Pub Date : 2025-10-01DOI: 10.1016/j.lanhl.2025.100774
Prof Rupert A Payne PhD , Prof Peter S Blair PhD , Barbara Caddick PhD , Prof Carolyn A Chew-Graham MD , Prof Tobias Dreischulte PhD , Lorna J Duncan PhD , Prof Bruce Guthrie PhD , Cindy Mann PhD , Roxanne M Parslow PhD , Prof Jeff Round PhD , Prof Chris Salisbury MD , Prof Katrina M Turner PhD , Nicholas L Turner PhD , Deborah McCahon PhD
<div><h3>Background</h3><div>Polypharmacy is a major and growing challenge for patient safety and health outcomes, and associated with inefficient use of resources. Management requires balancing therapeutic benefits and risks, aligned with clinical and patient priorities. High-quality evidence supporting current guidance for the management of polypharmacy is scarce. The aim of the Improving Medicines use in People with Polypharmacy in Primary Care (IMPPP) study was to examine whether a complex intervention could reduce potentially inappropriate prescribing among patients experiencing polypharmacy in primary care.</div></div><div><h3>Methods</h3><div>A pragmatic, open-label, two-arm, parallel cluster-randomised trial was conducted in UK general practices providing National Health Service primary medical care. Practices were required to use the EMIS electronic health records system and have more than 4000 registered patients. For inclusion in the study, participants were required to be aged 18 years or older, prescribed at least five regular medications (ie, medicines recorded in the clinical system as repeat prescriptions, and thus available for recurrent ordering by patients without having to see a clinician) irrespective of when the drug was last issued, and with at least one indicator of potentially inappropriate prescribing identified by an informatics tool. Practices were randomly allocated to deliver the polypharmacy intervention or continue usual care. The complex intervention comprised a structured, collaborative, and patient-centred approach to medication review, supported by informatics, clinician training, performance feedback, and financial incentivisation. In each practice, adults receiving five or more regular medications, with at least one indicator of potentially inappropriate prescribing, were reviewed over a 6-month period. The primary outcome was number of indicators of potentially inappropriate prescribing at 26 weeks’ follow-up, analysed on an intention-to-treat basis. The trial was registered with the ISRCTN registry (90146150) and is complete.</div></div><div><h3>Findings</h3><div>Between Jan 26, 2022, and June 20, 2022, 37 general practices were recruited. 33 745 patients were potentially eligible, and 11 022 of these were randomly sampled for study inclusion. 1471 were excluded after general practitioner screening, 9551 were invited to participate, and 1950 provided consent and were randomly assigned (944 patients from 18 practices assigned to usual care and 1006 patients from 19 practices assigned to the intervention). 1727 participants were enrolled in the trial (836 in the usual care group and 891 in the intervention group). Participants’ median age was 73 years (IQR 66−79), 881 (51%) were male and 846 (49%) were female, and they had a median of four long-term conditions and a median of eight medications. There was no evidence of a difference in the primary outcome of number of potentially inappropriate prescribing indi
背景：多种用药是对患者安全和健康结果的一个重大且日益严峻的挑战，并与资源的低效利用有关。管理需要平衡治疗益处和风险，与临床和患者优先事项保持一致。目前支持多药管理指南的高质量证据很少。改善初级保健中使用多种药物的患者的药物使用（IMPPP）研究的目的是检查复杂干预是否可以减少初级保健中使用多种药物的患者潜在的不适当处方。方法：在英国提供国家卫生服务初级医疗保健的全科实践中进行了一项实用的、开放标签的、双臂的、平行的集群随机试验。诊所被要求使用EMIS电子健康记录系统，并有超过4000名注册患者。为了纳入研究，参与者被要求年满18岁或以上，开具至少五种常规药物（即，临床系统中记录为重复处方的药物，因此患者无需见临床医生即可反复订购），而不考虑药物最后一次开具的时间，并且至少有一个由信息学工具确定的潜在不适当处方指标。实践随机分配，提供综合干预或继续常规护理。复杂的干预包括一个结构化的、协作的、以患者为中心的药物审查方法，由信息学、临床医生培训、绩效反馈和财政激励支持。在每个实践中，接受五种或更多常规药物治疗的成年人，至少有一个潜在的不当处方指标，在6个月的时间内进行审查。主要结果是26周随访时潜在不适当处方的指标数量，以意向治疗为基础进行分析。该试验已在ISRCTN注册中心注册（90146150），并且已经完成。研究结果：在2022年1月26日至2022年6月20日期间，招募了37名全科医生。33 745名患者可能符合条件，其中11 022名患者被随机抽样纳入研究。1471名全科医生筛查后被排除，9551名被邀请参加，1950名提供同意并随机分配（来自18个诊所的944名患者分配到常规护理组，来自19个诊所的1006名患者分配到干预组）。1727名参与者参加了试验（836名在常规护理组，891名在干预组）。参与者的中位年龄为73岁（IQR 66-79），男性881人（51%），女性846人（49%），他们有中位4种长期疾病和中位8种药物。在调整随机化前基线后的26周随访中，干预组和对照组之间潜在不适当的处方指标数量的主要结局没有证据差异（每组平均2.3；平均差异为- 0.007 [95% CI - 0.21至0.20];p= 0.95）。干预组有13人死亡，99人有一次或多次计划外入院，对照组有12人死亡，91人有一次或多次计划外入院。入院或死亡都不被认为与干预有关。解释：复杂的药物优化干预并没有减少多药患者潜在的不适当处方。这些发现与当前推动数字医疗保健解决方案的政策、对临床药学人员的投资以及促进结构化药物审查的政策不一致。应相应地重新审视有效利用这种战略的问题。资助：国家卫生和保健研究所。
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Pub Date : 2025-10-01DOI: 10.1016/j.lanhl.2025.100777
Harriet Demnitz-King PhD , Mariam Adeleke PhD , Prof Julie A Barber PhD , Michaela Poppe PhD , Jessica Budgett MSc , Sweedal Alberts MRes , Larisa Duffy BSc , Prof Anne-Marie Minihane PhD , Rachel Gillings MSc , Hannah Chapman MSc , Rosario Isabel Espinoza Jeraldo MSc , Oliver Kelsey MSc , Malvika Muralidhar MSc , Sedigheh Zabihi MSc , Elisa Aguirre PhD , Nicholas Bass MD , Anna Betz BA , Henry Brodaty MD , Alexandra Burton PhD , Prof Paul Higgs PhD , Prof Claudia Cooper PhD
<div><h3>Background</h3><div>Trials of high-intensity, multidomain interventions show that modifying lifestyle and psychological risk factors can slow cognitive decline. We aimed to evaluate the effectiveness of a lower-intensity, personally-tailored dementia prevention programme in improving cognition in adults with subjective cognitive decline or mild cognitive impairment.</div></div><div><h3>Methods</h3><div>We conducted a single-masked, multisite, randomised controlled clinical trial recruiting older adults with subjective cognitive decline or mild cognitive impairment across 11 sites in England. Participants were randomly assigned (1:1) to the 12-month Active Prevention in People at Risk of Dementia through Lifestyle, Behaviour Change and Technology to build Resilience (APPLE-Tree) intervention or to the control condition (usual care plus brief written information about dementia prevention). Randomisation was blocked and stratified by site, with allocations assigned via a remote web-based system. The intervention promoted healthy lifestyles, social connections, enjoyable activities, and self-management of long-term conditions. It comprised ten 1-h group video-call sessions over 6 months, supplemented with alternating, informal, 40-min video-call sessions (termed tea breaks) and individual goal-setting calls between sessions. From months 6 to 12, participants continued with monthly online tea breaks. The primary outcome was cognition (Neuropsychological Test Battery [NTB] score) at 24 months, analysed using an intention-to-treat approach. This trial was pre-registered with the ISRCTN Registry (ISRCTN17325135); further analyses are ongoing.</div></div><div><h3>Findings</h3><div>Between Oct 5, 2020, and Dec 31, 2022, we screened 1287 individuals for eligibility and randomly assigned 746 to the APPLE-Tree intervention (n=374) or control treatment (n=372). There were 177 (47%) women and 194 (52%) men in the intervention group and 173 (47%) women and 198 (53%) men in the control group. The primary outcome analysis included 635 (85%) of 746 participants. Mean NTB scores increased in both groups over time, with greater improvement in the intervention group than in the control group (mean 24-month NTB 0·33 [SD 0·67] <em>vs</em> 0·21 [0·75]; adjusted mean difference 0·06 [95% CI –0·001 to 0·128]; p=0·055). Serious adverse events occurred in 35 (9%) participants in the intervention group and 30 (8%) participants in the control group; none were intervention-related.</div></div><div><h3>Interpretation</h3><div>APPLE-Tree is an accessible intervention associated with small improvements in cognition, although these results were not statistically significant. Low-intensity interventions that can be delivered remotely by non-clinical facilitators have the potential for wide-scale implementation to support adults with memory concerns. However, further work is needed to optimise the intervention for delivery in routine settings.</div></div><div><h3>Funding</h3
背景：高强度、多领域干预的试验表明，改变生活方式和心理风险因素可以减缓认知能力下降。我们的目的是评估低强度、个性化的痴呆预防方案在改善主观认知能力下降或轻度认知障碍的成人认知方面的有效性。方法：我们在英国的11个地点进行了一项单蒙面、多地点、随机对照临床试验，招募有主观认知能力下降或轻度认知障碍的老年人。参与者被随机（1:1）分配到12个月的通过生活方式、行为改变和技术建立恢复力的痴呆症风险人群积极预防（苹果树）干预或控制条件（常规护理加关于痴呆症预防的简短书面信息）。随机化被阻止并按地点分层，通过远程网络系统分配分配。干预措施促进了健康的生活方式、社会联系、愉快的活动和对长期状况的自我管理。它包括在6个月内进行10次1小时的小组视频通话，辅以交替进行的40分钟非正式视频通话（称为茶点休息）和会议之间的个人目标设定电话。从第6个月到第12个月，参与者继续每月在网上喝茶。主要结果是24个月时的认知（神经心理测试电池[NTB]评分），使用意向治疗方法进行分析。该试验已在ISRCTN注册中心预注册（ISRCTN17325135）；进一步的分析正在进行中。研究结果：在2020年10月5日至2022年12月31日期间，我们筛选了1287名符合条件的个体，并将746名随机分配到苹果树干预组（n=374）或对照治疗组（n=372）。干预组女性177例（47%），男性194例（52%）；对照组女性173例（47%），男性198例（53%）。主要结局分析包括746名参与者中的635名（85%）。两组平均NTB评分均随时间增加，干预组比对照组改善更大（24个月平均NTB 0.33 [SD 0.67] vs 0.21[0.75]；调整后平均差异0.06 [95% CI - 0.001 ~ 0.128]; p= 0.055）。干预组35例（9%）、对照组30例（8%）发生严重不良事件；没有一个是干预相关的。解释：APPLE-Tree是一种可获得的干预措施，与认知能力的小幅改善有关，尽管这些结果没有统计学意义。可以由非临床辅助人员远程提供的低强度干预有可能大规模实施，以支持有记忆问题的成年人。然而，需要进一步的工作来优化在常规环境中实施的干预措施。资助：经济和社会研究理事会和国家卫生和保健研究所方案赠款。
{"title":"Remote, lower-intensity, multidomain lifestyle intervention for subjective cognitive decline or mild cognitive impairment (APPLE-Tree): a multicentre, single-masked, randomised controlled trial","authors":"Harriet Demnitz-King PhD , Mariam Adeleke PhD , Prof Julie A Barber PhD , Michaela Poppe PhD , Jessica Budgett MSc , Sweedal Alberts MRes , Larisa Duffy BSc , Prof Anne-Marie Minihane PhD , Rachel Gillings MSc , Hannah Chapman MSc , Rosario Isabel Espinoza Jeraldo MSc , Oliver Kelsey MSc , Malvika Muralidhar MSc , Sedigheh Zabihi MSc , Elisa Aguirre PhD , Nicholas Bass MD , Anna Betz BA , Henry Brodaty MD , Alexandra Burton PhD , Prof Paul Higgs PhD , Prof Claudia Cooper PhD","doi":"10.1016/j.lanhl.2025.100777","DOIUrl":"10.1016/j.lanhl.2025.100777","url":null,"abstract":"<div><h3>Background</h3><div>Trials of high-intensity, multidomain interventions show that modifying lifestyle and psychological risk factors can slow cognitive decline. We aimed to evaluate the effectiveness of a lower-intensity, personally-tailored dementia prevention programme in improving cognition in adults with subjective cognitive decline or mild cognitive impairment.</div></div><div><h3>Methods</h3><div>We conducted a single-masked, multisite, randomised controlled clinical trial recruiting older adults with subjective cognitive decline or mild cognitive impairment across 11 sites in England. Participants were randomly assigned (1:1) to the 12-month Active Prevention in People at Risk of Dementia through Lifestyle, Behaviour Change and Technology to build Resilience (APPLE-Tree) intervention or to the control condition (usual care plus brief written information about dementia prevention). Randomisation was blocked and stratified by site, with allocations assigned via a remote web-based system. The intervention promoted healthy lifestyles, social connections, enjoyable activities, and self-management of long-term conditions. It comprised ten 1-h group video-call sessions over 6 months, supplemented with alternating, informal, 40-min video-call sessions (termed tea breaks) and individual goal-setting calls between sessions. From months 6 to 12, participants continued with monthly online tea breaks. The primary outcome was cognition (Neuropsychological Test Battery [NTB] score) at 24 months, analysed using an intention-to-treat approach. This trial was pre-registered with the ISRCTN Registry (ISRCTN17325135); further analyses are ongoing.</div></div><div><h3>Findings</h3><div>Between Oct 5, 2020, and Dec 31, 2022, we screened 1287 individuals for eligibility and randomly assigned 746 to the APPLE-Tree intervention (n=374) or control treatment (n=372). There were 177 (47%) women and 194 (52%) men in the intervention group and 173 (47%) women and 198 (53%) men in the control group. The primary outcome analysis included 635 (85%) of 746 participants. Mean NTB scores increased in both groups over time, with greater improvement in the intervention group than in the control group (mean 24-month NTB 0·33 [SD 0·67] <em>vs</em> 0·21 [0·75]; adjusted mean difference 0·06 [95% CI –0·001 to 0·128]; p=0·055). Serious adverse events occurred in 35 (9%) participants in the intervention group and 30 (8%) participants in the control group; none were intervention-related.</div></div><div><h3>Interpretation</h3><div>APPLE-Tree is an accessible intervention associated with small improvements in cognition, although these results were not statistically significant. Low-intensity interventions that can be delivered remotely by non-clinical facilitators have the potential for wide-scale implementation to support adults with memory concerns. However, further work is needed to optimise the intervention for delivery in routine settings.</div></div><div><h3>Funding</h3","PeriodicalId":34394,"journal":{"name":"Lancet Healthy Longevity","volume":"6 10","pages":"Article 100777"},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145356260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-01DOI: 10.1016/j.lanhl.2025.100788
Sandrine Sourdet , Laurent Balardy
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Pub Date : 2025-10-01DOI: 10.1016/j.lanhl.2025.100773
Jian Hua Tay BSc , Duarte Barros MSc , Weilan Wang PhD , Vanessa Kristina Wazny PhD , Andrea B Maier MD
Background
Frailty is an age-related condition characterised by multisystem physiological decline, which increases vulnerability to adverse outcomes. Biomarkers of ageing might identify individuals at risk and enable early interventions. This systematic review and meta-analysis aimed to examine cross-sectional and longitudinal associations between DNA methylation-based biological age metrics (eg, DNA methylation age, epigenetic-age acceleration [EAA], and age deviation) and frailty.
Methods
In a systematic search of six databases (Embase, Cochrane Central Register of Controlled Trials, PubMed, Ovid, Scopus, and Web of Science) from Jan 1, 2011, to June 6, 2025, we identified population-based cohort studies reporting associations between DNA methylation age, EAA, or age deviation and frailty from general or disease-specific populations with a control group. Risk of bias was assessed using an adapted Newcastle–Ottawa Scale. Random-effects meta-analyses with Hartung–Knapp adjustments were performed on standardised β coefficients and SEs. Publication bias, influence, and sensitivity analyses were conducted.
Findings
From 34 437 records screened, 24 studies met the inclusion criteria (17 cross-sectional studies, one longitudinal study, and six studies that were both cross-sectional and longitudinal), encompassing 28 325 participants (14 757 [52·1%] female; median of mean age 65·2 years [IQR 62·2–69·4]). DNA methylation age and age deviation showed no association with frailty. In cross-sectional meta-analyses, higher Hannum EAA (nine studies; n=11 162; standardised β coefficient 0·06 [95% CI 0·02–0·09], I2=71·4%), PhenoAge EAA (eight studies; n=10 371; 0·07 [0·03–0·11], I2=81·7%), GrimAge EAA (eight studies; n=10 371; 0·11 [0·06–0·15], I2=90·5%), and pace of ageing (five studies; n=7895; 0·10 [0·01–0·19], I2=91·0%) were significantly associated with higher frailty. In longitudinal meta-analyses, higher GrimAge EAA (five studies; n=6143; 0·02 [0·00–0·05], I2=46·0%, p=0·0481) was significantly associated with increases in frailty, whereas PhenoAge EAA and pace of ageing were not significantly associated with frailty.
Interpretation
Higher GrimAge EAA is consistently associated with higher frailty. Future research should focus on developing and validating DNA methylation clocks that integrate molecular surrogates of health risk and are specifically trained to predict frailty in large, harmonised, longitudinal cohorts, enabling their translation into clinical practice.
{"title":"Biological age measured by DNA methylation clocks and frailty: a systematic review and meta-analysis","authors":"Jian Hua Tay BSc , Duarte Barros MSc , Weilan Wang PhD , Vanessa Kristina Wazny PhD , Andrea B Maier MD","doi":"10.1016/j.lanhl.2025.100773","DOIUrl":"10.1016/j.lanhl.2025.100773","url":null,"abstract":"<div><h3>Background</h3><div>Frailty is an age-related condition characterised by multisystem physiological decline, which increases vulnerability to adverse outcomes. Biomarkers of ageing might identify individuals at risk and enable early interventions. This systematic review and meta-analysis aimed to examine cross-sectional and longitudinal associations between DNA methylation-based biological age metrics (eg, DNA methylation age, epigenetic-age acceleration [EAA], and age deviation) and frailty.</div></div><div><h3>Methods</h3><div>In a systematic search of six databases (Embase, Cochrane Central Register of Controlled Trials, PubMed, Ovid, Scopus, and Web of Science) from Jan 1, 2011, to June 6, 2025, we identified population-based cohort studies reporting associations between DNA methylation age, EAA, or age deviation and frailty from general or disease-specific populations with a control group. Risk of bias was assessed using an adapted Newcastle–Ottawa Scale. Random-effects meta-analyses with Hartung–Knapp adjustments were performed on standardised β coefficients and SEs. Publication bias, influence, and sensitivity analyses were conducted.</div></div><div><h3>Findings</h3><div>From 34 437 records screened, 24 studies met the inclusion criteria (17 cross-sectional studies, one longitudinal study, and six studies that were both cross-sectional and longitudinal), encompassing 28 325 participants (14 757 [52·1%] female; median of mean age 65·2 years [IQR 62·2–69·4]). DNA methylation age and age deviation showed no association with frailty. In cross-sectional meta-analyses, higher Hannum EAA (nine studies; n=11 162; standardised β coefficient 0·06 [95% CI 0·02–0·09], <em>I</em><sup>2</sup>=71·4%), PhenoAge EAA (eight studies; n=10 371; 0·07 [0·03–0·11], <em>I</em><sup><em>2</em></sup>=81·7%), GrimAge EAA (eight studies; n=10 371; 0·11 [0·06–0·15], <em>I</em><sup><em>2</em></sup>=90·5%), and pace of ageing (five studies; n=7895; 0·10 [0·01–0·19], <em>I</em><sup><em>2</em></sup>=91·0%) were significantly associated with higher frailty. In longitudinal meta-analyses, higher GrimAge EAA (five studies; n=6143; 0·02 [0·00–0·05], <em>I</em><sup><em>2</em></sup>=46·0%, p=0·0481) was significantly associated with increases in frailty, whereas PhenoAge EAA and pace of ageing were not significantly associated with frailty.</div></div><div><h3>Interpretation</h3><div>Higher GrimAge EAA is consistently associated with higher frailty. Future research should focus on developing and validating DNA methylation clocks that integrate molecular surrogates of health risk and are specifically trained to predict frailty in large, harmonised, longitudinal cohorts, enabling their translation into clinical practice.</div></div><div><h3>Funding</h3><div>National University of Singapore.</div></div>","PeriodicalId":34394,"journal":{"name":"Lancet Healthy Longevity","volume":"6 10","pages":"Article 100773"},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145483225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-01DOI: 10.1016/j.lanhl.2025.100767
Hanadi A Oughli MD , Nicholas J Ainsworth MD PhD , Prof Meryl A Butters PhD , Patrick J Brown PhD , Marie Anne Gebara MD , Torie R Gettinger PhD , Prof Jordan F Karp MD , Helen Lavretsky MD MS , Emily Lenard LMSW , Prof J Philip Miller AB , Prof Benoit H Mulsant MD MS , Ginger E Nicol MD , Prof Charles F Reynolds 3rd MD , Michael Yingling MS , Prof Eric J Lenze MD , OPTIMUM Research Group
<div><h3>Background</h3><div>The cognitive effects of various antidepressant strategies for treatment-resistant depression in older adults are unclear. We aimed to evaluate acute cognitive changes associated with various pharmacotherapy treatment strategies for treatment-resistant depression in older adults.</div></div><div><h3>Methods</h3><div>We did a prespecified secondary analysis of the OPTIMUM trial, which was a pragmatic, randomised, comparative effectiveness trial of various augmentation or switch pharmacotherapy strategies, enrolling adults aged 60 years or older with treatment-resistant depression. Participants were recruited from five academic medical centres (four in the USA and one in Canada). In Step 1 (n=391), participants were randomly assigned 1:1:1 to augmentation of their antidepressant with aripiprazole (to a maximum of 15 mg per day) or bupropion (to a maximum of 450 mg per day) or to a switch to bupropion (same dose as the bupropion-augmentation group). In Step 2 (n=182), participants who were ineligible for Step 1 or did not reach remission in this step were randomly assigned 1:1 to augmentation with lithium (titrated to attain a plasma concentration range of 0·4–0·8 mEq/L) or to a switch to nortriptyline (to reach a therapeutic plasma concentration of 80–120 ng/mL). Each step lasted 10 weeks, with 12 months of follow-up after completion of Step 1 or Step 2. The primary outcome was cognitive function at the end of Step 1 and Step 2, as evaluated with the National Institutes of Health (NIH) Toolbox Fluid Cognition Composite Score, part of the NIH Toolbox Cognition Battery. The primary outcome was analysed in the intention-to-treat population. An exploratory post-hoc analysis conducted in both the intention-to-treat and per-protocol populations examined changes in the individual cognitive tasks constituting the Fluid Cognition Composite Score. OPTIMUM was registered with <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> (<span><span>NCT02960763</span><svg><path></path></svg></span>) and is complete.</div></div><div><h3>Findings</h3><div>Between Feb 22, 2017, and Dec 31, 2019, 742 participants were enrolled in the OPTIMUM study. In Step 1, 619 (83%) participants were randomly assigned to aripiprazole augmentation (n=211), bupropion augmentation (n=206), or a switch to bupropion monotherapy (n=202); cognitive data were available for 128, 136, and 127 participants, respectively. 248 participants were enrolled in Step 2 and randomly assigned to lithium augmentation (n=127) or to a switch to nortriptyline monotherapy (n=121); cognitive data were available for 89 and 93 participants, respectively. Over 10 weeks, there were no significant differences between pharmacotherapy strategies in the Fluid Cognition Composite Score. In Step 1, a time × group interaction was observed for the Flanker Inhibitory Control and Attention test (<em>F</em>[2,266]=3·97; p=0·020), with a contrast analysis showing that aripiprazole au
{"title":"Cognitive changes in older adults receiving pharmacotherapy for treatment-resistant depression: a secondary analysis of the OPTIMUM randomised controlled trial","authors":"Hanadi A Oughli MD , Nicholas J Ainsworth MD PhD , Prof Meryl A Butters PhD , Patrick J Brown PhD , Marie Anne Gebara MD , Torie R Gettinger PhD , Prof Jordan F Karp MD , Helen Lavretsky MD MS , Emily Lenard LMSW , Prof J Philip Miller AB , Prof Benoit H Mulsant MD MS , Ginger E Nicol MD , Prof Charles F Reynolds 3rd MD , Michael Yingling MS , Prof Eric J Lenze MD , OPTIMUM Research Group","doi":"10.1016/j.lanhl.2025.100767","DOIUrl":"10.1016/j.lanhl.2025.100767","url":null,"abstract":"<div><h3>Background</h3><div>The cognitive effects of various antidepressant strategies for treatment-resistant depression in older adults are unclear. We aimed to evaluate acute cognitive changes associated with various pharmacotherapy treatment strategies for treatment-resistant depression in older adults.</div></div><div><h3>Methods</h3><div>We did a prespecified secondary analysis of the OPTIMUM trial, which was a pragmatic, randomised, comparative effectiveness trial of various augmentation or switch pharmacotherapy strategies, enrolling adults aged 60 years or older with treatment-resistant depression. Participants were recruited from five academic medical centres (four in the USA and one in Canada). In Step 1 (n=391), participants were randomly assigned 1:1:1 to augmentation of their antidepressant with aripiprazole (to a maximum of 15 mg per day) or bupropion (to a maximum of 450 mg per day) or to a switch to bupropion (same dose as the bupropion-augmentation group). In Step 2 (n=182), participants who were ineligible for Step 1 or did not reach remission in this step were randomly assigned 1:1 to augmentation with lithium (titrated to attain a plasma concentration range of 0·4–0·8 mEq/L) or to a switch to nortriptyline (to reach a therapeutic plasma concentration of 80–120 ng/mL). Each step lasted 10 weeks, with 12 months of follow-up after completion of Step 1 or Step 2. The primary outcome was cognitive function at the end of Step 1 and Step 2, as evaluated with the National Institutes of Health (NIH) Toolbox Fluid Cognition Composite Score, part of the NIH Toolbox Cognition Battery. The primary outcome was analysed in the intention-to-treat population. An exploratory post-hoc analysis conducted in both the intention-to-treat and per-protocol populations examined changes in the individual cognitive tasks constituting the Fluid Cognition Composite Score. OPTIMUM was registered with <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> (<span><span>NCT02960763</span><svg><path></path></svg></span>) and is complete.</div></div><div><h3>Findings</h3><div>Between Feb 22, 2017, and Dec 31, 2019, 742 participants were enrolled in the OPTIMUM study. In Step 1, 619 (83%) participants were randomly assigned to aripiprazole augmentation (n=211), bupropion augmentation (n=206), or a switch to bupropion monotherapy (n=202); cognitive data were available for 128, 136, and 127 participants, respectively. 248 participants were enrolled in Step 2 and randomly assigned to lithium augmentation (n=127) or to a switch to nortriptyline monotherapy (n=121); cognitive data were available for 89 and 93 participants, respectively. Over 10 weeks, there were no significant differences between pharmacotherapy strategies in the Fluid Cognition Composite Score. In Step 1, a time × group interaction was observed for the Flanker Inhibitory Control and Attention test (<em>F</em>[2,266]=3·97; p=0·020), with a contrast analysis showing that aripiprazole au","PeriodicalId":34394,"journal":{"name":"Lancet Healthy Longevity","volume":"6 10","pages":"Article 100767"},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145521262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Time is an under-recognised social determinant of brain health, and is potentially as important as education or income for dementia risk. Temporal inequity refers to the unequal distribution of discretionary time owing to structural conditions shaping daily life. Temporal inequity encompasses insufficient time for rest, misaligned biological rhythms, fragmented leisure, and the encroachment of work or digital demands into personal time. Time poverty is a measurable manifestation, denoting insufficient time for brain health, disproportionately affecting structurally disadvantaged populations and exacerbated by performance-driven cultures. Although evidence for modifiable risk factors of dementia, such as sleep, physical activity, nutrition, and social engagement, is strong, adopting healthy behaviours requires time. In this Personal View, we integrate insights from epidemiology, neuroscience, and time-use research to argue that addressing temporal inequity is essential for brain health and dementia risk reduction. We call for temporal justice through research and policies that recognise time as both a resource and a site of inequity in ageing and dementia. Accordingly, we outline future research directions, including the development of metrics for temporal inequity, longitudinal studies linking time-use patterns to brain health outcomes, and intervention research to evaluate policies that expand equitable access to time.
{"title":"Making time for brain health: recognising temporal inequity in dementia risk reduction","authors":"Susanne Röhr PhD , Simone Reppermund PhD , Annabel Matison PhD , Suraj Samtani PhD , Prof Perminder S Sachdev MD PhD","doi":"10.1016/j.lanhl.2025.100768","DOIUrl":"10.1016/j.lanhl.2025.100768","url":null,"abstract":"<div><div>Time is an under-recognised social determinant of brain health, and is potentially as important as education or income for dementia risk. Temporal inequity refers to the unequal distribution of discretionary time owing to structural conditions shaping daily life. Temporal inequity encompasses insufficient time for rest, misaligned biological rhythms, fragmented leisure, and the encroachment of work or digital demands into personal time. Time poverty is a measurable manifestation, denoting insufficient time for brain health, disproportionately affecting structurally disadvantaged populations and exacerbated by performance-driven cultures. Although evidence for modifiable risk factors of dementia, such as sleep, physical activity, nutrition, and social engagement, is strong, adopting healthy behaviours requires time. In this Personal View, we integrate insights from epidemiology, neuroscience, and time-use research to argue that addressing temporal inequity is essential for brain health and dementia risk reduction. We call for temporal justice through research and policies that recognise time as both a resource and a site of inequity in ageing and dementia. Accordingly, we outline future research directions, including the development of metrics for temporal inequity, longitudinal studies linking time-use patterns to brain health outcomes, and intervention research to evaluate policies that expand equitable access to time.</div></div>","PeriodicalId":34394,"journal":{"name":"Lancet Healthy Longevity","volume":"6 10","pages":"Article 100768"},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145309369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-01DOI: 10.1016/j.lanhl.2025.100776
Natalia Dowgiałło-Gornowicz
{"title":"Metabolic and bariatric surgery in septuagenarians","authors":"Natalia Dowgiałło-Gornowicz","doi":"10.1016/j.lanhl.2025.100776","DOIUrl":"10.1016/j.lanhl.2025.100776","url":null,"abstract":"","PeriodicalId":34394,"journal":{"name":"Lancet Healthy Longevity","volume":"6 10","pages":"Article 100776"},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145422959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-01DOI: 10.1016/j.lanhl.2025.100791
Anna Hung , Yoon Hie Kim , Juliessa M Pavon
{"title":"Testing complex interventions for polypharmacy in real-world conditions","authors":"Anna Hung , Yoon Hie Kim , Juliessa M Pavon","doi":"10.1016/j.lanhl.2025.100791","DOIUrl":"10.1016/j.lanhl.2025.100791","url":null,"abstract":"","PeriodicalId":34394,"journal":{"name":"Lancet Healthy Longevity","volume":"6 10","pages":"Article 100791"},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145446062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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