Cognitive and neuropsychiatric effects of noradrenergic treatment in Alzheimer's disease: systematic review and meta-analysis.
Cognitive and neuropsychiatric effects of noradrenergic treatment in Alzheimer's disease: systematic review and meta-analysis.
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DOI：
10.1136/jnnp-2022-329136
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发表时间：
2022-07-05
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蓝斑-去甲肾上腺素能系统的功能障碍发生在阿尔茨海默病的早期，导致一些患者的认知和神经精神症状。该系统提供了一个潜在的治疗靶点，尽管去甲肾上腺素能治疗目前尚未用于临床实践。评估主要具有去甲肾上腺素能作用的药物在改善阿尔茨海默病认知和神经精神症状方面的疗效。检索了MEDLINE、Embase和ClinicalTrials.gov数据库，检索时间为1980年至2021年12月。我们使用随机效应荟萃分析生成汇总估计值。我们纳入了19项随机对照试验（1811例患者），其中6项被判定为“良好”质量，7项被判定为“一般”，6项被判定为“较差”。其中10项研究（1300例患者）的荟萃分析显示，去甲肾上腺素能药物对整体认知有显著的小的积极影响，使用简易精神状态检查或阿尔茨海默病评估量表-认知子量表进行测量（标准化平均差异（SMD）：0.14，95% CI：0.03至0.25，p=0.01; I2=0%）。对注意力指标无显著影响（SMD：0.01，95% CI：-0.17至0.19，p=0.91; I2=0）。冷漠荟萃分析包括8项试验（425例患者），并检测到去甲肾上腺素能药物的大量积极作用（SMD：0.45，95% CI：0.16至0.73，p=0.002; I2=58%）。在去除离群值以解释研究间的异质性后，仍存在这种积极效应。重新使用已建立的去甲肾上腺素能药物最有可能为阿尔茨海默病的一般认知和冷漠提供有效的治疗。然而，在设计未来的临床试验之前，应考虑几个因素。这些包括针对适当的患者亚组，了解单个药物的剂量效应及其与其他治疗的相互作用，以最大限度地降低风险并最大限度地提高治疗效果。CRD 42021277500。
Dysfunction of the locus coeruleus-noradrenergic system occurs early in Alzheimer’s disease, contributing to cognitive and neuropsychiatric symptoms in some patients. This system offers a potential therapeutic target, although noradrenergic treatments are not currently used in clinical practice. To assess the efficacy of drugs with principally noradrenergic action in improving cognitive and neuropsychiatric symptoms in Alzheimer’s disease. The MEDLINE, Embase and ClinicalTrials.gov databases were searched from 1980 to December 2021. We generated pooled estimates using random effects meta-analyses. We included 19 randomised controlled trials (1811 patients), of which six were judged as ‘good’ quality, seven as ‘fair’ and six ‘poor’. Meta-analysis of 10 of these studies (1300 patients) showed a significant small positive effect of noradrenergic drugs on global cognition, measured using the Mini-Mental State Examination or Alzheimer’s Disease Assessment Scale—Cognitive Subscale (standardised mean difference (SMD): 0.14, 95% CI: 0.03 to 0.25, p=0.01; I2=0%). No significant effect was seen on measures of attention (SMD: 0.01, 95% CI: −0.17 to 0.19, p=0.91; I2=0). The apathy meta-analysis included eight trials (425 patients) and detected a large positive effect of noradrenergic drugs (SMD: 0.45, 95% CI: 0.16 to 0.73, p=0.002; I2=58%). This positive effect was still present following removal of outliers to account for heterogeneity across studies. Repurposing of established noradrenergic drugs is most likely to offer effective treatment in Alzheimer’s disease for general cognition and apathy. However, several factors should be considered before designing future clinical trials. These include targeting of appropriate patient subgroups and understanding the dose effects of individual drugs and their interactions with other treatments to minimise risks and maximise therapeutic effects. CRD42021277500.
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