Current
Volume 3, Number 5, 2003
Contents
Recent Findings on the
Pathologies of Schizophrenia and Bipolar
Disorder: Potential for
Improved Therapeutic Strategies
Executive Editor: B. Dean
Schizophrenia and Bipolar Affective Disorder:
Perspectives for the Development of Therapeutics Pp.393-407
S.
Sundram , P.R. Joyce and M.A.
Kennedy
From Pharmacotherapy to Pathophysiology:
Emerging Mechanisms of Apolipoprotein D in Psychiatric Disorders Pp.408-418
E.A.
Thomas , D.L. Copolov and J.G. Sutcliffe
Muscarinic Receptors in Schizophrenia Pp.419-426
B.
Dean , F.P. Bymaster and E. Scarr
Cellular Pathology in the Dorsolateral
Prefrontal Cortex Distinguishes Schizophrenia from Bipolar Disorder Pp.427-436
L.D.
Selemon and G. Rajkowska
The Use of Microarrays to Characterize
Neuropsychiatric Disorders: Postmortem Studies of Substance Abuse and
Schizophrenia Pp.437-446
E.
Lehrmann , T.M. Hyde , M.P. Vawter , K.G. Becker , J.E. Kleinman and W.J. Freed
Proteomics in the Discovery of New
Therapeutic Targets for Psychiatric Disease Pp.447-458
Hans Voshol , Marc J. Glucksman and Jan van Oostrum
Neurodevelopmental Animal Models of
Schizophrenia: Effects on Prepulse Inhibition Pp.459-471
M.
Van den Buuse , B. Garner and M.
Koch
Neurodevelopment and Mood Stabilizers Pp.472-482
A.J. Harwood
Abstracts
[Back to top] Schizophrenia and Bipolar Affective Disorder:
Perspectives for the Development of Therapeutics
S.
Sundram , P.R. Joyce and M.A.
Kennedy
Schizophrenia and
bipolar disorder remain two of the most severe and difficult to treat psychotic
disorders hampered by our poor understanding of their pathologies. The
development of typical antipsychotic drugs opened an avenue of investigation
through the dopamine D2 receptor in schizophrenia. With the reintroduction of
the atypical antipsychotic clozapine came the development of a new generation
of atypical agents and hypotheses challenging the centrality of this receptor
in explaining antipsychotic effects. Evaluation of these competing theories
does not provide sufficient evidence to displace the importance of the dopamine
D2 receptor in antipsychotic efficacy, but does raise limitations of it as an
explanatory hypothesis. Further, the treatment of other symptom domains in
schizophrenia remains relatively neglected and open for the development of
novel therapies. Similar to schizophrenia, bipolar disorder presents a
diversity of clinical states but unlike schizophrenia, its mainstay of
treatment, lithium, has not had a clear receptor target impeding understanding
of the disorder's pathology and treatment. This has pushed investigation into
other domains emphasising a number of intracellular signalling pathways and
glial-neuronal interactions. The heavy genetic loading of bipolar disorder has
allowed linkage analyses to identify a number of putative regions, however, the
diversity of phenotypes complicates such studies. Polymorphisms of candidate
genes have yielded potential leads such as dopamine beta hydroxylase in mood
disorder and the serotonin transporter for treatment response. It is anticipated
that combining the above approaches may hold promise for the development of
more effective treatments.
[Back to top] From Pharmacotherapy to Pathophysiology:
Emerging Mechanisms of Apolipoprotein D in Psychiatric Disorders
E.A.
Thomas , D.L. Copolov and J.G. Sutcliffe
Apolipoprotein D
(apoD) is an atypical plasma apolipoprotein and, based on its primary
structure, it is a member of the lipocalin protein superfamily. Lipocalins have
been extensively used as disease markers and, accordingly, apoD has become
increasingly recognized as an important factor in the pathology of human
neurodegenerative and neuropsychiatric disorders. ApoD expression is increased
in the plasma and brains of subjects with schizophrenia and bipolar disorder,
suggesting that it acts as a marker for disease pathology. ApoD also exhibits
complex regulation by antipsychotic drug treatment and may represent a
distinguishing mechanism of typical versus atypical drugs. The precise role of
apoD in the CNS and disease remains to be elucidated, but recent findings have
suggested that it plays an important role in the regulation of arachidonic acid
signaling and metabolism providing further support for phospholipid membrane
pathology in schizophrenia.
[Back to top] Muscarinic Receptors in Schizophrenia
B.
Dean , F.P. Bymaster and E. Scarr
An increasing body
of evidence suggests that the muscarinic receptors may present a potential
therapeutic target for the treatment of schizophrenia. This argument is
supported by studies using postmortem CNS tissue and a neuroimaging study that
have shown there are regionally specific decreases in selective muscarinic
receptors in the CNS of subjects with schizophrenia. This raises the possibility
that drugs specific to individual muscarinic receptors could have beneficial
effects on the symptoms of schizophrenia, a posit supported by studies in
receptor knockout/knockdown mice where it has been shown that specific
behaviours affected by schizophrenia are also abnormal in mice lacking a single
muscarinic receptor. Moreover, drugs have been synthesised that are partial
agonists at muscarinic receptors and these drugs have been shown to improve the
behavioural deficits in humans which are modulated by the muscarinic receptor
family. The widespread distribution of muscarinic receptors in the human CNS
and the receptor specific changes identified in postmortem CNS from subjects
with schizophrenia would suggest that drugs targeting specific muscarinic
receptors would also need to partition into selected CNS regions to achieve
optimal responses. Some existing compounds show regional selectivity for the
same muscarinic receptor in different CNS regions, suggesting that this
characteristic could be engineered into muscarinic receptor targeting drugs.
This review presents data from diverse areas of research to argue that it is
now imperative that the therapeutic potential of manipulating the activity of
muscarinic receptors for the treatment of schizophrenia is fully explored.
[Back to top] Cellular Pathology in the Dorsolateral
Prefrontal Cortex Distinguishes Schizophrenia from Bipolar Disorder
L.D.
Selemon and G. Rajkowska
The classification
of schizophrenia and bipolar disorder as two separate disease entities has been
hotly debated almost from the moment of its inception with Kraepelin’s
descriptions of “dementia praecox” and “manic-depressive insanity” in 1896.
Kraepelin’s nosologic distinction was based on clinical observation of
symptomatology and outcome, and even today, despite major advances in science
and technology, differential diagnosis of psychosis relies on the clinical
course of illness. However, new evidence from diverse fields, e.g., genetics,
neuropsychology, and brain imaging, have refueled the debate about whether or
not schizophrenia and bipolar disorder represent distinct diseases, leading
some to postulate that schizophrenia and bipolar disorder represent different
manifestations of psychosis along a continuum with schizoaffective disorder
representing an intermediate subtype. To this discourse, we add our own recent
postmortem anatomic findings indicating that cellular pathology in the
dorsolateral prefrontal cortex in schizophrenia and bipolar disorder differs
not just in magnitude but also in direction, in laminar scope, and in relative
involvement of neuronal and glial cell types. Thus, distinct morphometric
alterations in the dorsolateral prefrontal cortex underlie what appear on
neuroimaging analysis to be similar abnormalities in structural and metabolic
function in the prefrontal cortex, and the diverse cellular pathology in the
dorsolateral prefrontal cortex in these two disorders may account for the
greater deficit in schizophrenia on cognitive tasks involving memory, problem
solving and abstraction.
[Back to top] The Use of Microarrays to Characterize
Neuropsychiatric Disorders: Postmortem Studies of Substance Abuse and
Schizophrenia
E. Lehrmann , T.M. Hyde , M.P. Vawter , K.G. Becker , J.E. Kleinman and W.J. Freed
Neuropsychiatric
disorders are generally diagnosed based on a classification of behavioral and,
in some cases, specific neurological deficits. The lack of distinct
quantitative and qualitative biological descriptors at the anatomical and
cellular level complicates the search for and understanding of the neurobiology
of these disorders. The advent of microarray technology has enabled large-scale
profiling of transcriptional activity, allowing a comprehensive
characterization of transcriptional patterns relating to the pathophysiology of
neuropsychiatric disorders. We review some of the unique methodological
constraints related to the use of human postmortem brain tissue in addition to
the generally applicable requirements for microarray experiments. Microarray
studies undertaken in neuropsychiatric disorders such as schizophrenia and
substance abuse by the use of postmortem brain tissue indicate that
transcriptional changes relating to synaptic function and plasticity,
cytoskeletal function, energy metabolism, oligodendrocytes, and distinct
intracellular signaling pathways are generally present. These have been
supported by microarray studies in experimental models, and have produced
multiple avenues to be explored at the functional level. The quality and
specificity of information obtained from human postmortem tissue is rapidly
increasing with the maturation and refinement of array-related methodologies
and analysis tools, and with the use of focused cell populations. The
development of experimental models of gene regulation in these disorders will
serve as the initial step towards a comprehensive genome-linked analysis of the
brain and associated disorders, and help characterize the integration and
coordinate regulation of complex functions within the CNS.
[Back to top] Proteomics in the Discovery of New
Therapeutic Targets for Psychiatric Disease
Hans
Voshol , Marc J. Glucksman and Jan
van Oostrum
In terms of impact
on and cost to society psychiatric disorders are among the most important
health problems of today. Current estimates from the US suggest that the
collective cost of psychiatric diseases could amount to one-third of the total
health care budget with a cumulative lifetime prevalence of 30%. While
undoubtedly improvements have been made in the diagnosis and treatment of at
least the symptoms of mental illness, there has been frustratingly little
progress in elucidating the molecular mechanisms. However, a fundamentally
different approach to study molecular mechanisms of psychiatric diseases is
emerging as a result of technological advances in expression profiling methods.
This comprises the investigation of the expressed disease ‘phenotypes’,
developing from the differential gene and protein expression in the central
nervous system as a result of the complex interaction between genetic
predisposition and environmental modulation. This paper will focus on
proteomics, expression profiling at the protein level, reviewing some of the
available tools and their application in the molecular analysis of psychiatric
disease.
[Back to top] Neurodevelopmental Animal Models of
Schizophrenia: Effects on Prepulse Inhibition
M.
Van den Buuse , B. Garner and M.
Koch
Epidemiological
studies have shown increased incidence of schizophrenia in patients subjected
to different forms of pre- or perinatal stress. However, as the onset of
schizophrenic illness does not usually occur until adolescence or early
adulthood, it is not yet fully understood how disruption of early brain
development may ultimately lead to malfunction years later. In order to
elucidate a possible role for neurodevelopmental factors in the pathogenesis of
schizophrenia and to highlight potential new treatments, animal models are
needed. Prepulse inhibition (PPI) is a model of sensorimotor gating mechanisms
in the brain. It is disrupted in schizophrenia patients and the disruption can
be reversed with atypical antipsychotics. It has been widely used in animal
studies to explore central mechanisms possibly involved in schizophrenia. There
has been a recent surge of behavioural and neurochemical animal studies on
neurodevelopmental models, particularly on the effects of postweaning
isolation, maternal separation and neonatal lesions of the hippocampus. In
these models, long lasting alterations in behaviour and/or molecular changes in
specific brain regions are observed, comparable to those seen in schizophrenia.
The aim of this article is to critically review the available literature on
such neurodevelopmental animal models with special focus on the effects on PPI
and brain regions that are putatively involved in regulation of PPI.
[Back to top] Neurodevelopment and Mood Stabilizers
A.J.
Harwood
Mood disorders and
schizophrenia share a number of common properties, including: genetic
susceptibility; differences in brain structure and drug based therapy. Some
genetic loci may even confer susceptibility for bipolar mood disorder and
schizophrenia, and some atypical antipsychotic drugs are used as mood
stabilizers. As schizophrenia is associated with aberrant neurodevelopment,
could this also be true for mood disorders? Such changes could arise pre- or post-natal,
however the recent interest in neurogenesis in the adult brain has suggested
involvement of these later processes in the origins of mood disorders.
Interestingly, the common mood stabilizing drugs, lithium, valproic acid (VPA)
and carbamazepine, are teratogens, affecting a number of aspects of animal
development. Recent work has shown that lithium and VPA interfere with normal
cell development, and all three drugs affect neuronal morphology. The molecular
basis for mood stabilizer action in the treatment of mood is unknown, however
these studies have suggested both targets and potential mechanisms.
Lithium directly
inhibits two evolutionarily conserved signal transduction pathways: the protein
kinase Glycogen Synthase Kinase-3 (GSK-3) and inositol signaling. VPA can
up-regulate gene expression through inhibition of histone deacetylase (HDAC)
and indirectly reduce GSK-3 activity. VPA effects are not conserved between
cell types, and carbamazepine has no effect on the GSK-3 pathway. All three
mood stabilizers suppress inositol signaling, results further supported by
studies on the enzyme prolyl oligopeptidase (PO) and the sodium myo-inositol
transporter (SMIT). Despite these intriguing observations, it remains unclear
whether GSK-3, inositol signaling or both underlie the origins of bipolar
disorder.