Dettling M, Sachse C, Brockmöller J, Schley J, Müller-Oerlinghausen B, Pickersgill I, Rolfs A, Schaub R T, Schmider J
Department of Psychiatry, University Clinic Charité, Humboldt University, Berlin, Germany.
Psychopharmacology (Berl). 2000 Sep;152(1):80-6. doi: 10.1007/s002130000503.
Clozapine is a unique antipsychotic drug, outstanding for its lack of extrapyramidal side-effects and its superior efficacy in refractory schizophrenia. However, an unambiguous concentration-response relationship has not yet been established.
We investigated serum concentrations of clozapine, norclozapine and clozapine-N-oxide in psychiatric in- and outpatients to identify particular metabolic patterns in clozapine responders and non-responders and putative threshold levels for clozapine response.
Psychiatric assessments, CYP2D6 genotype, and weekly serum concentrations of clozapine, norclozapine and clozapine-N-oxide were obtained in 34 adult schizophrenic in-and outpatients (18 men, 16 women) during 10 weeks of clozapine treatment with a naturalistic dose design.
Responders (n=21) displayed significantly lower serum concentrations of clozapine corrected for dose compared to non-responders (n=13; P<0.05), while none of the other parameters (absolute clozapine concentration, metabolite ratios, gender) were different. Smokers had significantly lower dose-corrected clozapine concentrations. A positive correlation was observed between age and average steady state clozapine concentrations.
These findings indicate a possible link between CYP activity and response to clozapine that is not mediated through differences in serum concentrations. No clinically meaningful pattern in serum parameters could be identified that differentiates responders from non-responders. Thus, clozapine TDM seems ineffective for predicting clinical response. Smoking behavior is a major determinant of clozapine clearance while CYP2D6 genotype does not impact clozapine disposition.
氯氮平是一种独特的抗精神病药物，因其缺乏锥体外系副作用以及在难治性精神分裂症中具有卓越疗效而突出。然而，尚未确立明确的浓度-反应关系。
我们调查了精神科门诊和住院患者中氯氮平、去甲氯氮平和氯氮平氮氧化物的血清浓度，以确定氯氮平反应者和无反应者的特定代谢模式以及氯氮平反应的假定阈值水平。
在34名成年精神分裂症门诊和住院患者（18名男性，16名女性）接受为期10周的氯氮平自然剂量治疗期间，获取精神科评估、CYP2D6基因型以及氯氮平、去甲氯氮平和氯氮平氮氧化物的每周血清浓度。
与无反应者（n = 13；P < 0.05）相比，反应者（n = 21）经剂量校正后的氯氮平血清浓度显著更低，而其他参数（氯氮平绝对浓度、代谢物比率、性别）均无差异。吸烟者经剂量校正后的氯氮平浓度显著更低。观察到年龄与氯氮平平均稳态浓度之间呈正相关。
这些发现表明CYP活性与对氯氮平的反应之间可能存在联系，这种联系并非由血清浓度差异介导。未发现血清参数中有可区分反应者与无反应者的具有临床意义的模式。因此，氯氮平治疗药物监测似乎对预测临床反应无效。吸烟行为是氯氮平清除率的主要决定因素，而CYP2D6基因型不影响氯氮平的处置。
