Previous cross-sectional studies have found clozapine to N-desmethylclozapine (CLZ:NDMC) ratio to be negatively correlated with cognition in clozapine-treated patients with schizophrenia. However, no work has examined the association between CLZ:NDMC ratio and cognition using a within-subjects design. Here, we investigate the longitudinal effects of changes in the clozapine load and the CLZ:NDMC ratio on cognition whilst controlling for a range of independent factors. We analyzed data from a cohort of seventeen clozapine-treated patients who have been repeatedly assessed with the Brief Assessment of Cognition for Schizophrenia (BACS). The Positive symptoms sub-score of the Clinical Global Impression for Schizophrenia (CGI-P) was used to assess severity of psychosis. Blood samples were collected to measure the plasmatic levels of clozapine (CLZ) and of N-desmethylclozapine, allowing calculation of the CLZ:NDMC ratio. Our analyses included bivariate and partial correlations, along with a mediation model analysis. We found that both plasmatic levels of CLZ and the CLZ:NDMC ratio were negatively correlated with cognitive performance, and that these associations were independent of changes in both daily clozapine dose and severity of psychotic symptoms. Mediation analyses further revealed the association between CLZ concentration and cognition to be partially mediated by changes in the CLZ:NDMC ratio. This is the first longitudinal analysis of the influence of CLZ concentration and CLZ:NDMC ratio on cognition. Our findings suggest that reduction of CLZ concentration and the CLZ:NDMC ratio might favorably affect cognition. Thus, the CLZ:NDMC ratio may represent a promising target for novel therapeutic strategies aiming to ameliorate cognitive impairment in clozapine-treated patients.

中文翻译：

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氯氮平浓度和氯氮平与 N-去甲基氯氮平比例对认知的纵向影响：中介模型

先前的横断面研究发现，氯氮平与 N-去甲基氯氮平 (CLZ:NDMC) 的比率与接受氯氮平治疗的精神分裂症患者的认知能力呈负相关。然而，没有任何工作使用受试者内设计检查 CLZ:NDMC 比率与认知之间的关联。在这里，我们研究了氯氮平负荷和 CLZ:NDMC 比率变化对认知的纵向影响，同时控制了一系列独立因素。我们分析了一组 17 名接受氯氮平治疗的患者的数据，这些患者已通过精神分裂症认知简要评估 (BACS) 反复评估。精神分裂症临床总体印象 (CGI-P) 的阳性症状子评分用于评估精神病的严重程度。收集血样以测量氯氮平 (CLZ) 和 N-去甲基氯氮平的血浆水平，从而计算 CLZ:NDMC 比率。我们的分析包括双变量和偏相关，以及中介模型分析。我们发现 CLZ 的血浆水平和 CLZ:NDMC 比率均与认知能力呈负相关，并且这些关联与每日氯氮平剂量和精神病症状严重程度的变化无关。中介分析进一步揭示了 CLZ 浓度和认知之间的关联部分由 CLZ:NDMC 比率的变化介导。这是对 CLZ 浓度和 CLZ:NDMC 比率对认知的影响的第一次纵向分析。我们的研究结果表明 CLZ 浓度和 CLZ 的降低：NDMC 比率可能会有利地影响认知。因此，CLZ:NDMC 比率可能代表旨在改善氯氮平治疗患者认知障碍的新型治疗策略的有希望的目标。