Thümmler Susanne, Dor Emmanuelle, David Renaud, Leali Graziella, Battista Michele, David Alexia, Askenazy Florence, Verstuyft Céline
University Department of Child and Adolescent Psychiatry, Children's Hospitals of Nice CHU-Lenval, Nice, France.
CoBTek, Université Côte d'Azur, Nice, France.
Front Psychiatry. 2018 Jan 24;9:2. doi: 10.3389/fpsyt.2018.00002. eCollection 2018.
Severe mental health disorders in children and adolescents represent a major public health problem. Despite adequate drug treatment, some patients develop pharmacoresistant disease. As a consequence, physicians are confronted with prescribing challenges, prolonged hospitalization and increased risk of adverse events, thus aggravating short-, medium-, and long-term prognosis. The majority of psychotropic treatments, particularly antipsychotics and antidepressants, are metabolized at hepatic level by cytochrome P450 (CYP), particularly by CYP3A4 and CYP2D6. Several genetic polymorphisms are described to be associated with ultrarapid (UM) or poor drug metabolism (PM), inducing clinical resistance and/or adverse events, and might therefore be related to pharmacoresistant severe mental health disease.
A total of nine pharmacoresistant patients (four females, five males) aged 11-16 (mean 14.1) years have been genotyped for between January, 2015 and April, 2016. Patients were diagnosed with schizophrenia ( = 5), autism spectrum disorders ( = 2), intellectual disability with challenging behavior ( = 2), oppositional defiant disorder ( = 1), and post-traumatic stress and borderline personality disorders ( = 1). They had a treatment history with on average 6.1 (3-9) psychotropic, 5 (3-7) antipsychotic, and 3.4 (2-5) CYP2D6-metabolized antipsychotic and antidepressant molecules. Five patients (56%) presented functional anomalies of the gene: three patients were UM metabolizers with gene duplication and two patients were PM with *4/*41 and *3/*4 polymorphisms.
Functional anomalies of concerned more than half of our pediatric inpatient sample with pharmacoresistant disease. However, our case reports are limited by the low sample size. Nevertheless, knowledge of individual metabolism and in particular genotyping should be considered for clinical workup and therapy adjustment in resistant patients in child and adolescent psychiatry and might permit better treatment outcome, increased treatment adherence and diminished adverse events.
儿童和青少年的严重精神健康障碍是一个重大的公共卫生问题。尽管有足够的药物治疗，但一些患者会出现药物抵抗性疾病。因此，医生面临着处方挑战、住院时间延长以及不良事件风险增加的问题，从而加重了短期、中期和长期预后。大多数精神药物治疗，特别是抗精神病药和抗抑郁药，在肝脏水平由细胞色素P450（CYP）代谢，尤其是由CYP3A4和CYP2D6代谢。有几种基因多态性被描述为与超快（UM）或药物代谢不良（PM）相关，可导致临床耐药和/或不良事件，因此可能与药物抵抗性严重精神健康疾病有关。
在2015年1月至2016年4月期间，对9名年龄在11至16岁（平均14.1岁）的药物抵抗性患者（4名女性，5名男性）进行了基因分型。患者被诊断为精神分裂症（n = 5）、自闭症谱系障碍（n = 2）、伴有挑战行为的智力残疾（n = 2）、对立违抗障碍（n = 1）以及创伤后应激障碍和边缘型人格障碍（n = 1）。他们平均有6.1（3 - 9）种精神药物、5（3 - 7）种抗精神病药以及3.4（2 - 5）种由CYP2D6代谢的抗精神病药和抗抑郁药的治疗史。5名患者（56%）出现了CYP2D6基因的功能异常：3名患者是具有基因重复的超快代谢者，2名患者是具有*4/41和3/*4多态性的慢代谢者。
CYP2D6的功能异常在我们患有药物抵抗性疾病的儿科住院患者样本中占比超过一半。然而，我们的病例报告受到样本量小的限制。尽管如此，在儿童和青少年精神病学中，对于耐药患者的临床检查和治疗调整，应考虑了解个体代谢情况，尤其是基因分型，这可能会带来更好的治疗效果、提高治疗依从性并减少不良事件。
