In this study, we found an increased risk for sooner MACCE onset for individuals treated with both APs and cognitive enhancers, as well as for those prescribed higher drug dosages. Our findings also indicate that the following patient characteristics may also explain the occurrence of sooner MACCE onset: history of MACCE before dementia diagnosis, race (African American/Black, Asian, or Hispanic), and sex (male).

The association of AP and cognitive enhancer drug use with MACCE occurrence has been previously described in the literature. Previous research has demonstrated that the risk of stroke is elevated shortly after the initiation of AP treatment in individuals with AD [42]. Commencing APs is linked to a higher age-standardized incidence rate and an increased likelihood of experiencing a stroke within the first 2 months compared with those who do not initiate AP treatment. Additionally, a meta-analysis of three randomized controlled trials on ziprasidone and quetiapine revealed a rise in the prolongation of the QTc interval, increasing the risk of ventricular tachyarrhythmias [43]. Moreover, two retrospective cohort studies have linked the use of APs to a significantly increased risk of sudden cardiac mortality in patients with other psychiatric illnesses. Straus et al. [44] found that the current use of APs in the general population is associated with an increased risk of sudden cardiac death, even at a low dose and in persons who use APs for indications other than schizophrenia. These instances indicate that APs, frequently administered to individuals with diverse psychiatric disorders, including dementia, are linked to sudden cardiac mortality, raising significant concerns for all populations, particularly those with dementia who might receive such prescriptions. As for cognitive enhancers, several possible cholinergic cardiac side effects have been reported including hypotension, bradycardia, heart block, and QT/QTc prolongation [43]. While adverse cardiac events with cognitive enhancers are less common [44], older adults treated with these drugs may be more susceptible to adverse events due to the high prevalence of cardiac comorbidities. Thus, prescribers are becoming more concerned about the possibility of severe side effects from AChEIs, particularly in older adult patients with AD [45].

Our findings have shown that there is a significant decrease in the time to MACCE onset for those prescribed both APs and cognitive enhancers. Of the 259 patients in our sample who were diagnosed with BPSD and treated with both APs and cognitive-enhancing drugs, approximately 212 patients (82%) were diagnosed with MACCE within 6 years of beginning BPSD treatment. In comparison, approximately 80% of those solely taking APs and 70% of those only taking cognitive enhancers to reduce BPSD symptomology had experienced a MACCE within 6 years. This may be explained by the fact that certain APs tend to cause weight gain in addition to cardiovascular and metabolic abnormalities, such as increased risk of obesity, metabolic syndrome, type 2 diabetes mellitus, and related cardiovascular morbidity [46, 47]. Studies on APs, particularly second-generation APs (SGAs) such as olanzapine and risperidone, have been associated with weight gain, dyslipidemia, and insulin resistance in older adults [48]. Comparatively, the use of APs in dementia has been consistently linked to a 1.5–1.7 times increased risk of mortality, and a 2-3-fold increased risk of cerebrovascular events (CVAE) [46]. Another study found that, among hospitalized adults, typical APs were linked to elevated mortality or cardiopulmonary arrest rates, whereas atypical APs showed increased risk solely among adults aged 65 years and older, with a total of 691 outcome events (0.5% of total hospitalizations), comprising 515 deaths and 176 cardiopulmonary arrests [49]. A less noticeable but comparable pattern was observed in nursing home residents. Other literature suggests that atypical or conventional AP users are more likely to experience avoidable adverse events such as infections, falls, and worsening cognitive function [50]. Our study is consistent with previous findings and provides an estimated timeframe for the onset of MACCE. However, to our knowledge, ours is the first study to examine the relationship between AP medications, cognitive enhancers, and MACCE within dementia populations, specifically focusing on the context of treating BPSD and examining the impact of medication dosage on the time to MACCE onset. Therefore, we must interpret these findings in the context of similar but limited previous research.

There are nonpharmacological interventions for the treatment of BPSD including indirect techniques aimed at decreasing symptoms of BPSD by working with caregivers, adapting to the environment, or directly targeting problematic symptoms. Indirect interventions (caregiver training, multidisciplinary team approaches, individualized treatment plans, and modifying environmental factors) primarily focus on educating care staff, physicians, and pharmacists. However, according to a systematic review, these techniques are effective in the short term and do not address the complexity of BPSD or the factors that influence symptoms long term [50]. Direct interventions include (1) cognitive/emotion-oriented interventions (validation therapy, simulate presence therapy), (2) sensory stimulation interventions (light therapy, music therapy, transcutaneous electrical nerve stimulation), and (3) behavioral management techniques [51]. Cognitive training involves the targeted practice and training of specific cognitive domains, while cognitive rehabilitation takes a more tailored therapeutic approach and aims to improve functioning in daily life rather than cognitive performance [52]. In addition, psychosocial therapies are intended to enhance self-esteem, well-being, and social/communication skills [53]. Regardless of one’s cognitive capacity or functional ability, these strategies attempt to introduce a range of tailored meaningful activities for patients with dementia, in hopes of ensuring that individuals are fully able to participate and benefit. Studies on the effects of physical activity have shown improvements in patient mood, quality of life, falls, cardiovascular health, and rates of disability [54, 55]. Frequent exercise can also increase cardiovascular fitness, muscle mass, arterial compliance, energy metabolism, and overall functional capacity [56]. Therefore, the current literature suggests there are alternatives to medication for treatment of BPSD, with varying levels of effectiveness.

This study has some limitations worth acknowledging. First, data were obtained through a Loma Linda University Medical Center database, which included deidentified data from patients in a blue zone. In this region, there is a particularly high number of centenarians, as people tend to live longer than average and maintain good health. Many people utilizing Loma Linda Health Care are affiliated with the Seventh Day Adventist religion, who adhere to a vegan or vegetarian diet, prioritize exercise, and refrain from smoking and drinking. However, no data on religion/spirituality or individual lifestyle were obtained in this study. Thus, the sample used for our study may not be representative of true survival rates or MACCE occurrences in the general population. Second, in our study, smoking status did not consider exposure to second-hand smoke, which is known to be a risk factor for heart disease [57]. Third, the impact of drug use on health outcomes, particularly regarding anticholinergic burden (ACB) (the cumulative effect of taking multiple drugs with anticholinergic activities), may be influenced by both cumulative and time-related effects. The duration of exposure to medications containing anticholinergic properties, coupled with the quantity of these medications taken, can amplify their potential health effects. This cumulative effect signifies the collective strain placed on the body from the continuous use of various drugs with anticholinergic activity over an extended period. Within the scope of this study, the individual anticholinergic burden of each participant remains undetermined. Fourth, comorbidities and geriatric syndromes such as malnutrition, sarcopenia, and frailty can significantly increase the risk of developing MACCE [58]. While no data on these comorbidities were obtained in this study, these conditions do tend to increase with age, and age and years since onset of dementia were included as covariates in our analyses. Fifth, while it is important to consider the adherence to AP or cognitive enhancers prescriptions to evaluate the relationship with MACCE, no information on this was available to us considering the data were derived from a university healthcare system database. Sixth, this study did not account for the severity of dementia as there were no available data in the Loma Linda Health Care database. Thus, we could not account for the influence these factors may have had on calculated survival rates. Seventh, the cognitive enhancer variable included ChEIs and memantine, which is a NMDA receptor antagonist, into the same category. Thus, it is unclear whether ChEIs and NMDA receptor antagonists have different influences on time until MACCE onset. Eighth, given the limited scope of this study, we did not examine other treatments. Our analysis focused solely on the use of cognitive enhancers, APs, a combination of both, and no medication treatment. Thus, we did not investigate the prescription of other pharmacological treatments, such as antidepressants, nor did we have data on the use of nonpharmacological treatments. However, SSRIs [59] and tricyclic antidepressants [60] have been associated with a higher risk of hospitalizations for cardiovascular events in older adults. Therefore, further studies should include other classes of medications in their analysis. Ninth, the current study does not compare the risk profile for different AP and cognitive-enhancing medications. It remains for future studies to determine whether some AP or cognitive-enhancing medications have a different risk pattern than the one reported for the aggregate data in this study.

We also speculate on several measures and future directions based on these findings. First, there may be a need for more precise risk assessment tools to identify individuals with BPSD who are at the highest risk of MACCE associated with medication use. Additionally, further research could explore alternative treatment modalities, such as nonpharmacological interventions or lower-risk medications, for managing BPSD symptoms. Longitudinal studies tracking medication use and cardiovascular outcomes in larger and more diverse populations could provide additional insights into the long-term risks and benefits of pharmacological treatments for BPSD. Further, due to the association of SSRIs and antidepressants with MACCE among older adults, future research should analyze the impact of other types of pharmacological treatments on MACCE onset among older adults with BPSD. Lastly, enhancing healthcare provider education and awareness regarding the potential cardiovascular risks associated with AP and cognitive enhancer use in individuals with dementia could help optimize treatment decisions and improve patient outcomes.

The strengths of this study lie in its innovative approach and unique contributions to the existing literature on the intersection of AP medications, cognitive enhancers, and MACCE within dementia populations, specifically focusing on the context of treating BPSD. Firstly, while previous research has explored the individual impacts of MACCE on dementia and the use of AP in dementia separately, this study stands out for its comprehensive examination of the relationship between these factors. By investigating how both APs and cognitive enhancers contribute to the risk of MACCE within dementia populations, the study provides a more holistic understanding of the potential cardiovascular and cerebrovascular risks associated with these commonly prescribed medications. This integrative approach is vital for clinicians and researchers seeking to optimize treatment strategies and mitigate potential adverse effects in patients with dementia experiencing BPSD. Secondly, the study’s focus on medication dosage represents a significant methodological advancement. While previous studies have explored the overall association between medication use and MACCE risk, this study goes a step further by specifically examining the impact of dosage on the time to MACCE onset. By quantifying the relationship between medication dosage and cardiovascular/cerebrovascular health outcomes, the study offers valuable insights into the dose–response relationship and helps elucidate the potential dose-dependent risks associated with AP and cognitive enhancer use in dementia populations. This nuanced understanding of dosage effects can inform more precise prescribing practices and facilitate personalized treatment approaches tailored to individual patient needs and risk profiles. Overall, the current study’s innovative approach, combined with its novel contributions to understanding the relationship between medication use, dosage, and MACCE risk in dementia populations, strengthens its significance within the field of geriatric psychiatry and has important implications for clinical practice, research, and policymaking aimed at improving the safety and efficacy of pharmacological interventions for BPSD.

The results of this study suggest a persistent, increasing risk of MACCE onset with long-term use of AP or cognitive-enhancing medications in those with BPSD. However, our findings indicate that higher doses of APs are particularly risky and present many adverse effects on cardiovascular/cerebrovascular health, some of which are medically serious. Predicting an estimate of the expected survival after beginning drug treatment for BPSD is a useful measure for individuals and their families, as well as for clinicians providing treatment for these symptoms. These research findings underscore the importance of carefully balancing the benefits and risks of pharmacological interventions for BPSD. Clinicians need to weigh the urgency of treating severe symptoms against the potential risks of MACCE associated with medication use. Often, there is a sense of urgency when treating more severe symptoms of BPSD; however, clinicians should consider the risk of MACCE for these individuals and which factors influence the length of survival until MACCE onset. Moreover, considering factors that influence the length of survival until MACCE onset should be an integral part of treatment decision-making for individuals with BPSD.

There is a persistent, increased risk of major adverse cardiovascular/cerebrovascular event onset with long-term use of AP or cognitive-enhancing medications in those with behavioral and psychological symptoms of dementia. Both APs and cognitive enhancers are associated with decreased time to negative cardiovascular event onset, and APs had a greater negative impact compared with cognitive enhancers. In addition, higher doses of medications decreased time to a MACCE onset, with the greatest risk for those taking high doses of AP medications compared with cognitive enhancers. These novel findings highlight the need for cardiovascular/cerebrovascular monitoring in patients with dementia and BPSD.