Development Of Antipsychotic Drugs Research Articles

Combined α2 and D2/3 receptor blockade enhances cortical glutamatergic transmission and reverses cognitive impairment in the rat

The alpha(2) adrenoceptor antagonist idazoxan enhances antipsychotic efficacy of classical dopamine D(2) antagonists in treatment-resistant schizophrenia. The mechanisms are not fully understood, but we have previously shown that the combination of idazoxan with the D(2/3) receptor antagonist raclopride, similarly to clozapine but not classical antipsychotic drugs, augments dopamine efflux in the prefrontal cortex, and also generates an enhanced suppression of the conditioned avoidance response. We have now investigated the effects of clozapine, raclopride, idazoxan and the combination of raclopride and idazoxan on (i) electrically evoked excitatory post-synaptic potentials and currents in pyramidal cells of the rat medial prefrontal cortex, using intracellular electrophysiological recording in vitro, (ii) the impaired cognitive function induced by the selective N-methyl-D-aspartate (NMDA) receptor antagonist MK-801, using the 8-arm radial maze test, (iii) the in-vivo D2, alpha(2A) and alpha(2C) receptor occupancies of these pharmacological treatments, using ex-vivo autoradiography. Whereas neither idazoxan nor raclopride alone had any effect, the combination exerted the same facilitation of glutamatergic transmission in rat prefrontal pyramidal neurons as clozapine, and this effect was found to be mediated by dopamine acting at D(1) receptors. Similarly to clozapine, the combination of idazoxan and raclopride also completely reversed the working-memory impairment in rats induced by MK-801. Moreover, these effects of the two treatment regimes were obtained at similar occupancies at D(2), alpha(2A) and alpha(2C) receptors respectively. Our results provide novel neurobiological and behavioural support for a pro-cognitive effect of adjunctive use of idazoxan with antipsychotic drugs that lack appreciable alpha(2) adrenoceptor-blocking properties, and define presynaptic alpha(2) adrenoceptors as major targets in antipsychotic drug development.

Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs.

The treatment of schizophrenia has evolved over the past half century primarily in the context of antipsychotic drug development. Although there has been significant progress resulting in the availability and use of numerous medications, these reflect three basic classes of medications (conventional (typical), atypical and dopamine partial agonist antipsychotics) all of which, despite working by varying mechanisms of actions, act principally on dopamine systems. Many of the second-generation (atypical and dopamine partial agonist) antipsychotics are believed to offer advantages over first-generation agents in the treatment for schizophrenia. However, the pharmacological properties that confer the different therapeutic effects of the new generation of antipsychotic drugs have remained elusive, and certain side effects can still impact patient health and quality of life. Moreover, the efficacy of antipsychotic drugs is limited prompting the clinical use of adjunctive pharmacy to augment the effects of treatment. In addition, the search for novel and nondopaminergic antipsychotic drugs has not been successful to date, though numerous development strategies continue to be pursued, guided by various pathophysiologic hypotheses. This article provides a brief review and critique of the current therapeutic armamentarium for treating schizophrenia and drug development strategies and theories of mechanisms of action of antipsychotics, and focuses on novel targets for therapeutic agents for future drug development.

Current issues in schizophrenia: overview of patient acceptability, functioning capacity and quality of life.

The increasing interest in the subjective wellbeing and quality of life (QoL) of patients with schizophrenia represents a conceptual extension of therapeutic outcome criteria. For a long time, the reduction of positive symptoms alone was the most important outcome parameter, but the development of atypical antipsychotic drugs in the early 1990s resulted in the adoption of more wide-reaching measures of therapeutic outcome. Patient satisfaction appears to be strongly related to their willingness to be or stay engaged in psychosocial and pharmacological treatment, and therefore to the symptomatic and functional outcome. Existing studies that deal with QoL and subjective wellbeing differ in their methodology and are difficult to compare because of varying underlying concepts of QoL or subjective wellbeing, different assessment scales or small sample sizes. Although QoL is a heterogeneous concept, it is clearly correlated with a number of factors, including illness, medication and stress process-related variables. Various protective factors have been identified; among these are personality traits, the degree of social support and treatment interventions. In clinical studies, atypical antipsychotic agents are associated with greater improvements in QoL and subjective wellbeing than are conventional agents. The reason for this is probably the ability of atypical agents to have a positive impact on factors most associated with QoL, such as negative and affective symptoms and drug tolerability. The most appropriate clinical approach to maximize QoL and subjective wellbeing for patients with schizophrenia is to use atypical antipsychotic drugs as a first-line treatment approach. Ideally, an atypical drug which is known not to have a negative effect on attention, affect or motivation should be chosen.

Atypical Antipsychotics as First-Line Treatments for Schizophrenia

The poor efficacy and tolerability of conventional antipsychotic treatment in schizophrenia, together with discovery of the ‘atypical’ antipsychotic Clozapine, led to the development of several other atypical antipsychotic drugs. Those now available manifest clinically relevant differences in symptom efficacy and adverse effects, and most evidence supports their superior efficacy and tolerability compared with conventional treatment. Alongside these novel drugs have arrived concerns regarding new adverse effects, instead of the extrapyramidal phenomena which were one of the main drawbacks of conventional antipsychotics. These adverse effects comprise weight gain, diabetes mellitus and QTc interval prolongation. Overall, however, there is no evidence that atypical antipsychotics are more problematic than conventional antipsychotics, as there are marked differences between individual drugs in both classes. Current guidelines recommend the use of atypical antipsychotics as first-line treatments in a wide range of patients with schizophrenia, despite significant caveats regarding the quality of evidence to support use of these drugs in general. Advantages claimed over conventional antipsychotics are greater cost effectiveness, superior relapse prevention and possible benefits regarding quality of life and the natural course of schizophrenia. These advantages, if valid, will benefit stakeholders, whether they are consumers or providers of mental healthcare. However, major discrepancies remain between guidelines for first-line use and current practice. Poor take-up of atypical treatment and off-license use of both conventional and atypical drugs, particularly in primary care, are substantial problems that remain unaddressed. If guidance on first-line atypical therapy for schizophrenia is to be followed, processes such as audit must be applied widely to facilitate implementation of best-practice guidelines. Only then will the supposed benefits of first-line use be verified, or otherwise.

Pharmacological Studies of Smooth Pursuit and Antisaccade Eye Movements in Schizophrenia: Current Status and Directions for Future Research

Smooth pursuit (SPEM) and antisaccade eye movements have been studied to elucidate the genetics and the pathophysiology of schizophrenia. In recent years, a rapidly growing literature has emerged on pharmacological influences on eye movements. This review focuses on pharmacological studies of the SPEM and antisaccade tasks with relevance to schizophrenia and aims to answer the particular questions: (1) whether pharmacological compounds with relevance to the treatment or pathophysiology of schizophrenia affect performance, and (2) whether SPEM or antisaccade measures may be useful in the development of novel therapeutic targets for this illness. We conclude that (i) short- or medium-term typical antipsychotic treatment of schizophrenia patients has no or little effect on either measure, (ii) treatment with clozapine appears to impair SPEM, (iii) treatment with risperidone and 5-HT2 antagonists improves schizophrenia patients antisaccade error rate deficit, (iv) anticholiner gics, ofte n use d to contr ol extr apyra midal symptoms induc ed by typical a ntipsychotics, may w orsen pe rf ormance, ( v) be nzodiaze pines impa ir SPEM and antisacc ade per for ma nce in hea lthy individuals, (vi) nicotine, selfadministered via cigarette smoking or given via experimental procedures, improves SPEM and antisaccade performance, and (vii) SPEM has the potential to be a useful phenotype for the ketamine model of psychosis, with implications for antipsychotic drug development. Finally, we discuss methodological issues pertaining to the study of eye movements in pharmacological and genetic schizophrenia research and suggest that the SPEM and antisaccade tasks may be profitably used in the development of antipsychotic drugs. Keywords: smooth pursuit eye movements, antisaccade, schizophrenia, neuroleptic, antipsychotic, treatment, endophenotype, drug development

New developments in antipsychotic therapy.

Article AbstractClick to enlarge pageW. Wolfgang Fleischhacker, M.D., began the meeting by reviewing the history of the mechanism-based development of antipsychotic drugs. Mechanism-based studies commenced with Paul Janssen's clinical observation in Belgian cyclists that the dopamine agonist amphetamine led to psychosis and abnormal movements similar to those seen in schizophrenia patients. Expanded knowledge about the pathophysiology of schizophrenia, especially the development and acceptance of the dopamine hypothesis, has also motivated more mechanism-based research.

Decrease of serotonin receptor 2C in schizophrenia brains identified by high-resolution mRNA expression analysis

Background RNA expression profiling can provide hints for the selection of candidate susceptibility genes, for formulation of hypotheses about the development of a disease, and/or for selection of candidate gene targets for novel drug development. We measured messenger RNA expression levels of 16 candidate genes in brain samples from 55 schizophrenia patients and 55 controls. This is the largest sample so far used to identify genes differentially expressed in schizophrenia brains. Methods We used a sensitive real-time polymerase chain reaction methodology and a novel statistical approach, including the development of a linear model of analysis of covariance type. Results We found two genes differentially expressed: monoamine oxidase B was significantly increased in schizophrenia brain ( p = .001), whereas one of the serotonin receptor genes, serotonin receptor 2C, was significantly decreased ( p = .001). Other genes, previously proposed to be differentially expressed in schizophrenia brain, were invariant in our analysis. Conclusions The differential expression of serotonin receptor 2C is particularly relevant for the development of new atypical antipsychotic drugs. The strategy presented here is useful to evaluate hypothesizes for the development of the disease proposed by other investigators.

Schizophrenia and bipolar affective disorder: perspectives for the development of therapeutics.

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 combiningthe above approaches may hold promise for the development of more effective treatments.

Current strategies for the development of novel antipsychotic drugs.

While classical neuroleptics are characterized by dopamine D(2) antagonism, this is also considered to be the cause of their neurological side effects. In recent years, novel antipsychotic drugs with improved efficacy, devoid of extrapyramidal effects are being developed. The mechanisms of action of these new atypical antipsychotics can be classified into three general groups: a) binding to D(2) together with non-dopaminergic receptors, b) interaction with dopamine receptor subtypes other than D(2) and c) selective binding to non-dopaminergic systems, such as glutamatergic, sigma, neurotensin, and cannabinoid.

Metabotropic glutamate subtype 5 receptors modulate locomotor activity and sensorimotor gating in rodents.

Use-dependent N-methyl-d-aspartate receptor (NMDAR) antagonists produce behaviors in human volunteers that resemble schizophrenia and exacerbate those behaviors in schizophrenic patients, suggesting that hypofunction of NMDAR-mediated neuronal circuitry may be involved in the etiology of clinical schizophrenia. Activation of the metabotropic glutamate receptor subtype 5 (mGluR5) enhances NMDAR-mediated currents in vitro. Thus, activation of mGluR5 could potentiate hypofunctional NMDARs in neuronal circuitry relevant to schizophrenia. To further elucidate the role of mGluR5, the present study examined the effects of mGluR5 antagonist administration, with and without coadministration of the use-dependent NMDAR antagonist phencyclidine (PCP), on locomotor activity and prepulse inhibition (PPI) of the acoustic startle response in rodents. We further examined PPI in mGluR5 knockout mice. Finally, we examined PPI after administration of the mGluR5 agonist 2-chloro-5-hydroxyphenylglycine (CHPG) alone and in combination with amphetamine. The data indicate that the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine has no effect on locomotor activity or PPI by itself but does potentiate both PCP-induced locomotor activity and disruption of PPI. We further found that mGluR5 knockout mice display consistent deficits in PPI relative to their wild-type controls. Finally, the data indicate that CHPG has no effect on PPI by itself, but ameliorates amphetamine-induced disruption of PPI. Collectively, these data suggest that mGlu5 receptors play a modulatory role on rodent PPI and locomotor behaviors and are consistent with the hypothesis that mGlu5 agonist/potentiators may represent a novel approach for antipsychotic drug development.

Marketing Drugs to Mend Minds

The Creation of Psychopharmacology . David Healy. Harvard University Press, Cambridge, MA, 2002. 479 pp. $39.95, £27.50, € 39.95. ISBN 0-674-00619-4 In this follow-up to his earlier The An-tidepressant Era , Healy offers a history of the discovery and development of antipsy-chotic drugs. He argues that financial as well as clinical pressures led to ever more aggressively marketed medications.

Schizophrenia: genesis, receptorology and current therapeutics.

Schizophrenia is a debilitating mental disease affecting approximately 1% of the population worldwide. Since the discovery of the first modern treatment for schizophrenia, chlorpromazine, in 1952 there have been many new structures investigated, only a small fraction of which have resulted in clinically useful drugs. Of these, haloperidol may be regarded as the drug for first line treatment. Since then, clozapine has emerged as the benchmark therapeutic ameliorating positive and negative symptoms and devoid of movement disorders, with its greatest feature being improvement of treatment-resistant patients. However, a major, potential lethal side-effect of clozapine is the induction of agranulocytosis, a blood disorder with unknown mechanism that results in lowered white-blood cell counts and consequent susceptibility to infections. In the 50 years of antipsychotic drug development, several novel theories have evolved that focus on receptor sub-types (serotonin 5-HTsub>2A, dopamine D(2) and D(4)) and the degree to which they need to be selectively attenuated by the drugs. Also of significance is the location of these receptors in the brain in relation to the disease state, the myriad of side-effects associated with antipsychotics and physicochemical properties of antipsychotic molecules relative to models of the drugs and the GPCR receptors involved. The techniques for investigation have shown increasing sophistication and refinement over this period, involving cloned receptors and PET scanning for determination of receptor location, density and binding, and rate constants at receptors. Knowledge of receptor structure, although in its infancy since no membrane bound CNS-receptor has yet been crystallized, is likely to benefit substantially with advances in computer-aided modelling. Overall, these new techniques have resulted in a number of novel antipsychotics such as risperidone, sertindole, olanzapine, seroquel, zotepine and ziprasidone, whose design, synthesis and testing has benefited enormously from the accumulated knowledge base of the past 50 years. In this review, we will provide a comprehensive update of the theories of action and clinical profiles of the latest drugs listed. The following appraisal of the literature will provide the practising medicinal chemist interested in this critical area of research with sufficient insight and understanding, to embark on productive investigations into the design and development of new therapeutic agents devoid of clinically limiting side-effects.

Treating schizophrenia now and developing strategies for the next decade.

This paper focuses on treatments for schizophrenia (SZ)--treatments we have now and those we hope to have in the future. The treatments we have are based on serendipity, but are effective nonetheless. Pharmacologic characteristics of the most-prescribed drugs are reviewed. It is apparent that a spectrum of effective drugs exist to support individualized therapy. With a view to future discovery, a strategy is proposed for rational antipsychotic drug development. A few concrete examples from the author's own laboratory illustrate an application of the proposal. These data would support the existence of a drug target in the anterior cingulate and/or hippocampal cortex. The studies suggest a focus on the limbic cortex for SZ pathophysiology. It would depend on future discovery to test whether this proposal will be productive. For sure, the rapid advance of basic neuroscience provides untold promise for the future

Development of novel antipsychotic drugs

The development of the current generation of antipsychotics has depended on animal, biochemical and pharmacological models of the action of drugs discovered serentipidously. They have focused on the dopamine hypothesis of schizophrenia. More recent studies of the structural abnormalities in schizophrenia, coupled with an understanding of the genetics and developmental biology of brain development, point to a new generation of novel medicines and therapies for patients with this disorder.

The discriminative stimulus properties of the atypical antipsychotic olanzapine in rats

Analysis of the preclinical behavioral effects of atypical antipsychotic agents will provide a better understanding of how they differ from typical antipsychotics and aid in the development of future atypical antipsychotic drugs. The present study was designed to provide information about the discriminative stimulus properties of the atypical antipsychotic olanzapine. Rats were trained to discriminate the atypical antipsychotic olanzapine (either 0.5 mg/kg OLZ or 0.25 mg/kg OLZ, i.p.) from vehicle in a twolever drug discrimination procedure. The atypical antipsychotic clozapine fully substituted for olanzapine in both the 0.5-mg/kg OLZ group (99.3% drug lever responding [DLR]) and the 0.25-mg/kg OLZ group (99.9% DLR). The typical antipsychotic chlorpromazine also substituted for olanzapine in both the 0.5-mg/kg OLZ group (87.5% DLR) and in the 0.25-mg/kg OLZ group (98.9% DLR); whereas, haloperidol displayed partial substitution for olanzapine in the 0.5-mg/kg OLZ group (56.1% DLR) and in the 0.25-mg/kg OLZ group (76.4% DLR). The 5.0-mg/kg dose of thioridazine produced olanzapine-appropriate responding in the 0.5-mg/kg OLZ group (99.6% DLR), but only partial substitution was seen with the 0.25-mg/kg OLZ training dose (64.0% DLR). The atypical antipsychotics raclopride (53.9% DLR) and risperidone (60.1% DLR) displayed only partial substitution in the 0.5-mg/kg OLZ group. Both the muscarinic cholinergic antagonist scopolamine (90.0% DLR) and the 5-HT2A/2C serotonergic antagonist ritanserin (86.0% DLR) fully substituted for olanzapine in the 0.5-mg/kg OLZ group. In contrast to previous discrimination studies with clozapine-trained rats, the typical antipsychotic agents chlorpromazine and thioridazine and the serotonin antagonist ritanserin substituted for olanzapine. These results demonstrate that there are differences in the mechanisms underlying the discriminative stimulus properties of clozapine and olanzapine. Specifically, olanzapine's discriminative stimulus properties appear to be meditated in part by both cholinergic and serotonergic mechanisms.

Methodological challenges in the clinical development of antipsychotic drugs

Correspondence to W. Wolfgang Fleischhacker, MD, Department of Biological Psychiatry, University of Innsbruck, Innsbruck, Austria Abbreviation EMEA: European Agency for the Evaluation of Medicinal Products

A history of antipsychotic drug development

The history of antipsychotic drug development has had a long and torturous course, often based on chance findings that bear little relationship to the intellectual background driving observations. In 1891, Paul Ehrlich observed the antimalarial effects of methylene blue, a phenothiazine derivative. Later, the phenothiazines were developed for their antihistaminergic properties. In 1951, Laborit and Huguenard administered the aliphatic phenothiazine, chlorpromazine, to patients for its potential anesthetic effects during surgery. Shortly thereafter, Hamon et al. and Delay et al. extended the use of this treatment in psychiatric patients and serendipitously uncovered its antipsychotic activity. Between 1954 and 1975, about 15 antipsychotic drugs were introduced in the United States and about 40 throughout the world. Thereafter, there was a hiatus in the development of antipsychotics until the introduction of clozapine treatment in the United States in 1990 opened the era of “atypical” antipsychotic drugs, which show a reduced potential to induce extrapyramidal symptoms (EPS), an increased efficacy for the negative symptoms of schizophrenia, no elevation of prolactin after chronic use (except risperidone), and, at least for clozapine, effectiveness in some patients previously regarded as treatment-refractory. This review describes the available atypical antipsychotic drugs and their characteristics, and concludes by highlighting those in the pharmaceutical “pipeline.”

Behavioral effects of chronic phencyclidine in monkeys.

Phencyclidine (PCP) and other NMDA receptor antagonists such as ketamine induce psychotic symptoms that are difficult to reverse with current medications and which closely resemble those of schizophrenia. This study investigated the behavioral effects of continuous PCP administration in six socially-housed Cebus apella monkeys. Chronic treatment was associated with a sustained decrease in stereotyped locomotion (pacing) and a sustained increase in scanning behavior. Treatment was also associated with a modest decrease in self- and environment-directed behavior and goal-directed locomotion and an increase in affiliative behavior at lower doses. Four animals had one or more episodes of extreme motoric and physiological responses precipitated by stressful events. The results indicate that behavioral effects of chronic PCP in primates differ from those seen following acute treatments and represent an appropriate model system for new antipsychotic drug development.

The role of positron emission tomography in the drug development of M100907, a putative antipsychotic with a novel mechanism of action.

Antipsychotic drug development has been a slow process since the discovery of chlorpromazine more than 45 years ago. Researchers identify a large number of potential compounds; screen them for antipsychotic activity in in vitro and animal test models; devise appropriate formulations; perform preclinical pharmacology, pharmacokinetic, and toxicology studies; perform healthy volunteer and then patient clinical studies; and finally negotiate with regulatory agencies for drug approval. In the United States, this process takes an average of 10 to 12 years and costs more than $500 million per approved drug. More recently, the pharmaceutical industry is benefiting from a new wave of technologic innovations that have advanced our understanding of the biology of disease processes and increased the efficiency of the research and development process. However, while these new technologies may appear to be expensive, by providing the basis for early go/no-go decisions, technologies such as PET can actually be cost-effective. To ensure that innovative drug research continues, a practical strategy (rational drug design) to evaluate drugs more efficiently in terms of both time and cost (fewer studies with fewer patients) must be developed for each new drug candidate. One of the most important and difficult steps in the drug development process is defining the dose-response relationship. Using M100907 as an example, we demonstrated that mechanism-based research promotes cost-effective drug development. The therapeutic index of M100907 was defined in phase I single- and multiple-dose tolerability studies. Nuclear imaging using PET technology was then used to confirm the mechanism of action of M100907 in the target organ (living human brain) and to target an appropriate dose range and regimen. With these data, clear go/no-go decision points could be established early within the clinical drug development process, and the selection of M100907 doses to carry forward into large-scale clinical trials in patients with schizophrenia could be narrowed.

The Role of Serotonin in Antipsychotic Drug Action

Recent interest in the role of serotonin (5-HT) in antipsychotic drug action is based mainly upon the fact that antipsychotic drugs such as clozapine, olanzapine, quetiapine, risperidone, sertindole, and ziprasidone are potent 5-HT2a receptor antagonists and relatively weaker dopamine D2 antagonists. These agents share in common low extrapyramidal side effects at clinically effective doses and possibly greater efficacy to reduce negative symptoms. As a group, they also have a superior effect on cognitive function and greater ability to treat mood symptoms in both patients with schizophrenia or affective disorders than typical antipsychotic drugs. The atypical antipsychotic agents vary in their affinities for other types of 5-HT as well as dopamine, muscarinic, adrenergic, and histaminic receptors, some, or all of which, may contribute to their differences in efficacy and side effect profile. Of the other 5-HT receptors which these drugs directly, the 5-HT1a and 5-HT2c receptors are the strongest candidates for contributing to their antipsychotic action and low EPS profile. The 5-HT6 and 5-HT7 receptors may also be of some importance. Stimulation of the 5-HT1a receptor appears to produce many of the same effects as antagonism of the 5-HT2a receptor while antagonism of the 5-HT2c receptor appears to diminish some of the actions of 5-HT2a receptor antagonism. Future antipsychotic drug development can include targeting multiple serotonin receptor subtypes.