Neuropharmacology of second-generation antipsychotic drugs: a validity of the serotonin–dopamine hypothesis

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Abstract

Newer atypical antipsychotic drugs such as risperidone, olanzapine, quetiapine, ziprasidone and aripiprazole that have been modelled on the prototype agent clozapine and developed since the 1990s are now referred to as second-generation antipsychotic drugs (SGAs). It has been proposed that the interaction between serotonin (5-HT) and dopamine systems may play a critical role in the mechanism of action of atypical antipsychotic drugs because a relatively potent blockade of 5-HT2A receptors coupled with the weaker antagonism of the dopamine D2 receptors is found to be the only pharmacological feature which most atypical antipsychotic drugs have in common. This so-called ‘serotonin–dopamine hypothesis’ has become a useful model for developing new SGAs to achieve superior antipsychotic efficacy with a lower incidence of extrapyramidal side effects compared to those with first-generation antipsychotic drugs (FGAs) such as haloperidol and chlorpromazine, although it has not been validated yet. In contrast, it has been proposed as the alternative ‘fast-off’ theory according to which atypical profile of SGAs can be determined by the loose D2-binding kinetics alone, while the blockade of the 5-HT2A receptor may be neither necessary nor sufficient. This chapter reviews the current issues on the serotonin–dopamine hypothesis together with further advances in research on the role of 5-HT receptor subtypes in the mechanism of action for SGAs. In particular, SGA-induced dopamine release in the prefrontal cortex, possibly through the functional activation of 5-HT1A receptors by 5-HT2A and D2 receptor-mediated interaction, has been thought to be the basis for the neurocognitive effects of these drugs on schizophrenia. Thus, the novel antipsychotic aripiprazole may not only be a simply partial D2 agonist but also a significant 5-HT1A agonist and 5-HT2A antagonist. These complex properties of antipsychotic aripiprazole may contribute to dopaminergic activation of the local circuitry in the prefrontal cortex of schizophrenic patients.

Introduction

Kane et al. (1988) demonstrated that the atypical antipsychotic clozapine was superior to the typical antipsychotic drugs such as haloperidol and chlorpromazine for improving both positive and negative symptoms of treatment-resistant schizophrenia while producing few incidences of extrapyramidal symptoms (EPS). Thereafter, the general use of clozapine was approved in the United States and many other countries, with the requirement of weekly blood monitoring because of its fatal side effect: agranulocytosis. Newer atypical antipsychotic drugs such as risperidone, olanzapine, quetiapine and ziprasidone that have been modelled on clozapine and developed since the 1990s are now referred to as second-generation antipsychotic drugs (SGAs) (Lohr and Braff, 2003). Today, SGAs, except for the prototype agent clozapine, are chosen for the first-line treatment of schizophrenia.

For the past two decades, neuropharmacological studies on SGAs have generally focused on the mechanism of action by which clozapine as well as SGAs can produce superior therapeutic efficacy. The serotonin–dopamine hypothesis was originally proposed by Meltzer (1989) and since then it has become a representative of the theories regarding the pharmacological basis of SGAs. Meltzer (1989) suggests that the interaction between serotonin (5-HT) and dopamine systems may play an important role in the mechanism of action of atypical antipsychotic drugs because the relatively potent blockade of 5-HT2A receptors coupled with the weaker antagonism of dopamine D2 receptors has been found to be the only pharmacological feature which most atypical antipsychotic drugs share (Meltzer et al., 1989). This hypothesis has become a useful model for developing new SGAs to achieve superior antipsychotic efficacy with a lower incidence of EPS compared to first-generation antipsychotic drugs (FGAs), formerly called typical antipsychotic drugs. However, since the latter half of the 1990s, some neuroimaging studies on in vivo occupancies of D2 and 5-HT2A receptors by SGAs in medicated patients have disputed the validity of the serotonin–dopamine hypothesis. Based on these findings, Kapur and Seeman (2001) argue the alternative hypothesis that the difference between typical and atypical antipsychotic drugs may be fully explained by the pharmacokinetics of their interaction with the D2 receptor alone. This ‘fast-off’ theory has provoked controversy about the role of 5-HT2A receptors in the mechanism of antipsychotic actions of SGAs.

The purpose of this review is to consider the current issues on the serotonin–dopamine hypothesis and the possible role of 5-HT receptor subtypes in the pharmacological basis for clinical effects of SGAs.

Section snippets

SGAs and the serotonin–dopamine hypothesis

Clozapine, a prototype of SGAs, is exactly ‘atypical’ with regard to the binding potency to D2 receptors, which is much weaker for clozapine than for typical antipsychotic drugs (Farde and Nordström, 1992; Seeman, 1995; Pilowsky et al., 1997). Based on the initial finding that clozapine rapidly induces down-regulation of 5-HT2A receptors in the rat cerebral cortex (Matsubara and Meltzer, 1989), Meltzer et al. (1989) examined in vitro binding potencies of a number of antipsychotic drugs to D1, D2

PET imaging of SGAs

Recent advances in neuroimaging have made it possible to investigate the receptor occupancy in vivo of antipsychotic drugs in medicated patients. Positron emission tomography (PET) studies using specific radioactive ligands to D2 receptors have demonstrated that for FGAs such as haloperidol, an almost 70% of D2 receptor blockade is the optimal level for antipsychotic response, and occupancies greater than 80% are associated with increased incidence of EPS (Farde and Nordström, 1992; Seeman, 1995

Controversy in the ‘fast-off’ theory

D2 receptor occupancy of quetiapine, even at doses of 450–600 mg/day, is not more than 30% 12 h after the last dose (Kapur et al., 2000; Gefvert et al., 2001). However, Kapur et al. (2000) demonstrate that quetiapine as well as clozapine show higher D2 occupancy (45–60%) within 2–3 h following its administration, subsequently declining rather rapidly. They consider that this phenomenon may be due to the loose binding property of these drugs to the D2 receptor. Therefore, the injected radioactive

5-HT1A receptors and prefrontal dopamine

Many SGAs have significant affinities not only for 5-HT2A receptors but also for other 5-HT receptor subtypes including 5-HT1A, 5-HT2C, 5-HT6 and 5-HT7 (Roth et al., 1992, Roth et al., 1994, Roth et al., 2004; Schotte et al., 1996). It is therefore possible that these 5-HT receptor subtypes may also be involved in the mechanisms of action of SGAs. Although physiological roles of the central 5-HT receptor subtypes have yet to be fully understood, the serotonin–dopamine interaction via 5-HT

Interactions with 5-HT2C, 5-HT6 and 5-HT7 receptors

Clozapine, olanzapine, ziprasidone and aripiprazole have comparable affinities (Ki<10 nM) for 5-HT2C receptors to 5-HT2A receptors, while affinities of quetiapine and risperidone for 5-HT2C receptors are lower than those for 5-HT2A receptors (Roth et al., 1992; Schotte et al., 1996; Shapiro et al., 2003). Roth et al. (1992) have suggested that a relatively higher binding potency of the 5-HT2C receptor could not differentiate typical and atypical antipsychotic drugs. It is therefore unlikely

Towards future research to elucidate the role of serotonin–dopamine interaction in SGAs

For the past two decades, drug discovery research has vigorously attempted to develop a novel antipsychotic drug modelled on clozapine. The serotonin–dopamine hypothesis is the most important landmark, and has contributed to the development of a number of SGAs. Nevertheless, to date, an antipsychotic drug having comparable or superior effects on treatment-resistant schizophrenia has yet to be found (Chakos et al., 2001; Davis et al., 2003; McEvoy et al., 2006). Many attempts have unexpectedly

Abbreviations

    EPS

    extrapyramidal symptoms

    FGAs

    first-generation antipsychotic drugs

    Ki

    dissociation constant

    SGAs

    second-generation antipsychotic drugs

    5-HT

    serotonin

    VTA

    ventral tegmental area

Acknowledgements

The authors acknowledge fruitful discussion with Junji Ichikawa, MD. The research reported here was supported in part by KAKENHI (17591219) and a grant from Otsuka Pharmaceuticals.

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