Ralph H. Johnson VA Medical Center, Medical University of South Carolina, Charleston.
Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada.
JAMA Neurol. 2021 Nov 1;78(11):1324-1332. doi: 10.1001/jamaneurol.2021.3356.
Apathy, characterized by diminished will or initiative and one of the most prevalent neuropsychiatric symptoms in individuals with Alzheimer disease, is associated with significant caregiver burden, excess disability, increased medical costs, and mortality.
To measure whether methylphenidate compared with placebo decreases the severity of apathy in individuals with Alzheimer disease.
DESIGN, SETTING, AND PARTICIPANTS: This multicenter randomized placebo-controlled clinical trial was conducted from August 2016 to July 2020 in 9 US clinics and 1 Canadian clinic specializing in dementia care. A total of 307 potential participants were screened. Of those, 52 did not pass screening and 55 were not eligible. Participants with Alzheimer disease, mild to moderate cognitive impairment, and frequent and/or severe apathy as measured by the Neuropsychiatric Inventory (NPI) were included.
Ten milligrams of methylphenidate, twice daily, vs matching placebo.
The coprimary outcomes included (1) change from baseline to 6 months in the NPI apathy subscale or (2) improved rating on the Alzheimer's Disease Cooperative Study Clinical Global Impression of Change. Other outcomes include safety, change in cognition, and quality of life.
Of 200 participants, 99 were assigned to methylphenidate and 101 to placebo. The median (interquartile range) age of study participants was 76 (71-81) years; 68 (34%) were female and 131 (66%) were male. A larger decrease was found from baseline to 6 months in the NPI apathy score in those receiving methylphenidate compared with placebo (mean difference, -1.25; 95% CI, -2.03 to -0.47; P = .002). The largest decrease in the NPI apathy score was observed in the first 100 days, with a significant hazard ratio for the proportion of participants with no apathy symptoms receiving methylphenidate compared with placebo (hazard ratio, 2.16; 95% CI, 1.19-3.91; P = .01). At 6 months, the odds ratio of having an improved rating on the Alzheimer's Disease Cooperative Study Clinical Global Impression of Change for methylphenidate compared with placebo was 1.90 (95% CI, 0.95-3.84; P = .07). The difference in mean change from baseline to 6 months estimated using a longitudinal model was 1.43 (95% CI, 1.00-2.04; P = .048). Cognitive measures and quality of life were not significantly different between groups. Of the 17 serious adverse events that occurred during the study, none were related to the study drug. No significant differences in the safety profile were noted between treatment groups.
This study found methylphenidate to be a safe and efficacious medication to use in the treatment of apathy in Alzheimer disease.
ClinicalTrials.gov Identifier: NCT02346201.
淡漠是阿尔茨海默病患者最常见的神经精神症状之一，其特征为意志或主动性减弱，与 caregiver负担加重、残疾程度增加、医疗费用增加和死亡率升高显著相关。
评估哌醋甲酯与安慰剂相比是否能降低阿尔茨海默病患者的淡漠严重程度。
设计、地点和参与者：这是一项多中心随机安慰剂对照临床试验，于 2016 年 8 月至 2020 年 7 月在 9 个美国诊所和 1 个专门从事痴呆症护理的加拿大诊所进行。共有 307 名潜在参与者接受了筛选。其中，52 名未通过筛选，55 名不符合条件。纳入患有阿尔茨海默病、轻度至中度认知障碍且频繁和/或严重淡漠（通过神经精神疾病问卷[NPI]测量）的患者。
每日两次给予 10 毫克哌醋甲酯，或给予匹配的安慰剂。
主要结局包括（1）基线至 6 个月时 NPI 淡漠量表的变化，或（2）阿尔茨海默病合作研究临床总体印象变化的改善评分。其他结局包括安全性、认知变化和生活质量。
在 200 名参与者中，99 名接受哌醋甲酯治疗，101 名接受安慰剂治疗。研究参与者的中位（四分位距）年龄为 76（71-81）岁；68 名（34%）为女性，131 名（66%）为男性。与安慰剂相比，接受哌醋甲酯治疗的患者在基线至 6 个月时 NPI 淡漠评分下降幅度更大（平均差值，-1.25；95%CI，-2.03 至-0.47；P=0.002）。在最初的 100 天内，NPI 淡漠评分下降幅度最大，与安慰剂相比，接受哌醋甲酯治疗的无淡漠症状参与者的比例具有显著更高的风险比（风险比，2.16；95%CI，1.19-3.91；P=0.01）。在 6 个月时，与安慰剂相比，哌醋甲酯治疗组在阿尔茨海默病合作研究临床总体印象变化方面有改善评分的优势比为 1.90（95%CI，0.95-3.84；P=0.07）。使用纵向模型估计的从基线到 6 个月的平均变化差异为 1.43（95%CI，1.00-2.04；P=0.048）。两组的认知测量和生活质量没有显著差异。在研究期间发生的 17 例严重不良事件中，没有一例与研究药物有关。两组的安全性特征没有显著差异。
这项研究发现，哌醋甲酯是治疗阿尔茨海默病淡漠的一种安全有效的药物。
ClinicalTrials.gov 标识符：NCT02346201。
