Servicio de Salud del Principado de Asturias (SESPA), Oviedo, Spain; Área de Psiquiatría, Universidad de Oviedo, Oviedo, Spain; Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain; Instituto de Neurociencias del Principado de Asturias (INEUROPA), Oviedo, Spain; Department of Psychiatry and Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK.
Department of Psychiatry and Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK.
Eur Neuropsychopharmacol. 2020 Apr;33:158-163. doi: 10.1016/j.euroneuro.2020.01.016. Epub 2020 Feb 10.
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.
先前的横断面研究发现，氯氮平与去甲氯氮平（CLZ：NDMC）的比值与氯氮平治疗的精神分裂症患者的认知能力呈负相关。然而，尚无研究使用受试者内设计来检查 CLZ：NDMC 比值与认知之间的关联。在这里，我们通过反复评估Brief Assessment of Cognition for Schizophrenia（BACS）来研究氯氮平负荷和 CLZ：NDMC 比值变化对认知的纵向影响，同时控制一系列独立因素。我们分析了 17 名氯氮平治疗患者的队列数据，这些患者已被反复评估。精神分裂症的临床总体印象量表（CGI-P）的阳性症状子量表用于评估精神病的严重程度。采集血样以测量氯氮平（CLZ）和去甲氯氮平的血浆水平，从而计算 CLZ：NDMC 比值。我们的分析包括双变量和偏相关分析，以及中介模型分析。我们发现，CLZ 和 CLZ：NDMC 的血浆水平均与认知表现呈负相关，并且这些关联独立于每日氯氮平剂量和精神病症状严重程度的变化。中介分析进一步表明，CLZ 浓度与认知之间的关联部分由 CLZ：NDMC 比值的变化介导。这是首次对 CLZ 浓度和 CLZ：NDMC 比值对认知影响的纵向分析。我们的研究结果表明，CLZ 浓度和 CLZ：NDMC 比值的降低可能有利于认知。因此，CLZ：NDMC 比值可能代表一种有前途的治疗策略，旨在改善氯氮平治疗的患者的认知障碍。
