Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Md, USA
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Carol A. Tamminga, Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Md, USA ;
* E-mail: ude.dnalyramu.crpm@gnimmatc
Copyright : © 2000 LLS
This is an open-access article distributed under the terms of the Creative Commons Attribution License [//creativecommons.org/licenses/by-nc-nd/3.0/], which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
The first generation of antipsychotic drugs was discovered in the 1960s and 1970s, These agents were effective in treating psychosis, but were accompanied by significant side effects, including severe parkinsonism and akathisia. Second-generation antipsychotics were introduced in the 1990s, These drugs have at least equal efficacy to their predecessors, but far fewer side effects. Some data suggest a broader efficacy profile. Clozapine remains the only superior antipsychotic in terms of the magnitude of psychotic symptom reduction. Clinical and animal studies are consistent in suggesting that the antipsychotic component of antidopaminergic treatments is initiated by dopamine receptor blockade in the striatum and that the signal is transmitted to the neocortex through the established basal ganglia-thalamo-cortical neuronal circuits. Other neurotransmitter actions [eg, antiserotonergic] can be exerted locally, in the neocortex. Defining tissue targets of drug action may suggest additional strategies for developing new antipsychotic drugs.
Keywords: schizophrenia, therapeutics, basal ganglia, thalamus, new antipsychotic drug, dopamine receptor
Abstract
La primera generación de fármacos antipsicóticos se descubrió en los años '60 y '70. Estos agentes fueron efectivos para el tratamiento de la psicosis, pero se acompañaron de significativos efectos laterales, que incluyeron parkinsonismo severo y acatisia, La segunda generación de antipsicóticos se introdujo en los '90, Estos fármacos son tan efectivos como sus predecesores, pero con mucho menos efectos secundarios. Algunos datos sugieren un perfil de eficacia mayor. La clozapina se mantiene como el único antipsicótico superior, en términos de la magnitud de la reducción de los síntomas psicóticos. Tanto estudios clínicos como en animales son consistentes al sugerir que el componente antipsicótico de los tratamientos antidopaminérgicos se inicia por el bloqueo del receptor de dopamina en el estriado y que la señal se transmite al neocórtex a través del circuito neuronal ganglio basal-tálamo-cortical. Las acciones sobre otros neurotransmisores [ej. antiserotoninérgica] se pueden ejercer localmente en el neocórtex. El definir tejidos blanco para la acción de fármacos puede sugerir estrategias adicionales para el desarrollo de nuevos fármacos antipsicóticos.
Résumé
La première génération de médicaments antipsychotiques a été découverte dans les années 60 et 70, Ces produits étaient efficaces dans le traitement des psychoses mais leurs effets secondaires, dont un syndrome extra-pyrimidal sévère et une akathisie, étaient importants. Les antipsychotiques de seconde génération sont apparus dans les années 90. D'efficacité comparable aux précédents, leurs effets indésirables se sont révélés bien moins importants. Certaines données ont suggéré un profil d'efficacité plus large, La clozapine est le seul à induire une réduction plus importante des symptômes psychotiques. Les études cliniques et chez l'animal se rejoignent sur l'origine probable de la composante antipsychotique des traitements antidopaminergiques: blocage des récepteurs dopaminergiques dans le striatum et transmission du signal au néocortex au travers des circuits neuronaux cortico-thalamoganglions de la base. D'autres actions neurotransmettrices [antisérotoninergiques par exemple] peuvent s'exercer localement dans le néocortex, La définition de nouvelles cibles tissulaires pour l'action médicamenteuse pourrait constituer d'autres stratégies de développement des nouvelles molécules antipsychotiques.
Several different classes of antipsychotic medications have been reliably shown to reduce active psychotic symptoms in schizophrenia and other psychoses1; all these drugs block the D2 family of dopamine receptors. Unfortunately, the drug action is accompanied by side effects, which have inevitably limited their use. The first antipsychotic drug, chlorpromazin, was discovered serendipitously by Delay and Deniker,2 who were testing preanesthetic agents in schizophrenia for their “calming” action. Shortly after their discovery, a mechanism of action was proposed,3 and subsequently many similar drugs were synthesized and marketed; these are called traditional or first-generation antipsychotics. Between 1975 and 1990, almost no new drug discovery occurred in schizophrenia. Then, in the 1990s, a second generation of antipsychotic drugs was developed - drugs with at least the same, possibly greater, antipsychotic action, but with significantly reduced motor side effects.4 The loss of motor side effects has produced a generation of medications far better tolerated by psychotic patients, and thus critically improving compliance. These secondgeneration drugs still possess the ability to block the D2 family of dopamine receptors, but have broader receptor affinity profiles, particularly affinity at the serotonin-2 [5 -hydroxy tryptamine-2 [5-HT2]] receptors.
The mechanism of the antipsychotic action of these drug families certainly involves blockade of the D2 dopamine receptor. However, the mechanism whereby the brain translates this primary antidopaminergic action into a reduction in psychosis remains unclear. Moreover, the additional new “ingredients” of action in the secondgeneration drugs also remain obscure, although 5-HT2 receptor antagonism has been often invoked.5 Recently, new technologies have been applied to human brain research to address these important questions, and the results have been supplemented by data from new directions in animal pharmacology.
This paper will review the new antipsychotic agents, and then propose an overall mechanism of antipsychotic action. This “working” hypothesis of antipsychotic drug action is itself testable using contemporary techniques of human brain imaging.
Drug actions and side effects: traditional and new drugs
The first antipsychotic to be discovered and developed was chlorpromazine. Very soon after the initial reports of its selective antipsychotic action, it was tested and applied around the world in psychotic patients.1 The drug was responsible for “emptying out” mental hospitals worldwide. Today's clinicians may underappreciate the potency of chlorpromazine in those neurolepticnaive individuals: the average symptom diminution was 80% or more. Although a potent antipsychotic, the drug has significant motor, sedative, and cardiovascular side effects; consequently, its use in schizophrenia has gradually diminished over the years.
After chlorpromazine, dozens of antipsychotics were developed. All were characterized by dopamine receptor blockade and catalepsy [in rats] or parkinsonism [in humans]. Gradually, the compounds became purer dopamine receptor antagonists, without other monoaminergic, cholinergic, or histaminergic blockade. Haloperidol is a typical example of these newer agents, which still acted predominantly via D2 dopamine receptor blockade. It was introduced in the 1960s, and soon became the most widely used antipsychotic drug. Haloperidol had the same antipsychotic potency as chlorpromazine, but lacked several of its more significant side effects, including cardiovascular side effects, and much of its sedative effect.
The efficacy of haloperidol was established in controlled trials in the 1960s, and it was used by clinicians thereafter over a wide dose range, often up to hundreds of milligrams per day. Pharmacokinetic studies suggested that its active antipsychotic dose range was 4 to 16 mg/day/6 However, a random assignment dose-response trial with haloperidol was not carried out until the early 1990s. This dose-response study compared doses of 0, 4, 8, and 16 mg/day.7 The results showed a significant difference only between placebo and the 8 mg/day and 16 mg/day doses, but no differences between any of the doses either statistically or in overall magnitude of response. None of the items of the Brief Psychiatric Rating Scale [BPRS] had a linear dose-response relationship, not even the positive symptom scores. Moreover, parkinsonism and akafhisia were significantly present with the 4 mg/day dose, and remained at a maximal score at all higher dose levels. These results demonstrate that haloperidol is a potent antipsychotic and has significant motor side effects, even at its lowest threshold of antipsychotic dose [4 mg/day]. Clozapine was the first of the “new” antipsychotics, even though it was not new at all at the time of its introduction to the US market. It was marketed in Europe in the 1970s, and its widespread European inpatient use allowed the detection of its most serious side effect, agranulocytosis. The clinical use of clozapine led to the hypothesis that it was a superior antipsychotic, which was tested by Kane et al in a controlled trial.8 Their initial study, carried out in fully treatment-resistant schizophrenic individuals, was followed up by a clozapine vs haloperidol comparison in schizophrenic “partial” responders. In both studies, the data show that clozapine has a significantly greater antipsychotic action than chlorpromazine or haloperidol in schizophrenic individuals. Clozapine remains the only antipsychotic whose efficacy has been demonstrated to be superior to other agents in the antipsychotic class.
Unfortunately, in addition to the serious side effect of agranulocytosis [which can be successfully managed by weekly plasma monitoring], clozapine also has a diverse array of additional side effects, some of which are serious, others merely bothersome. These include tachycardia, hypotension, sedation, seizures, akathisia, drooling, and significant weight gain. The disincentives to clinical use produced by these many side effects are significant, but the drug is still used around the world, indicating its superior efficacy. Most psychiatrists would agree that clozapine is underutilized in the US, given its superior antipsychotic efficacy.
Four new antipsychotics have since followed clozapine to market. With these, there has been an attempt to reduce motor side effects and increase treatment efficacy. To some extent, this has been achieved with the new antipsychotics; most prominently, they lack motor side effects. The approval of the new compounds by the US Food and Drug Administration [FDA] [first risperidone, then olanzapine, quetiapine, and finally ziprasidone] fails to recognize the significant number of drugs that nearly reached general approval, but failed for safety or efficacy reasons. This list includes drugs like remoxipridc, which caused aplastic anemia; sertindole, which prolongs the QT interval on the electrocardiogram; and Ml 00907, which failed because of reduced efficacy. These failures illustrate some of the risks involved in developing a successful antipsychotic. The difficulty in the development of drugs for schizophrenia is primarily due to the lack of a pathophysiologic understanding of the illness and, consequently, the lack of a known drug target. Animal testing to help focus drug candidate choices is not usually helpful because of the obvious difficulties in modeling psychosis. Nonetheless, it is an area of the highest medical need and, for that reason, pharmaceutical companies continue to invest in antipsychotic drug development. It is fortunate that each new drug candidate introduced to the market to date has provided additional advances in patient response and has been widely used.
Risperidone, the first drug to market after clozapine, is predominantly a D2 dopamine receptor antagonist and a 5-HT2 receptor antagonist at clinical doses. It was shown to be effective against placebo with an antipsychotic response comparable to that of haloperidol. In several studies, greater efficacy is apparent at a lower dose [