Background

Treatment-resistant schizophrenia affects approximately 30% of individuals with the disorder. Clozapine is the medication of choice in treatment-resistant schizophrenia, but optimizing administration and dose titration is complex. The identification of factors influencing clozapine prescription and response, including genetics, is of interest in a precision psychiatry framework.

Methods

We used linear regression models accounting for demographic, pharmacological, and clinical covariates to determine whether a polygenic risk score (PRS) for schizophrenia would be associated with the highest dose recorded during clozapine treatment. Analyses were performed across 2 independent multiancestry samples of individuals from a UK patient monitoring system, CLOZUK2 (n = 3133) and CLOZUK3 (n = 909), and a European sample from a Norwegian therapeutic drug monitoring service (n = 417). In a secondary analysis merging both UK cohorts, logistic regression models were used to estimate the relationship between schizophrenia PRSs and clozapine doses classified as low, standard, or high.

Results

After controlling for relevant covariates, the schizophrenia PRS was correlated with the highest clozapine dose on record for each individual across all samples: CLOZUK2 (β = 12.22, SE = 3.78, p = .001), CLOZUK3 (β = 12.73, SE = 5.99, p = .034), and the Norwegian cohort (β = 46.45, SE = 18.83, p = .014). In a secondary analysis, the schizophrenia PRS was associated with taking clozapine doses >600 mg/day (odds ratio = 1.279, p = .006).

Conclusions

The schizophrenia PRS was associated with the highest clozapine dose prescribed for an individual in records from 3 independent samples, suggesting that the genetic liability for schizophrenia might index factors associated with therapeutic decisions in cohorts of patients with treatment-resistant schizophrenia.

中文翻译：

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使用精神分裂症多基因评分对氯氮平处方模式进行基因组分层

背景

难治性精神分裂症影响大约 30% 的患者。氯氮平是治疗难治性精神分裂症的首选药物，但优化给药和剂量滴定很复杂。确定影响氯氮平处方和反应的因素，包括遗传学，在精确精神病学框架中很有意义。

方法

我们使用考虑人口统计学、药理学和临床协变量的线性回归模型来确定精神分裂症的多基因风险评分 (PRS) 是否与氯氮平治疗期间记​​录的最高剂量相关。对来自英国患者监测系统 CLOZUK2 ( n  = 3133) 和 CLOZUK3 ( n  = 909) 以及来自挪威治疗药物监测服务的欧洲样本 ( n = 417)的 2 个独立多血统个体样本进行了分析 。在合并两个英国队列的二次分析中，使用逻辑回归模型来估计精神分裂症 PRS 与分类为低、标准或高的氯氮平剂量之间的关系。

结果

控制相关协变量后，精神分裂症 PRS 与所有样本中每个个体记录的最高氯氮平剂量相关：CLOZUK2（β = 12.22，SE = 3.78，p = .001），CLOZUK3（β = 12.73，SE = 5.99  ） , p  = .034) 和挪威队列 (β = 46.45, SE = 18.83, p  = .014)。在二次分析中，精神分裂症 PRS 与服用剂量 >600 毫克/天的氯氮平有关（比值比 = 1.279，p  = .006）。

结论

精神分裂症 PRS 与来自 3 个独立样本的记录中为个体开出的最高氯氮平剂量相关，这表明精神分裂症的遗传责任可能是与难治性精神分裂症患者队列中的治疗决策相关的指标。