Dopamine D2 receptors and their role in atypical antipsychotic action: still necessary and may even be sufficient
Introduction
It is an interesting irony that in the treatment of schizophrenia, the most commonly used medications are called “atypical.” This terminology probably reflects that fact that we know much more about what differentiates these drugs from the “typical” antipsychotics, rather than what unites this class of drugs. This article is not presented as a comprehensive synthesis of all views regarding atypicals but expands on one competing idea of what makes antipsychotics “atypical” Kapur and Remington 2001, Kapur and Seeman 2001. Competing perspectives on this issue are defended elsewhere (Meltzer 1999), and the reader is referred to more comprehensive reviews Arnt and Skarsfeldt 1998, Arnt et al 1997. Although we do not review all perspectives in detail, we do point out how our ideas differ from them. Furthermore, it is not the intent of this article to examine the differences between atypicals, although there may be significant differences between drugs within the class of “atypical.”
The article is presented in four sections. In the first section, we review the clinical feature that most reliably distinguishes the atypical antipsychotics from typical antipsychotics. In the second section, we examine the molecular pharmacologic features of these drugs in preclinical models and the different hypotheses that have been forwarded to explain atypicality. In the context of these findings, we review the receptor imaging studies of typical and atypical antipsychotics. Finally, we provide a heuristic model that tries to unite current understanding regarding the pathophysiology of schizophrenia to the mechanism of action of atypical antipsychotics.
Section snippets
Atypical antipsychotics—distinguishing clinical features
The current use of the term atypical antipsychotics can be traced to the earliest preclinical studies with clozapine, in which it was distinguished from the other typical antipsychotics of that era by not inducing catalepsy in animal models or extrapyramidal side effects (EPS) in patients (Hippius 1989). As clinical trials with clozapine mounted, other unique clinical features were proposed, including efficacy in patients refractory to “typical” antipsychotics (Kane et al 1988) and increased
Atypical antipsychotics: what is atypical about their molecular pharmacology?
Given that all antipsychotics, typical as well as atypical, block dopamine D2 receptors Creese et al 1976, Kapur and Seeman 2001, Seeman et al 1975, Seeman and Lee 1975, it is reasonable to expect that differences between typical and atypical antipsychotics arise from some non-D2-receptor activity. Various candidates have been proposed: 5-HT2(Meltzer et al 1989a), D4(Van Tol et al 1991), glutamate Olney and Farber 1994, Olney and Farber 1995, alpha adrenergic receptors (Svensson et al 1995),
Studies of typical antipsychotics
The advent of neuroimaging has made it possible to investigate the receptor occupancy of antipsychotics in patients while they are treated. The usefulness of this was first demonstrated by Farde et al (1988), who showed that most antipsychotics, with the exception of clozapine, showed high (70% and above) D2 occupancy at usual clinical doses. The data also suggest that those who experienced EPS had higher levels of D2 occupancy (Farde et al 1992). This suggestion has been replicated in several
What makes an antipsychotic “atypical”? a short summary
We propose that at present the definition of atypicality should read something like this: a drug that improves the psychotic/positive and negative symptoms of schizophrenia, with minimal or no EPS, and with minimal or no sustained prolactin elevation. The enhanced efficacy on positive and negative symptoms is not a universally achieved attribute among atypicals.
What then leads to an atypical antipsychotic? We propose that a blockade of dopamine D2 receptors with a drug that shows a relatively
Linking pathophysiology and therapeutics: a heuristic model
To help integrate the foregoing ideas about antipsychotics with the current ideas about the etiology and pathophysiology of schizophrenia, we provide a simple model illustrated in Figure 1. This is a heuristically useful, rather than an empirically verified, model but has the virtue of integrating etiopathogenesis, phenomenology, and therapeutics. Although the etiology of schizophrenia is unknown, a number of genes and environmental factors are likely to be implicated—to differing degrees in
Acknowledgements
The authors thank their colleagues, particularly Dr. Robert Zipursky and Dr. Phil Seeman, who have been helpful in the development of some of the ideas presented here. SK is supported by Canada Research Chair and by research grants from the CIHR of Canada.
Aspects of this work were presented at the conference, “New Perspectives on the Neurobiology of Schizophrenia and the Role of Atypical Antipsychotics,” held November 10–12, 2000, in Key West, Florida. The conference was sponsored by the
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