Centre de Recherche de l'Institut Philippe-Pinel de Montréal, 10 905, boul. Henri-Bourassa Est, Montréal, QC, Canada.
Med Hypotheses. 2013 Jun;80(6):689-91. doi: 10.1016/j.mehy.2012.12.024. Epub 2013 Mar 13.
Although clozapine is the only antipsychotic agent to have demonstrated superior efficacy in treatment-refractory schizophrenia, one- to two-thirds of patients do not respond adequately despite acceptable dosages and plasma levels. Moreover, a significant number of patients stop the therapy for various reasons, including its side effects, many of which are thought to be related to its active metabolite, norclozapine. However, combining clozapine with the SSRI antidepressant fluvoxamine decreases norclozapine formation by inhibiting the CYP450 1A2 isoenzyme. Lowering norclozapine levels in this way while maintaining therapeutic clozapine levels increases the clozapine: norclozapine ratio; the potential benefits include both a reduction of such side effects as sedation, weight gain, metabolic disturbances, and neutropenia, and an increase in efficacy. The optimal ratio of clozapine to norclozapine has not yet been defined, but a ratio of two or more implies that saturation of clozapine metabolism has been reached. We hypothesize that co-administration of clozapine and fluvoxamine at dosages that will produce therapeutic plasma levels of clozapine and a clozapine: norclozapine ratio of two or more will increase efficacy and tolerability of clozapine therapy in treatment-resistant schizophrenic patients.
虽然氯氮平是唯一一种在治疗难治性精神分裂症方面显示出优越疗效的抗精神病药物，但仍有 1/3 至 2/3 的患者尽管接受了可接受的剂量和血浆水平，仍不能充分应答。此外，由于各种原因，包括其副作用，许多副作用被认为与它的活性代谢物去甲氯氮平有关，相当数量的患者停止了治疗。然而，将氯氮平与 SSRI 抗抑郁药氟伏沙明联合使用可通过抑制 CYP450 1A2 同工酶来减少去甲氯氮平的形成。以这种方式降低去甲氯氮平水平，同时保持治疗性氯氮平水平，可增加氯氮平与去甲氯氮平的比值；潜在的益处包括减少镇静、体重增加、代谢紊乱和中性粒细胞减少等副作用，以及提高疗效。氯氮平与去甲氯氮平的最佳比值尚未确定，但比值为 2 或更高表明氯氮平代谢已达到饱和。我们假设，以产生治疗性氯氮平血浆水平和氯氮平与去甲氯氮平比值为 2 或更高的剂量联合使用氯氮平和氟伏沙明，将增加治疗抵抗性精神分裂症患者的氯氮平治疗的疗效和耐受性。
