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