Neuropsychiatric Hospital Dr. Ivan Barbot, Popovaca, Croatia.
Psychiatr Danub. 2010 Mar;22(1):112-6.
Malignant neuroleptic syndrome (MNS) is a serious and potentially fatal side-effect of neuroleptic treatment. Beside antipsychotic drugs, other psychotropic drugs such as antidepressants and lithium carbonate can cause this life threatening side-effect. Underlying mechanism of this side-effect is still unknown and debated. So far some risk factors have been identified, with clinical observations and recent pharmacogenetic research suggesting (with inconsistent findings) correlation between genetic mechanisms and predisposition to MNS. Polymorphisms of CYP2D6 enzyme through which most psychotropic drugs are metabolized and TaqIA DRD2 which is target for antipsychotic drugs could be the link between pharmacogenetic factors and potential for development of MNS. In this paper we present two case reports with clinical presentation of three consecutive MNS. One patient developed MNS while he was taking combination of drugs: first time haloperidol, promazine and fluphenazine, second time fluphenazine and perazine and third time clozapine, promazine and valproic acid consecutively. The other patient developed MNS while taking following combination of drugs: first time haloperidol and lithium carbonate, second time risperidone and third time clozapine consecutively. Pharmacogenetic analysis for CYP2D6 and TaqI A DRD2 polymorphisms for both patients was done. Genotypisation of CYP2D613456 in both patients showed no evidence of poor metabolizer phenotype. On the other hand, first patient was heterozygous for CYP2D64 (genotype *1/*4). CYP2D6 polymorphisms could have clinical significance because may lead to toxicity and unwanted side-effects in standard usual antipsychotic dose ranges. Analysis Taql A DRD2 polymorphism for first patient showed that he is heterozygous for A1 allele (genotype A1A2) which is commonly associated with predisposition to MNS. According to our literature three consecutive MNS are rarely described, and incidence of MNS generally is too low to perform clinical research. Many patophysiological mechanisms may probably underlie this complex and potentially fatal syndrome, still unknown etiology. But, genetic mechanisms could be significant. Further pharmacogenetic research, findings and analysis in patients who develop single or repeated MNS are strongly recommended. In long term, pharmacogenetic analysis, implemented in daily clinical practice, could help in prevention of this extremely serious side-effect.
恶性神经阻滞剂综合征（MNS）是一种严重且潜在致命的神经阻滞剂治疗副作用。除了抗精神病药物外，其他精神药物，如抗抑郁药和碳酸锂，也可能导致这种危及生命的副作用。这种副作用的潜在机制仍不清楚，目前存在争议。到目前为止，已经确定了一些危险因素，临床观察和最近的药物遗传学研究表明（发现结果不一致），遗传机制与 MNS 的易感性之间存在相关性。大多数精神药物通过细胞色素 P450 2D6 酶代谢，而 TaqIA DRD2 是抗精神病药物的靶点，这种酶和靶点可能是药物遗传学因素与 MNS 发展潜力之间的联系。本文介绍了两例连续三次出现 MNS 的临床病例报告。一名患者在服用氟哌啶醇、丙嗪和氟奋乃静、氟奋乃静和培嗪以及氯氮平、丙嗪和丙戊酸的组合药物时出现 MNS。另一名患者在服用氟哌啶醇和碳酸锂、利培酮和氯氮平的组合药物时出现 MNS。对两名患者的细胞色素 P450 2D6 和 TaqI A DRD2 多态性进行了药物遗传学分析。对两名患者的 CYP2D613456 进行基因分型，未发现表现不佳的代谢表型。另一方面，第一名患者为 CYP2D64（基因型*1/*4）杂合子。CYP2D6 多态性可能具有临床意义，因为它可能导致标准常用抗精神病药物剂量范围内的毒性和不良反应。对第一名患者的 Taql A DRD2 多态性分析表明，他是 A1 等位基因（基因型 A1A2）的杂合子，这通常与 MNS 的易感性有关。根据我们的文献，连续三次出现 MNS 的情况很少见，而且 MNS 的发病率通常太低，无法进行临床研究。许多病理生理机制可能是这种复杂且潜在致命综合征的基础，其病因仍不清楚。但是，遗传机制可能很重要。建议对出现单次或多次 MNS 的患者进行进一步的药物遗传学研究、发现和分析。从长远来看，在日常临床实践中实施药物遗传学分析，可以帮助预防这种极其严重的副作用。
