Department of Psychiatry, UMC Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Psychiatry, Sheba Medical Center, Tel Hashomer, Israel.
Lancet Psychiatry. 2023 Mar;10(3):197-208. doi: 10.1016/S2215-0366(23)00005-6. Epub 2023 Jan 27.
Schizophrenia is a severe psychiatric disorder with periods of remission and relapse. As discontinuation of antipsychotic medication is the most important reason for relapse, long-term maintenance treatment is key. Whether intramuscular long-acting (depot) antipsychotics are more efficacious than oral medication in preventing medication discontinuation is still unresolved. We aimed to compare time to all-cause discontinuation in patients randomly allocated to long-acting injectable (LAI) versus oral medication.
EULAST was a pragmatic, randomised, open-label trial conducted at 50 general hospitals and psychiatric specialty clinics in 15 European countries and Israel. Patients aged 18 years and older, with DSM-IV schizophrenia (as confirmed by the Mini International Neuropsychiatric Interview 5 plus) and having experienced their first psychotic episode from 6 months to 7 years before screening, were randomly allocated (1:1:1:1) using block randomisation to LAI paliperidone, LAI aripiprazole, or the respective oral formulations of these antipsychotics. Randomisation was stratified by country and duration of illness (6 months up to 3 years vs 4 to 7 years). Patients were followed up for up to 19 months. The primary endpoint was discontinuation, regardless of the reason, during 19 months of treatment. We used survival analysis to assess the time until all-cause discontinuation in the intention-to-treat (ITT) group, and per protocol analyses were also done. This trial is registered with ClinicalTrials.gov, NCT02146547, and is complete.
Between Feb 24, 2015, and Dec 15, 2018, 533 individuals were recruited and assessed for eligibility. The ITT population included 511 participants, with 171 (33%) women and 340 (67%) men, and a mean age of 30·5 (SD 9·6) years. 410 (80%) of 511 participants were White, 35 (7%) were Black, 20 (4%) were Asian, and 46 (9%) were other ethnicity. In the combined oral antipsychotics treatment group of 247 patients, 72 (29%) patients completed the study and 175 (71%) met all-cause discontinuation criteria. In the combined LAI treatment arm of 264 patients, 95 (36%) completed the study and 169 (64%) met the all-cause discontinuation criteria. Cox regression analyses showed that treatment discontinuation for any cause did not differ between the two combined treatment groups (hazard ration [HR] 1·16, 95% CI 0·94-1·43, p=0·18). No significant difference was found in the time to all-cause discontinuation between the combined oral and combined LAI treatment groups (log rank test χ=1·87 [df 1]; p=0·17). During the study, 121 psychiatric hospitalisations occurred in 103 patients, and one patient from each of the LAI groups died; the death of the patient assigned to paliperidone was assessed to be unrelated to the medication, but the cause of other patient's death was not shared with the study team. 86 (25%) of 350 participants with available data met akathisia criteria and 70 (20%) met parkinsonism criteria at some point during the study.
We found no substantial advantage for LAI antipsychotic treatment over oral treatment regarding time to discontinuation in patients with early-phase schizophrenia, indicating that there is no reason to prescribe LAIs instead of oral antipsychotics if the goal is to prevent discontinuation of antipsychotic medication in daily clinical practice.
Lundbeck and Otsuka.
精神分裂症是一种严重的精神疾病，会经历缓解期和复发期。由于抗精神病药物的停药是复发的最重要原因，因此长期维持治疗是关键。长效（储库）抗精神病药物在预防停药方面是否优于口服药物仍未解决。我们旨在比较随机分配至长效注射（LAI）与口服药物的患者的所有原因停药时间。
EULAST 是一项在 15 个欧洲国家和以色列的 50 家综合医院和精神科专科诊所进行的实用、随机、开放性试验。年龄在 18 岁及以上、符合 DSM-IV 精神分裂症（通过 Mini 国际神经精神访谈 5 加证实）且在筛选前 6 个月至 7 年内经历过首次精神病发作的患者，使用按块随机化（1:1:1:1）随机分配至 LAI 帕利哌酮、LAI 阿立哌唑或这些抗精神病药物的相应口服制剂。随机分配按国家和疾病持续时间（6 个月至 3 年与 4 至 7 年）分层。患者接受了长达 19 个月的随访。主要终点是在 19 个月的治疗期间无论原因如何的停药。我们使用生存分析评估意向治疗（ITT）组中所有原因停药的时间，并进行了方案分析。这项试验在 ClinicalTrials.gov 上注册，编号为 NCT02146547，现已完成。
2015 年 2 月 24 日至 2018 年 12 月 15 日期间，共招募了 533 名符合条件的患者。意向治疗人群包括 511 名参与者，其中 171 名（33%）为女性，340 名（67%）为男性，平均年龄为 30.5（SD 9.6）岁。511 名参与者中有 410 名（80%）为白人，35 名（7%）为黑人，20 名（4%）为亚洲人，46 名（9%）为其他种族。在 247 名联合口服抗精神病药物治疗组的患者中，72 名（29%）患者完成了研究，175 名（71%）符合所有原因停药标准。在 264 名联合 LAI 治疗组的患者中，95 名（36%）完成了研究，169 名（64%）符合所有原因停药标准。Cox 回归分析表明，两组联合治疗之间的治疗停药原因无差异（危险比[HR]1.16，95%CI 0.94-1.43，p=0.18）。联合口服和联合 LAI 治疗组之间的所有原因停药时间无显著差异（对数秩检验 χ=1.87[df 1]；p=0.17）。在研究期间，103 名患者发生了 121 次精神病住院治疗，每个 LAI 组各有 1 名患者死亡；评估分配给帕利哌酮的患者的死亡与药物无关，但其他患者的死亡原因未与研究团队分享。350 名有可用数据的参与者中有 86 名（25%）符合静坐不能标准，70 名（20%）在研究期间的某个时间点符合帕金森病标准。
我们发现，对于早期精神分裂症患者，长效抗精神病药物治疗在停药时间方面没有明显优势，这表明如果目标是预防日常临床实践中抗精神病药物的停药，没有理由开长效注射剂而不是口服抗精神病药物。
Lundbeck 和 Otsuka。
