NORMENT, Centre, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
Schizophr Res. 2020 Apr;218:55-62. doi: 10.1016/j.schres.2020.03.006. Epub 2020 Mar 11.
One third of people diagnosed with schizophrenia fail to respond adequately to antipsychotic medication, resulting in persisting disabling symptoms, higher rates of hospitalization and higher costs for society. In an effort to better understand the mechanisms behind resistance to antipsychotic treatment in schizophrenia, we investigated its potential relationship to the genetic architecture of the disorder.
Patients diagnosed with a schizophrenia spectrum disorder (N = 321) were classified as either being treatment-resistant (N = 108) or non-treatment-resistant (N = 213) to antipsychotic medication using defined consensus criteria. A schizophrenia polygenic risk score based on genome-wide association studies (GWAS) was calculated for each patient and binary logistic regression was performed to investigate the association between polygenetic risk and treatment resistance. We adjusted for principal components, batch number, age and sex. Additional analyses were performed to investigate associations with demographic and clinical variables.
High levels of polygenic risk score for schizophrenia significantly predicted treatment resistance (p = 0.003). The positive predictive value of the model was 61.5% and the negative predictive value was 71.7%. The association was significant for one (p = 0.01) out of five tested SNP significance thresholds. Season of birth was able to predict treatment-resistance in the regression model (p = 0.05).
The study indicates that treatment-resistance to antipsychotic medication is associated with higher polygenetic risk of schizophrenia, suggesting a link between antipsychotics mechanism of action and the genetic underpinnings of the disorder.
三分之一被诊断为精神分裂症的患者对抗精神病药物治疗反应不足，导致持续存在致残症状、住院率更高，给社会带来更高的成本。为了更好地理解精神分裂症对抗精神病治疗产生耐药的机制，我们研究了它与该疾病遗传结构之间的潜在关系。
根据既定共识标准，将被诊断为精神分裂症谱系障碍的患者（N=321）分为抗精神病药物治疗耐药（N=108）或非耐药（N=213）。为每个患者计算基于全基因组关联研究（GWAS）的精神分裂症多基因风险评分，并进行二元逻辑回归分析，以调查多基因风险与治疗抵抗之间的关联。我们调整了主成分、批次号、年龄和性别。还进行了额外的分析，以调查与人口统计学和临床变量的关联。
高水平的精神分裂症多基因风险评分显著预测了治疗耐药性（p=0.003）。该模型的阳性预测值为 61.5%，阴性预测值为 71.7%。该关联在五个测试的 SNP 显著性阈值中的一个（p=0.01）上显著。出生季节能够预测回归模型中的治疗耐药性（p=0.05）。
该研究表明，抗精神病药物治疗的耐药性与更高的精神分裂症多基因风险相关，这表明抗精神病药物的作用机制与该疾病的遗传基础之间存在联系。
