Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, ON, Canada.
CNS Drugs. 2022 Feb;36(2):143-165. doi: 10.1007/s40263-021-00883-0. Epub 2022 Jan 10.
Apathy is a highly prevalent symptom of dementia. Despite its association with faster cognitive and functional decline, decreased quality of life and increased mortality, no therapies are currently approved to treat apathy. The objective of this review was to summarize the drugs that have been studied for apathy treatment in patients with dementia (specifically Alzheimer's disease [AD], Huntington's disease [HD] and Parkinson's disease [PD] dementia; dementia with Lewy bodies [DLB]; vascular dementia [VaD]; and frontotemporal dementia [FTD]) based on their putative mechanisms of action. A search for relevant studies was performed using ClinicalTrials.gov and PubMed. Eligible studies were randomized controlled trials that were available in English and included at least one drug intervention and an apathy measure scale. A total of 52 studies that included patients with AD (n = 33 studies), PD (n = 5), HD (n = 1), DLB (n = 1), FTD (n = 3), VaD (n = 1), VaD and AD (n = 4), VaD and mixed dementia (n = 1), and AD, VaD and mixed dementia (n = 3) were eligible for inclusion. These studies showed that methylphenidate, olanzapine, cholinesterase inhibitors, choline alphoscerate, citalopram, memantine, and mibampator are the only beneficial drugs in AD-related apathy. For PD-related apathy, only methylphenidate, rotigotine and rivastigmine showed benefits. Regarding FTD- and DLB-related apathy, initial studies with agomelatine and rivastigmine showed benefits, respectively. As for HD- and only-VaD-related apathy, no drugs demonstrated benefits. With regards to mixed populations, memantine, galantamine and gingko biloba showed effects on apathy in the AD plus VaD populations and nimodipine in the VaD plus mixed dementia populations. Of the drugs with positive results, some are already prescribed to patients with dementia to target other symptoms, some have characteristics-such as medical contraindications (e.g., cardiovascular) and adverse effects (e.g., gastrointestinal disturbances)-that limit their clinical use and some require further study. Future studies should investigate apathy as a primary outcome, making use of appropriate sample sizes and study durations to ensure durability of results. There should also be a consensus on using scales with high test/retest and interrater reliabilities to limit the inconsistencies between clinical trials. In conclusion, there are currently no US FDA-approved drugs that target apathy in dementia, so there is an ongoing need for the development of such drugs.
淡漠是痴呆的一种常见症状。尽管它与认知和功能下降更快、生活质量下降和死亡率增加有关，但目前尚无批准用于治疗淡漠的疗法。本综述的目的是根据其潜在的作用机制，总结已在痴呆患者（特别是阿尔茨海默病[AD]、亨廷顿病[HD]和帕金森病[PD]痴呆；路易体痴呆[DLB]；血管性痴呆[VaD]；额颞叶痴呆[FTD]）中研究用于治疗淡漠的药物。使用 ClinicalTrials.gov 和 PubMed 进行了相关研究的搜索。合格的研究是随机对照试验，这些试验为英文，并且至少包括一种药物干预和一种淡漠量表。共有 52 项研究符合纳入标准，其中包括 AD 患者（n = 33 项研究）、PD（n = 5 项）、HD（n = 1 项）、DLB（n = 1 项）、FTD（n = 3 项）、VaD（n = 1 项）、VaD 和 AD（n = 4 项）、VaD 和混合性痴呆（n = 1 项）以及 AD、VaD 和混合性痴呆（n = 3 项）。这些研究表明，哌醋甲酯、奥氮平、胆碱酯酶抑制剂、胞磷胆碱、西酞普兰、美金刚和米巴喷丁是 AD 相关淡漠的唯一有效药物。对于 PD 相关的淡漠，只有哌醋甲酯、罗替戈汀和利斯的明显示出益处。对于 FTD 和 DLB 相关的淡漠，曲拉唑酮和利斯的明的初步研究分别显示出益处。至于 HD 和仅 VaD 相关的淡漠，没有药物显示出益处。对于混合人群，美金刚、加兰他敏和银杏叶在 AD 加 VaD 人群中以及尼莫地平在 VaD 加混合性痴呆人群中对淡漠有影响。在具有阳性结果的药物中，一些药物已用于治疗痴呆症以针对其他症状，一些药物具有特征（例如医学禁忌症（例如心血管）和不良反应（例如胃肠道紊乱）），限制了其临床应用，一些药物需要进一步研究。未来的研究应该将淡漠作为主要结果进行调查，使用适当的样本量和研究持续时间来确保结果的持久性。还应该就使用具有较高测试/重测和评分者间可靠性的量表达成共识，以限制临床试验之间的不一致性。总之，目前没有美国食品和药物管理局（FDA）批准的针对痴呆淡漠的药物，因此仍需要开发此类药物。
