| Vol 7 n° 2 - New Psychiatric Classification based on Endophenotypes |
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9 3
I n
t h i s i s s u e . . .
Advances in molecular genetics,
cellular biology, and
imaging technology justify
optimism for the successful
uncovering of the neurobiological
bases for many neuro-
psychiatric disorders. These
disorders are, however, com-
plex, heterogeneous phenomena
that, in all but the
rarest cases, are not caused
by a single dysfunctional
protein or gene. Thus, despite
the heritability of disor-
ders like depression and
schizophrenia (which implies a
genetic basis), no single
genetic abnormality is likely to
account for more than a
vanishingly small part of the
variance in their appearance
and expression. An alter-
native approach described
in this issue of Dialogues in
Clinical
Neuroscience is to identify and study endophe-
notypes: neuropsychological,
biochemical, physiological,
cognitive, and neuroanatomical
traits that are more ele-
mentary components of the
disorder and hence reflect
the influence of a manageable
number of genes. In this
fashion, psychiatric disorders
may be deconstructed in a
way that amplifies the
genetic signal relative to the
background noise and aids
the search for gene variants
that contribute to the
susceptibility to, and expression
of, the illness.
In the State
of the art article, Wade H. Berrettini (page
95) introduces the reader
to the concept of, and criteria
for, endophenotypes. After
presenting two examples of
endophenotypes that are
stable and heritable—the P50
auditory evoked potential
and working memory deficits
in schizophrenia—Berrettini
raises the argument that
endophenotypes may not
need to meet the criterion of
heritability in order to
be valuable constructs, despite the
obvious usefulness of this
criterion in the search for can-
didate genes contributing
to psychiatric disorders.
In the first Basic
research article, Michael J. Meaney and
Moshe Szyf (page 103) provide
a brilliant discussion of
the means by which environmental
events (in this case,
licking and grooming behavior
of rat pups) can be trans-
duced into epigenomic changes
that in a lifelong fashion
alter stress adaptation
and behavior. This article then elu-
cidates the neurobiological
mechanisms of environmen-
tal modulation and programming
of behavior and further
demonstrates that changes
in gene expression rather
than sequence differences
may encode differences in
behavior.
In the second Basic
research article, David L. Braff and
Gregory A. Light (page
125) lucidly review studies of
endophenotypes in schizophrenia
and then focus on
neurophysiological endophenotypes.
The clinical, neuro-
biological, and interspecies
justifications for focusing on
prepulse inhibition and
P50 suppression are presented,
and a case is made for
the potential therapeutic impact
of successful endophenotype-based
strategies for the dis-
section of genetic vulnerability
and gene–environment
interactions in schizophrenia.
In the Poster,
Michael F. Egan (page 136) provides an
example of “imaging
genomics," ie, the use neuroimag-
ing as a means for amplifying
the ability to detect genet-
ic contributions to schizophrenia.
His studies of brain-
derived neurotropic factor
(BDNF) demonstrate how
neuroimaging phenotypes
can be used in conjunction
with biochemical and neuropathological
data to clarify
the role of specific genes
in brain function and in the risk
for psychiatric disorders.
In the first Clinical
research article, Larry J. Siever (page
139) deconstructs several
personality disorders (border-
line, schizotypal, and
avoidant) into phenomenological
dimensions and biological
characteristics that, he per-
suasively argues, will
permit the construction of a more
meaningful nosology and
clarify the interaction between
environmental influences
and underlying genetic vulner-
abilities. Once again,
it is proposed that subsyndromal
dynamic phenomena such
as impulsive aggression, affec-
tive instability, and
altered emotional information pro-
cessing are more genetically
transparent than the parent
syndromes.
In the second Clinical
research article, Lisa M. Hines, Lara
Ray, Kent Hutchison, and
Boris Tabakoff (page 153) sum-
marize the literature
on promising endophenotypes in
alcoholism. This comprehensive
review describes physio-
logical, metabolic, electrophysiological,
behavioral, neuro-
imaging, and biochemical
traits that can be used to parti-
tion alcoholics into endophenotypes
that suggest both
candidate susceptibility
genes and novel pathophysiologi-
cal mechanisms underlying
alcohol dependence.
Finally, in the last Clinical
research article, Gilbert A. Pre-
ston and Daniel R. Weinberger
(page 165) review the
promise and limitations
of the endophenotype concept
as it applies to schizophrenia.
After reviewing cognitive,
neurophysiological, and
neuroimaging data as they relate
to specific candidate
gene polymorphisms, they focus on
