Current Drug Targets-CNS
& Neurological Disorders, Volume 1, No. 2, 2002
Current
Status of Antipsychotic Treatment Pp. 123-128
Robert
R. Conley and Deanna L. Kelly
Treatment
of Schizophrenia and Comorbid Substance Use Disorder Pp. 129-139
Alan
I. Green, Melinda S. Salomon, Mark J. Brenner and Kimberly Rawlins
Partial
Dopamine Agonists and Dopaminergic Stabilizers, in the Treatment of Psychosis
Pp. 141-147
C.A.
Tamminga and A. Carlsson
Nicotinic
Agonists and Psychosis Pp. 149-162
J.K. Simosky, K.E. Stevens and R. Freedman
Muscarinic
Receptors as a Target for Drugs Treating SchizophreniaPp. 163-181
Frank
P. Bymaster, Christian Felder, Saeed Ahmed and David McKinzie
Ionotropic
Glutamate Receptors as Therapeutic Targets in SchizophreniaPp. 183-189
Joseph
T. Coyle, Guochuan Tsai and Donald C. Goff
N-Methyl-D-Aspartate
Receptor-Coupled GlycineB Receptors in the Pathogenesis and Treatment of Schizophrenia:
A Critical Review Pp. 191-213
M.J. Millan
Preclinical
Pharmacology of mGlu2/3 Receptor Agonists: Novel Agents for Schizophrenia?
Pp. 215-225
Darryle
D. Schoepp and Gerard J. Marek
Novel
Directions in Antipsychotic Target Identification using Gene Arrays Pp.
227-238
Michael
G. Palfreyman, Derek J. Hook, Leszek J. Klimczak, Jeffery A. Brockman, David M.
Evans and C. Anthony Altar
[Back to top] Current Status of
Antipsychotic Treatment
Robert R. Conley and Deanna L. Kelly
With
the use of chlorpromazine and other traditional antipsychotics for psychosis,
it was soon discovered that the antipsychotic efficacy of this class of
medications was closely associated with their ability to block dopamine D2
receptors in the brain. This prompted the hypothesis that the etiology of
schizophrenia and other psychotic illnesses might be caused by a dysregulation
of dopamine. This hypothesis, that the dopamine system explains schizophrenia
symptoms, however, is far from complete and the treatment with conventional
antipsychotic medications is far from ideal. There has been a great deal of
speculation regarding the role of serotonin receptor antagonism in regards to
antipsychotic effects. The second generation antipsychotics (SGAs), clozapine,
risperidone, olanzapine, quetiapine and ziprasidone all have relatively high
serotonin to dopamine binding ratios. Serotonin receptor binding may be
important to these drugs’ actions, possibly by stimulating dopamine activity in
mesocortical pathways. Yet, while the mechanism of action of SGAs as a group
remain unsolved, it is important to note that the SGAs offer many clinical
benefits to treatment as compared to traditional antipsychotics and are quickly
emerging as first-line therapy for schizophrenia. In addition to lower rates of
EPS and tardive dyskinesia, other benefits to treatment with this class of
antipsychotics include better treatment of negative symptoms, better
compliance, possible benefits for cognitive impairments, lower rates of relapse
and rehospitalization, and more cost-effective therapy. Within the class of
SGAs, however, differences exist both in efficacy and side effects and these
will be described. Optimization of treatment and understanding the exact
mechanism of action of current antipsychotic medications will help pave the way
for new drug targets in the future.
[Back to top] Treatment of Schizophrenia and Comorbid
Substance Use Disorder
Alan
I. Green, Melinda S. Salomon, Mark J. Brenner and Kimberly Rawlins
Comorbid
alcohol and substance use disorders occur commonly among patients with
schizophrenia and contribute to the morbidity of schizophrenia. These comorbid
disorders add greatly to the financial costs and emotional toll that
schizophrenia places on patients, families and the entire mental health system.
While the basis for the increased abuse of alcohol and other substances in
patients with schizophrenia have been linked by some investigators to
“self-medication” of negative symptoms of schizophrenia or extrapyramidal
system effects of typical antipsychotics, we have presented a neurobiologic
formulation suggesting that alcohol or other substances may transiently correct
a dysfunction of the dopamine-mediated mesocorticolimbic pathways in patients with
schizophrenia – pathways linked to brain reward circuits. This formulation
further suggests that alcohol or other substances serve to transiently enhance
the functioning of this circuit by improving the “signal detection” capability
of the dopamine-rich mesocorticolimbic pathways. Treatment of comorbid
substance use disorder in patients with schizophrenia involves careful use of
psychosocial approaches aimed at fostering program participation and at
enhancing the likelihood of abstinence. While the typical antipsychotics do not
limit the comorbid substance use, and may actually worsen it, preliminary data
suggest the novel antipsychotic clozapine may have the unusual ability to
dramatically decrease alcohol and other substance use in patients with schizophrenia.
It is not clear whether other novel antipsychotics share this ability of
clozapine to limit alcohol and substance abuse. We have proposed that the
effect of clozapine in this population may relate to its broad pharmacological
effects, including its relatively weak blockade of the dopamine D2 receptor and
its potent blockade of the serotonergic 5-HT2 receptor and the noradrenergic
alpha 1 and alpha 2 receptors. Studies of other agents, employed in the
pharmacotherapy of alcohol and substance use disorders without schizophrenia,
are currently underway in patients with schizophrenia and comorbid disorders.
[Back to top] Partial Dopamine Agonists and
Dopaminergic Stabilizers, in the Treatment of Psychosis
C.A.
Tamminga and A. Carlsson
The
early demonstration of chlorpromazine efficacy in schizophrenia and its
subsequent identification as a dopamine receptor antagonist, established the
only known mechanism for antipsychotic development to date. By extension, it is
easy to hypothesize that any mechanism shown to reduce dopamine-mediated
transmission in brain will have antipsychotic properties. The evaluation of
partial dopamine agonists for antipsychotic efficacy and their application in
the treatment of psychosis has derived from this background. Partial dopamine
agonists at the D2 dopamine receptor, have high affinity for that receptor, but
reduced intrinsic activity. These agonists have higher affinity for the
presynaptic autoreceptor than for the postsynaptic receptor. Hence, these
compounds reduce dopamine synthesis and release through an agonist action at
the dopamine autoreceptor. Moreover, the agonists have lower intrinsic activity
at the postsynaptic receptor than its natural ligand dopamine. Therefore, they
diminish the dopaminergic signal at postsynaptic sites as well through
delivering a reduced message; this component of drug action becomes more
prominent the lower the intrinsic activity of the drug. Several partial
dopamine agonists have been evaluated in schizophrenia. One of them,
aripiprazole, is nearing approval for marketing. With partial dopamine agonist
treatment, advantages should accrue to schizophrenia treatment in the areas of
affect control and cognitive performance.
[Back to top] Nicotinic Agonists and Psychosis
J.K. Simosky, K.E. Stevens and R. Freedman
Schizophrenia patients have insufficient inhibitory processing of identical paired auditory stimuli. This deficient “auditory gating” is thought to have physiological relevance, and its severity correlates with certain measures of both positive and negative symptoms. Schizophrenia patients also represent the heaviest smoking population subgroup. Because smoking temporarily normalizes their auditory gating deficit, this may represent a form of self-medication. Although this deficit is unresponsive to treatment with typical antipsychotic drugs, it does respond to the atypical antipsychotic clozapine. The normalization of this deficit by smoking may account for some of the intense drive to smoke that is experienced by schizophrenia patients. However, the normalizing effect of nicotine is transient and is not observed with repeated administration. Auditory gating is modulated by the a7 nicotinic receptor subtype, a rapidly desensitizing low-affinity nicotinic receptor. Agents that selectively activate the a7 receptor represent a novel class of therapeutic agents for use in the treatment of schizophrenia. Whether selective a7 agonists will have beneficial effects on symptoms other than the auditory gating deficit has not yet been established. The first developed a7-selective agonist, 3-2,4-dimethoxybenzylidene anabaseine (DMXB-A), normalizes auditory gating in three distinct animal models of the deficit. DMXB-A is a prototype for this potential new drug class, but proof-of-concept for this type of pharmacotherapy will not be available until the completion of planned clinical trials assessing DMXB-A’s effects in schizophrenia patients. Additional avenues to the potential normalization of auditory gating deficits are also discussed, focusing on the novel efficacy of clozapine and the potential utility of allosteric modulators of nicotinic receptors.
[Back to top] Muscarinic Receptors as a
Target for Drugs Treating Schizophrenia
Frank P. Bymaster, Christian Felder, Saeed Ahmed and David McKinzie
The family of 5 muscarinic acetylcholine receptors belongs to the superfamily of G protein coupled neurotransmitter receptors that serve in part as regulators of synaptic function. Muscarinic receptors are anatomically positioned in cortical and subcortical areas and modulate dopaminergic and glutamatergic neurotransmission thought to be dysfunctional in schizophrenia. Neurochemical studies have shown that dopamine and muscarinic receptors reciprocally modulate one another. For example, the muscarinic agonist xanomeline increases extracellular levels of dopamine and Fos expression in cortical areas greater than subcortical areas, similar to effects of atypical antipsychotics. In electrophysiological studies, xanomeline with acute and chronic administration decreased firing of the mesocorticolimbic dopamine A10 tract, but not the motoric dopamine A9 tract. Behavioral investigations have shown that muscarinic agonists, like dopamine antagonists, inhibit conditioned-avoidance responding and dopamine-agonist-induced behaviors including hyperactivity, climbing behavior and disruption of prepulse inhibition, models for positive symptoms of schizophrenia. Transgenic knockout mice lacking M4 receptors are hyperactive and hyper-responsive to dopamine D1 agonists, suggesting a dynamic balance between the dopamine and M4 receptors. Muscarinic agonists had activity in animal models of negative symptoms, cognitive dysfunction and affective disorders, symptoms that are prominent in schizophrenic patients. Consistent with effects in animal models, preliminary clinical investigation indicates that muscarinic agonists like xanomeline may be effective in the pharmacotherapy of schizophrenia. Thus, we hypothesize that a combined M1 agonist to promote cognition and a M4 agonist for antipsychotic-like effects would treat the symptom domains of schizophrenia without parasympathomimetic side effects.
[Back to top] Ionotropic Glutamate Receptors as
Therapeutic Targets in Schizophrenia
Joseph
T. Coyle, Guochuan Tsai and Donald C. Goff
Evidence
implicating dysfunction of glutamatergic neurotransmission rests largely on the
finding that antagonists of the NMDA subtype of glutamate receptor, especially
the dissociative anesthetics like ketamine, can reproduce the full range of
symptoms as well as the physiologic manifestation of schizophrenia such as
hypofrontality, impaired prepulse inhibition and enhanced subcortical dopamine
release. To test the hypothesis that schizophrenia may result from NMDA
receptor hypofunction a number of clinical trials have examined the effects of
agents that act on the glycine modulatory site on the NMDA receptor. Glycine,
D-serine, and the partial agonist, D-cycloserine, have been shown to improve
cognition and decrease negative symp-toms in schizophrenic subjects receiving
typical antipsychotics. Results with D-cycloserine suggest that clozapine may
enhance glycine modulatory site occupancy. Preliminary results with an
allosteric modulator of the AMPA subtype of glutamate receptor suggest enhanced
cognitive functions in subjects treated with clozapine.
[Back to top] N-Methyl-D-Aspartate
Receptor-Coupled GlycineB Receptors in the Pathogenesis and Treatment of
Schizophrenia:A CriticalReview
M.J. Millan
Glutamatergic
pathways, metabotropic receptors, and ionotropic a-amino-3-hydroxy-5-methylisoxazole-4-proprionic
acid (AMPA), kainate and N-methyl-D-aspartate (NMDA) receptors are all
implicated in the etiology and management of schizophrenia. As concerns NMDA
receptors, open channel blockers (OCBs) such as phencyclidine (PCP) elicit
psychotic symptoms in human subjects. This observation underpins biochemical
studies indicating that a deficit in activity at NMDA receptors may be
associated with psychotic states. Inasmuch as agonists at the NMDA recognition
site are excitotoxic, drugs acting via the co-agonist, glycineB (GLYB)
site are more promising clinical candidates as antipsychotic agents. Glycine
(GLY) itself, a further endogenous agonist, D-Serine, and inhibitors of GLY
reuptake are active in certain experimental models predictive of antipsychotic
properties. Further, in controlled clinical trials, GLY and D-Serine enhance
the ability of conventional neuroleptics such as haloperidol to improve
cognitive and negative symptoms. Their actions are mimicked by the partial
agonist, D-cycloserine (DCS). However, these agents exert little effect alone
and may interfere with therapeutic actions of the atypical antipsychotic,
clozapine. An important issue in the interpretation of drug actions at GLYB
sites is their degree of occupation by endogenous GLY and D-Serine - although
they are unlikely to be saturated. Further, distinct "subtypes" of
GLYB site-bearing NMDA receptor may fulfill differential roles in
psychotic states Finally, blockade of certain populations of NMDA receptor may
be of use in the management of schizophrenia. This article reviews the complex
role of GLYB sites/NMDA receptors and their endogenous ligands in
the pathogenesis and treatment of psychotic states.
[Back to top]
Preclinical Pharmacology of mGlu2/3 Receptor Agonists: Novel Agents for
Schizophrenia?
Darryle D. Schoepp and Gerard J. Marek
Agonists
for mGlu2/3 receptors decrease the evoked release of glutamate at certain (ie.
forebrain / limbic) glutamatergic synapses, indicating that the functional role
of mGlu2 and/or mGlu3 receptors is to suppress glutamate excitations. This
offers a mechanism for dampening glutamate excitation under pathological states
resulting from excessive glutamate release. Based, in part, on the
psychotomimetic actions of phencyclidine (PCP)- like drugs, excessive or
pathological glutamate release has been implicated in a number of clinical
conditions including psychosis. With this in mind, the pharmacology of multiple
mGlu2/3 receptor agonists have been investigated in PCP treated rats. Agonists
for mGlu2/3 receptors such as LY354740 and LY379268 have been shown to block
certain behavioral responses to PCP in rats. The effects of mGlu2/3 agonists on
PCP-induced behaviors are blocked by a low doses of a selective mGlu2/3
receptor antagonist, indicating that these actions are mediated via mGlu2/3
receptors. In addition, mGlu2/3 agonists potently suppress glutamate release in
rat prefrontal cortex, as relfected by excitatory post-synaptic potentials
(EPSPs) induced by serotonin (5-HT) acting on 5HT2A receptors. These
actions of LY354740 and LY379268 are also blocked by a selective mGlu2/3
antagonist. Atypical antipsychotic drugs such as clozapine also suppress
5-HT-induced EPSPs in this brain region, thus suggesting a common pathway for
the actions of atypical antipsychotic drugs and mGlu2/3 receptor agonists. As
glutamatergic dysfunction has been implicated in psychotic states and possibly
in the etiology of schizophrenia, clinical studies with mGlu2/3 agonists may be
warranted to further explore the validity of the glutamatergic hypothesis of
schizophrenia.
[Back to top] Novel Directions in Antipsychotic
Target Identification using Gene Arrays
Michael G. Palfreyman, Derek J. Hook, Leszek J. Klimczak, Jeffery A. Brockman,David M. Evans and C. Anthony Altar
Schizophrenia is a major health problem that affects 2 million individuals in the United States. Antipsychotics offer considerable symptomatic relief and, although commonly discovered by screening with single biological targets, most interact with multiple receptors and signaling pathways. Considerable evidence from family and twin studies demonstrates genetic components and multiple chromosomal regions associated with schizophrenia. The polygenic nature of schizophrenia and multiple mechanisms for most effective agents indicate the need for broader approaches to target identification. Gene expression profiling of post-mortem human brain tissue simultaneously reveals the expression of many thousands of genes. A comparison of tissue from normals and patients provides a ‘disease signature’ of aberrantly expressed genes. ‘Drug signatures’ are the gene expression changes of cultured human or animal neurons treated with psychiatric drugs, and from animals chronically treated with these drugs. A selection of genes from disease and drug signatures can create a set of targets whose changes may better predict disease and its treatment by effective agents. This multi-parameter high throughput screening (MPHTSSM) approach evaluates the mRNA expression pattern of cultured cells exposed to candidate compounds. Compounds that normalize genes altered in schizophrenia may better address its underlying causes. Drugs that mimic gene expression changes that are consistently altered by effective antipsychotic agents provide a drug improvement strategy if efficacy is enhanced or side effects are attenuated.