutamate compounds are currently
in development, including allosteric modulators of NMDAR (glycine
site), inhibitors of glycine reuptake, positive modulators of AMPAR
(AMPAkines) and agonists of type II metabotropic receptors. A
recent phase 2 clinical study showed that LY2140023, an mGluR2/3
agonist, displays short-term antipsychotic properties similar to olanzapine,
suggesting that glutamate drugs could represent a viable alternative
for treatment of schizophrenia.
US22.3.
GABAERGIC GENE PROMOTER
HYPERMETHYLATION DOMINATES PSYCHOSIS
PATHOPHYSIOLOGY AND COULD BE A TARGET
FOR TREATMENT
A. Guidotti, E. Dong, D.R. Grayson, E. Costa
Department of Psychiatry, University of Illinois at Chicago,
IL, USA
Post-mortem brain studies of schizophrenia (SZ) and bipolar (BP)
disorder show a downregulation of GAD67 and reelin expression in
specific populations of GABAergic neurons, very probably associated
with promoter hypermethylation mediated by an overexpression of
DNA methyltrasferase-1 (DNMT1). This is supported by clinical
studies with methionine. Administered for 2-3 weeks in doses of 10-
20g/day, this amino acid increases the brain levels of the methyl
donor S-adenosyl-methionine and exacerbates psychotic symptoms
in 40-50% of SZ patients. In addition to an increase of DNMT1, the
hypermethylation of reelin and GAD67 promoters may be related to
a decrease of a putative DNA-methyl-CpG demethylase (DNAdemethylase).
The nature and kinetics of this process remain a pressing
concern in the study of psychosis. However, it is now clear that, in
the brain, DNA-demethylase activity can be induced by valproate. In
order to understand the molecular nature of the benefits elicited by a
combination of valproate and antipsychotics in the treatment of SZ
and BP disorder, we studied whether this beneficial action is dependent
upon the induction of a DNA-demethylase activity that targets
GAD67 and reelin promoters. In mice receiving clinically relevant
doses of clozapine, both GAD67 and reelin promoters are demethylated
in a manner that is facilitated by valproate. In contrast, even in
the presence of valproate, haloperidol does not share these properties.
This probably explains the greater antipsychotic efficacy of clozapine
compared to haloperidol in association with valproate. The data
suggest that drugs which downregulate promoter hypermethylation in
GABAergic neurons may offer a new approach to treatment for SZ
and related psychiatric disorders.
US23.
INTERMEDIATE PHENOTYPES IN PSYCHIATRY
US23.1.
INTERMEDIATE PHENOTYPES IN SCHIZOPHRENIA
GENETICS
D.R. Weinberger
Genes, Cognition and Psychosis Program, Intramural Research
Program, National Institute of Mental Health, Bethesda,
MD, USA
It is a given that genes related to psychopathology are not about psychiatric
diagnoses per se, but are likely related to the development
and function of brain circuits involved in the processing of cognitive
and emotional information. This has encouraged interest in characterizing
so-called intermediate phenotypes or endophenotypes related
to genetic risk for schizophrenia, which are expected to show
greater penetrance of genetic risk factors. A similar approach has
been employed in the investigation of other complex genetic disorders,
such as adult onset diabetes, in which multiple genes each
account for only a very small share of risk but show stronger effects
on related intermediate phenotypes even in normal subjects – e.g.,
body mass index or glucose induced insulin release. Potential biologic
intermediate phenotypes related to genetic risk for schizophrenia
have included abnormalities in hippocampal and prefrontal cortices,
which are consistently reported in patients with schizophrenia and
are also found with increased frequency in their healthy relatives. For
example, schizophrenia patients and their healthy relatives show
impairments in multiple measures of hippocampal function and biology,
and in prefrontal cortical function and biology. Various physiologic
investigations of cortical activity reveal abnormal activation in
hippocampus and prefrontal cortex within schizophrenia patients
and their healthy relatives. Thus, it follows that genes associated with
susceptibility for schizophrenia might show relatively robust effects
on prefrontal and hippocampal function in risk-allele carrying populations,
even in healthy subjects. Examples of the greater effect size of
potential schizophrenia susceptibility genes on variability in the
expression of these biological phenotypes related to schizophrenia
are reviewed, including COMT, NRG1, DISC1, GRM3, DAARP,
KCNH2, and AKT1.
US23.2.
INTERMEDIATE PHENOTYPES
OR ENDOPHENOTYPES IN PSYCHOSIS:
DATA FROM THE MAUDSLEY STUDIES
R.M. Murray
Institute of Psychiatry, London, UK
Data are presented from the Maudsley twin, family and singleton
studies, which show: a) that deficits in IQ in schizophrenia are largely
determined by the same genetic factors which contribute to the
onset of schizophrenia, b) that there is overlap in the white matter diffusion
tension imaging (DTI) phenotypes between schizophrenia and
bipolar disorder, but that the former, but not the latter, illness is associated
with developmental abnormalities and extensive grey matter
deficits, and c) that certain psychosis susceptibility genes are associated
with differences in brain activation during cognitive challenges.
In particular, variations in COMT, DISC 1, dysbindin and neuregulin
influence cortical function.
25