Pani L, Gessa G L
Center for Neuropharmacology, National Research Council, Neuroscienze Scarl, via Porcell 4, 09124-I Cagliari, Italy.
Mol Psychiatry. 2002;7(3):247-53. doi: 10.1038/sj.mp.4001040.
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.
本文将回顾促使在两种明显不相关的临床病症即心境恶劣障碍和精神分裂症中使用取代苯甲酰胺的历史和科学背景，以了解是否存在共同的作用机制来支持这一双重治疗指征。自20世纪70年代末以来，已有多位作者提出取代苯甲酰胺（如舒必利）具有多巴胺能抗抑郁作用，并且我们小组在临床前实验中对其进行了广泛研究。在意大利，新型取代苯甲酰胺阿立哌唑获得的首个上市许可仅用于治疗心境恶劣，因此在使用取代苯甲酰胺治疗轻度抑郁症方面已有丰富的临床经验，在过去7年中已有超过100万患者接受治疗。取代苯甲酰胺的作用机制推测是对中脑皮质边缘系统区域的多巴胺能系统进行选择性调节，该区域对与生存相关的内外部线索的认知加工很重要。有人提出，小至中等剂量（即50 - 100毫克/天）时，多巴胺D2 - D3受体的选择性拮抗作用可解释其抗抑郁作用，而在中等至大剂量（100 - 400毫克/天）时，可解释其对精神分裂症阴性症状的疗效。因此，取代苯甲酰胺可能是第一类成功用于治疗抑郁状态和精神分裂症的非典型抗精神病药物。有趣的是，文献中的最新证据表明，属于双相谱系的抑郁发作是其他非典型抗精神病药物（如奥氮平和利培酮）的“替代指征”之一。
