Citation

Goldstein JM. Emerging Drugs 1999; 4: 127-151.

Copyright

(Copyright © 1999)

DOI

10.1517/14728214.4.1.127

PMID

unavailable

Abstract

Schizophrenia is the most serious of the mental illnesses, affecting more than 1% of the population. Typically, symptoms begin in early adulthood and too often are followed by a lifetime of interpersonal, social, and vocational dysfunction. A measure of the disorder's devastation is that over 10% of individuals with schizophrenia commit suicide. Given the age of onset and chronicity of the illness, schizophrenia presents a major public health challenge. In the US, the direct costs for care annually exceed US$65 bn and consume 2.5% of total healthcare expenditure. In the past two decades, new developments at the basic science, pharmaceutical and clinical levels have increased our understanding of schizophrenia and have resulted in improved, more targeted, pharmacotherapies. As a result, clinicians are no longer satisfied with symptom reduction but now strive for and are achieving improvements in function, quality of life, and patient satisfaction. Although many of the older, or so-called conventional, antipsychotics are effective and continue to play a role in patient care, their high association with extrapyramidal symptoms (EPS) and tardive dyskinesia (TD; abnormal, involuntary movements of the mouth, face, or extremities) has greatly interfered with their effectiveness. These disturbing and, at times, disfiguring adverse effects have been the driving force behind the thrust to develop effective and better tolerated antipsychotic medications. The introduction of the atypical antipsychotics has resulted in the availability of agents with improved safety and tolerability as well as a broader base of efficacy - drugs that better fit the parameters of an ideal antipsychotic (Table 1). Compounds have been sought that effectively block dopamine (D2) receptors in the mesolimbic and mesocortical tracts (a blockade associated with antipsychotic efficacy) while avoiding blocking D2 receptors in nigrostriatal pathways (a blockade that often results in EPS) and tuberoinfundibular pathways (a blockade that results in hyperprolactinaemia). This tailoring of receptor selectivity is the foundation for both the efficacy of atypical antipsychotics and their considerably lower incidence and severity of EPS, TD and hyperprolactinaemia. The disabling and, at times, disfiguring effects of EPS and TD have significantly hampered the optimal use of conventional agents. Therefore, above all other attributes, it is the low propensity to produce EPS and TD that distinguish the atypicals from the conventional antipsychotics. Collectively, these properties have lead to a change in the way antipsychotics are prescribed. The broad range of receptor affinities associated with the atypical antipsychotics and, in particular, their greater affinity for the serotonin (5-HT2) receptors relative to the D2 receptors in specific brain regions is believed to be at the heart of why these medications have fewer side-effects but a wider range of therapeutic benefits. There are currently four atypical antipsychotics in use: clozapine (Clozari(TM) [Novartis]), risperidone (Risperidal(TM) [Janssen]), olanzapine (Zyprexa(TM) [Eli Lilly]), and quetiapine (Seroquel(TM) [Zeneca]). This review will focus on the data from the controlled trials with these four agents and explore the evolving clinical experience as they are increasingly being prescribed. As clinicians learn more about these compounds, both similarities and differences have become apparent. For example, with respect to having minimal EPS and no elevation of prolactin, clozapine and quetiapine remain atypical independent of dose, whereas olanzapine and risperidone exhibit dose-dependent atypicality, becoming more like the conventional agents at the higher doses. These and other characteristics will be discussed. In addition, this review will cover the change in treatment perspectives as clinicians and patients have come to expect a reduced or almost negligible burden of EPS, and look toward functional improvements and increased tolerability as the target goals of therapy (Table 2). Increasingly, clinicians are intent on improving the quality of life of their patients while striving to limit the risks of long-term adverse effects, thereby maximising the possibilities for patients with schizophrenia to reintegrate into and become productive members of society. This change in attitude and goals, which has been made possible by the advent of the atypical antipsychotics, will be described, as will the search for new products to further improve the management of schizophrenia.

Language: en

Keywords

clozapine; dopamine 2 receptor; drug efficacy; drug safety; drug tolerability; extrapyramidal symptom; human; hyperprolactinemia; limbic system; neuroleptic agent; nigroneostriatal system; olanzapine; patient satisfaction; prolactin; quality of life; quetiapine; review; risperidal; schizophrenia; serotonin 2 receptor; tardive dyskinesia; unclassified drug