Lewis S W, Davies L, Jones P B, Barnes T R E, Murray R M, Kerwin R, Taylor D, Hayhurst K P, Markwick A, Lloyd H, Dunn G
Division of Psychiatry, Wythenshawe Hospital, Manchester, UK.
Health Technol Assess. 2006 May;10(17):iii-iv, ix-xi, 1-165. doi: 10.3310/hta10170.
To determine the clinical and cost-effectiveness of different classes of antipsychotic drug treatment in people with schizophrenia responding inadequately to, or having unacceptable side-effects from, their current medication.
Two pragmatic, randomised controlled trials (RCTs) were undertaken. The first RCT (band 1) compared the class of older, inexpensive conventional drugs with the class of new atypical drugs in people with schizophrenic disorders, whose current antipsychotic drug treatment was being changed either because of inadequate clinical response or owing to side-effects. The second RCT (band 2) compared the new (non-clozapine) atypical drugs with clozapine in people whose medication was being changed because of poor clinical response to two or more antipsychotic drugs. Both RCTs were four-centre trials with concealed randomisation and three follow-up assessments over 1 year, blind to treatment.
Adult mental health settings in England.
In total, 227 participants aged 18-65 years (40% of the planned sample) were randomised to band 1 and 136 (98% of the planned sample) to band 2.
Participants were randomised to a class of drug. The managing clinician selected the individual drug within that class, except for the clozapine arm in band 2. The new atypical drugs included risperidone, olanzapine, quetiapine and amisulpride. The conventional drugs included older drugs, including depot preparations. As in routine practice, clinicians and participants were aware of the identity of the prescribed drug, but clinicians were asked to keep their participating patient on the randomised medication for at least the first 12 weeks. If the medication needed to be changed, the clinician was asked to prescribe another drug within the same class, if possible.
The primary outcome was the Quality of Life Scale (QLS). Secondary clinical outcomes included symptoms [Positive and Negative Syndrome Scale (PANSS)], side-effects and participant satisfaction. Economic outcomes were costs of health and social care and a utility measure.
Recruitment to band 1 was less than anticipated (40%) and diminished over the trial. This appeared largely due to loss of perceived clinical equipoise (clinicians progressively becoming more convinced of the superiority of new atypicals). Good follow-up rates and a higher than expected correlation between QLS score at baseline and at follow-up meant that the sample as recruited had 75% power to detect a difference in QLS score of 5 points between the two treatment arms at 52 weeks. The recruitment to band 2 was approximately as planned. Follow-up assessments were completed at week 52 in 81% of band 1 and 87% of band 2 participants. Band 1 data showed that, on the QLS and symptom measures, those participants in the conventional arm tended towards greater improvements. This suggests that the failure to find the predicted advantage for new atypicals was not due to inadequate recruitment and statistical power in this sample. Participants reported no clear preference for either class of drug. There were no statistically significant differential outcomes for participants entering band 1 for reasons of treatment intolerance to those entering because of broadly defined treatment resistance. Net costs over the year varied widely, with a mean of 18,850 pounds sterling in the conventional drug group and 20,123 pounds sterling in the new atypical group, not a statistically significant difference. Of these costs, 2.1% and 3.8% were due to antipsychotic drug costs in the conventional and atypical group, respectively. There was a trend towards participants in the conventional drug group scoring more highly on the utility measure at 1 year. The results for band 2 showed an advantage for commencing clozapine in quality of life (QLS) at trend level (p = 0.08) and in symptoms (PANSS), which was statistically significant (p = 0.01), at 1 year. Clozapine showed approximately a 5-point advantage on PANSS total score and a trend towards having fewer total extrapyramidal side-effects. Participants reported at 12 weeks that their mental health was significantly better with clozapine than with new atypicals (p < 0.05). Net costs of care varied widely, but were higher than in band 1, with a mean of 33,800 pounds sterling in the clozapine group and 28,400 pounds sterling in the new atypical group. Of these costs, 4.0% and 3.3%, respectively, were due to antipsychotic drug costs. The increased costs in the clozapine group appeared to reflect the licensing requirement for inpatient admission for commencing the drug. There was a trend towards higher mean participant utility scores in the clozapine group.
For band 1, there is no disadvantage in terms of quality of life and symptoms, or associated costs of care, over 1 year in commencing conventional antipsychotic drugs rather than new atypical drugs. Conventional drugs were associated with non-significantly better outcomes and lower costs. Drug costs represented a small proportion of the overall costs of care (<5%). For band 2, there is a statistically significant advantage in terms of symptoms but not quality of life over 1 year in commencing clozapine rather than new atypical drugs, but with increased associated costs of care. The results suggest that conventional antipsychotic drugs, which are substantially cheaper, still have a place in the treatment of patients unresponsive to, or intolerant of, current medication. Further analyses of this data set are planned and further research is recommended into areas such as current antipsychotic treatment guidance, valid measures of utility in serious mental illness, low-dose 'conventional' treatment in first episode schizophrenia, QLS validity and determinants of QLS score in schizophrenia, and into the possible financial and other mechanisms of rewarding clinician participation in trials.
确定不同种类抗精神病药物治疗对当前药物治疗反应不佳或出现不可接受副作用的精神分裂症患者的临床疗效和成本效益。
进行了两项实用的随机对照试验（RCT）。第一项RCT（第1组）在精神分裂症患者中，将一类较老的、便宜的传统药物与一类新型非典型药物进行比较，这些患者因临床反应不佳或出现副作用而正在改变当前的抗精神病药物治疗。第二项RCT（第2组）在因对两种或更多种抗精神病药物临床反应不佳而正在改变药物治疗的患者中，将新型（非氯氮平）非典型药物与氯氮平进行比较。两项RCT均为四中心试验，采用隐蔽随机分组，并在1年内进行三次随访评估，治疗过程设盲。
英国的成人心理健康机构。
共有227名年龄在18 - 65岁之间的参与者（占计划样本的40%）被随机分配到第1组，136名（占计划样本的98%）被随机分配到第2组。
参与者被随机分配到一类药物。除第2组的氯氮平组外，主治医生在该类药物中选择具体药物。新型非典型药物包括利培酮、奥氮平、喹硫平和氨磺必利。传统药物包括较老的药物，包括长效制剂。与常规临床实践一样，临床医生和参与者知道所开药物的名称，但要求临床医生让其参与试验的患者至少在最初12周内使用随机分配的药物。如果需要更换药物，要求临床医生尽可能在同一类药物中开另一种药。
主要结局指标是生活质量量表（QLS）。次要临床结局包括症状[阳性和阴性症状量表（PANSS）]、副作用和参与者满意度。经济结局包括卫生和社会护理成本以及一项效用指标。
第1组的招募人数低于预期（40%），且在试验过程中逐渐减少。这似乎主要是由于临床 equipoise 的丧失（临床医生逐渐更加确信新型非典型药物的优越性）。良好的随访率以及基线和随访时QLS评分之间高于预期的相关性意味着，所招募的样本有75%的把握度在52周时检测到两个治疗组之间QLS评分5分的差异。第2组的招募情况大致符合计划。第1组81%的参与者和第2组87%的参与者在第52周完成了随访评估。第1组的数据显示，在QLS和症状指标方面，传统药物组的参与者改善趋势更明显。这表明未发现新型非典型药物预期优势并非由于该样本招募不足和统计效能问题。参与者报告对两类药物均无明显偏好。因治疗不耐受进入第1组的参与者与因广义的治疗抵抗进入第1组的参与者在统计学上没有显著的差异结局。一年的净成本差异很大，传统药物组平均为18,850英镑，新型非典型药物组平均为20,123英镑，差异无统计学意义。在这些成本中，传统药物组和非典型药物组分别有2.1%和3.8%是由于抗精神病药物成本。在1年时，传统药物组的参与者在效用指标上得分有更高的趋势。第2组的结果显示，在1年时，开始使用氯氮平在生活质量（QLS）方面有趋势性优势（p = 0.08），在症状（PANSS）方面有统计学显著优势（p = 0.01）。氯氮平在PANSS总分上显示出约5分的优势，且总的锥体外系副作用有减少的趋势。参与者在12周时报告，使用氯氮平时他们的心理健康状况明显优于使用新型非典型药物（p < 0.05）。护理的净成本差异很大，但高于第1组，氯氮平组平均为33,800英镑，新型非典型药物组平均为28,400英镑。在这些成本中，分别有4.0%和3.3%是由于抗精神病药物成本。氯氮平组成本增加似乎反映了开始使用该药物时住院许可的要求。氯氮平组的参与者平均效用得分有更高的趋势。
对于第1组，在开始使用传统抗精神病药物而非新型非典型药物的1年时间里，在生活质量、症状或相关护理成本方面没有劣势。传统药物与非显著更好的结局和更低的成本相关。药物成本占护理总成本的比例较小（<5%）。对于第2组，在开始使用氯氮平而非新型非典型药物的1年时间里，在症状方面有统计学显著优势，但在生活质量方面没有，且护理相关成本增加。结果表明，成本低得多的传统抗精神病药物在治疗对当前药物无反应或不耐受的患者中仍有一席之地。计划对该数据集进行进一步分析，并建议对以下领域进行进一步研究，如当前抗精神病治疗指南、严重精神疾病效用的有效测量、首发精神分裂症的低剂量“传统”治疗、QLS的有效性以及精神分裂症患者QLS评分的决定因素，以及奖励临床医生参与试验可能的财务和其他机制。
