Amisulpride: limbic specificity and the mechanism of antipsychotic atypicality

Abstract

Amisulpride clearly has the clinical profile of an atypical antipsychotic, characterised in particular by its lower propensity to induce extrapyramidal side effects as well as its greater efficacy in treating negative symptoms compared with classical neuroleptics. In addition to the clinical advantages over classical neuroleptics, it has also been demonstrated that the clinical profile of amisulpride is comparable to that of other modern atypical neuroleptics. Animal data also allow the conclusion to be drawn that amisulpride has an atypical profile. For example, amisulpride does not provoke catalepsy which is characteristic of postsynaptic D₂ blockade in the rat. The induction of catalepsy in animal models is usually seen as an indicator of the propensity to induce extrapyramidal side effects in patients. In relation to the widely accepted hypothesis that the inclusion of 5-HT_2A antagonism in addition to D₂ antagonism is of great relevance for the atypicality of an antipsychotic, and given the fact that amisulpride lacks 5-HT_2A antagonism, the pharmacological explanation of the clinically well-proven atypicality of amisulpride is of great interest. Based on basic research and in vivo imaging studies, two mechanisms in particular seem to explain the atypicality of amisulpride: preferential action on limbic D₂/D₃ receptors and preferential blockade of presynaptic D₂/D₃ receptors. In addition, the fast dissociation hypothesis can contribute to the explanation of the atypical clinical profile of amisulpride. The relevance of the D₃ blockade in the context of atypicality is not yet completely clear.

Introduction

Amisulpride clearly has the clinical profile of an atypical antipsychotic, characterised in particular by its lower propensity to induce extrapyramidal side effects as well as its greater efficacy in treating negative symptoms compared to classical neuroleptics, particularly haloperidol which was used as the comparative substance in most studies. These advantages have been well established by several controlled clinical trials Möller, 2001, Möller et al., 1997, Curran and Perry, 2001, Puech et al., 1998. In addition to the clinical advantages over classical neuroleptics, it has also been demonstrated that the clinical profile of amisulpride, as far as efficacy on positive as well as negative symptoms and extrapyramidal tolerability in acute schizophrenia is concerned, is comparable to that of other modern atypical neuroleptics of the class of D₂/5-HT_2A antagonists such as risperidone or multiple receptor antagonists like olanzapine Peuskens et al., 1999, Martin et al., 2002, Rein and Fleurot, 2002. The atypical profile of amisulpride in comparison to that of both classical neuroleptics and atypical antipsychotics has been confirmed by a meta-analysis, which included all available data from clinical trials on modern antipsychotics (Leucht et al., 2002). In addition and in contrast to other newer antipsychotics, amisulpride also showed clinical efficacy in chronic schizophrenic patients with predominant persistent negative symptoms Loo et al., 1997, Danion et al., 1999.

In the definition of atypicality of antipsychotics, some experts include not only the criteria of no or a lower risk of inducing extrapyramidal side effects and better improvement of negative symptoms; but also efficacy in schizophrenic patients refractory to treatment with classical neuroleptics, and/or lack of drug-induced hyperprolactinaemia. However, this amplification of the definition for an atypical neuroleptic can be seen critically as it results in a rigorous definition that is too extreme and that can possibly only be fulfilled by very few modern neuroleptics, if any at all (Möller, 2000). As to efficacy in treatment-refractory schizophrenics, no strong data are available for amisulpride. With respect to hyperprolactinaemia, amisulpride induces high levels of prolactin (Wetzel et al., 1994), a phenomenon that will be discussed later in the context of its pharmacological background.

The amelioration of cognitive disturbances (which are seen as a core symptom of schizophrenic patients), as well as the improvement of affective symptoms (which are often associated with schizophrenia), may also be produced by atypical neuroleptics. As to the ameriolation of cognitive disturbances, there are few data for amisulpride but appropriate studies are ongoing. So far, it can only be stated that results from early studies in healthy volunteers and schizophrenic patients indicate that amisulpride exhibits no significant or only minimal detrimental effects in psychometric and memory tests, in contrast to classical neuroleptics such as haloperidol Rosenzweig et al., 2002, Adler et al., 2000. Concerning affective symptoms, the available data show that amisulpride is superior to haloperidol and at least equal to risperidone in reducing depressive symptoms Wetzel et al., 1998, Peuskens et al., 2001.

Animal data also allow the conclusion to be drawn that amisulpride has an atypical profile Curran and Perry, 2001, Perrault et al., 1997. For example, amisulpride does not provoke catalepsy in the rat, which is characteristic of postsynaptic D₂ blockade, even at high doses (Perrault et al., 1997). The provocation of catalepsy in animal models is usually seen as indicator for the propensity to induce extrapyramidal side effects in patients.

Under the widely accepted hypothesis that the inclusion of 5-HT_2A antagonism in addition to the D₂ antagonism is of great relevance for the atypicality of an antipsychotic Meltzer, 1995, Möller, 2000, and given the fact that amisulpride lacks 5-HT_2A antagonism, the pharmacological explanation of the clinically well-proven atypicality of amisulpride is of great interest and is the topic of this paper.