Background

Combining antipsychotics is common in schizophrenia treatment, despite evidence-based guidelines generally not recommending such practice. Otherwise, evidence remains inconclusive, especially regarding specific combinations. The trial aimed to test whether a combination of amisulpride plus olanzapine is more effective than either intervention as a monotherapy.

Methods

A multicentre, 16-week, randomised, double-blind, controlled trial was done at 16 psychiatric in-patient centres throughout Germany. Inclusion criteria were adults aged 18–65 years with non-first episode schizophrenia or schizoaffective disorder and with a Positive and Negative Syndrome Scale (PANSS) total score of at least 70 and at least two items of the positive symptoms subscale rated at least 4. Patients were randomly assigned to receive 16 weeks of treatment with either amisulpride plus olanzapine, amisulpride plus placebo, or olanzapine plus placebo (1:1:1), and block randomisation was stratified by study site. To keep patients and investigators masked throughout the duration of the trial, amisulpride, olanzapine, and placebo were administered as identical capsules. Flexibly dosed monotherapy of oral amisulpride (amisulpride plus placebo, 200–800 mg per day) or olanzapine (olanzapine plus placebo, 5–20 mg per day) was compared with a combination of amisulpride plus olanzapine. The primary outcome was symptom reduction measured by the PANSS total score after 8 weeks, in the modified intention-to-treat population (all patients randomly assigned to an intervention and receiving at least one study drug dose). As determined a priori, group differences were examined by t tests (Bonferroni-Holm-adjustment) followed by pre-planned Bayesian analyses as well as imputation methods based on mixed models to account for missing values and post-hoc ANCOVA adjusting for PANSS baseline scores. The study was registered on ClinicalTrials.gov, NCT01609153; the German Clinical Trials Register, DRKS00003603; and the European Union Drug Regulating Authorities Clinical Trials Database, EudraCT-No. 2011-002463-20.

Findings

Between June 15, 2012, and Dec 15, 2018, 13 692 patients were assessed for eligibility. 13 364 patients were excluded (including for not meeting inclusion criteria, declining to participate, or inappropriate reasons for changing pharmacological treatment), and 328 were then randomly assigned to an intervention group. 112 patients were randomly assigned to receive amisulpride plus olanzapine, 109 were randomly assigned to receive amisulpride plus placebo, and 107 were randomly assigned to receive olanzapine plus placebo. 321 patients were analysed for the primary outcome in the modified intention-to-treat population after exclusion of screening failures and patients who did not receive the intervention (110 for amisulpride plus olanzapine, 109 for amisulpride plus placebo, and 102 for olanzapine plus placebo). Among the 321 patients who were randomly assigned to intervention groups and analysed for the primary outcome, 229 (71%) were male, 92 (29%) were female; the mean age was 40·2 years (SD 11·7); and 296 (92%) were White and 25 (8%) were classified as other ethnicity. PANSS total score improved significantly more at 8 weeks in the amisulpride plus olanzapine group (−29·6 [SD 14·5]) than in the olanzapine plus placebo group (−24·1 [13·4], p=0·049, Cohen's d=0·396). A significant difference was not observed in reduction of PANSS total score between the amisulpride and olanzapine group compared with the amisulpride and placebo group (−25·2 [SD 15·9], p=0·095, Cohen's d=0·29). After 8 weeks and 16 weeks, sexual dysfunction, weight, and waist circumference increase were significantly higher for patients receiving amisulpride plus olanzapine than for those receiving amisulpride plus placebo, with no differences in serious adverse events. Two patients died during study participation; one randomly assigned to the amisulpride plus olanzapine group, and one assigned to the olanzapine plus placebo group (both assessed with no relation to treatment).

Interpretation

The advantages of amisulpride plus olanzapine have to be weighed against a higher propensity for side-effects. The use of this specific combination therapy could be an alternative to monotherapy in certain clinical situations, but side-effects should be considered.

Funding

German Federal Ministry of Education and Research.

中文翻译：

---

德国急性精神分裂症患者氨磺必利和奥氮平联合治疗与每种单一疗法的比较（COMBINE）：一项双盲随机对照试验

背景

尽管基于证据的指南通常不推荐这种做法，但在精神分裂症治疗中联合抗精神病药很常见。否则，证据仍然没有定论，特别是关于特定组合。该试验旨在测试氨磺必利联合奥氮平是否比任一干预作为单一疗法更有效。

方法

在德国各地的 16 个精神病住院中心进行了一项为期 16 周的多中心、随机、双盲、对照试验。纳入标准为 18-65 岁非首发精神分裂症或分裂情感障碍且阳性和阴性综合征量表 (PANSS) 总分至少为 70 分且至少两项阳性症状分量表评分至少为 4 分的成年人。患者被随机分配接受 16 周的氨磺必利联合奥氮平、氨磺必利联合安慰剂或奥氮平联合安慰剂 (1:1:1) 治疗，并按研究地点分层随机分组。为了在整个试验过程中对患者和研究人员不知情，氨磺必利、奥氮平和安慰剂作为相同的胶囊给药。口服氨磺必利的灵活剂量单药治疗（氨磺必利加安慰剂，每天 200-800 毫克）或奥氮平（奥氮平加安慰剂，每天 5-20 毫克）与氨磺必利联合奥氮平进行比较。主要结果是 8 周后通过 PANSS 总分测量的症状减轻，在改良的意向治疗人群中（所有患者被随机分配到干预并接受至少一种研究药物剂量）。正如先验确定的那样，通过 t 检验（Bonferroni-Holm 调整）检查组差异，然后是预先计划的贝叶斯分析以及基于混合模型的插补方法，以解释缺失值和针对 PANSS 基线分数的事后 ANCOVA 调整. 该研究在 ClinicalTrials.gov 上注册，NCT01609153；德国临床试验注册，DRKS00003603；和欧盟药物监管机构临床试验数据库，EudraCT-No.

发现

在 2012 年 6 月 15 日至 2018 年 12 月 15 日期间，对 13 692 名患者进行了资格评估。排除了 13 364 名患者（包括不符合纳入标准、拒绝参与或改变药物治疗的不当原因），然后将 328 名患者随机分配到干预组。112 名患者被随机分配接受氨磺必利联合奥氮平治疗，109 名患者被随机分配接受氨磺必利联合安慰剂治疗，107 名患者被随机分配接受奥氮平联合安慰剂治疗。在排除筛选失败和未接受干预的患者（氨磺必利加奥氮平组 110 例，氨磺必利加安慰剂组 109 例，奥氮平加安慰剂组 102 例）后，对 321 名患者进行了主要结局分析. 在被随机分配到干预组并分析主要结局的 321 名患者中，229 名（71%）为男性，92 名（29%）为女性；平均年龄为 40·2 岁（SD 11·7）；296 人（92%）是白人，25 人（8%）被归类为其他种族。8 周时，氨磺必利加奥氮平组的 PANSS 总分改善显着（-29·6 [标准差 14·5]）比奥氮平加安慰剂组（-24·1 [13·4]，p=0·049 , 科恩d =0·396)。与氨磺必利和安慰剂组相比，氨磺必利和奥氮平组在 PANSS 总分降低方面未观察到显着差异（-25·2 [SD 15·9]，p=0·095，Cohen's d =0·29） . 8 周和 16 周后，接受氨磺必利联合奥氮平的患者的性功能障碍、体重和腰围增加显着高于接受氨磺必利联合安慰剂的患者，严重不良事件无差异。两名患者在参与研究期间死亡；一名随机分配到氨磺必利加奥氮平组，一名分配到奥氮平加安慰剂组（均评估与治疗无关）。

解释

必须权衡氨磺必利加奥氮平的优势与更高的副作用倾向。在某些临床情况下，使用这种特定的联合疗法可以替代单一疗法，但应考虑副作用。

资金

德国联邦教育和研究部。