Marazziti Donatella, Palego Lionella, Betti Laura, Giannaccini Gino, Massimetti Enrico, Baroni Stefano, Ciapparelli Antonio, Lucacchini Antonio, Mucci Federico, DellʼOsso Liliana
Psychiatry Section, Department of Experimental and Clinical Medicine, University of Pisa.
Department of Pharmacy, University of Pisa, Pisa, Italy.
Ther Drug Monit. 2018 Aug;40(4):443-451. doi: 10.1097/FTD.0000000000000513.
The aim of the present study was to appraise retrospectively the influence of valproate (VPA) and antidepressants (ADs) on the steady-state plasma concentrations of clozapine (CLZ), the prototype of various second-generation antipsychotics, norclozapine (NCLZ, its main metabolite), and their ratio (NCLZ:CLZ).
Sixty-seven psychotic patients with a prevalent diagnosis of bipolar disorder were studied. We then analyzed data altogether and subdivided them into 4 groups, according to pharmacological treatments: #1 CLZ (n = 21), #2 CLZ plus ADs (n = 13), #3 CLZ plus VPA (n = 16), and #4 CLZ plus ADs plus VPA (n = 17).
First, significant positive between CLZ and NCLZ plasma levels (in nanograms/milliliter) and the drug daily dosages (in milligrams/kilogram of body weight) (n = 67) were observed (Spearman: rCLZ = 0.49; rNCLZ = 0.61; P < 0.001). We then normalized by given doses CLZ and NCLZ plasma levels, natural log transformed them, and performed analysis of variance factor analyses followed by pairwise comparisons, performed on the 4 groups and the 3 CLZ parameters. We identified significant drug effects on (1) CLZ plasma levels, significantly higher in group #2 versus group #1, and (2) NCLZ:CLZ ratio, lower in group #2 versus groups #1 and #3. Significant drug × gender interactions were observed in group #3, showing higher NCLZ levels and NCLZ:CLZ ratios in men compared with women.
Despite its inherent limitations, this observational study confirms the significant increase in plasma CLZ concentrations and reduction in NCLZ:CLZ ratio when this drug was coadministered with ADs (group #2), an effect apparently counteracted by VPA (group #4). The drug × gender interactions in patients taking both CLZ and VPA (group #3) warrant further prospective study.
本研究的目的是回顾性评估丙戊酸盐（VPA）和抗抑郁药（ADs）对氯氮平（CLZ，各种第二代抗精神病药物的原型）、去甲氯氮平（NCLZ，其主要代谢产物）的稳态血浆浓度及其比值（NCLZ:CLZ）的影响。
对67例主要诊断为双相情感障碍的精神病患者进行了研究。然后我们对数据进行了综合分析，并根据药物治疗将他们分为4组：#1氯氮平组（n = 21），#2氯氮平加抗抑郁药组（n = 13），#3氯氮平加丙戊酸盐组（n = 16），#4氯氮平加抗抑郁药加丙戊酸盐组（n = 17）。
首先，观察到氯氮平和去甲氯氮平的血浆水平（以纳克/毫升为单位）与药物每日剂量（以毫克/千克体重为单位）之间存在显著正相关（n = 67）（斯皮尔曼相关性：rCLZ = 0.49；rNCLZ = 0.61；P < 0.001）。然后，我们用给定剂量对氯氮平和去甲氯氮平的血浆水平进行标准化，对其进行自然对数转换，并对4组和3个氯氮平参数进行方差分析因子分析，随后进行两两比较。我们确定药物对以下方面有显著影响：（1）氯氮平血浆水平，#2组显著高于#1组；（2）NCLZ:CLZ比值，#2组低于#1组和#3组。在#3组中观察到显著的药物×性别交互作用，表明男性的去甲氯氮平水平和NCLZ:CLZ比值高于女性。
尽管本观察性研究存在固有局限性，但它证实了氯氮平与抗抑郁药联合使用时（#2组）血浆氯氮平浓度显著升高，NCLZ:CLZ比值降低，而丙戊酸盐（#4组）似乎抵消了这种作用。同时服用氯氮平和丙戊酸盐的患者（#3组）中的药物×性别交互作用值得进一步进行前瞻性研究。
