麦普替林改善老年抑郁症临床效应与血药浓度的关系

Clinical effect of maprotiline on elderly depression associated with blood concentration

目的:分析老年抑郁症患者采用麦普替林治疗后其血药浓度与临床效应的关系。方法:于2002-10/2003-12选取首都医科大学附属北京安定医院老年科住院及门诊符合ICD-10诊断标准的老年抑郁症患者48例为观察对象,汉密顿抑郁量表(17项)评分≥18分。麦普替林初始治疗剂量25mg/d,在2～3周内加至治疗量25～175mg,2次/d,中午和晚上给药,第3周末达到个体恒定剂量后维持固定剂量不变,疗程6周。于治疗前及治疗第4,6周末采用汉密顿抑郁量表、汉密顿焦虑量表、副反应量表各评定一次。并分别测定血、尿常规,血液生化,ECG等。评估标准:以汉密顿抑郁量表评分≤7分为症状消失,汉密顿抑郁量表减分率≥50%为显著进步,≥25%为进步,<25%为无效。全部病例于治疗第4,6周末中午进药前取5mL非抗凝血,采用高效液相色谱紫外检测法测定麦普替林、去甲麦普替林浓度。结果:44例患者均完成治疗并测得血药浓度进入结果分析,4例因失访脱落。①在日剂量校正后麦普替林血药浓度为0.53～3.18μg/(L·g),平均(1.54±0.60)μg/(L·g);去甲麦普替林为0.19～1.05μg/(L·g),平均(0.61±0.21)μg/(L·g);活性部分(麦普替林与去甲麦普替林浓度之和)为0.89～4.20μg/(L·g),平均(2.15±0.68)μg/(L·g);存在个体差异。②治疗第4,6周末患者汉密顿抑郁量表和汉密顿焦虑量表的评分分别比治疗前显著降低,差异有显著性意义(t=13.708,P≤0.000);(t=14.329,P≤0.000)。③治疗后患者症状消失25例(57%),显著进步9例(21%),进步3例(6%),无效7例(16%)。有效率为77%。④不良反应总发生率75%,其中抗胆碱能作用的发生率为71%(31/44),拟交感作用10%(5/44),心血管不良反应6%(3/44),转氨酶升高16%(7/44),其他不良反应8%(4/44)。⑤麦普替林浓度、活性部分浓度与日剂量存在显著相关性(r=0.314,0.418,P<0.05),活性部分血药浓度与抗胆碱能不良反应之间存在显著相关性(r=0.342,P<0.05)。⑥去甲麦普替林浓度79.435μg/L时,灵敏度为70.0%,特异度为80.0%。曲线下面积为0.797mm2,P=0.005;活性部分浓度为248.330μg/L时,灵敏度为80.0%,特异度为80.0%。曲线下面积为0.817mm2,P=0.003;可作为预测出现不良反应的阈浓度。结论:在老年抑郁症患者中,麦普替林、去甲麦普替林及活性部分血药浓度存在个体差异,增加麦普替林日剂量会提高血药浓度,但不一定会增加疗效;去甲麦普替林、活性部分的浓度高于阈浓度时,会增加出现不良反应的可能。

AIM： To assess the relationship between serum concentrationand clinical effects in elderly patients with depressive disorder treated by mapretiline. METHODS： Forty-eight elderly inpatients or outpatients with depression from October 2002 to December 2003, who met the ICD-10 criteria geriatric depression with the HAMD-17 score ≥18 points, were selected from Beijing Anding Hospital Affiliated to Capital Medical University. Patients were treated by mapretiline at the original dosage of 25 mg per day, which was increased to 25-175 mg in 2-3 weeks, twice a day respectively at noon and evening. At the end of 3rd week, dosages were fixed after reached to individual constant dosage with the course of 6 weeks. Patients were evaluated with Hamilton rating scale for depression （HAMD）, Hamil- ton anxiety scale （HAMA） and treatment emergent symptom scale （TESS） once respectively before treatment and at the end of 4th and 6th week, and the blood and urine normal test, blood biochemical test as well as ECG etc. were determined. The standard was that H.AMD score ≤ 7 points represented as symptoms disappeared, the decreasing rate of HAMD score ≥50% as significant progress, those ≥25% as progress and those 〈 25% as inefficacy. 5 mL of blood samples were obtained at the end of 4^th and 6^th weeks to measure the concentratiosn of mapretiline and N-demethylmaprotiline by using high performance liquid chromatography ultraviolet detection. RESULTS： A total of 44 patients received the treatment and were measured of the drug concentration, who were involved in the analysis of results, and 4 patients withdrew from the study.①The measured concentration of mapretiline and N-demethylmapretiline after dally dose correction were 0.53-3.18 μg/（L .g） and 0.19-1.05 μg/（L·g） with the average concentration of （1.54±0.60） μg/L ·g and （0.61 ±0.21） μg/L .g respectively. The active moiety （the total concentration of mapretiline and Ndemethylmaprotiline） was 0.89-4.20 μg/（L.g） with an average concentration of （2.15±0.68） μg/（L-g）. There was individual differences.②HAMD and HAMA scores at the 4^th and 6^th week of treatment were significantly decreased than those before treatment with marked differences （t=13.708,P≤ 0.000）;（t=14.329,P ≤ 0.000）.③Mter treatment, 25 patients （57%） got symptom disappeared, 9 patients （21%） achieved significant progress, 3 patients （6%） achieved progress and inefficient in 7 patients （16%） with a efficiency rate of 77%. ④The total rate of adverse effect was 75%, in which anticholinergic adverse effect was 71% （31/44）, imitate-interaction effect was 10% （5/44）, cardiovascular adverse effect was 6% （3/44）, aminotransferase increased by 16% （7/44） and other adverse effect was 8% （4/44）. ⑤There was significant relationship among concentration of maprotiline, active moiety and dosages （r=0.314, 0.418, P 〈 0.05）. The concentration of active moiety was significantly related to anticholinergic adverse effect （r =0.342,P 〈 0.05）. ⑥ The concentration of Ndemethylmaprotiline was 79,435 μg/L .g with a sensitivity of 70% and a specificity of 80%, The area under curve wass 0.797 mm^2, P =0.005. The threshold concentration of active moiety was 248.330 μg/L.g with a sensitivity of 80% and a specificity of 80%, and area under curve was 0.817 mm^2, P=0.003, which could be taken as the threshold concentration in prediction of side effects. CONCLUSION： In the elderly patients with depression, there are interindividual variations in the concentration of mapretiline, N-demet hylmapretiline and active moiety. Increased dosage of mapretiline will enhance the concentration of drug, while the clinical effects may not be improved. When the concentrations of N-demethylmapretiline and active moiety are higher than threshold concentration, the possibility of side effects may be increased.