Goldman S A
United States Food and Drug Administration, Rockville, Maryland, USA.
J Clin Pharmacol. 1996 Oct;36(10):951-62. doi: 10.1002/j.1552-4604.1996.tb04763.x.
Neurotoxicity in relation to concomitant administration of lithium and neuroleptic drugs, particularly haloperidol, has been an ongoing issue. This study examined whether use of lithium with neuroleptic drugs enhances neurotoxicity leading to permanent sequelae. The Spontaneous Reporting System database of the United States Food and Drug Administration and extant literature were reviewed for spectrum cases of lithium/neuroleptic neurotoxicity. Groups taking lithium alone (Li), lithium/haloperidol (LiHal) and lithium/ nonhaloperidol neuroleptics (LiNeuro), each paired for recovery and sequelae, were established for 237 cases. Statistical analyses included pairwise comparisons of lithium levels using the Wilcoxon Rank Sum procedure and logistic regression to analyze the relationship between independent variables and development of sequelae. The Li and Li-Neuro groups showed significant statistical differences in median lithium levels between recovery and sequelae pairs, whereas the LiHal pair did not differ significantly. Lithium level was associated with sequelae development overall and within the Li and LiNeuro groups; no such association was evident in the LiHal group. On multivariable logistic regression analysis, lithium level and taking lithium/haloperidol were significant factors in the development of sequelae, with multiple possibly confounding factors (e.g., age, sex) not statistically significant. Multivariable logistic regression analyses with neuroleptic dose as five discrete dose ranges or actual dose did not show an association between development of sequelae and dose. Database limitations notwithstanding, the lack of apparent impact of serum lithium level on the development of sequelae in patients treated with haloperidol contrasts notably with results in the Li and LiNeuro groups. These findings may suggest a possible effect of pharmacodynamic factors in lithium/neuroleptic combination therapy.
锂盐与抗精神病药物（尤其是氟哌啶醇）联合使用时的神经毒性一直是个持续存在的问题。本研究探讨了锂盐与抗精神病药物联合使用是否会增强神经毒性并导致永久性后遗症。对美国食品药品监督管理局的自发报告系统数据库和现有文献进行了回顾，以查找锂盐/抗精神病药物神经毒性的各类病例。针对237例病例，分别设立了单独服用锂盐（Li）组、锂盐/氟哌啶醇（LiHal）组和锂盐/非氟哌啶醇类抗精神病药物（LiNeuro）组，每组均按恢复情况和后遗症情况进行配对。统计分析包括使用Wilcoxon秩和检验对锂盐水平进行成对比较，以及使用逻辑回归分析自变量与后遗症发生之间的关系。Li组和Li - Neuro组在恢复组与后遗症组之间的锂盐水平中位数存在显著统计学差异，而LiHal组则无显著差异。总体而言，以及在Li组和LiNeuro组中，锂盐水平与后遗症的发生相关；在LiHal组中未发现此类关联。在多变量逻辑回归分析中，锂盐水平和服用锂盐/氟哌啶醇是后遗症发生的显著因素，而多个可能的混杂因素（如年龄、性别）无统计学意义。将抗精神病药物剂量分为五个离散剂量范围或实际剂量进行多变量逻辑回归分析，未显示后遗症发生与剂量之间存在关联。尽管数据库存在局限性，但血清锂盐水平对接受氟哌啶醇治疗患者后遗症发生缺乏明显影响，这与Li组和LiNeuro组的结果形成显著对比。这些发现可能提示在锂盐/抗精神病药物联合治疗中存在药效学因素的可能作用。
