Potentially inappropriate medication and associated factors such as depression and dementia: An analysis of middle-aged and elderly people

1 Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Graduate Program in Biomedical Gerontology. Porto Alegre, RS, Brasil 2 Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Institute of Geriatrics and Gerontology. Porto Alegre, RS, Brasil 3 Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), School of Health and Life Sciences. Porto Alegre, RS, Brasil 4 Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), School of Medicine and Graduate Program in Biomedical Gerontology. Porto Alegre, RS, Brasil Vanessa Sgnaolin1 orcid.org/0000-0002-9914-7146 vanessasgnaolin@yahoo.com.br


INTRODUCTION
People worldwide are living longer. Between 2015 and 2050, the proportion of the world's population over 60 years will nearly double from 12% to 22% [1]. The elderly population is one of the most vulnerable in terms of health.
One related factor to poor health in the elderly is socioeconomic disadvantage (SED) status.
Education, place of residence, health beliefs and behavior, occupation, income, access to health services and the environment in which people live contribute to low health status in the middleaged and elderly [2].
Aging has a great impact on social and health care policy planning, because there is a growing burden of underlying diseases. One difficulty in prescribing for multimorbid patients is the risk of Potentially Inappropriate Medication (PIM).
PIM use may occur whenever the benefits of using some medications are outweighed by the risks and/or whenever avoidance of drug use in specific settings is suggested by scientific evidence [3]. It is a common problem in older persons, ranging from a prevalence of 11.5% to 62.5% of the elderly population. It is associated with adverse effects, hospitalization, morbidity, mortality and high health services cost [4].
One way to identify PIM prescribing is to use validated screening tools that incorporate explicit prescribing indicators, such as the Beers criteria that is the most widely used approach to assess the quality of drug prescribing among the elderly [5]. This tool provides a list of PIM or drug classes that should generally be avoided in the treatment of elderly [6]. There are other international criteria have been defined with the intent of preventing PIM for elderly [7][8][9][10].
Traditionally, the focus of PIM has been on older people (especially those ≥65 years) due to the high frequency of medication use in this age group and the organic aging process. However, there is evidence that multimorbidity is also prevalent in middle-aged people [11]. As yet, there has been little consideration of PIM in this age group [2].
Depression and cognitive disorders, including dementia, are common in aging [12,13]. Most research on PIM has focused on the elderly rather than depression and dementia specifically [14,15]. Barbiturates, phenytoin, and benzodiazepines are some examples of drug classes that cause deterioration of several basic human abilities: concentration, mental energy, mood and memory [13].
The objectives were to determine the frequency of PIM use and associated factors, among them signs and symptoms of depression and cognitive deficit in middle-aged and elderly people.

Setting
This study involved a subset of patients of

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The FHS is a proactive community public health care approach implemented by the Brazilian Ministry of Health. It is characterized by active and continued health promotion and monitoring at the community level. The FHS prioritizes locations with people living in SED and identifies and enrolls all local inhabitants based on their dwelling place (geographic-based registration) covered by each FHS team. For the constitution of PENCE, initially and continuously, the community health agents of the FHS teams were trained to use the research tools.

Study Design and Population
A cross-sectional population-based survey study design was developed to evaluate the association between the presence of PIM and sociodemographic, lifestyle and health predictors, with a focus on the signs and symptoms of depression and cognitive deficit. The target population of the study was individuals of both sexes that were 55 years of age or older. Adults aged 55 to 59 years were classified as middleaged, and those aged 60 years or more were called the elderly. For inclusion in the study, it was necessary that the patients used at least one medication continuously.

Outcome and variables studied
The primary determinant was the presence of PIM, which was initially identified using the 2015 Beers criteria [16]. In 2019 Beers criteria went through an update which implied an adjustment of the data presented for this new version [6]. To Organization [17]. The community health workers have previously received training in order to qualify and standardize the data collection.
In this study, 48 PIM items were identified irrespective of disease diagnoses or conditions. Dimenhydrinate, meclizine, meperidine and mineral oil were not used by any patient.
Acetylsalicylic acid and insulin, which are inappropriate only for certain conditions, were not included in this study, because we did not have the information on the dosages and the form of release of these drugs. Drugs that are not available in the Brazil were not considered.
The following covariates from the PENCE study were examined as potential associated factors: • Socioeconomic status (sex, age, education level, marital status/living with a partner, individual and family income; the last measured in relation to the minimum Brazilian wage of USD 280); • Lifestyle information, including smoking habits (current, ex, or never) and alcohol use (dichotomous); • Self-perceived health (examined as very good/good vs. regular vs. bad/very bad), number of comorbidities (according to number of chronic diseases by self-report of the patient); • Number of drugs prescribed. As polypharmacy users were classified individuals who used five or more medications.    Among the drugs which were most frequently prescribed, the study found that the most common was omeprazole (25.5% total population; 39.2% PIM-users) followed by glibenclamide (8.9% total population; 13.6% PIM-users), amitriptyline (6.1% total population; 9.3% PIM-users), ibuprofen (5.5% total population; 8.5% PIM-users) and diazepam (4.3% total population; 6.7% PIM-users).   [24,25]. Poorer health has been reported in SED areas [26], especially in patients with multimorbidity [11,27] and exposed to polypharmacy [28], with an increased frequency of long-term conditions including depression, anxiety, pain and coronary heart disease [29].
However, most of these studies were carried out in high-income countries and deserve some careful  [14,36]. Prior research in dementia patients has described that PIM may exacerbate cognitive impairment [37,38], or relied on prescription medication data to calculate PIM rates in dementia patients [39] or sought to demonstrate that PIM use increases the risk of developing dementia [40]. pump inhibitors (e.g., omeprazole) and described the possible molecular basis of this association [41]. There is some biological plausibility to the hypothesis that proton pump inhibitors can cross the blood-brain barrier [42]. They may increase both production [43] and degradation [44] of amyloid, at least in animal models, and bind to tau [42]. There is also evidence of reduced levels  [20].
The patterns of inappropriate prescriptions vary considerably within therapeutic classes.
The most frequently reported PIM classes are psychotropic or cardiovascular drugs, since most PIM has been identified in these groups of drugs [20,46]. Individuals with cognitive impairment and depression symptoms were at increased use of antiarrhythmics. Amiodarone was the most widely used medication of this class and is associated with multiple toxicities such as thyroid disorders, QT prolongation and pulmonary disorders [16]. In the management of arrhythmias in the elderly, it is important to evaluate the risk and benefit of amiodarone and, when indicated, it is essential to monitor the process of its use to enable the prevention or early identification of adverse events.
There are previous evidence suggesting that patients with cognitive impairment and dementia make greater use of antidepressants with anticholinergic properties (e.g., amitriptyline) and anxiolytics (e.g., benzodiazepines) [47,48].
Amitriptyline, the third most frequent active agent in our analysis, is often used to treat neuropathic pain. However, it is common to use this medication for psychiatric symptoms, such as a depressive mood or insomnia. The use of antidepressants may cause clinically relevant adverse effects due to their anticholinergic activity, and their ability to induce sedation and orthostatic hypotension, and to stimulate the central nervous system [6]. They should be used with caution, due to the damage they can cause in the psychomotor function, increasing the risk of falls and fractures [49]. Benzodiazepines also were often used in older adults for the treatment of insomnia, depression, or anxiety. But in older adults, they may increase sensitivity to benzodiazepines and decrease metabolism of long-acting agents; in general, all benzodiazepines increase risk of cognitive impairment, delirium, falls, fractures, and motor vehicle crashes in older adults [6]. In addition,  This study has shown that PIM is frequent in middle-aged people, a population previously under-researched, and elderly people. By targeting the aging population, the middle-aged individuals will be the focus for health provision in the future.
The knowledge of the pharmacoepidemiology of PIM is important information for the promotion of the rational use of drugs in primary health care.

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Cognitive impairment alone, or together with depressive symptoms, was an associated factor for a PIM prescription. Antiarrhythmics (classes I and III), centrally acting antiadrenergics, antihistamines, anxiolytics and antidepressants were the most commonly PIM class used. The prevention and recognition of PIM represents an area of concern in the delivery of healthcare. Conducting medication reviews is a method often recommended to identify and solve PIM, to optimize drug treatment and to improve patient health outcomes. These

Funding
This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nivel Superior -Brasil (CAPES) -Finance Code 001.

Conflicts of interest disclosure
The authors declare no competing interests relevant to the content of this study.