| Current
Neuropharmacology
ISSN: 1570-159X
Current Neuropharmacology
Volume 3, Number 1, January 2005
Contents
Editorial Pp. 1-2
Gene G. Kinney and P. Jeffrey Conn
[Editorial
In PDF]
Partial Dopamine Agonists and the Treatment of
Psychosis Pp. 3-8
Carol A. Tamminga
[Abstract] [Full
text article]
Novel Potential Therapeutics for Schizophrenia:
Focus on the Modulation of Metabotropic Glutamate Receptor
Function Pp. 9-34
Laura E. Chavez-Noriega, Michael J. Marino, Herve Schaffhauser,
Una C. Campbell and P. Jeffrey Conn
[Abstract] [Full
text article]
Glycine Site Modulators and Glycine Transporter-1
Inhibitors as Novel Therapeutic Targets for the Treatment
of Schizophrenia Pp. 35-43
Gene G. Kinney and Cyrille Sur
[Abstract] [Full
text article]
GABA Targets for the Treatment of Cognitive Dysfunction
in Schizophrenia Pp. 45-62
David W. Volk and David A. Lewis
[Abstract] [Full
text article]
Selective Targeting of Muscarinic Receptors: Novel
Therapeutic Approaches for Psychotic Disorders Pp.
63-71
Cyrille Sur and Gene G. Kinney
[Abstract] [Full
text article]
Gender Differences in Pharmacokinetics and Side
Effects of Second Generation Antipsychotic Drugs Pp.
73-85
W. Aichhorn, M. Gasser, E.M. Weiss, C. Adlassnig and J.
Marksteiner
[Abstract] [Full
text article]
Abstracts[Back
to top]
Editorial
Gene G. Kinney and P. Jeffrey Conn
[Editorial
In PDF]
New and Emerging Approaches to Treatment of Schizophrenia
The dopamine hypothesis of schizophrenia has played a dominant
role in driving both basic research and drug discovery efforts
in the schizophrenia field for several decades, leading to
several clinically useful treatments that alter dopamine neurotransmission.
It is notable that blockade of the dopamine D2 receptor produces
an antipsychotic effect in humans. However, these treatments
are not typically effective against the full scope of symptoms
found in this disease and D2 antagonists also induce a number
of adverse effects that limit their use. However, recent years
have seen major advances in our understanding of dopaminergic
systems in the central nervous system as well as pathophysiological
changes that may underlie different aspects of schizophrenia.
These advances have led to a number of novel approaches that
are currently being pursued in efforts to develop new treatments
that have fewer adverse effects than and are effective in
treatment of symptom clusters that are not effectively treated
by current drugs.
Regulation of dopamine systems remains the most well validated
approach to treatment of schizophrenia and recent advances
suggest the possibility of using novel approaches to regulating
dopaminergic function. Tamminga offers a review of studies
that have led to interesting extension of the dopamine hypothesis
of schizophrenia. In this review, the paradoxical idea of
using dopamine agonists to reduce dopaminergic neurotransmission
through activation of autoreceptors is considered. The history
of this concept is outlined and the use of partial agonists
both clinically and preclinically is discussed.
The glutamatergic or NMDA receptor hypofunction hypotheses
of schizophrenia represent separate, albeit non-exclusive,
alternatives to the dopamine hypothesis of schizophrenia.
This hypothesis holds that pathological changes in circuits
involving glutamatergic neurotransmission and/or decreased
NMDA receptor function may account for the positive, negative
and cognitive symptoms that occur in this disease. Accordingly,
multiple approaches targeting relevant biological targets
involved in regulating glutamatergic transmission are considered.
Chavez-Noriega and Coauthors provide a comprehensive overview
of the biological significance of metabotropic glutamate receptors
on these systems. Recent progress in identifying pharmacological
potentiators of mGlu2/3 and mGlu5 receptors is particularly
encouraging. This review outlines preclinical studies suggesting
that such potentiators may ultimately prove efficacious for
schizophrenia by decreasing excessive prefrontal glutamate
release (mGluR2/3) or via a modulatory potentiation of NMDA
receptors (mGluR5). Kinney and Sur suggest additional approaches
that could modulate NMDA receptors appropriately. In this
review, modulation of the glycineB site is discussed. Since
activation of the glycineB binding site is a necessary prerequisite
for glutamatergic binding and activity, potentiation of this
binding site has been considered as a possible approach towards
the development of therapeutics. Several such approaches are
discussed, including the use of direct activators and reuptake
inhibitors. It is notable that these approaches both appear
to have some clinical proof of concept.
Two additional reviews are offered by Volk and Lewis and
separately by Sur and Kinney, which focus on approaches that
may involve both dopaminergic and glutamatergic systems to
differing extents. Volk and Lewis provide a compelling pathologically-based
argument that implicates a subtype of inhibitory neuronal
population in the control of prefrontal information flow.
The identification of these chandelier neurons as potential
mediators of the prominent working memory deficits found in
schizophrenic patients suggest that enhancement of this inhibitory
function may improve this symptom of schizophrenia. In this
regard, drugs that specifically interact with a2 containing
GABAA receptors and/or CB1 receptors are contemplated to provide
benefit. Sur and Kinney outline a complex role for muscarinic
receptors in the possible treatment of this disease. Subtype
selective potentiators of muscarinic receptor subtypes have
been lacking. Thus, the role of this highly homologous receptor
family has not been fully elucidated. The present review considers
the use of recently described murine knockout models and more
selective pharmacological agents and suggests that M1 and
M4 receptors may be particularly useful as novel drug targets
for this disease. More preliminary evidence also suggests
that M2 and M5 receptors could represent additionally interesting
targets. Recent progress in developing selective pharmacological
tools by targeting less-conserved ectopic binding sites is
also discussed.
Finally, Aichhorn and Coauthors review gender based differences
in the side-effect profile of newer atypical antipsychotic
medications. This review outlines multiple differences that
may contribute to male-female differences in disease presentation,
therapeutic efficacy and side-effect profile.
The present edition of Current Neuropharmacology provides
a comprehensive overview of the current state of the newest
emerging targets contemplated for the treatment of schizophrenia.
The high level of interest within academia and industry for
each of the reviewed approaches suggests that there is a high
likelihood that some of these approaches may be clinically
tested with new pharmacological agents in the near future.
The impetus for such research is high, as is the need for
additional treatments. In that regard, it is rewarding to
offer this edition of Current Neuropharmacology for all neurophamacologists
and neuroscientists with an interest in schizophrenia research
and therapeutics.
[Back to top]
Partial Dopamine Agonists and the Treatment of Psychosis
Carol A. Tamminga
[Full text
article]
Pharmacologic approaches that diminish dopamine-mediated
neural transmission in brain have antipsychotic actions in
humans. Blockade of D2 family dopamine receptors is the most
common strategy. A paradoxical strategy of using dopamine
agonists in particular circumstances to similarly diminish
dopaminergic transmission is based on the known function of
dopamine autoreceptors and on consideration of the intrinsic
activity of dopamine agonists. It was apomorphine that first
suggested the effectiveness of dopamine agonist treatment
for schizophrenia. Now a partial dopamine agonist aripiprazole
has come to market for psychosis and others are in development.
This chapter reviews the clinical pharmacology of partial
dopamine agonists and their development for the treatment
of schizophrenia.
[Back to top]
Novel Potential Therapeutics for Schizophrenia: Focus
on the Modulation of Metabotropic Glutamate Receptor Function
Laura E. Chavez-Noriega, Michael J. Marino, Herve
Schaffhauser, Una C. Campbell and P. Jeffrey Conn
[Full text
article]
Schizophrenia is the most disabling psychiatric disorder
and one of the world’s top ten causes of long-term disability,
affecting 1% of the population worldwide. The major symptoms
of schizophrenia, psychosis (positive symptoms), apathy, social
withdrawal (negative symptoms) and cognitive impairment, become
manifest in late adolescence/early adulthood and persist thereafter,
resulting in chronic disability. The pharmacotherapy of schizophrenia
has evolved from typical antipsychotics (dopamine D2
receptor antagonists) to atypical antipsychotics (mixed D2
and serotonin 5-HT2A antagonists with activity at various
other receptors) with improved efficacy and side effect profile.
More recently, the glutamate/ N-methyl-D-aspartate glutamate
receptor (NMDAR) hypothesis of schizophrenia has been formulated.
This hypothesis is supported by the observation that administration
of NMDAR blockers to human volunteers is psychotomimetic and
administration to schizophrenic patients exacerbates pre-existing
symptoms. This has generated an interest to develop novel
antipsychotics focused on the identification of novel molecular
targets and susceptibility genes that result in deregulation
of glutamatergic, GABAergic and dopaminergic neurotransmission.
In particular, metabotropic glutamate (mGlu) receptors mGlu2/3
and mGlu5 are prominently expressed in relevant forebrain
regions and their activation modulates glutamatergic transmission
and NMDAR function in the mammalian brain. The activity of
mGlu2/3 and mGlu5 receptor agonists and more recently, the
activity shown by selective mGlu2 and mGlu5 receptor allosteric
potentiators in preclinical models of psychosis are promising.
Further evaluation of the efficacy and side effect profile
of potent, selective and brain-penetrant mGlu receptor activators
may provide novel therapeutic avenues for the treatment of
schizophrenia.
[Back to top]
Glycine Site Modulators and Glycine Transporter-1 Inhibitors
as Novel Therapeutic Targets for the Treatment of Schizophrenia
Gene G. Kinney and Cyrille Sur
[Full text article]
Current antipsychotic medications are efficacious for the
positive symptoms of schizophrenia. However, there remains
a significant unmet need for alternate strategies that could
result in improved tolerability and/or efficacy for negative
and cognitive symptoms. A growing body of research suggests
that NMDA mediated neuronal activity is involved in the etiology
of schizophrenia. Glycine binds to a modulatory glycineB strychnine-insensitive
binding site on the NR1 subunit of the NMDA receptor complex
and acts necessary co-agonist for activation of the NMDA receptor.
Thus, several approaches have emerged aimed towards modulating
this glycine binding site. To date, the glycineB site agonists
glycine and D-serine, the partial agonist, D-cycloserine and
the glycine reuptake inhibitor, sarcosine, have been shown
to provide relief to schizophrenic patients. These clinical
findings, combined with a growing body of preclinical literature,
support the notion that enhancing synaptic glycineB activity
leads to an increase in the effectiveness of normal glutamatergic
signaling at the NMDA receptor complex and provides efficacy
for schizophrenic patients. Accordingly, the present review
examines the role of glycineB site modulation as a therapeutic
approach for the treatment of schizophrenia.
[Back to top]
GABA Targets for the Treatment of Cognitive Dysfunction
in Schizophrenia
David W. Volk and David A. Lewis
[Full text
article]
Cognitive deficits, including impairments in working memory
that have been linked to the prefrontal cortex, are among
the most debilitating and difficult to treat features of schizophrenia.
Consequently, the identification of potential targets informed
by the pathophysiology of the illness is needed to develop
novel pharmacological approaches for ameliorating these deficits.
Postmortem studies of the prefrontal cortex in schizophrenia
subjects have revealed disturbances restricted to a subpopulation
of inhibitory neurons that includes chandelier neurons, whose
axon terminals synapse on the axon initial segment of pyramidal
neurons. Chandelier neurons play an important role in synchronizing
pyramidal neuron activity and appear to be a critical component
of the prefrontal cortical circuitry that subserves working
memory function. Therefore, in this paper we review evidence
suggesting that drugs which selectively enhance chandelier
neuron-mediated inhibition of prefrontal pyramidal neurons
may improve working memory dysfunction in schizophrenia. Potential
novel targets for such agents include GABAA receptors
that contain the α2
subunit. In addition, we discuss potential complementary mechanisms
for enhancing inhibitory input to pyramidal cell bodies, including
drugs with activity at the CB1 receptor of the endocannabinoid
system. The development of pathophysiologically-based treatments
that selectively remediate disturbances in specific neural
circuits underlying working memory may provide an effective
approach to improving cognitive deficits in schizophrenia.
[Back to top]
Selective Targeting of Muscarinic Receptors: Novel
Therapeutic Approaches for Psychotic Disorders
Cyrille Sur and Gene G. Kinney
[Full text
article]
Schizophrenia is a well recognized and debilitating psychiatric
disorder composed of several symptoms. Despite the clinical
efficacy of present typical and atypical antipsychotics to
alleviate positive symptoms, negative symptoms and cognitive
disorders are not optimally controlled. Thus, there is an
unmet medical need to develop novel medications with improved
tolerability and efficacy for the treatment of these symptoms.
Clinical observations over the past four decades have accumulated
to support a role of central muscarinic cholinergic neurotransmission
in psychosis. Indeed, recent studies have shown that acetylcholine
esterase inhibitors as well as weakly selective muscarinic
agonists such as xanomeline improved neuropsychiatric symptoms
and cognitive function in Alzheimer’s disease patients.
Preclinically, a large body of studies has highlighted the
involvement of muscarinic cholinergic signaling in cognition
and psychosis. However the lack of truly selective drugs for
the five muscarinic receptors has prevented an unambiguous
determination of the role of each receptor subtypes in these
behaviors. Recent progress in behavioral studies of mice deficient
for the muscarinic receptors and in the discovery of selective
muscarinic agonists have started to unravel the contribution
of muscarinic receptor subtypes to complex behaviors. Accordingly,
this review examines the potential of selectively targeting
muscarinic receptor subtypes as a therapeutic approach for
the treatment of psychotic disorders.
[Back to top]
Gender Differences in Pharmacokinetics and Side Effects
of Second Generation Antipsychotic Drugs
W. Aichhorn, M. Gasser, E.M. Weiss, C. Adlassnig
and J. Marksteiner
[Full text
article]
Significant gender differences have been described for psychiatric
disease prevalence and receipt of psychotropic medication.
Second generation antipsychotic (SGAs) drugs are not a homogenous
group as they differ in their receptor profiles, clinical
efficacy and side effects. Gender differences in pharmacokinetics
and side effects of second generation antipsychotic drugs
have been investigated in several studies indicating that
there is a distinct differences between men and women both
for the SGAs as a whole group and for specific drugs in particular.
Nevertheless the influence of gender on efficacy and side
effects of antipsychotic agents is still not well established.
Even though higher rates of side effects are reported in women,
recommended pharmacological dosage regimes do not differ between
male and female patients.
For SGAs, the reasons for a higher risk in females may be
multi-causal including gender-related differences in pharmacokinetics,
pharmacodynamics, pharmacogenetics, immunological and hormonal
factors as well as differences in the use of medications by
women compared with men. In this review we give a brief overview
of gender-specific pharmacokinetic factors leading probably
to distinguished clinical outcome in both sexes.
Furthermore the implication of gender on common side effects
of SGAs such as weight gain, glucose and lipid abnormalities,
hyperprolactinemia, cardiac and sexual side effects is discussed
with specific reference to studies done on schizophrenic patients.
| 
