Current Medicinal Chemistry, Volume 11, No. 3, 2004
Contents
Pharmacological Treatment of Schizophrenia:Recent
Antipsychotic Drugs and New Therapeutic Strategies
Guest Editor: Maria Augusta Raggi
Schizophrenia: From Dopamine to Glutamate and
Back Pp.267-277
M.L.
Carlsson, A. Carlsson and M. Nilsson
Atypical Antipsychotics: Pharmacokinetics,
Therapeutic Drug Monitoring and Pharmacological Interactions Pp.279-296
Maria
Augusta Raggi, Roberto Mandrioli, Cesare Sabbioni and Vincenzo Pucci
Pharmacogenomic-Guided Rational Therapeutic
Drug Monitoring: Conceptual Framework and Application Platforms for Atypical Antipsychotics Pp.297-312
A Critical Review of Atypical Antipsychotic
Utilization: Comparing Monotherapy with Polypharmacy and Augmentation Pp.313-327
S.M. Stahl and M.M. Grady
Naturalistic Studies of Second Generation
Antipsychotics in the Treatment of Schizophrenia Pp.329-342
C. Simon Sebastian, William Glazer and Peter F. Buckley
New Antipsychotics and Schizophrenia: A
Review on Efficacy and Side Effects Pp.343-358
Alessandro Serretti, Diana De Ronchi, Cristina Lorenzi and Domenico Berardi
Mode of Action of Endotoxin: Role of Free
Radicals and Antioxidants
Pp.359-368
Jharna Bhattacharyya, Sabyasachi Biswas and Asoke G. Datta
Oxidative Stress-Induced Ischemic Heart
Disease: Protection by Antioxidants Pp.369-387
Debashis Bandyopadhyay, Aindrila Chattopadhyay, Goutam Ghosh and Asoke G. Datta
The NMDA Receptor NR2B Subunit: A Valid
Therapeutic Target for Multiple CNS Pathologies Pp.389-396
Paul L. Chazot
Abstracts
[Back to top] Schizophrenia: From Dopamine to Glutamate and
Back
M.L.
Carlsson, A. Carlsson and M. Nilsson
The first part of the present review describes the exciting journey of dopamine stabilizers, starting in the early eighties with the development of the partial dopamine agonist (-)-3-PPP of phenylpiperidine structure, via various compounds with aminotetraline structure with preferential autoreceptor antagonist properties, and then back again to phenylpiperidine compounds carrying substituents on the aromatic ring that transformed them from partial dopamine agonists to partial dopamine receptor antagonists, such as OSU6162. OSU6162 was brought to the clinic and has in preliminary trials showed antidyskinetic and antipsychotic efficacy. The second part of this review describes results from a hypoglutamatergia mouse model for cognitive symptoms of schizophrenia, where we have tested traditional neuroleptics, new generation antipsychotics with marked 5-HT2 vs dopamine D2 receptor blockade as well as a dopamine stabilizer belonging to the partial dopamine receptor antagonist category.
[Back to top] Atypical Antipsychotics: Pharmacokinetics,
Therapeutic Drug Monitoring and Pharmacological Interactions
Maria
Augusta Raggi, Roberto Mandrioli, Cesare Sabbioni and Vincenzo Pucci
The development of new "atypical" antipsychotic agents, which are safer than classical neuroleptics and also active against the negative symptoms and neurocognitive deficits caused by the illness, has produced a significant advancement in the treatment of schizophrenia.
The atypical (or "second generation") antipsychotics have several therapeutical properties in common, however they can significantly differ with regard to clinical potency and side effects. The main features regarding pharmacodynamics, pharmacokinetics and pharmacological interactions of the most important atypical antipsychotics, namely clozapine, olanzapine, quetiapine and risperidone, are treated herein. Several analytical methods available for the therapeutic drug monitoring of these drugs are also presented, as well as the novel formulations, which can notably improve the therapy of schizophrenia. Other very recent atypical agents, such as ziprasidone, aripiprazole, iloperidone, sertindole and zotepine will also be briefly described.
[Back to top] Pharmacogenomic-Guided Rational Therapeutic
Drug Monitoring: Conceptual Framework and Application Platforms for Atypical
Antipsychotics
Lawrence
J. Albers and Vural Ozdemir
Atypical antipsychotic agents such as aripiprazole, clozapine, olanzapine, quetiapine and ziprasidone offer many advantages over conventional neuroleptics. These agents reduce negative symptoms of schizophrenia, are effective in treatment refractory cases, and have a markedly lower incidence of extrapyramidal symptoms and tardive dyskinesia. However, there is considerable patient-to-patient variability in therapeutic dose requirements of atypical antipsychotics and the propensity for side effects. Hence, the initial excitement since the introduction of atypical antipsychotics in late 1980s is now shifting towards a focus on individualization of pharmacotherapy and elucidation of the mechanistic basis of interindividual variability in drug response with use of pharmacokinetic and pharmacodynamic biomarkers. Pharmacogenomics, introduced in late 1990s, is the study of variability in drug response using information from the entire genome of a given individual patient. Both pharmacogenomics and conventional therapeutic drug monitoring (TDM) share the similar goal of improving pharmacotherapy through better explanation of individual variability in drug response. Hence, pharmacogenomic biomarkers offer a unique opportunity to complement and expand the scope of traditional TDM in clinical psychopharmacology. Importantly, pharmacogenomics enables the investigation of factors distal to drug exposure in the plasma compartment (e.g. drug targets at the biophase), thereby providing a more complete portrayal of sources of variability in psychotropic drug response. We discuss (1) the definitions for biomarkers and surrogate endpoints in the context of pharmacogenomics, (2) genetic variations in isozyme-specific atypical antipsychotic metabolism in vivo, (3) selected examples of pharmacogenomic variability in pertinent drug targets and, (4) the anticipated roadmap from implementation of pharmacogenomics to changes in healthcare and therapeutic policy. In addition, a conceptual framework that outlines the theoretical advantages of pharmacogenomics-guided TDM is presented using recent clinical applications as precedence.
[Back to top] A Critical Review of Atypical Antipsychotic
Utilization: Comparing Monotherapy with Polypharmacy and Augmentation
S.M.
Stahl and M.M. Grady
The atypical antipsychotics risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole have become first-line treatment for schizophrenia because they reduce the positive symptoms of psychosis but do not have a high incidence of extrapyramidal symptoms. However, these agents, like other antipsychotics, may take as long as 16 or more weeks to produce a response, and even with prolonged treatment are unlikely to evoke responses greater than 50% improvement in symptoms. This has led to the experimental use of high atypical antipsychotic doses, antipsychotic polypharmacy, and augmentation with other psychotropic drugs, all of which occur commonly in clinical practice. This article reviews the current evidence for these increasingly common means of treating schizophrenia and psychosis, with particular emphasis on polypharmacy and augmentation. To date, there are only two controlled studies of antipsychotic polypharmacy involving an atypical antipsychotic; the rest of the data are uncontrolled trials and case reports that describe a mixture of positive and negative findings. One multicenter, double-blind trial shows a faster onset of action when divalproex is added to risperidone or olanzapine than with antipsychotic monotherapy. A small double-blind study demonstrates efficacy when lamotrigine is added to clozapine. The rest of the data on augmentation with anticonvulsants are uncontrolled, and most report adverse effects. With the exception of divalproex, there are currently no compelling data to justify the use of antipsychotic polypharmacy or augmentation. Existing evidence suggests that the best treatments for schizophrenia and psychosis may be long-term trials of a sequence of atypical antipsychotic monotherapies at therapeutic doses.
[Back to top] Naturalistic Studies of Second Generation
Antipsychotics in the Treatment of Schizophrenia
C.
Simon Sebastian, William Glazer and Peter F. Buckley
Undoubtedly, the pharmacological treatment of schizophrenia has changed dramatically over the last 10 years. Large, double-blind, placebo-controlled trials have ushered the availability of each new antipsychotic. However, there has been an information lag because of the relative paucity of long term, comparative studies among second-generation antipsychotics. While we await such evidence, naturalistic studies have helped to provide useful information on the pattern of use, patient response, and tolerability of these new agents in clinical practice. This review provides an account of representative studies for each second generation antipsychotic, which illustrate the contributions of naturalistic studies to our understanding of the evolving pharmacotherapy of schizophrenia.
[Back to top] New Antipsychotics and Schizophrenia: A
Review on Efficacy and Side Effects
Alessandro
Serretti, Diana De Ronchi, Cristina Lorenzi and Domenico Berardi
The first compounds showing efficacy in the treatment of schizophrenia and other psychotic disorders was chlorpromazine, an anti-histaminic compound casually observed to possess antipsychotic effects. The discovery of the real mechanism of action of antipsychotic substances dates back to the 1960s, when researchers found that these compounds act as dopamine receptor antagonists. Unfortunately, this type of drugs cannot block the D2 receptors only in the mesolimbic dopaminergic pathway (which mediates their therapeutic effects), because of their non-selective D2 receptor blockage in both the mesolimbic and striatal regions, and the consequent appearance of side effects related to striatal interaction in the same dosage range as is needed for the therapeutical effects. Clozapine, discovered in the early 1970s, seemed to represent the solution to contrast these side effects, as it possesses antipsychotic activity without inducing extrapyramidal disorders in humans or catalepsy in rats; for this reason, it was defined as an "atypical" antipsychotic drug. Later, other beneficial properties, such as improvement of negative symptoms and of cognitive dysfunction and efficacy in neuroleptic-resistant schizophrenia, were included in the definition of "atypical". In recent years, the appearance of new atypical antipsychotics (risperidone, olanzapine, quetiapine, ziprasidone) has opened new ways to therapy. The aim of this paper is to review literature about newer antipsychotics, focusing on their advantages in terms of efficacy and side effect profiles when compared to classical and older atypical antipsychotics, and to evaluate the efficacy of the different new antipsychotics when compared to one another.
[Back to top] Mode of Action of Endotoxin: Role of Free
Radicals and Antioxidants
Jharna
Bhattacharyya, Sabyasachi Biswas and Asoke G. Datta
The pathogenetic sequence of reactions mediated by endotoxin (LPS) leading to the production of sepsis involves the oxygen radicals or reactive oxygen species, which has been evaluated in the present review. Among reactive oxygen species hydroxyl radical either singly or in combination with peroxynitrite, produces tissue damage often observed during septic injury. Inactivation of these damaging radicals by antioxidants or nitric oxide inhibitor(s) may be helpful for protecting sepsis mediated derangements but the application of these agents as drugs in humans has not been fully successful. Transcription factor NF-kB is reported to be the oxygen sensor in LPS induced endotoxemia. Polyphenols, especially the catechin group of compounds, are important therapeutic agents, which may be used for the treatment of endotoxin mediated sepsis.
[Back to top] Oxidative Stress-Induced Ischemic Heart Disease:
Protection by Antioxidants
Debashis
Bandyopadhyay, Aindrila Chattopadhyay, Goutam Ghosh and Asoke G. Datta
Heart disease is one of the major health problems of advanced as well as developing countries of the world. Extensive research through the last decade has shown beyond doubt that free radicals, particularly, reactive oxygen species play a cardinal role in the pathogenesis of oxidative myocardial damage with consequential cardiac malfunction. This review presents a comprehensive account of the present day knowledge regarding the oxygen free radicals involved in the genesis of ischemic heart disease, the mechanism(s) of oxidative myocardial damage and the endogenous as well as exogenous antioxidant defense systems. Furthermore, the role of ischemic pre-conditioning, some antioxidants and the ability of some cardioprotective drugs in providing protection against the ischemic myocardial damage are also discussed. The text of the article comes to an end with a commentary on the future research perspective in the concerned area, which throws a light on the development of combinatorial therapeutics in the treatment of ischemic myocardial disease.
[Back to top] The NMDA Receptor NR2B Subunit: A Valid
Therapeutic Target for Multiple CNS Pathologies
Paul L. Chazot
The NMDAR2B subunit is the focus of increasing interest as a therapeutic target in a wide range of CNS pathologies, including acute and chronic pain, stroke and head trauma, drug-induced dyskinesias, and dementias. Due to significant pharmaceutical endeavor, an impressive collection of chemical leads has been developed which target the NR2B subunit, some of which appear to discriminate between closely related subtypes. We now have the benefit of a structural template for the ifenprodil binding site which should further improve future structure activity relationships. A growing appreciation of the likely extrasynaptic localisation of the NR2B receptor subtype and importance of NR2B protein modification, notably tyrosine phosphorylation, may explain its therapeutic importance. The apparent superior preclinical and clinical data for the second and third generation NR2B compounds is likely to reflect subtype selectivity, a unique mode of action and cellular location of the NR2B receptors in the CNS.