Tiihonen Jari, Tanskanen Antti, Mittendorfer-Rutz Ellenor, Howes Oliver D, Correll Christoph U, Siskind Dan, Taipale Heidi
Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Kuopio, Finland.
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
World Psychiatry. 2025 Jun;24(2):250-259. doi: 10.1002/wps.21316.
Although clozapine is the most effective medication for treatment-resistant schizophrenia, response is inadequate in over half of people with that condition. There is limited guidance available on effective clozapine augmentation strategies. We studied the comparative effectiveness of specific doses of oral olanzapine, quetiapine, risperidone and aripiprazole augmentation of clozapine treatment on the risk of hospitalization due to a psychotic episode, as a marker for severe relapse, among patients with schizophrenia or schizoaffective disorder. In this population-based study, patients with one of those diagnoses receiving clozapine were identified from Finnish (years 1995-2017, N=14,053) and Swedish (years 2006-2021, N=8,743) nationwide registers. The risk of hospitalization due to a psychotic episode associated with periods of antipsychotic augmentation of clozapine treatment vs. same-dose clozapine monotherapy was assessed by a within-individual design, using each individual as his/her own control to eliminate selection bias, and analyzed with stratified Cox models. The two national cohorts were first analyzed separately; then results were combined using a random-effect meta-analysis. Secondary outcomes were somatic hospitalization, and hospitalization for psychosis or a somatic cause. The only augmentation associated with a significantly decreased risk of hospitalization due to psychosis in both countries was medium-dose (9 to <16.5 mg/day) aripiprazole combined with high-dose (≥330 mg/day) clozapine, and this combination was associated with the best outcome in the meta-analysis (adjusted hazard ratio, aHR=0.68, 95% CI: 0.62-0.75, p<0.0001). Among patients using medium-dose (180 to <330 mg/day) clozapine, medium-dose aripiprazole augmentation was the only treatment more effective than clozapine monotherapy after Bonferroni correction (aHR=0.79, 95% CI: 0.70-0.91, p=0.0006). The use of all high-dose augmentations was associated with an increased risk of hospitalization due to psychosis. Only aripiprazole augmentations were associated with a decreased risk of hospitalization for psychosis or a somatic cause, and the lowest risk was observed for medium-dose aripiprazole plus high-dose clozapine (aHR=0.70, 95% CI: 0.58-0.84, p=0.0001). This meta-analysis of two nationwide cohorts, totaling almost 23,000 patients using clozapine, indicates that medium-dose aripiprazole augmentation of clozapine treatment is associated with a 20-30% decreased risk of severe relapse compared with clozapine monotherapy within the same individuals, while augmentation with higher doses of aripiprazole (as well as with high doses of all other antipsychotics) is associated with an increased relapse risk.
尽管氯氮平是治疗难治性精神分裂症最有效的药物，但超过半数的此类患者对其反应并不充分。关于有效的氯氮平增效策略的指导有限。我们研究了在精神分裂症或分裂情感性障碍患者中，特定剂量的口服奥氮平、喹硫平、利培酮和阿立哌唑增强氯氮平治疗对因精神病性发作而住院风险（作为严重复发的指标）的比较有效性。在这项基于人群的研究中，从芬兰（1995 - 2017年，N = 14,053）和瑞典（2006 - 2021年，N = 8,743）的全国登记册中识别出接受氯氮平治疗的上述诊断之一的患者。通过个体内设计评估与氯氮平治疗的抗精神病药物增效期相关的精神病性发作导致的住院风险与同剂量氯氮平单一疗法的风险，将每个个体作为其自身对照以消除选择偏倚，并使用分层Cox模型进行分析。两个国家队列首先分别进行分析；然后使用随机效应荟萃分析合并结果。次要结局是躯体疾病住院以及因精神病或躯体原因住院。在两个国家中，唯一与因精神病导致的住院风险显著降低相关的增效治疗是中等剂量（9至<16.5毫克/天）阿立哌唑联合高剂量（≥330毫克/天）氯氮平，并且在荟萃分析中这种联合治疗的结局最佳（调整后风险比，aHR = 0.68，95%置信区间：0.62 - 0.75，p < 0.0001）。在使用中等剂量（180至<330毫克/天）氯氮平的患者中，中等剂量阿立哌唑增效是在Bonferroni校正后唯一比氯氮平单一疗法更有效的治疗（aHR = 0.79，95%置信区间：0.70 - 0.91，p = 0.0006）。所有高剂量增效治疗的使用均与因精神病导致的住院风险增加相关。只有阿立哌唑增效与因精神病或躯体原因住院的风险降低相关，并且中等剂量阿立哌唑加用高剂量氯氮平的风险最低（aHR = 0.70，95%置信区间：0.58 - 0.84，p = 0.0001）。这项对两个全国队列（总计近23,000名使用氯氮平的患者）的荟萃分析表明，与同一患者的氯氮平单一疗法相比，中等剂量阿立哌唑增强氯氮平治疗与严重复发风险降低20 - 30%相关，而更高剂量阿立哌唑（以及所有其他抗精神病药物的高剂量）增效与复发风险增加相关。
