Polypharmacy in Older Adults with Alzheimer’s Disease: Comparison
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The number of patients with Alzheimer’s disease is increasing annually. Most of these patients are older adults with comorbid physical illnesses, which means that they are often treated with a combination of medications for the disease they have and those for Alzheimer’s disease. Thus, older adults with Alzheimer’s disease are potentially at risk for polypharmacy. In addition, the drug interactions between Alzheimer’s disease medications and those for the treatment of physical illnesses may reduce their efficacy and increase side effects.

  • Alzheimer’s disease
  • polypharmacy
  • drug interactions

1. Introduction

It is widely known that the number of older adults with dementia is increasing worldwide. In the United States, the number of people aged 65 years and older was 52 million in 2018 and is predicted to increase to 95 million by 2060, 50 million of which will have dementia by 2050 [1,2][1][2]. Similarly, the number of elderly with dementia in Asia is increasing. According to a meta-analysis published in 2014, the prevalence of dementia among patients aged 65 years and older in South Korea is 9.2%, which is higher than that of patients of similar age in Europe, the United States, and other Asian countries [3,4][3][4]. Furthermore, the odds ratio for death from dementia and other neurodegenerative diseases is reportedly higher in Korea than that in other countries. In Japan, there were an estimated 3.5 million people with dementia in 2012 (approximately 8% of the global population), and the number of dementia patients is projected to reach 4.9 million by 2034, when the population over 65 years of age reaches its peak [5]. In addition, the cost of informal care for patients with dementia is estimated at approximately $54 billion.
Most patients with Alzheimer’s disease are elderly and have two or more chronic conditions [6,7,8][6][7][8]. For example, a revisewarch of Medicare claims data revealed that 67% of beneficiaries over the age of 65 years had two or more chronic diseases [9]. Patients with Alzheimer’s disease and related dementias often have comorbid physical diseases [10]. Considering the barriers to communication and cognitive decline associated with this disease, polypharmacy is more likely to occur in patients with dementia than in the general elderly population [11,12][11][12]. According to the currently accepted definition, polypharmacy is defined as taking five or more medications per day, with a prevalence of 30–60% among the elderly (65 years and older) [13,14,15,16,17][13][14][15][16][17]. Although in most cases polypharmacy results from prescribing necessary medications to treat diseases in the elderly, there are reports that polypharmacy is associated with adverse outcomes. Inappropriate polypharmacy leads to an increased incidence of falls, frailty, and decreased quality of life [18,19,20,21][18][19][20][21]. Such adverse events further increase the cost and burden of care for dementia patients.
Patients with dementia have a high incidence of potentially inappropriate medication (PIM), estimated to be 14–74% [22,23,24][22][23][24]. PIMs are medications whose benefits do not exceed the risks associated with taking them, such as adverse events, and are a common cause of adverse drug reactions in the elderly [25,26][25][26]. They have been associated with a decreased quality of life, poor nutrition, and depression in nursing home residents with dementia [27,28,29][27][28][29]. According to a survey of PIM use among older adults with dementia in seven European countries, patients with dementia had a high incidence of PIM intake, regardless of severity, even those with mild Alzheimer’s disease [30,31][30][31]. Inadequate communication between patients with dementia and healthcare providers triggers a prescription cascade in which healthcare providers misidentify the side effects of drugs as new symptoms and prescribe drugs to treat drug-related problems, thereby triggering polypharmacy [32,33,34][32][33][34]. In other words, prescribing additional drugs for adverse reactions to PIM may lead to polypharmacy, which is associated with many more adverse events, greater healthcare utilisation, and even mortality [35,36][35][36].

2. Polypharmacy in Alzheimer’s Disease Patients

The main symptoms of Alzheimer’s disease, namely memory impairment and behavioural and psychological symptoms, cause great distress to patients with dementia as well as caregivers [37,38][37][38]. Cognitive dysfunction in Alzheimer’s disease can be treated with cognitive-improving drugs, such as acetylcholinesterase inhibitors (donepezil) and NMDA-type glutamate receptor antagonists (memantine). Memantine and acetylcholinesterase inhibitors are sometimes used in combination to enhance efficacy; however, cognitive enhancers are generally used as a single medication [39]. Some countries do not have access to insurance coverage for cognitive-improving drugs because their effectiveness is limited [40]. The behavioural and psychological symptoms of dementia (BPSD) are customarily and widely treated symptomatically with psychotropic drugs [41,42][41][42]. Because of the wide variety of BPSD, including depression and delusions, the polypharmacy of psychotropic medication is increasing among the elderly, including patients without dementia [43]. The Beers Criteria, published by the American Geriatrics Society recommend avoiding use of more than three central nervous system (CNS)-active drugs, such as antidepressants, antipsychotics, benzodiazepines and “Z-drugs”, because they are associated with the risk of falls and fractures [44]. It is widely known that these drugs can produce falls due to sedation, daytime sleepiness, orthostatic hypotension, and motor disturbances. Using Medicare claims data, a study examining psychotropic polypharmacy in patients with dementia revealed that 13.9% of older adults with dementia had “psychotropic polypharmacy” (three or more psychotropic medications for 30 or more consecutive days), and 29.4% of them were exposed to five or more psychotropic medications [1]. The drugs most frequently prescribed to patients with psychotropic polypharmacy were antidepressants (92.0% of days in polypharmacy during the study period), followed by antiepileptic drugs (62.1%), antipsychotics (47.1%), benzodiazepines (40.7%), opioids (32.3%), and benzodiazepine receptor agonists (6.0%). Although cognitive-improving drugs were not included in this study, considering that most dementia cases involve Alzheimer’s disease [45], it is assumed that the polypharmacy of CNS-acting drugs is even more serious with the added influence of cognitive-improving drugs. A cross-sectional analysis using the National Ambulatory Medical Care Survey (NAMCS) showed that the number of medications was significantly higher in the elderly with dementia than in those without, although the number of outpatient visits did not differ based on dementia status [12]. In addition, the mean number of medications expected to be prescribed per visit was higher in patients with dementia when compared by age, sex, and number of comorbidities (standardised). Interestingly, elderly patients with dementia were more likely to be prescribed drugs that act on the CNS, as well as those that act on the gastrointestinal and urological systems and drugs for diabetes, indicating that polypharmacy with all drugs, not just CNS drugs for dementia symptoms, is likely to develop in patients with dementia. Certain medications frequently included in polypharmacy, such as anticholinergics and sedatives, are associated with an increased risk of hospitalisation and death in patients with dementia [46]. Therefore, it is necessary to prescribe safer drugs and reduce the incidence of polypharmacy in this population [47,48][47][48]. The number of prescribed drugs should be reduced to a level consistent with the risk of hospitalisation and death in patients with dementia.

3. Cognitive Impairment Induced by Polypharmacy

Several reports have examined the association between polypharmacy and cognitive dysfunction, where polypharmacy is defined as the use of five or more drugs that are commonly used in clinical practice [9,17][9][17]. In a cross-sectional study on the association between polypharmacy and cognitive function and related comorbidities (depression, hypertension, and/or diabetes) in rural America, older adults afflicted with polypharmacy had 3.71 times higher odds of having cognitive impairment than older adults who were not [49]. In addition, even after adjusting for confounding factors using multivariate analysis, the odds of cognitive impairment were 2.86 times higher in patients with polypharmacy, whereas there was no significant association between comorbidities and cognitive impairment. Based on these results, it is considered that polypharmacy is independently associated with cognitive dysfunction. In general, patients with cognitive impairment have poor medication compliance. However, healthcare providers are unable to ascertain whether patients are taking their medications. Polypharmacy is thought to result from the addition of medications after determining that the prescribed medications are ineffective. Several reports have shown a negative correlation between the number of medications prescribed and adherence (i.e., the higher the number of medications, the worse the adherence) [50,51,52,53][50][51][52][53]. Future large cohort studies are needed to prospectively evaluate whether polypharmacy induces cognitive dysfunction or vice versa.

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