Vasudev K, Goswami U, Kohli K
Department of Pharmacology, Lady Hardinge Medical College & Associated Hospitals, New Delhi, India.
Psychopharmacology (Berl). 2000 May;150(1):15-23. doi: 10.1007/s002130000380.
Search for alternatives to lithium therapy for mood disorders commenced with anticonvulsants, carbamazepine (CBZ) and valproic acid (VPA), in the late 1970s. The comparative safety and efficacy data of CBZ and VPA monotherapy in patients with bipolar disorder remain to be established.
The main objectives of the study were to assess the relative antimanic efficacy and safety of CBZ and VPA; to study the feasibility of using either, as a first line anti-manic agent; to investigate and generate clinically relevant parameters involving therapeutic drug monitoring of the two drugs.
After a 2-day screening period, suitable patients (n = 30) were randomly assigned to treatment with CBZ or VPA. Both the drugs were started with an average dose of approximately 20 mg/kg body weight per day. Further increment in dose was carried out at weekly intervals, guided by clinical improvement, serum levels and treatment emergent adverse events. The primary efficacy measure in the protocol was defined as a change from baseline to endpoint in total score on the Young Mania Rating Scale. A favourable clinical response was defined a priori as a decrease of more than 50% from baseline in Young Mania Rating Scale total score.
Both CBZ and VPA were found to be efficacious as single first-line anti-manic agents, however VPA proved to be better. Using the intent-to-treat analysis, the VPA group showed a significant fall in YMRS total scores after week 1 while the CBZ group showed a significant fall after week 2. In the primary efficacy analysis, valproate group experienced significantly greater mean improvement in Young Mania Rating Scale total score than the CBZ group. Of the VPA treated patients, 73% showed a favourable clinical response while 53% of the patients on CBZ responded favourably. In the CBZ group, significantly more patients received rescue medication during the week 2 and the requirement was quantitatively more as compared to the VPA group. The steady state serum concentration (Css) of CBZ ranged from 3 to 9 micrograms/ml; however, it did not appear to correlate with the dose or clinical response. The Css of VPA ranged from 50 to 100 micrograms/ml; a linear correlation was found between the dose and serum levels of VPA as well as between weekly rise in serum levels and clinical response. Weekly dose escalations of VPA also correlated positively with corresponding rise in serum levels. Significantly more patients in the CBZ group reported adverse events, including nausea, vomiting and dizziness, than VPA.
The findings from this study suggest that both CBZ and VPA monotherapy is feasible for treatment of acute mania; however, VPA is more efficacious in terms of its early onset of action, lesser requirement for rescue medication and better tolerability. Further work needs to be undertaken to characterise the manic patients in terms of their differential psychopharmacologic response profile.
20世纪70年代末开始寻找用于治疗情绪障碍的锂盐疗法的替代药物，即抗惊厥药卡马西平（CBZ）和丙戊酸（VPA）。双相情感障碍患者中CBZ和VPA单药治疗的相对安全性和疗效数据仍有待确定。
本研究的主要目的是评估CBZ和VPA的相对抗躁狂疗效和安全性；研究将二者作为一线抗躁狂药物使用的可行性；调查并生成涉及这两种药物治疗药物监测的临床相关参数。
经过2天的筛查期后，将合适的患者（n = 30）随机分配接受CBZ或VPA治疗。两种药物均以每天约20mg/kg体重的平均剂量开始使用。根据临床改善情况、血清水平和治疗中出现的不良事件，每周间隔增加剂量。方案中的主要疗效指标定义为从基线到终点时杨氏躁狂评定量表总分的变化。预先将良好的临床反应定义为杨氏躁狂评定量表总分较基线下降超过50%。
发现CBZ和VPA作为单一的一线抗躁狂药物均有效，但VPA被证明效果更好。采用意向性分析，VPA组在第1周后YMRS总分显著下降，而CBZ组在第2周后显著下降。在主要疗效分析中，丙戊酸盐组在杨氏躁狂评定量表总分上的平均改善明显大于CBZ组。在接受VPA治疗的患者中，73%显示出良好的临床反应，而接受CBZ治疗的患者中这一比例为53%。在CBZ组中，第2周有明显更多患者接受了抢救药物，且需求量在数量上比VPA组更多。CBZ的稳态血清浓度（Css）范围为3至9微克/毫升；然而，它似乎与剂量或临床反应无关。VPA的Css范围为50至100微克/毫升；发现VPA的剂量与血清水平之间以及血清水平的每周升高与临床反应之间存在线性相关性。VPA的每周剂量递增也与血清水平的相应升高呈正相关。CBZ组报告不良事件（包括恶心、呕吐和头晕）的患者明显多于VPA组。
本研究结果表明，CBZ和VPA单药治疗急性躁狂均可行；然而，VPA在起效早、抢救药物需求少和耐受性更好方面更有效。需要进一步开展工作，根据躁狂患者不同的精神药理反应特征对其进行分类。
