Authors: Misha Choudry, Murdoc Gould, Latha Ganti
Categories: Research, Dementia, Systematic review, Agitation
Source: International Journal of Emergency Medicine
Authors: Misha Choudry, Murdoc Gould, Latha Ganti
Dementia, including Alzheimer’s disease (AD), affects millions worldwide, leading to cognitive decline, memory loss, and behavioral disturbances. Agitation, a common symptom, poses significant challenges for patients and caregivers. This systematic review evaluates pharmacological and non-pharmacological interventions for managing agitation in dementia. Nine clinical studies were analyzed, encompassing medications like brexpiprazole and non-pharmacological approaches such as music therapy and digital care programs. Pharmacological treatments showed mixed efficacy and safety profiles, with brexpiprazole demonstrating dose-dependent benefits and mirtazapine associating with higher mortality rates. Non-pharmacological interventions exhibited promising results in reducing agitation without adverse effects. The review underscores the importance of personalized care strategies tailored to individual patient needs and preferences to enhance treatment efficacy and quality of life, highlighting the shift toward holistic, individualized care.
Dementia, including Alzheimer’s disease (AD), affects over 55 million people worldwide, with nearly 10 million new cases each year according to the World Health Organization (WHO) [1]. This progressive condition is characterized by cognitive decline, memory loss, and behavioral disturbances, significantly impacting patients’ quality of life and imposing a considerable burden on caregivers [2]. One of the most challenging behavioral symptoms associated with dementia is agitation, which can manifest as verbal outbursts, physical aggression, and restlessness. Effective management of agitation is crucial for improving the overall well-being of both patients and their caregivers [3]. Agitation in dementia can significantly worsen the patient’s condition, leading to increased caregiver stress, higher healthcare costs, and a greater likelihood of institutionalization [3].
Pharmacological treatments for agitation in dementia have traditionally included antipsychotics, antidepressants, and other psychotropic medications. However, these drugs often come with significant side effects and varying degrees of efficacy. For instance, antipsychotics are associated with an increased risk of stroke, cardiovascular events, and mortality in dementia patients [4]. Thus, there is a growing interest in exploring safer, non-pharmacological interventions that can effectively manage agitation without the adverse effects of medications.
Non-pharmacological approaches such as music therapy, light therapy, and digital care programs have shown promise in reducing agitation and improving the quality of life for patients. These therapies focus on providing sensory stimulation, enhancing mood, and promoting social interaction, which can help alleviate behavioral symptoms [5–7]. Moreover, personalized care strategies tailored to individual patients’ preferences and needs have been found to be particularly effective in managing agitation [8].
This systematic review aims to evaluate the efficacy of various pharmacological and non-pharmacological interventions in managing agitation among dementia and Alzheimer’s disease patients. Three of these studies examine pharmacological interventions, while the remaining six focus on non-pharmacological therapies. The studies employ the Cohen-Mansfield Agitation Inventory (CMAI), a widely used tool for measuring agitation levels in dementia patients, to assess the efficacy of these interventions [9, 10]. Our goal is to offer evidence-based recommendations for managing agitation in dementia, contributing to the ongoing efforts to improve the care and quality of life for patients and their caregivers.
This systematic review adhered to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Articles were sourced in June 2024 from the PubMed database, encompassing MEDLINE, PMC, and Bookshelf, using keywords and Boolean operators including “Alzheimer’s AND treatment,” “Alzheimer’s AND agitation,” “Non-pharmacologic treatments for Alzheimer’s Disease,” and “Pharmacologic treatments for Alzheimer’s Disease.” A total of 153 studies were initially identified.
The inclusion criteria
Population: Adults aged 65 or older diagnosed with Alzheimer’s or related dementias.Interventions: Studies involving pharmacological (e.g., brexpiprazole, mirtazapine) or non-pharmacological (e.g., music therapy, lighting interventions) treatments.Comparators: Inclusion of control groups.Outcomes: Measurement of agitation using validated tools like the Cohen-Mansfield Agitation Inventory (CMAI).Study Design: Randomized Controlled Trials (RCTs) or quasi-experimental studies published in peer-reviewed journals.Time Frame: Studies published between 2015 and 2024.
Exclusion criteria
Studies focusing solely on observational data without direct interventions.Non-English publications.Papers without accessible full text.
Following an initial title and abstract screening, duplicates were removed. Two independent reviewers assessed the remaining 68 studies against inclusion criteria, resolving discrepancies through consensus. Data extracted included study characteristics, intervention details, outcomes, and key findings. Nine studies were finalized for inclusion. The selection process is outlined in a PRISMA flowchart (Fig. 1).
Fig. 1PRISMA diagram
Articles were assessed for relevance based on Population, Intervention, Controls, Outcome, Study design, and Time (PICOS) criteria. Studies included adults (65 years of age and older) diagnosed with Alzheimer’s disease. Therapeutic interventions included technological, light-based, medication, magnetic stimulation, and musical therapies. All studies needed a control group, and randomized controlled trials (RCTs) were required.
The articles yielded from the PubMed search query for inclusion in this systematic review were then compared against the eligibility criteria by all reviewers. A chart was made to illustrate the data of the included articles containing information on the study titles, year, and a brief summary of the methods and outcomes. Agreement was reached on the summarization of these articles, and the chart served as a means of grouping and comparison during the review process.
Nine clinical studies exploring treatments for agitation in dementia and Alzheimer’s disease patients were included in the review. Three of the nine studies were conducted with the implementation of medication. One of those three was an outline for a study that was included due to its relevance to the topic of the review, but it is noted that the paper is only a study outline and has little impact on the data and information collected from this review. The other six studies detailed therapeutic, non-medicative approaches such as light therapy, music therapy, and high-frequency treatments. One study was excluded due to its lack of relevance to this review [11].
Grossberg et al. conducted two 12-week, randomized, double-blind, placebo-controlled trials to evaluate the efficacy and safety of brexpiprazole for treating agitation in Alzheimer’s dementia. They found that patients treated with brexpiprazole at a dosage of 2 mg/day exhibited significant improvements in their CMAI scores compared to the placebo group [12]. Banerjee et al. assessed the use of mirtazapine for agitated behaviors in dementia. The trial revealed no significant benefit of mirtazapine compared to placebo and was associated with a higher mortality rate [13]. Ehrhardt et al. designed the S-CitAD trial to investigate the effects of escitalopram on agitation in Alzheimer’s disease, but no outcome data were provided [14].
Among the articles referring to non-medicated options, Harrison et al. conducted a randomized controlled study comparing music and auditory books among long-term care residents with Alzheimer’s disease or related dementia. The study found that both interventions were associated with decreased agitation in three of the four agitation subscales. However, in the fourth subscale (non-staff-directed physical agitation), music initially reduced agitation, but overall agitation increased over time with audiobooks. This suggests that while both interventions can be beneficial, the type of auditory stimulation and duration of intervention play crucial roles in managing agitation [5]. Sitsi et al. evaluated the effects of a personalized music intervention on agitated behaviors and mood in nursing home residents with dementia. The results indicated that residents who received the personalized music intervention experienced fewer verbally agitated behaviors and more frequent experiences of pleasure compared to those receiving usual care [8]. Zhang et al. examined the impact of high-frequency rTMS combined with cognitive training on cognitive function and agitation in Alzheimer’s disease. The study found a significant reduction in neuropsychiatric behaviors, including agitation, following four weeks of rTMS-CT treatment [15]. Figueiro et al. conducted a randomized clinical trial on the effects of a tailored lighting intervention on sleep quality, rest-activity, mood, and behavior in older adults with Alzheimer’s disease and related dementias. The study found significant improvements in sleep, mood, and behavior, with greater reductions in CMAI scores for those in the active lighting intervention group compared to the control group [6]. McDermid et al. investigated the impact of the iWHELD digital person-centered care program on agitation and psychotropic medication use in people with dementia during the COVID-19 pandemic. The study showed a decrease in the use of psychotropic medications without worsening agitation, indicating that the digital care program may be beneficial for managing agitation in dementia patients [16].
The purpose of this systematic review was to evaluate the effectiveness of various interventions in managing agitation among patients with dementia and Alzheimer’s disease (AD). As the global prevalence of dementia surpasses 55 million and new cases continue to rise at nearly 10 million annually, managing symptoms such as agitation is increasingly central to improving quality of life for patients and caregivers. Agitation encompasses verbal behaviors, such as shouting or complaining, as well as physical behaviors, including pacing and aggression. These symptoms not only cause distress for patients but also contribute to caregiver burden and institutionalization, emphasizing the urgent need for effective interventions.
This review explored nine clinical studies, shedding light on the nuanced role of pharmacological and non-pharmacological interventions in addressing agitation. Pharmacological treatments included brexpiprazole, which demonstrated dose-dependent efficacy, and mirtazapine, which was associated with concerning mortality rates and negligible benefits. Non-pharmacological approaches, including music therapy, tailored lighting interventions, and digital person-centered care programs, exhibited significant promise, offering therapeutic benefits without the adverse effects commonly associated with medications. These findings align with broader trends in dementia care, where non-pharmacological strategies have gained prominence as safe, effective, and patient-centered solutions.
The trajectory of dementia treatment underscores a gradual but significant shift in care paradigms over the past two centuries. In the 19th century, dementia care was largely custodial, relying on physical restraint and institutional confinement [13]. Advances in psychiatry during the early 20th century introduced rudimentary interventions, such as hydrotherapy and sedatives, though these remained largely experimental and were often ineffective [17]. The mid-20th century marked the advent of psychotropic medications, including antipsychotics and benzodiazepines, which offered some relief for agitation but carried substantial risks, including sedation and increased morbidity [18].
By the late 20th century, dementia care began to integrate non-pharmacological approaches, reflecting an evolving understanding of the disease as more than a purely biological disorder. Behavioral therapy, cognitive stimulation, and environmental modifications became increasingly common, and the development of cholinesterase inhibitors introduced a targeted approach to managing cognitive symptoms [19]. The findings of this review highlight the current state of this evolution, where person-centered care, such as music therapy and tailored lighting, aligns with a more holistic understanding of dementia and its impact on patients and their social environments.
This review’s findings contribute to a growing body of evidence supporting non-pharmacological interventions for agitation. For example, music therapy has been shown to activate preserved neural pathways in dementia patients, fostering emotional connections and reducing distress [5]. Personalized music interventions, in particular, stand out for their ability to alleviate verbally agitated behaviors without exacerbating physical agitation, echoing findings from other studies on individualized care [8]. Similarly, tailored lighting interventions align with research on circadian rhythm disruptions in dementia, demonstrating how environmental modifications can mitigate neuropsychiatric symptoms [6].
Pharmacological treatments, while effective in some cases, underscore the limitations of current medication-based approaches. For instance, brexpiprazole’s efficacy at higher doses contrasts sharply with the lack of benefits observed for mirtazapine, raising critical questions about the risk-benefit balance of such therapies [12, 13]. These findings reflect a broader challenge in dementia the limited efficacy of medications that primarily address symptoms rather than underlying disease mechanisms [20, 21].
Despite advancements in treatment strategies, several challenges persist in dementia care. Non-pharmacological interventions, while beneficial, often require substantial caregiver involvement and resources, making them less accessible for many families. This is particularly concerning given the growing population of dementia patients and the strain on healthcare systems worldwide. Additionally, variability in treatment responses—driven by genetic, environmental, and lifestyle factors—highlights the need for personalized approaches to care.
Diagnosis also remains a critical hurdle. Many patients are diagnosed at advanced stages when treatment options are less effective. Current diagnostic methods, such as neuroimaging and cerebrospinal fluid analysis, are often invasive, costly, and not widely available, contributing to delays in intervention [22]. These barriers underscore the need for scalable, early-detection strategies that integrate with treatment planning.
Emerging therapies hold promise for addressing these limitations and advancing dementia care. Disease-modifying drugs targeting beta-amyloid plaques and tau protein accumulation aim to slow or halt disease progression, representing a potential paradigm shift from symptom management to modifying underlying pathology [23]. Gene therapy, which seeks to address genetic mutations associated with dementia, offers long-term possibilities for disease prevention and management [24].
In non-pharmacological domains, technology-driven solutions are expected to play a transformative role. Virtual reality (VR) and brain-computer interfaces (BCIs) are being developed to enhance cognitive rehabilitation and engagement, bridging the gap between traditional therapies and modern technological capabilities [25]. Digital care platforms, such as the iWHELD program reviewed here, emphasize the importance of human interaction and personalized care in reducing agitation, further underscoring the potential of scalable, technology-enabled solutions [16].
The findings of this review suggest that the future of dementia care lies in integrative and holistic approaches that combine pharmacological and non-pharmacological treatments. By situating dementia care within broader theoretical frameworks, such as the biopsychosocial model, clinicians and researchers can better address the multifaceted nature of the disease. Innovations in personalized medicine, including individualized care plans informed by genetic and biomarker data, are likely to redefine standards of care, improving treatment outcomes and quality of life for patients and caregivers alike [22].
TreatmentStudyFindingsBrexpiprazole for Agitation in Alzheimer’s DementiaGrossberg et al. [12]Significant improvements in CMAI scores for patients treated with brexpiprazole at a dosage of 2 mg/day compared to placebo. Lower doses were not effective, indicating the dose-dependent efficacy of brexpiprazole [12]. Mirtazapine for Agitated Behaviors in DementiaBanerjee et al. [13]No significant benefit of mirtazapine over placebo and a higher mortality rate in patients treated with mirtazapine, suggesting caution in its use for agitation in dementia [13]. Escitalopram for Agitation in Alzheimer’s DiseaseEhrhardt et al. [14]Provided a study design but no outcome data, limiting its applicability [14]. Music Therapy and AudiobooksHarrison et al. [5]found that both music and audiobooks decreased agitation in three of four subscales, although audiobooks increased overall agitation in one subscale. This highlights the importance of the type and duration of auditory stimulation [5]. Personalized Music InterventionSitsi et al. [8]Showed that personalized music interventions reduced verbally agitated behaviors and increased experiences of pleasure, without affecting physical agitation or negative emotions [8]. High-Frequency Repetitive Transcranial Magnetic Stimulation (rTMS) Combined with Cognitive TrainingZhang et al. [15]reported significant reductions in neuropsychiatric behaviors, including agitation, following four weeks of rTMS-CT treatment [15]. Tailored Lighting InterventionFigueiro et al. [6]Significant improvements in sleep, mood, and behavior, with greater reductions in CMAI scores for those in the active lighting intervention group [6]. Digital Person-Centered Care Program (iWHELD)McDermid et al. [16]The iWHELD program decreased the use of psychotropic medications without worsening agitation, suggesting the benefits of digital interventions in dementia care [16].
One study by Aigbogun (2020) [11] was excluded due to its lack of relevance to the primary focus of this review, which was on direct interventions for agitation in dementia rather than observational treatment patterns.
In conclusion, managing agitation in dementia requires a combination of pharmacological and non-pharmacological treatments. While medications like brexpiprazole can be effective, non-pharmacological interventions such as music therapy, tailored lighting, and digital care programs offer valuable benefits without the risk of adverse effects. Future research should continue to explore the synergy between these approaches to optimize outcomes for individuals with dementia. Emphasizing personalized care and integrating various treatment modalities can enhance the overall quality of life and reduce agitation in dementia patients.