de Leon Jose, Odom-White Aruby, Josiassen Richard C, Diaz Francisco J, Cooper Thomas B, Simpson George M
Mental Health Research Center, Eastern State Hospital, 627 West Fourth Street, Lexington, KY 40508, USA.
J Clin Psychopharmacol. 2003 Aug;23(4):336-41. doi: 10.1097/01.jcp.0000085405.08426.73.
This study attempts: (1) to verify that serum antimuscarinic activity is related to clozapine dose, and more importantly to clozapine plasma concentrations; (2) to explore whether norclozapine has serum antimuscarinic activity; (3) to explore whether antimuscarinic activity is related to clozapine side effects; and (4) to compare the serum antimuscarinic activities of clozapine with those of antiparkinsonian drugs and other antipsychotics. In 39 patients participating in a double-blind clozapine study, the [3H]QNB assay was used to measure serum antimuscarinic activity: (1) on baseline medications; (2) after a 4-week haloperidol trial; (3) after a 16-week clozapine trial of either 100, 300, or 600 mg/d; and (4) after 1 or 2 consecutive 16-week clozapine trials with remaining doses in nonresponders. Clozapine levels predicted serum antimuscarinic activity better than clozapine dose. At the end of the 1st clozapine trial, the correlation with the levels explained 69% of the variance of serum antimuscarinic activity (r = 0.83, P < 0.001, N = 34). Clozapine levels were good predictors of serum antimuscarinic activity only in patients taking 300 or 600 mg/d. After correcting for clozapine levels, the within-subject correlation between norclozapine levels and serum antimuscarinic activity was relatively high and significant (r = 0.54, F = 26.7, df = 1.65, P < 0.001). Constipation was significantly associated with higher serum antimuscarinic activity during the 1st clozapine trial. Clozapine was associated with clearly higher antimuscarinic activity than other antipsychotics or low doses of antiparkinsonians. In vitro studies and new clinical studies are needed to verify whether norclozapine may significantly contribute to antimuscarinic activity during clozapine treatment.
（1）验证血清抗毒蕈碱活性与氯氮平剂量相关，更重要的是与氯氮平血药浓度相关；（2）探究去甲氯氮平是否具有血清抗毒蕈碱活性；（3）探究抗毒蕈碱活性是否与氯氮平副作用相关；（4）比较氯氮平与抗帕金森病药物及其他抗精神病药物的血清抗毒蕈碱活性。在39例参与氯氮平双盲研究的患者中，采用[3H]QNB分析法测定血清抗毒蕈碱活性：（1）在基线用药时；（2）在进行为期4周的氟哌啶醇试验后；（3）在进行为期16周、剂量分别为100、300或600mg/d的氯氮平试验后；（4）在无反应者中进行1次或连续2次为期16周、使用剩余剂量的氯氮平试验后。氯氮平血药浓度比氯氮平剂量能更好地预测血清抗毒蕈碱活性。在第1次氯氮平试验结束时，与血药浓度的相关性解释了血清抗毒蕈碱活性变异的69%（r = 0.83，P < 0.001，N = 34）。仅在服用300或600mg/d氯氮平的患者中，氯氮平血药浓度是血清抗毒蕈碱活性的良好预测指标。校正氯氮平血药浓度后，去甲氯氮平血药浓度与血清抗毒蕈碱活性之间的受试者内相关性较高且具有显著性（r = 0.54，F = 26.7，df = 1.65，P < 0.001）。在第1次氯氮平试验期间，便秘与较高的血清抗毒蕈碱活性显著相关。与其他抗精神病药物或低剂量抗帕金森病药物相比，氯氮平具有明显更高的抗毒蕈碱活性。需要进行体外研究和新的临床研究来验证去甲氯氮平在氯氮平治疗期间是否可能对抗毒蕈碱活性有显著贡献。
