Efficacy and safety of pharmacotherapy for Alzheimer’s disease and for behavioural and psychological symptoms of dementia in older patients with moderate and severe functional impairments: a systematic review of controlled trials

Abstract

Background Many patients with Alzheimer’s disease (AD) are physically frail or have substantial functional impairments. There is growing evidence that such patients are at higher risk for medication-induced adverse events. Furthermore, frailty seems to be more predictive of poor clinical outcomes than chronological age alone. To our knowledge, no systematic review of clinical trials examining drug therapy of AD or behavioural and psychological symptoms of dementia (BPSD) has specifically focused on the topic of physical frailty. Our objective was to evaluate the efficacy and safety of pharmacotherapy in AD patients with frailty or significant functional impairments. Methods We performed a systematic literature search in MEDLINE, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) for randomized controlled trials (RCTs) of drug therapy of AD and BPSD in patients with significant functional impairments according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and Cochrane research criteria. Significant functionally impaired patient populations were identified using the recommendations of the Medication and Quality of Life in frail older persons (MedQoL) Research Group. Screening, selection of studies, data extraction and risk of bias assessment were performed independently by two reviewers. Outcomes including functional status, cognitive function, changes in BPSD symptoms, clinical global impression and quality of life were analysed. For assessing harm, we assessed adverse events, drop-outs as a proxy for treatment tolerability and death. Results were analysed according to Cochrane standards and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Results Of 45,045 search results, 38,447 abstracts and 187 full texts were screened, and finally, 10 RCTs were included in the systematic review. Selected articles evaluated pharmacotherapy with acetylcholinesterase-inhibitors (AChEI), anticonvulsants, antidepressants and antipsychotics. Studies of AChEIs suggested that patients with significant functional impairments had slight but significant improvements in cognition and that AChEIs were generally well tolerated. Studies of antidepressants did not show significant improvements in depressive symptoms. Antipsychotics and anticonvulsants showed small effects on some BPSD items but also higher rates of adverse events. However, due to the very small number of identified trials, the quality of evidence for all outcomes was low to very low. Overall, the small number of eligible studies demonstrates that significantly functional impaired older patients have not been adequately taken into consideration in most clinical trials investigating drug therapy of AD and BPSD. Conclusion Due to lack of evidence, it is not possible to give specific recommendations for drug therapy of AD and BSPD in frail older patients or older patients with significant functional impairments. Therefore, clinical trials focussing on frail older adults are urgently required. A standardized approach to physical frailty in future clinical studies is highly desirable.

Mechanisms Involved in Epileptogenesis in Alzheimer’s Disease and Their Therapeutic Implications

“…Valproic acid (VPA) is a broad-spectrum ASM currently not indicated in AD-related epilepsy due to its suboptimal cognitive and motor security profile. It has, however, also shown evidence in animal models and cell cultures to: 1) reduce the amount of Aβ oligomers and neuritic plaques [73,124]; 2) inhibit the activity of GSK-3β and thus the amount of hyperphosphorylated tau [124,125]; 3) reduce neuronal loss activating the antiapoptotic protein Bcl-2 and promotes neurogenesis by its histone deacetylase inhibitor capacity [126]; 4) stimulate GABAergic neuron differentiation and 5) reduce glial differentiation [118,126,127]. Only one study including LOEU patients suggested improvement of verbal fluency, but not other cognitive domains with the use of VPA [9] (Table 5).…”

Physician-Assisted Suicide in Dementia: Paradoxes, Pitfalls and the Need for Prudence

“…For the purpose of the review and analysis presented below, the PubMed, ProQuest and Scopus literature databases were searched using the broad search terms “dementia” AND either “euthanasia,” “assisted suicide,” “physician-assisted suicide” or “medical assistance in dying.” After removal of duplicates, a total of 642 citations were retrieved via this initial search. Further searches were conducted within these results using the additional search terms “caregiver,” “caregiver burden,” “stress,” “behavioral and psychological symptoms of dementia,” “BPSD,” “economic,” “financial,” “autonomy,” “dignity,” “identity,” “personhood” and “ethics.” By this method, a total of 103 citations were retained ( Pereira, 2011 ; Schuurmans et al, 2021 ; Kemmelmeier et al, 2002 ; Bradley, 2009 ; Baeke et al, 2011 ; Chakraborty et al, 2017 ; Madadin et al, 2020 ; Nichols, 2013 ; Emanuel et al, 2000 ; Krag, 2014 ; Trachtenberg and Manns, 2017 ; Bilchik, 1996 ; Lazar and Davenport, 2018 ; Karrer et al, 2020 ; Stakišaitis et al, 2019 ; Finucane et al, 2007 ; Finucane, 1999 ; Sachs et al, 2004 ; Dominguez et al, 2021 ; Meier, 1997 ; Liu et al, 2020 ; Gao et al, 2019 ; Gilhooly et al, 2016 ; Watson et al, 2019 ; Cheng, 2017 ; Biggs et al, 2019 ; Fam et al, 2019 ; Dening et al, 2013 ; Owen et al, 2001 ; Cohen-Mansfield and Brill, 2020 ; Anderson et al, 2019 ; O'Dwyer et al, 2016 ; Bravo et al, 2018 ; Wicher and Meeker, 2012 ; Stolz et al, 2015 ; Seike et al, 2021 ; Kashimura et al, 2021 ; Zwingmann et al, 2018 ; Gitlin et al, 2019 ; von Känel et al, 2019 ; Zwingmann et al, 2019 ; Gerk, 2017 ; Kipke, 2015 ; Deardorff and Grossberg, 2019 ; Tiel et al, 2015 ; Borroni et al, 2008 ; Kim et al, 2021 ; Yunusa et al, 2019 ; Seibert et al, 2021 ...…”

“…In addition to impairing the quality of life of both patients and caregivers, some of these symptoms – particularly agitation, aggression and hallucinations – are associated with a marked elevation in the burden faced by caregivers ( Kim et al, 2021 ). Though such symptoms are conventionally treated with medications such as atypical antipsychotics and antidepressants, their efficacy is modest and their use is often limited by adverse drug reactions ( Yunusa et al, 2019 ; Seibert et al, 2021 ). For these reasons, BPSD is sometimes cited as an “indication,” or at least as a contributory factor, for the approval of PAS in patients with moderate or severe dementia ( Dierickx et al, 2017 ).…”

Personalised treatment for cognitive impairment in dementia: development and validation of an artificial intelligence model

“…The guidelines are informed by double-blind placebo-controlled randomised trials showing that decline in cognitive performance stabilises for a period of 3–6 months after treatment initiation and have been replicated in a large real-world observational study [ 7 ]. However, previous studies that assessed the efficacy of these medications on dementia focused on the average effect of these interventions and did not investigate the potential differences at the level of individual patients [ 8 ]. There is a strong movement in clinical research advocating for a more personalised approach in medicine, using more advanced analytical approaches so that nonlinear relationships among multiple factors can be explored together [ 9 ].…”