Spina E, Avenoso A, Salemi M, Facciolá G, Scordo M G, Ancione M, Madia A
Institute of Pharmacology, University of Messina, Policlinico Universitario di Messina, Italy.
Pharmacopsychiatry. 2000 Nov;33(6):213-7. doi: 10.1055/s-2000-8361.
The effect of paroxetine or sertraline on steady-state plasma concentrations of clozapine and its major metabolites was studied in 17 patients with schizophrenia or schizoaffective disorder stabilized on clozapine therapy (200-400 mg/day). In order to treat negative symptomatology or concomitant depression, 9 patients received additional paroxetine (20-40mg/day) and 8 patients sertraline (50-100 mg/day). After 3 weeks of paroxetine administration, mean plasma concentrations of clozapine and norclozapine increased significantly by 31% (p<0.01) and by 20% (p<0.05), respectively, while levels of clozapine N-oxide remained almost unchanged. The mean plasma norclozapine/clozapine and clozapine N-oxide/clozapine ratios were not modified during paroxetine treatment. No significant changes in plasma concentrations of clozapine and its major metabolites were observed after 3 weeks of combined therapy with sertraline. Clozapine coadministration with either paroxetine or sertraline was well tolerated. Our findings suggest that the metabolism of clozapine is not affected by sertraline treatment at typical therapeutic doses, while paroxetine, a potent inhibitor of CYP2D6, appears to inhibit the metabolism of clozapine, possibly by affecting pathways other than N-demethylation and N-oxidation. While sertraline may be added safely to patients on maintenance treatment with clozapine, careful clinical observation and monitoring of plasma clozapine levels may be useful whenever paroxetine is coadministered with clozapine.
在17例接受氯氮平治疗（200 - 400毫克/天）病情稳定的精神分裂症或分裂情感性障碍患者中，研究了帕罗西汀或舍曲林对氯氮平及其主要代谢产物稳态血浆浓度的影响。为了治疗阴性症状或并发的抑郁症，9例患者额外服用帕罗西汀（20 - 40毫克/天），8例患者服用舍曲林（50 - 100毫克/天）。服用帕罗西汀3周后，氯氮平和去甲氯氮平的平均血浆浓度分别显著升高31%（p<0.01）和20%（p<0.05），而氯氮平N - 氧化物水平几乎保持不变。在帕罗西汀治疗期间，去甲氯氮平/氯氮平和氯氮平N - 氧化物/氯氮平的平均血浆比值未改变。舍曲林联合治疗3周后，氯氮平及其主要代谢产物的血浆浓度未观察到显著变化。氯氮平与帕罗西汀或舍曲林联合使用耐受性良好。我们的研究结果表明，在典型治疗剂量下，舍曲林治疗不影响氯氮平的代谢，而强效CYP2D6抑制剂帕罗西汀似乎抑制氯氮平的代谢，可能是通过影响N - 去甲基化和N - 氧化以外的途径。虽然舍曲林可安全地添加到接受氯氮平维持治疗的患者中，但当帕罗西汀与氯氮平联合使用时，仔细的临床观察和监测血浆氯氮平水平可能是有用的。
