The substituted benzamides and their clinical potential on dysthymia and on the negative symptoms of schizophrenia

Abstract

In this paper the historical and scientific background that led to the use of substituted benzamides in two apparently unrelated clinical conditions namely dysthymic disorder and schizophrenia will be reviewed, in order to understand if a common mechanism of action may support this dual therapeutic indication. The dopaminergic antidepressant action of substituted benzamides such as sulpiride, has been proposed, since the late 1970s, by several authors and extensively explored in preclinical experiments by our group. In Italy the first marketing authorization obtained for the new substituted benzamide amisulpride, was with the sole indication of dysthymia and therefore a solid clinical experience exists in the use of substituted benzamides in mild forms of depression, with more than 1 000 000 patients being treated in the last 7 years. The proposed mechanism of action of substituted benzamides implies a selective modulation of the dopaminergic system in the mesocorticolimbic area, important for cognitive processing of internal and external cues, related to survival. The selective antagonism of dopamine D2-D3 receptors has been evoked to explain, in small to moderate doses (ie 50-100 mg day −1 ), the antidepressant effect and, in moderate to medium doses (100-400 mg day −1 ), the reported efficacy on negative symptoms of schizophrenia. Thus, substituted benzamides could represent the first class of atypical antipsychotics successfully employed for both depressive states and schizophrenia. Interestingly, recent evidence in the literature suggests that depressive episodes belonging to the bipolar spectrum are among 'alternative indications' of other atypical antipsychotics such as olanzapine and risperidone.

Upregulation of CB1 receptors and agonist-stimulated [35S]GTPγS binding in the prefrontal cortex of depressed suicide victims

“…20 It has been suggested that the clinical signs of chronic cannabis consumption may resemble negative symptoms of schizophrenia. 39 Several common symptomatologies do exist between schizophrenia and mood disorders. From a neuopharmacological standpoint, the psychoses of schizophrenia and the mania of bipolar disorder can both be treated with antipsychotic drugs.…”

How Does the Benzamide Antipsychotic Amisulpride get into the Brain?—An In Vitro Approach Comparing Amisulpride with Clozapine

“…The predominant action of AMS in extrastriatal areas became especially obvious at low concentrations (Möller, 2001;Xiberas et al, 2001). Although it was speculated that at these low dosages mainly D 3 autoreceptors in cortical areas were antagonized Pani and Gessa, 2002), the reason for the limbic selectivity of AMS remains unclear. Like its predecessor, sulpiride, it reveals some physicochemical peculiarities.…”

“…Striatal dopamine D 2 receptor occupancy in man was recently assessed by positron emission tomography (PET) (Martinot et al, 1996, Xiberas et al, 2001. It should be emphasized here that the striatum might be not the best region to elucidate the therapeutic action of AMS, which is suggested to be more active in extrastriatal areas Schoemaker et al, 1997;Pani and Gessa, 2002). This was corroborated by the study of Xiberas et al (2001), who revealed an accelerated occupancy of dopamine receptors in the extrastriatal compared with striatal areas at relatively low serum concentrations of AMS.…”

The pharmacogenomics of depression

“…Therefore, it is likely that their rapid effects on monoamines may not be the direct cause of the clinical effects of antidepressants. Moreover, antidepressants of various classes, affecting serotonin, norepinephrine, or dopamine 7,8 have a common clinical effect. It has been hypothesized that the efficacy of the effects of various types of antidepressants after chronic treatment is due to their effects on new genomic targets.…”