Serotonin receptors : their key role in drugs to treat schizophrenia

Abstract

Serotonin (5-HT)-receptor-based mechanisms have been postulated to play a critical role in the action of the new generation of antipsychotic drugs (APDs) that are usually referred to as atypical APDs because of their ability to achieve an antipsychotic effect with lower rates of extrapyramidal side effects (EPS) compared to first-generation APDs such as haloperidol. Specifically, it has been proposed by Meltzer et al. [J. Pharmacol. Exp. Ther. 251 (1989) 238] that potent 5-HT_2A receptor antagonism together with weak dopamine (DA) D₂ receptor antagonism are the principal pharmacologic features that differentiate clozapine and other apparent atypical APDs from first-generation typical APD. This hypothesis is consistent with the atypical features of quetiapine, olanzapine, risperidone, and ziprasidone, which are the most common treatments for schizophrenia in the United States and many other countries, as well as a large number of compounds in various stages of development. Subsequent research showed that 5-HT_1A agonism may be an important consequence of 5-HT_2A antagonism and that substitution of 5-HT_1A agonism for 5-HT_2A antagonism may also produce an atypical APD drug when coupled with weak D₂ antagonism. Aripiprazole, the most recently introduced atypical APD, and a D₂ receptor partial agonist, may also owe some of its atypical properties to its net effect of weak D₂ antagonism, 5-HT_2A antagonism and 5-HT_1A agonism [Eur. J. Pharmacol. 441 (2002) 137]. By contrast, the alternative “fast-off” hypothesis of Kapur and Seeman [Am. J. Psychiatry 158 (2001) 360] applies only to clozapine and quetiapine and is inconsistent with the “slow” off rate of most atypical APDs, including olanzapine, risperidone and ziprasidone. 5-HT_2A and 5-HT_1A receptors located on glutamatergic pyramidal neurons in the cortex and hippocampus, 5-HT_2A receptors on the cell bodies of DA neurons in the ventral tegmentum and substantia nigra and GABAergic interneurons in the cortex and hippocampus, and 5-HT_1A receptors in the raphe nuclei are likely to be important sites of action of the atypical APDs. At the same time, evidence has accumulated for the important modulatory role of 5-HT_2C and 5-HT₆ receptors for some of the effects of some of the current APDs. Thus, 5-HT has joined DA as a critical target for developing effective APDs and led to the search for novel drugs with complex pharmacology, ending the exclusive search for single-receptor targets, e.g., the D₃ or D₄ receptor, and drugs that are selective for them.

Introduction

Interest in the role of serotonin (5-HT) in the mechanism of action of antipsychotic drugs (APDs) is the result, in large part, of the evidence that the superior efficacy and tolerability of the “atypical” APDs clozapine, quetiapine, olanzapine, risperidone, and ziprasidone for some aspects of schizophrenia may be due, in part, to their direct or indirect effects on various 5-HT receptors, especially 5-HT_2A and 5-HT_1A receptors Meltzer, 1999, Meltzer et al., 1989, Millan et al., 1998b, Millan et al., 1998c, Liégeois et al., 2002, Ichikawa and Meltzer, 1999, Carlsson, 1978, Gefvert et al., 1998, Lieberman, 1993, Maurel-Remy et al., 1995. Relatively potent blockade of 5-HT_2A receptors coupled to weaker antagonism of dopamine (DA) D₂ receptors has been found to be the only classical pharmacologic features those atypical APDs share in common Creese et al., 1976, Meltzer, 1999, Meltzer and Stahl, 1976, Kapur and Seeman, 2000, Reynolds, 1996. The atypical APDs related to clozapine, e.g., risperidone, olanzapine, quetiapine and ziprasidone, increase the release of DA in the prefrontal cortex and hippocampus. DA terminals synapse on the dendritic spines and shafts of pyramidal cells as well as on GABAergic inhibitory interneurons (Sesack et al., 1995). The effect of atypical APDs to release DA in the cortex and hippocampus may be critical to their ability to improve cognition and negative symptoms Meltzer and McGurk, 1999, Farde et al., 1988. As will be discussed, the so-called “5-HT_2A/D₂” model continues to be generative of novel APDs with efficacy for psychosis, cognitive dysfunction, and low extrapyramidal side effects (EPS). The purpose of this review is to consider the role of 5-HT in the efficacy and side effects of the novel antipsychotic agents and possible strategies for developing other antipsychotic agents that depend upon serotonergic function in ways that differ from those of clozapine.