背景:精神分裂症的抗炎药的临床试验没有显示出明显和可复制的益处,可能是因为未基于炎症状态升高招募患者.血清中白细胞介素1β(IL-1β)mRNA和蛋白水平升高,等离子体,脑脊液,一些患有精神分裂症的慢性病患者的大脑,首发精神病,和临床高风险样本。Canakinumab,已批准的抗IL-1β单克隆抗体,干扰IL-1β的生物活性并中断下游信号传导。然而,canakinumab减少外周炎症标志物的程度,例如,高敏C反应蛋白(hsCRP)与精神分裂症伴炎症患者的症状严重程度未知.
方法:我们进行了随机,安慰剂对照,双盲,平行组,canakinumab在外周炎症升高的慢性精神分裂症患者中的8周试验。
方法:27例精神分裂症或分裂情感性障碍并伴有外周炎症标志物升高的患者(IL-1β,IL-6,hsCRP和/或中性粒细胞与淋巴细胞的比率:NLR)随机分为一次性,皮下注射canakinumab(150mg)或安慰剂(生理盐水)作为辅助抗精神病药物治疗。外周血hsCRP,NLR,IL-1β,IL-6,IL-8水平在基线(注射前)和1-,注射后4周和8周。在基线和注射后4和8周评估症状严重程度。
结果:随着时间的推移,Canakinumab显著降低外周hsCRP,F(3,75)=5.16,p=0.003。仅在1、4和8周时在canakinumab组中检测到相对于基线的显著hsCRP降低(分别为p=0.0003、0.000002和0.004)。安慰剂组hsCRP无明显变化。在canakinumab组的第8周(p=0.02)和安慰剂组的第4周(p=0.02),阳性症状严重程度评分显着降低。第8周与基线之间(b=1.9,p=0.0002)和第4周与基线之间(b=6.0,p=0.001)的CRP变化是PANSS阳性症状严重程度评分第8周变化的高度显著预测因子。阴性症状无明显变化,任何一组的一般精神病理学或认知。Canakinumab耐受性良好,仅7%停用。
结论:Canakinumab可迅速降低精神分裂症和炎症患者的外周血hsCRP水平;canakinumab治疗8周后,hsCRP降低与阳性症状严重程度降低相关.未来的研究应该考虑增加剂量或更长期的治疗,以确认辅助康纳单抗在精神分裂症中的潜在益处。澳大利亚和新西兰临床试验登记号:ACTRN12615000635561。
Clinical trials of anti-inflammatories in schizophrenia do not show clear and replicable benefits, possibly because patients were not recruited based on elevated inflammation status. Interleukin 1-beta (IL-1β) mRNA and protein levels are increased in serum, plasma, cerebrospinal fluid, and brain of some chronically ill patients with schizophrenia, first episode psychosis, and clinical high-risk individuals. Canakinumab, an approved anti-IL-1β monoclonal antibody, interferes with the bioactivity of IL-1β and interrupts downstream signaling. However, the extent to which canakinumab reduces peripheral inflammation markers, such as, high sensitivity C-reactive protein (hsCRP) and symptom severity in schizophrenia patients with inflammation is unknown.
We conducted a randomized, placebo-controlled, double-blind, parallel groups, 8-week
trial of canakinumab in chronically ill patients with schizophrenia who had elevated peripheral inflammation.
Twenty-seven patients with schizophrenia or schizoaffective disorder and elevated peripheral inflammation markers (IL-1β, IL-6, hsCRP and/or neutrophil to lymphocyte ratio: NLR) were randomized to a one-time, subcutaneous injection of canakinumab (150 mg) or placebo (normal saline) as an adjunctive antipsychotic treatment. Peripheral blood hsCRP, NLR, IL-1β, IL-6, IL-8 levels were measured at baseline (pre injection) and at 1-, 4- and 8-weeks post injection. Symptom severity was assessed at baseline and 4- and 8-weeks post injection.
Canakinumab significantly reduced peripheral hsCRP over time, F(3, 75) = 5.16, p = 0.003. Significant hsCRP reductions relative to baseline were detected only in the canakinumab group at weeks 1, 4 and 8 (p\'s = 0.0003, 0.000002, and 0.004, respectively). There were no significant hsCRP changes in the placebo group. Positive symptom severity scores were significantly reduced at week 8 (p = 0.02) in the canakinumab group and week 4 (p = 0.02) in the placebo group. The change in CRP between week 8 and baseline (b = 1.9, p = 0.0002) and between week 4 and baseline (b = 6.0, p = 0.001) were highly significant predictors of week 8 change in PANSS Positive Symptom severity scores. There were no significant changes in negative symptoms, general psychopathology or cognition in either group. Canakinumab was well tolerated and only 7 % discontinued.
Canakinumab quickly reduces peripheral hsCRP serum levels in patients with schizophrenia and inflammation; after 8 weeks of canakinumab treatment, the reductions in hsCRP are related to reduced positive symptom severity. Future studies should consider increased doses or longer-term treatment to confirm the potential benefits of adjunctive canakinumab in schizophrenia. Australian and New Zealand Clinical Trials Registry number: ACTRN12615000635561.