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Frailty, depression and mortality in a cohort of community-dwelling older adults

Abstract

Objective

To estimate the risk represented by the combined conditions of frailty and depression in relation to mortality in a cohort of older adults in a prospective measure.

Method

Prospective cohort study derived from baseline (2008/2009) and follow-up (2016/2017) measurements of the FIBRA Study - Polo Unicamp. Data from 739 older adults (67,2% female; 73,1+5.87 years) living in two urban centers in the state of São Paulo (Brazil) were analyzed to examine survival curves and to estimate mortality risk. The analyzes included four conditions resulting from the combination of depression (presence x absence of symptoms) and frailty (frail x robust) and the covariates sex, age, education, cognitive performance and comorbidities.

Results

The percentage of deaths was 25.7%. There were significant differences between the survival curves regarding the combinations between frailty and depression. Male sex, age over 75 years, low education, low cognitive performance and the combinations “depression-robust”, “depression-frail” and “no depression-frail” presented independent risks for mortality. In the multivariate model, the highest risks were given, respectively, by older ages, the combinations “depression-robust”, “depression-frail”, “no depression-frail”, male sex and lower cognitive performance.

Conclusion

Combinations between frailty and depression can result in differences in survival and mortality among older adults. In the nine-year period, depression proved to be the ordering variable of the groups in relation to risk estimates, even in the presence of important covariates. Investments in the prevention of both syndromes and their associations may result in a decrease in mortality in older people from general causes.

Keywords
Frailty; Depression; Mortality; Survival Analysis; Older adults

Resumo

Objetivo

Estimar o risco representado por condições combinadas de fragilidade e depressão em relação à mortalidade de uma coorte de idosos em medida prospectiva.

Método

Estudo de coorte prospectivo derivado das medidas de linha de base (2008/2009) e seguimento (2016/2017) do Estudo Fibra - Polo Unicamp. Foram analisados dados de 739 idosos (67,2% feminino; 73,1+5,87 anos) residentes em dois centros urbanos do estado de São Paulo (Brasil) para o exame de curvas de sobrevida e para estimar risco de mortalidade. As análises incluíram quatro condições resultantes da combinação entre depressão (presença x ausência de sintomas) e de fragilidade (frágil x robusto) e as covariáveis sexo, idade, escolaridade, desempenho cognitivo e comorbidades.

Resultados

A porcentagem de óbitos foi de 25,7%. Houve diferenças significativas entre as curvas de sobrevida referentes às combinações entre fragilidade e depressão. Sexo masculino, idade acima de 75 anos, baixa escolaridade, baixo desempenho cognitivo e as combinações “depressão-robusto”, “depressão-frágil” e “sem depressão-frágil” apresentaram riscos independentes para mortalidade. No modelo multivariado, os maiores riscos foram dados, respectivamente, por idades mais avançadas, as combinações “depressão-robusto”, “depressão-frágil”, “sem depressão-frágil”, sexo masculino e menor desempenho cognitivo.

Conclusão

Combinações entre fragilidade e depressão podem resultar em diferenças em sobrevida e mortalidade entre idosos. No período de nove anos, depressão revelou ser a variável de ordenação dos grupos em relação às estimativas de risco, mesmo na presença de covariáveis importantes. Investimentos na prevenção de ambas as síndromes e de suas associações podem resultar diminuição na mortalidade de idosos por causas gerais.

Palavras-Chave:
Fragilidade; Depressão; Mortalidade; Análise de Sobrevida; Idosos

INTRODUCTION

Since the proposition of a characteristic phenotype of frailty in older adults11 Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001; 56 (3): M146-M156. doi: 10.1093/gerona/56.3.M146., it has been recognized that associations between this syndrome and the presence of depressive symptoms have important effects on clinical management and lead to different impacts on quality of life and on the risk of morbidity and mortality in older adults22 Cesari M, Calvani R, Marzetti E. Frailty in Older Persons. Clin Geriatr Med. 2017;33(3):293-303. doi: 10.1016/j.cger.2017.02.002.,33 Nascimento PPP, Batistoni SST. Depression and frailty in old age: a narrative review of the literature published between 2008 and 2018. Interface (Botucatu). 2019; 23: e180609. doi: 10.1590/interface.180609.. There is evidence that both conditions are associated with greater functional dependence, cognitive impairment, greater use of health services and risk of institutionalization22 Cesari M, Calvani R, Marzetti E. Frailty in Older Persons. Clin Geriatr Med. 2017;33(3):293-303. doi: 10.1016/j.cger.2017.02.002.,44 Coventry PA, McMillan D, Clegg A, Bown L, Feltz-Cornelis C, Gilbody S, et al. Frailty and depression predict instrumental activities of daily living in older adults: A population-based longitudinal study using the CARE75+ cohort. PLoS One. 2020;15(12): e0243972. Published 2020 Dec 15. doi: 10.1371/journal.pone.0243972.

5 Feng L, Nyunt MSZ, Feng L, Yap KB, Ng TP. Frailty predicts new and persistent depressive symptoms among community-dwelling older adults: finding from Singapore Longitudinal Aging Study. JAMDA. 2014; 15(1): 76e.7-e12. doi: 10.1016/j.jamda.2013.10.001.
-66 McCall WV, Kintziger KW. Late-Life Depression: a global problem with few resources. Psychiatr Clin North Am. 2013; 36 (4). doi: 10.1016/j.psc.2013.07.001.. However, a smaller number of investigations have been devoted to the effects resulting from the associations between different combinations of frailty and depression on the mortality of older adults in prospective surveys77 Ruiz-Grao MC, Sánchez-Jurado PM, Molina-Alarcón M, Hernández-Martínez A, Céspedes AA, Abizanda P. Frailty, depression risk, and 10-year mortality in older adults: the FRADEA study. Int Psychogeriatr. 2020; 33 (8): 803-12. doi:10.1017/s1041610220003506..

Meta-analysis strategies applied to recent studies have suggested that there is a prevalence of 38.6% of depression among frail older adults and a 40.4% prevalence of frailty in depressive older adults88 Soysal P, Veronese N, Thompson T, Kahl KG, Fernandes BS, Prina AM, et al. Relationship between depression and frailty in older adults: a systematic review and meta-analysis. Ageing Res Rev. 2017; 36: 78-87. doi: 10.1016/j.arr.2017.03.005.. The possibility of shared pathophysiological factors, such as inflammatory markers, and antecedent conditions of a psychosocial nature, are considered in the production of common manifestations between the syndromes99 Brown PJ, Rutherford BR, Yaffe K, Tandler JM, Ray JL, Pott E, et al. The Depressed Frail Phenotype: the clinical manifestation of increased biological aging. Am J Geriatric Psychiatry. 2016; 24 (11): 1084-94. doi: 10.1016/j.jagp.2016.06.005.. Older adults with depressive symptoms present complaints that, in addition to changes in mood, physical and cognitive disposition and social withdrawal, coincide with the criteria for identifying frailty associated with reports of fatigue, unintentional loss of body mass, and low physical activity levels, gait speed and handgrip strength88 Soysal P, Veronese N, Thompson T, Kahl KG, Fernandes BS, Prina AM, et al. Relationship between depression and frailty in older adults: a systematic review and meta-analysis. Ageing Res Rev. 2017; 36: 78-87. doi: 10.1016/j.arr.2017.03.005.

9 Brown PJ, Rutherford BR, Yaffe K, Tandler JM, Ray JL, Pott E, et al. The Depressed Frail Phenotype: the clinical manifestation of increased biological aging. Am J Geriatric Psychiatry. 2016; 24 (11): 1084-94. doi: 10.1016/j.jagp.2016.06.005.
-1010 Collard RM, Comijs HC, Naarding P, Oude Voshaar RC. Physical frailty: vulnerability of patients suffering from late-life depression. Aging Ment Health. 2014; 18 (5): 570-8. doi: 10.1080/13607863.2013.827628..

Both frailty and depression represent risks for mortality, according to evidence generated by examining each of these conditions separately or by statistically controlling for the presence of the other1111 Prina AM, Stubbs B, Veronese N, Guerra M, Kralj C, Llibre RJJ, et al. Depression and incidence of frailty in older people from six Latin American countries. Am J Geriatr Psychiatry. 2019;27(10):1072–1079. doi: 10.1016/j.jagp.2019.04.008.. A meta-analysis study showed an increase in all-cause mortality, attributed to frailty, a higher risk among frail older adults than among pre-frail and robust older adults, and greater risks for males1212 Chang S-F, Lin P-L. Frail phenotype and mortality prediction: A systematic review and meta-analysis of prospective cohort studies. Int J Nurs Stud. 2015; 52(8): 1362-74. doi: 10.1016/j.ijnurstu.2015.04.005.. These results were interpreted as indicators of the progression of the syndrome and its reflexes on the reduced availability of resources to maintain the integrity of the organism, culminating in death1313 Xue Q, Bandeen-Roche K, Tian J, Kasper JD, Fried LP. Progression of physical frailty and the risk of all-Cause mortality: Is there a point of no return? J Am Geriatr Soc. 2020; 69(4): 908-15. doi: 10.1111/jgs.16976..

The increased risk of mortality attributed to depression in the general population reveals more heterogeneous evidence resulting from the variety of measurements and criteria used and from the peculiarities of the presentation of this condition at different stages of life66 McCall WV, Kintziger KW. Late-Life Depression: a global problem with few resources. Psychiatr Clin North Am. 2013; 36 (4). doi: 10.1016/j.psc.2013.07.001.. Differences in age, sex, health behaviors, comorbidities, functional and cognitive impairments, and intensity and duration of depressive symptoms can act as potential moderators of the outcome of death1414 Diniz BS, Reynolds CF 3rd, Butters MA, Dew MA, Firmo JO, Lima-Costa MF, et al. The effect of gender, age, and symptom severity in late-life depression on the risk of all-cause mortality: the Bambuí Cohort Study of Aging. Depress Anxiety. 2014; 31(9): 787-95. doi: 10.1002/da.22226.. However, in a review and meta-analysis of prospective cohort studies with older adult samples, Wei et al.1515 Wei J, Ruixue H, Zhang X, XU H, Xie L, Chandrasekar EK, et al. The association of late-life depression with all-cause and cardiovascular mortality among Community-dwelling older adults: systematic review and meta-analysis. Br J Psychiatry. 2019; 215: 449-55. doi: 10.1192/bjp.2019.74. estimated that depression increases the risk of all-cause mortality by 34% and of specific mortality from cardiovascular diseases by 31%.

Chang et al66 McCall WV, Kintziger KW. Late-Life Depression: a global problem with few resources. Psychiatr Clin North Am. 2013; 36 (4). doi: 10.1016/j.psc.2013.07.001. reported results from the combination of frailty (measured as accumulation of functional deficits) and depression over time (18 years). Frail and depressed older adults showed a lower chance for the remission of depressive symptoms. This profile also presented a higher probability of mortality when compared with frail, non-depressed older adults. Ruiz-Grao et al.77 Ruiz-Grao MC, Sánchez-Jurado PM, Molina-Alarcón M, Hernández-Martínez A, Céspedes AA, Abizanda P. Frailty, depression risk, and 10-year mortality in older adults: the FRADEA study. Int Psychogeriatr. 2020; 33 (8): 803-12. doi:10.1017/s1041610220003506. compared the proportional hazards represented by six different combinations of presence or absence of depression and frailty at baseline to mortality recorded over a subsequent 10-year period. After adjusting for sociodemographic variables, institutionalization, comorbidities and polypharmacy, only the combination of depression and pre-frailty represented a risk of death in the period under study.

In order to obtain and explore evidence from a sample of Brazilian older adults, this study sought to estimate the risk for mortality represented by different combinations of depression and frailty in a cohort of older adults. The covariation of these combinations with sociodemographic characteristics, cognitive performance, and number of diseases at baseline in relation to the outcome of death recorded at follow-up was considered.

METHODS

A prospective cohort study developed from data derived from baseline (2008/2009) and follow-up (2016/2017) surveys from the Frailty Profile of Elderly Brazilians (FIBRA UNICAMP) study. This is a multicenter study, with a baseline sample composed of older adults living in seven Brazilian cities1717 Neri AL, Yassuda MS, Araújo, LF, Eulálio MC, Cabral BE, Siqueira MEC, et al. Metodologia e perfil sociodemográfico cognitivo e de fragilidade de idosos comunitários de sete cidades brasileiras: estudo FIBRA. Cad. Saúde Públ. 2013; 29 (4): 778-92. doi: 10.1590/S0102-311X2013000400015., which prospectively followed cohorts from two of these locations (Campinas and the subdistrict of Ermelino Matarazzo, São Paulo, Brazil) in a follow-up survey. At the time of the first data collection, Campinas (SP; human development index HDI= 0.852) had a general population of 1,083,113 inhabitants, 11.5% of which were people aged 65 years old and over. The sub-district of Ermelino Matarazzo (HDI= 0.730), located in the east of the city of São Paulo (SP), had 207,509 inhabitants, 10.8% of which were people aged 60 years old and over. Based on standardized protocols, the study aimed to investigate the frailty conditions of urban older adults residing in the community (not institutionalized). and the relationships between this condition and sociodemographic, psychosocial, health, and functionality variables. The study also obtained and recorded information concerning deaths that occurred between baseline and follow-up.

Baseline data were collected in 2008/2009, by recruiting older adult females and males, 65 years old or over, with different sociodemographic conditions, who resided in randomly selected census tracts. The older adults were invited to attend community service locations (primary health care units, community centers, parish halls and clubs) to be evaluated by trained interviewers. At the time, those who presented severe cognitive or physical deficits that made their participation unfeasible or difficult were not included in the study.

A total of 1,284 older adults living in the city of Campinas (n=900) and in the sub-district of Ermelino Matarazzo (n=384), in the city of São Paulo participated in the baseline study. The samples were selected by means of a simple drawing of urban census sectors in the two locations (90 in Campinas and 62 in Ermelino Matarazzo), for which quotas of men and women aged 65 to 69, 70 to 74, 75 to 79 and 80 years old or over, representative of the older adult population, in 2007, plus 25% to cover possible losses.

In the follow-up survey, conducted in 2016/2017, trained researchers returned to the households registered in the database at baseline. All the older adults who consented to participate responded to the Mini Mental State Examination (MMSE) cognitive screening test, adopting the criteria by Brucki et al.1818 Brucki SMD, Nitrini R. Mini-Mental State Examination among lower educational levels and illiterates: transcultural evaluation. Dement Neuropsychol. 2010; 4(2): 120-5. doi: 10.1590/S1980-57642010DN40200008. to define the cut-off scores. Older adults who scored below the criterion for their level of education responded only to the cognitive assessment, physical assessment and frailty items. Questions concerning health, functionality and psychosocial variables were answered by a family member. In the case of death of the older adult, a family member was invited to answer a questionnaire about signs and symptoms, and chronic non-communicable diseases in the last year of life and about the circumstances of their death.

In the follow-up study, 549 older adults were located and interviewed at home, among which 130 were helped by a family member, given the fact that they scored below the MMSE cut-off score. Another 192 had died and 543 were not located, refused to participate, abandoned the interview, were excluded by research criteria or were not interviewed because their place of residence posed risks to the interviewers’ safety (Figure 1).

Figure 1
Flowchart of the composition of the FIBRA Study sample at baseline and follow-up survey. FIBRA Study, Older adults, Campinas and Ermelino Matarazzo, SP, Brazil, 2008/2009 and 2016/2017.

As shown in Figure 1, the 1,284 participants in the baseline measurements of the FIBRA Campinas and Ermelino Matarazzo Study, both located in the State of São Paulo, were considered eligible for this study. Of this total, data were collected and analyzed from 549 older adults located at their former addresses, and from 192 deceased older adults whose data concerning their last year of life and the circumstances of their death were informed by a family member. These data were verified and confirmed by the death certificate of each deceased older adult and by consulting the Sistema de Informação sobre Mortalidade (SIM) [Mortality Information System] of the municipality of Campinas. It was not possible to access SIM data for the subdistrict of Ermelino Matarazzo.

Variables and measurements

The outcome of interest in this study was the occurrence of death from all causes, for the period between the baseline and follow-up surveys. The date of death was recorded to calculate survival during the period.

The presence of depression in the cohort was identified by applying the Geriatric Depression Scale-15 (GDS-15)1919 Almeida OP, Almeida AS. Confiabilidade da versão brasileira da Escala de Depressão Geriátrica (GDS) versão reduzida. Arq Neuropsiquiatr. 1999; 57 (2-B): 421-6. doi: 10.1590/S0004-282X1999000300013., determined as obtaining any score below 6 (>5 points) at baseline.

Frailty was identified by measurements of the five frailty phenotype criteria, as described by Fried et al.11 Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001; 56 (3): M146-M156. doi: 10.1093/gerona/56.3.M146.. According to the authors, individuals who meet one or two of the following criteria are considered pre-frail and those who meet three or more criteria are considered frail. Individuals that do not meet any of these criteria are considered robust:

1) Unintentional weight loss equal to or greater than 4.5 kg or 5% of body weight in the previous year, considering the sex of the older adult;

2) Fatigue, assessed by two items that correspond to this complaint on the CES-D (Center for Epidemiological Studies-Depression) screening scale. The criteria for frailty are the answers “always” or “most of the time” as the frequency of occurrence of fatigue to any of the two items2020 Batistoni SST, Neri AL, Cupertino APFB. Validade da escala de depressão do Center for Epidemiological Studies (CES-D) entre idosos brasileiros. Rev Saúde Públ. 2007; 41 (4): 598-605. doi: 10.1590/S0034-89102007000400014.;

3) Low hand grip strength, in kilogram-force, measured with a portable hydraulic dynamometer in the dominant hand2121 Marucci M, Barbosa A. Estado nutricional e capacidade física. In: Lebrão ML, Duarte YAO, organizadores. SABE – Saúde, Bem-estar e Envelhecimento. Projeto SABE no município de São Paulo: uma abordagem inicial. Brasília: Organização Pan-Americana da Saúde; 2003. p. 93-118. (Jamar® - Lafayette Instruments, Lafayette, Indiana, United States), over three attempts, with means adjusted for sex and body mass index (BMI). Older adults with a mean below the 1st quintile of the distribution score for frailty;

4) Physical activity level, assessed by self-reporting of physical exercise and housework performed in the preceding seven days, according to the items in the Minnesota Leisure Time Activities Questionnaire2222 Lustosa LP, Pereira DS, Dias RC, Britto RR, Parentoni NA, Pereira LSM. Tradução e adaptação transcultural do Minnesota Leisure Time Activities Questionnaire em idosos. Rev. Bras. Geriatr. Gerontol. 2011; 5 (2): 57-65. with means adjusted for sex. Older adults with a mean below the 1st quintile of the distribution score for frailty;

5) Slow gait speed indicated by the average time taken to walk a distance of 4 m three times, on a level floor, at their normal pace, with means adjusted according to sex and height2323 Nakano MM. Adaptação cultural do instrumento Short Physical Performance Battery - SPPB: adaptação cultural e estudo da confiabilidade [Dissertação de Mestrado]. Campinas: Universidade Estadual de Campinas; 2007.. Older adults with a mean above the 80th percentile of the sample score for frailty.

As covariates of the relationships between frailty, depression and mortality, the following information derived from baseline measures were selected:

a) Sociodemographic variables: sex, male or female; age, <75 years old, 75-79 years old, ≥80 years old; and education, number of years of formal education: 0, 1 to 4, 5 to 8, 9 or more;

b) Chronic diseases: identified by the number of self-reported diseases based on an inventory of nine dichotomous items composed of the most prevalent chronic non-communicable diseases in the older adult population;

c) Cognitive performance: estimated by the total score on the MMSE1818 Brucki SMD, Nitrini R. Mini-Mental State Examination among lower educational levels and illiterates: transcultural evaluation. Dement Neuropsychol. 2010; 4(2): 120-5. doi: 10.1590/S1980-57642010DN40200008.,2424 Folstein MF, Folstein SE, McHugh PR. Mini-Mental State: a practical method for grading the cognitive state of patients for clinician. J Psychiatr Res. 1975; 12:189-198. doi: 10.1016/0022-3956(75)90026-6. with scores ranging from 0 to 30 points and a specific cut-off point for number of years of education completed.

To describe the sample under study alone, certain indicators of functional capacity were included, in this case, the performance of instrumental activities of daily living (IADLs) in the baseline survey. The inventory and criteria described by Lawton & Brody2525 Lawton MP, Brody EM. Assesment of older people: self-maintaining and instrumental activities of daily living. Gerontologist. 1969; 9(3):179-86. doi: 10.1097/00006199-197005000-00029. were used, which involve a list of seven activities of practical life used to identify independence or total or partial dependence in their performance.

The FIBRA study baseline and follow-up surveys were approved by the Research Ethics Committee of the State University of Campinas (UNICAMP) under report no. 208/2007, on May 22, 2007, and report no. 1,332,651, on November 23, 2015. A term of free, informed consent was signed by all participants in both surveys. The use of data to conduct this study was also approved by the aforementioned committee, under report no. 3,097,048, on December 20, 2018.

The variables of interest were described according to their percentage distribution and position measurements (mean and standard deviation). Data from living and deceased older adults were compared using the Mann-Whitney and Fisher’s exact tests, due to the absence of normal data distribution. From the data on depression and frailty, four categories of association were generated, derived from the combinations between absence or presence of depression and frailty status (robust or frail): 1) no depression and robust; 2) no depression and frail; 3) with depression and robust; 4) with depression and frail. Kaplan-Maier survival curves were determined and nonparametric log-rank, Gehan-Breslow, and Tarone-Ware tests were performed to identify differences between the combined conditions of depression and frailty. To estimate the mortality risk for the groups of associations between depression and frailty, crude and adjusted Cox proportional hazards models were used, considering their covariation with sociodemographic variables (sex, age and education), cognitive performance and comorbidities. The significance level for the tests was 95% or p<0.05.

RESULTS

The sample was characterized by a higher percentage of female participants (67.2%), aged between 65 and 74 years (64%) with four years of education or less. The average cognitive performance on the MMSE was 23.8+4.14 points. There was also a higher percentage of older adults reporting at least one chronic disease, but a high degree of the preservation of functional independence when performing IADLs in baseline measurements (70.5%).

Considering only the current sample, in the follow-up survey, 190 deaths (25.7%) were recorded. The subsample of deceased older adults differed from the subsample of living participants in terms of distribution in all the variables of interest, with the exception of the number of self-reported diseases. Male sex, aged 80 years old and over, lack of formal education, greater functional disability, depression and frailty were present to a greater extent in the subsample of deceased than in the subsample of living participants. Compared with participating older adults, deceased older adults also showed lower mean scores on cognitive performance and a higher percentage of older adults who exhibited more unfavorable combinations of depression and frailty (Table 1).

Table 1
Characterization of the baseline sample and subsamples of participating and deceased older adults according to sociodemographic variables, number of diseases and functional disabilities, cognition and isolated and combined conditions of depression and frailty. FIBRA Study, Older adults, Campinas and Ermelino Matarazzo, SP, Brazil, 2008/2009 and 2016/2017.

Figure 2 shows the survival curves (Kaplan-Maier) corresponding to the combinations of frailty and depression conditions. The log-rank test (X22 Cesari M, Calvani R, Marzetti E. Frailty in Older Persons. Clin Geriatr Med. 2017;33(3):293-303. doi: 10.1016/j.cger.2017.02.002.=17.79; gl=3; p<0.001) resulted in significant differences between them. Measured in months, the mean survival of the robust and non-depressed older adults was 116.7+1 months (95%CI =114.8–1118.5); those without depression and frail was 112.8+0.9 months (95%CI =111.1–114.5); those with depression and robust was 106.7+3.9 months (95%CI=98.5–113.8); and those with depression and frail was 110.7+1.3 months (95%CI =108.1–113.3). The Gehan-Breslow (X22 Cesari M, Calvani R, Marzetti E. Frailty in Older Persons. Clin Geriatr Med. 2017;33(3):293-303. doi: 10.1016/j.cger.2017.02.002.=13.83; gl=3; p=0.003) and Tarone-Wade (X22 Cesari M, Calvani R, Marzetti E. Frailty in Older Persons. Clin Geriatr Med. 2017;33(3):293-303. doi: 10.1016/j.cger.2017.02.002.=14.74; gl=3; p=0.002) tests also showed differences between the combined conditions of frailty and depression. Graphic signs along the curves refer to the occurrence of assessments.

Figure 2
Survival curves according to combined conditions of depression and frailty. FIBRA Study, Older adults, Campinas and Ermelino Matarazzo, SP, Brazil, 2008/2009 and 2016/2017.

In Table 2, the crude and adjusted risk ratios (HR) are described for the variables sex, age, education, cognitive performance, number of diseases, and combined conditions of frailty and depression.

Table 2
Crude and adjusted Cox regression for overall survival (N=733). FIBRA Study, Older adults, Campinas and Ermelino Matarazzo, SP, Brazil, 2008/2009 and 2016/2017.

In the crude analysis, the highest risk ratio for mortality over time was determined for category age, with the oldest age group (>80 years) showing the highest rate compared with the age group 65 to 74 years old. The absence of formal education showed a risk ratio of 3.59 (95%CI = 1.70–7.56) compared with older adults with more years of education (>9 years); men showed a risk 33% higher than women. Compared with the condition “no depression and robust,” all other combinations represented a significant risk, the highest was that obtained for the condition “with depression and robust,” followed by “with depression and frail,” and “no depression and frail.” Regarding performance on the MMSE, the increase in total score by one point represented a reduction in the risk of death, or increase in survival, of 11.6%.

The results of the adjusted analysis revealed that education lost statistical significance. Higher indices were associated with the age groups >80 years old and 75 to 79 years old, for the condition “with depression and robust,” followed by “with depression and frail,” and “no depression and frail,” and by total score on the MMSE, in which one point represented a reduction in the risk of death, or an increase in survival, of 8%.

DISCUSSION

The results support the hypothesis that different combinations of frailty and depression in older adults have different probabilities of mortality over time. Here, sociodemographic conditions and cognitive performance contributed to the differentiation in risk indices.

In Brazil, the prevalence of depression in older adults, estimated by the application of screening scales, is 21.0% (95%CI: 18.0–25.0)2626 Meneguci J, Meneguci CAG, Moreira MM, Pereira KR, Tribess S, Sasaki JE, et al. (2019). Prevalência de sintomatologia depressiva em idosos brasileiros: Uma revisão sistemática com metanálise. J Bras de Psiquiatr, 68(4), 221–230. doi: 10.1590/0047-2085000000250., a value similar to that found in the baseline survey of this study. The identification of frailty by the phenotype described by Fried et al.11 Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001; 56 (3): M146-M156. doi: 10.1093/gerona/56.3.M146. requires the fulfilment of specific criteria. The presence of three or more criteria estimated for Brazil is 16%, and based on data from the FIBRA Study in the UNICAMP Pole, 9.1% of frail and 51.8% of pre-frail older adults were observed2727 Melo RC, Cipolli GC, Buarque GLA, Yassuda MS, Cesari M, Oude Voshaar RC, et al. Prevalence of Frailty in Brazilian Older Adults: A Systematic Review and Meta-analysis. J Nutr Health Aging. 2020;24(7):708-716. doi:10.1007/s12603-020-1398-0.. The combination of pre-frailty and frailty in this study showed a high percentage of older adults who meet some of the frailty criteria (69.8%). This percentage was similar to that reported by Ruiz-Grão et al.1515 Wei J, Ruixue H, Zhang X, XU H, Xie L, Chandrasekar EK, et al. The association of late-life depression with all-cause and cardiovascular mortality among Community-dwelling older adults: systematic review and meta-analysis. Br J Psychiatry. 2019; 215: 449-55. doi: 10.1192/bjp.2019.74. in Spain (75.6%), though their sample also included institutionalized older adults.

Frailty and depression screening measurements in the older adult population are used to determine different aspects of health, but have the potential to generate specific association subgroups77 Ruiz-Grao MC, Sánchez-Jurado PM, Molina-Alarcón M, Hernández-Martínez A, Céspedes AA, Abizanda P. Frailty, depression risk, and 10-year mortality in older adults: the FRADEA study. Int Psychogeriatr. 2020; 33 (8): 803-12. doi:10.1017/s1041610220003506.. The results suggested the importance of verifying this potential based on three forms of analyzing mortality: percentage distribution based on dichotomous outcomes, survival curves, and calculating risk ratios.

Concerning the dichotomous outcome, the subsample of deceased older adults differed from that of participating older adults, in terms of the percentage of deaths that occurred for the condition “no depression and frail”, that is, isolated frailty was present more often among older adults who died than among participating older adults.

However, when considering the time of occurrence of these deaths, the combinations of conditions revealed different survival trajectories. Regarding accumulated survival, the condition “with depression and robust” stood out from the first months of recorded deaths onwards, and was only surpassed by the condition “with depression and frail,” and later by “no depression and frail,” by the end of the last third of the period under study. Different non-parametric tests for comparing trajectories were used to capture possible biases in the distribution of deaths over time, given the long interval between the surveys. The log-rank test assigns the same weight to associations over time. In turn, the Gerhan-Breslow test is influenced by the initial portion and the Tarone-Ware test by the intermediate portion. All of them confirmed the differences in the curves of the groups.

To calculate the risk ratios, the condition “no depression and robust” was used as the reference for comparisons. The remaining conditions all presented significant risks independently or adjusted for covariates. The independent risks identified for the covariates were advanced age, male sex, and lack of formal education. An increase in the score for cognitive performance was associated with a reduced risk of death. Advanced age, male sex and cognitive performance significantly and jointly affected the risk-adjusted calculation represented by the different combinations.

As expected, advanced age is an independent indicator of mortality. However, age also acts as a source of variation for the relationship between depression and frailty. A study by Ji et al.2828 Ji L, Qiao X, Jin Y, Si H, Liu X, Wang C. Age differences in the relationship between frailty and depression among community-dwelling older adults. Geriatr Nurs. 2020; 41 (4): 485-489. doi:10.1016/j.gerinurse.2020.01.021. showed that the associations between frailty and depression and their effects on mortality became weaker with advancing age. The authors suggested that the performance of adaptive mechanisms of emotional regulation were more active in older adults, even in the presence of frailty criteria.

In studies on mortality in older adults with depression and studies on frailty, there is evidence of a higher risk for men77 Ruiz-Grao MC, Sánchez-Jurado PM, Molina-Alarcón M, Hernández-Martínez A, Céspedes AA, Abizanda P. Frailty, depression risk, and 10-year mortality in older adults: the FRADEA study. Int Psychogeriatr. 2020; 33 (8): 803-12. doi:10.1017/s1041610220003506.,2929 Almeida OP, Hankey GJ, Yeap BB, Golledge J, Norman PE, Flicker L. Depression, frailty, and all-cause mortality: a Cohort Study of Men Older than 75 years. J Am Med Dir Assoc. 2015; 16 (4): 296-300. doi: 10.1016/j.jamda.2014.10.023., possibly mediated by cardiovascular causes, in the context of depression and frailty3030 Arts MHL, van den Berg KS, Marijnissen RM, Jonge L, Hegeman AJM, Collard RM, et al. Frailty as a predictor of mortality in late-life depression: a Prospective Clinical Cohort Study. J Clin Psychiat. 2021; 82 (3). doi: 10.4088/JCP.20m13277.. Although there is a higher percentage of frail women than frail men, in the presence of depression, this condition represents an increased risk of death for men2828 Ji L, Qiao X, Jin Y, Si H, Liu X, Wang C. Age differences in the relationship between frailty and depression among community-dwelling older adults. Geriatr Nurs. 2020; 41 (4): 485-489. doi:10.1016/j.gerinurse.2020.01.021.,3030 Arts MHL, van den Berg KS, Marijnissen RM, Jonge L, Hegeman AJM, Collard RM, et al. Frailty as a predictor of mortality in late-life depression: a Prospective Clinical Cohort Study. J Clin Psychiat. 2021; 82 (3). doi: 10.4088/JCP.20m13277.. In a prospective study, depressive symptoms at baseline represented a risk of mortality in men, with or without adjustment for frailty2929 Almeida OP, Hankey GJ, Yeap BB, Golledge J, Norman PE, Flicker L. Depression, frailty, and all-cause mortality: a Cohort Study of Men Older than 75 years. J Am Med Dir Assoc. 2015; 16 (4): 296-300. doi: 10.1016/j.jamda.2014.10.023.. One of the explanatory hypotheses lies in shared vascular risk, which is associated both with mortality from general and specific causes in men and with depression, which manifests itself later in life1414 Diniz BS, Reynolds CF 3rd, Butters MA, Dew MA, Firmo JO, Lima-Costa MF, et al. The effect of gender, age, and symptom severity in late-life depression on the risk of all-cause mortality: the Bambuí Cohort Study of Aging. Depress Anxiety. 2014; 31(9): 787-95. doi: 10.1002/da.22226..

Cho et al.3131 Cho J, Lee I, Park SH, Jin Y, Kim D, Kong JY, et al. Socioeconomic Status, Frailty, and All-Cause Mortality in Korean Older Adults: A 3-Year Population-Based Prospective Study. Biomed Res Int. 2017; 2017:1903589. doi:10.1155/2017/1903589. observed associations between low socioeconomic status and frailty and risk of mortality, even after adjusting for covariates of health and functionality. In this study, the absence of formal education was associated with an independent risk of mortality. In the adjusted analyses, it is possible that it lost explanatory power when aligned with performance in the MMSE, a test that is highly sensitive to education level88 Soysal P, Veronese N, Thompson T, Kahl KG, Fernandes BS, Prina AM, et al. Relationship between depression and frailty in older adults: a systematic review and meta-analysis. Ageing Res Rev. 2017; 36: 78-87. doi: 10.1016/j.arr.2017.03.005..

The greatest difficulties and sources of criticism of mortality studies come from controlling confounding variables3232 Miloyan B, Fried E. A reassessment of the relationship between depression and all-cause mortality in 3,604,005 participants from 293 studies. World Psychiatry. 2017; 16 (2): 219-220. doi:10.1002/wps.20439.. In this study, we opted to control the number of self-reported diseases (those which did not show independent or joint effects), but not to control the presence of disabilities in performing instrumental activities of daily living (IADLs)44 Coventry PA, McMillan D, Clegg A, Bown L, Feltz-Cornelis C, Gilbody S, et al. Frailty and depression predict instrumental activities of daily living in older adults: A population-based longitudinal study using the CARE75+ cohort. PLoS One. 2020;15(12): e0243972. Published 2020 Dec 15. doi: 10.1371/journal.pone.0243972.. This choice was motivated by criticism directed at the study by Ruiz-Grao et al.77 Ruiz-Grao MC, Sánchez-Jurado PM, Molina-Alarcón M, Hernández-Martínez A, Céspedes AA, Abizanda P. Frailty, depression risk, and 10-year mortality in older adults: the FRADEA study. Int Psychogeriatr. 2020; 33 (8): 803-12. doi:10.1017/s1041610220003506. for saturating the regression model with variables of great influence on mortality, such as IADLs, weighted comorbidities and health behaviors, and for including older adults institutionalized in the sample. Their critics3333 Ward DD, Bhat R. Do frailty and depression interact to heighten risk of death? Int Psychogeriatr. 2021; 33 (8): 755-757. doi:10.1017/S1041610220003968. considered that the explanatory power of frailty was reduced, given that the only significant combination between depression and frailty in relation to the risk of mortality was “pre-frailty and depression.”

In the short term, the presence of functional disabilities is perhaps one of the most common consequences of the combination of depression and frailty44 Coventry PA, McMillan D, Clegg A, Bown L, Feltz-Cornelis C, Gilbody S, et al. Frailty and depression predict instrumental activities of daily living in older adults: A population-based longitudinal study using the CARE75+ cohort. PLoS One. 2020;15(12): e0243972. Published 2020 Dec 15. doi: 10.1371/journal.pone.0243972.,77 Ruiz-Grao MC, Sánchez-Jurado PM, Molina-Alarcón M, Hernández-Martínez A, Céspedes AA, Abizanda P. Frailty, depression risk, and 10-year mortality in older adults: the FRADEA study. Int Psychogeriatr. 2020; 33 (8): 803-12. doi:10.1017/s1041610220003506.,88 Soysal P, Veronese N, Thompson T, Kahl KG, Fernandes BS, Prina AM, et al. Relationship between depression and frailty in older adults: a systematic review and meta-analysis. Ageing Res Rev. 2017; 36: 78-87. doi: 10.1016/j.arr.2017.03.005.. The purpose of this study was to draw attention to groups of association based on mortality estimates, with adjustments only for less specific sociodemographic and health variables.

The available data set and our analytical choices could be considered methodological limitations. Frail older adults may not have been sufficiently included in the baseline survey. Baseline frailty results of older adults lost to the follow-up survey or the incidence of other chronic diseases during the period were not analyzed. These data may have biases from several sources, and these possibilities were not considered.

Similarly, due to the size of the sample and its distribution in subgroups, separating the status of pre-frailty and frailty was not considered in the best interests of the study. Thus, more than combinations of depression and frailty, the study analyzed the relationship between the presence of depressive symptoms in a significant number and some of the frailty criteria. We believe this strategy is justified, since the distinctive feature of the frailty phenotype lies in its continuous nature, in which the criteria have been useful to explain the mortality and morbidity of older adults from different cultural contexts22 Cesari M, Calvani R, Marzetti E. Frailty in Older Persons. Clin Geriatr Med. 2017;33(3):293-303. doi: 10.1016/j.cger.2017.02.002..

Whether the risks represented by the different combinations of frailty and their criteria are additive or synergistic falls outside the scope of this study, more so when considering that there is simply insufficient data for such a task. Park et al.3434 Park S, Cho J, Kim D, Jin Y, Lee I, Hong H, et al. Handgrip strength, depression, and all-cause mortality in Korean older adults. BMC Geriatr. 2019; 19 (1): 127. doi:10.1186/s12877-019-1140-0. suggested that there is a synergistic effect between depression and handgrip strength, especially among older adult males. Ward and Bhat3333 Ward DD, Bhat R. Do frailty and depression interact to heighten risk of death? Int Psychogeriatr. 2021; 33 (8): 755-757. doi:10.1017/S1041610220003968. affirmed that statements regarding interactions between risks is premature, given the lack of consensus on shared causal mechanisms.

In this study, it seems reasonable to affirm that depression was the ordering variable of the risks, since its presence in isolation, and again in combination with frailty, represented higher risks than the condition of frailty alone3535 Ozer FF, Akin S, Soysal T, Gokcekuyu BM, Durmus NS. Depression in Frail Older Adults: Associations and Gender Difference. North Clin Istanb. Epub ahead of print 26 October 2021. doi:10.14744/nci.2021.55938. In future research on the subject, analyzes of all-cause mortality should aim to compare the effects represented by the associations of depression with the levels of frailty, with each of its criteria and with pre-frailty, with adjustments for specific diseases, for example, cardiovascular diseases3030 Arts MHL, van den Berg KS, Marijnissen RM, Jonge L, Hegeman AJM, Collard RM, et al. Frailty as a predictor of mortality in late-life depression: a Prospective Clinical Cohort Study. J Clin Psychiat. 2021; 82 (3). doi: 10.4088/JCP.20m13277..

CONCLUSION

Screening measurements for frailty and depressive symptoms taken in community-dwelling older adults can help to compose specific risk stratification criteria, since different combinations of conditions manifest in different aging trajectories and, in particular, different mortality risks. The greatest risks were identified in the presence of the combinations “with depression and robust”, “with depression and frail”, and “no depression and frail”, respectively.

The presence of depressive symptoms may be the ordering factor of the combinations on mortality within a period of approximately a decade of life, especially when the older adults are men, 75 years old and over, who present lower cognitive performance. Depression in old age is an identifiable and treatable condition, and evidence and effective interventions in the management of the frailty syndrome are growing. Investment in the prevention of and interventions in these conditions can minimize indicators of excess mortality from general causes.

  • Funding: CAPES/PROCAD number 2972/2014-01 (Project nº 88881.068447/ 2014-01), FAPESP number 2016/00084-8 e CNPq number 424789/2016-7.

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Edited by

Edited by: Tamires Carneiro de Oliveira Mendes

Publication Dates

  • Publication in this collection
    29 June 2022
  • Date of issue
    2022

History

  • Received
    16 Nov 2021
  • Accepted
    11 Mar 2022
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