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Many of the symptoms, consequences, and risk factors for frailty are shared with late-life depression. However, thus far, few studies have addressed the conceptual and empirical interrelationships between these conditions. This review synthesizes existing studies that examined depression and frailty among older adults and provides suggestions for future research.
A search was conducted using PubMed for publications through 2010. Reviewers assessed the eligibility of each report and abstracted information on study design, sample characteristics, and key findings, including how depression and frailty were conceptualized and treated in the analysis.
Of 133 abstracted articles, 39 full-text publications met inclusion criteria. Overall, both cross-sectional (n = 16) and cohort studies (n = 23) indicate that frailty, its components, and functional impairment are risk factors for depression. Although cross-sectional studies indicate a positive association between depression and frailty, findings from cohort studies are less consistent. The majority of studies included only women and non-Hispanic Whites. None used diagnostic measures of depression or considered antidepressant use in the design or analysis of the studies.
A number of empirical studies support for a bidirectional association between depression and frailty in later life. Extant studies have not adequately examined this relationship among men or racial/ethnic minorities, nor has the potential role of antidepressant medications been explored. An interdisciplinary approach to the study of geriatric syndromes such as late-life depression and frailty may promote cross-fertilization of ideas leading to novel conceptualization of intervention strategies to promote health and functioning in later life.
In the past decade, a body of literature has developed on the characteristics of frailty, defined as a state or indication of being vulnerable to declining health in later life (Rockwood et al., 1994; Fried et al., 2001; Cigolle et al., 2009). Currently, there are three distinct conceptual models of frailty (Cigolle et al., 2009): the cumulative burden model (Rockwood et al., 1994), in which frailty is modeled as the sum of diseases and health conditions, including psychiatric conditions, over the lifespan; the functional domains model (Strawbridge et al., 1998), in which frailty is modeled as the accumulation in deficits in physical (i.e., balance), nutritive (i.e., weight loss), cognitive (i.e., memory impairments), and sensory (i.e., vision loss) domains; and the biological syndrome model (Fried et al., 2001), in which frailty is modeled as syndrome characterized by weight loss, exhaustion, inactivity, slowness, and weakness (Fried et al., 2001), akin to geriatric failure-to-thrive (Committee on a National Research Agenda on Aging, 1991). Frailty has also been linked to sacropenia (Frisoli et al., 2011), vitamin D deficiency (Ensrud et al., 2010), and related health conditions. Depending on the index used, the prevalence of frailty among adults 65 years and older is estimated to be 10.9%–20.3% (Cigolle et al., 2009). Frailty is more common among women, thosewho are socially isolated (Rockwood et al., 2004), and those who live in socioeconomically disadvantaged communities (Lang et al., 2009). Support for the clinical and public health relevance of the frailty construct has been derived from its utility in predicting functional decline, disability, fracture, and mortality; it has been argued that frailty may be a pre-clinical, and potentially reversible, indicator of health status for older adults (Woods et al., 2005; Ensrud et al., 2007).
Parallel to this work on frailty, gerontologists and psychiatrists have characterized variation in the etiology and presentation of depression in later life. In 1994, Gallo and colleagues determined empirically that older adults are less likely to report symptoms of dysphoria but generally not other symptoms of depression (i.e., fatigue, guilt, appetite disturbances) relative to younger adults (Gallo et al., 1994). They later described this phenomenon as “depression without sadness” (Gallo & Rabins, 1999) and argued that in the clinical context, “Older patients with depression may present with somatic complaints for which a medical etiology cannot be found or that are disproportionate to the extent of medical illness.” Other investigators have noted the difficulty in diagnosing depression in the context of comorbid medical conditions that are common in later life (Katon & Sullivan, 1990; Birrer & Vemuri, 2004), suggesting that one reason for the lower prevalence of depression among older adults is that this condition is often confused for or conflated with physical decline. One result of this work has been the development of psychiatric assessments designed specifically for older adults and for those with comorbid neurological conditions, including the Geriatric Depression Scale (GDS) (Yesavage et al., 1983) and the Cornell Scale for Depression in Dementia (Alexopoulos et al., 1988). Relative to traditional structured diagnostic depression measures (e.g., Schedules for Clinical Assessment in Neuropsychiatry (SCAN), Structured Clinical Interview for DSM (SCID), Diagnostic Interview Schedule (DIS), Composite International Diagnostic Inventory (CIDI)), these instruments emphasize vegetative and functional aspects of depression beyond the syndrome criteria set out in the Diagnostic and Statistical Manual of Mental Disorders (i.e., the GDS includes items Do you feel full of energy? Do you enjoy getting up in the morning?).
These conceptualizations of depression in later life share many characteristics with frailty. Depression in later life is predictive of many of the same kinds of out-comes as frailty, including cognitive impairment (Andersen et al., 2005), disability (Bruce, 2001), fracture (Whooley et al., 1999), and mortality (Rovner et al., 1991; Laursen et al., 2007). However, as yet, there has been relatively little attention paid in the literature as to how these two syndromes may be related. Because health conditions in later life are often predicted by a shared set of risk factors, Tinetti and colleagues have explicitly called for a unified approach to conceptualizing geriatric syndromes (Tinetti et al., 1995). Similarly, in a recent editorial, Katz noted that “Depending on the definitions [of frailty] used, it is possible to make a case for each of these conditions [depression and frailty] as a cause, consequence, or comorbidity of the other. It is also possible to argue for their congruence.” (Katz, 2004). Despite these calls, few studies have rigorously examined the interrelationships between depression and frailty syndromes.
The motivations of this paper are to link these parallel bodies of literature by reviewing existing studies that address the interrelationships between depression and frailty, to suggest conceptual and methodological approaches to synthesize these constructs, and to identify pressing areas in need of additional research in this context.
Literature searches were conducted in PubMed with the assistance of a research librarian using combinations of the Medical Subject Heading (MeSH) terms “depression,” “depressive disorder,” “depressive disorder, major,” “aging,” and the word “frailty.” The term “frailty” is not currently indexed as a MeSH term, and therefore, searches were conducted using the related MeSH terms “frail elderly,” “fatigue,” “mobility limitation,” “lethargy,” “disability,” “atrophy,” “movement,” “postural balance,” and “muscle weakness.” The search was restricted to papers published in print or online prior to 1 October 2010 and in English. The reference lists of the citations identified in these searches, including review articles, were also examined. General population-based samples are the focus of this review because these study designs provide the best methodology for understanding the natural history of frailty and depression; clinic-based populations probably reflect a host of selection factors that make them inappropriate for exploring these epidemiologic questions (Schwartzbaum et al., 2003).
The searches returned 573 unique, empirical research articles, from which a group of four reviewers selected 133 for full-text abstraction (Supplemental Figure 1). To characterize the study population and main findings, the following information was extracted fromeach article: author, year of publication, geographic location, study design (i.e., cross-sectional, cohort), sample characteristics (i.e., age, sex, racial/ethnic composition), measure of frailty, the measure of depression or depressive symptoms, and a qualitative summary of the key findings. Studies were too varied in their analytic approach and reporting of results to extract a quantitative effect measure or to summarize the results in a formal (e.g., meta-analytic) manner. A handful of studies selected the entire population on thebasis of psychiatric (e.g.,Pijpers et al., 2009) or frailty status (e.g., Smith Barusch et al., 1999; Landi et al., 2005). These reports were excluded because all study participants displayed some characteristics of frailty or disability, which precluded an examination of the differential relationship between depression and frailty. Several other reports were excluded because the study sample was selected from a clinic setting, including nursing homes (e.g., Parmelee et al., 1998; Jongenelis et al.,2004; Onishi et al., 2004) or from a specific patient population (e.g., stroke or cancer patients). Two studies were excluded because they were randomized controlled trials rather than community-based cohorts (Fitzpatrick et al., 2007; Gitlin et al., 2007). Two independent reviewers examined the abstractions and identified 39 unique articles for inclusion in this review.
As shown in Table 1, the majority of population-based cross-sectional studies reported a positive association between depressive symptomatology and frailty status. Six studies did not report the racial/ethnic composition of the sample, but the all those that did included primarily Whites, and three included only Asians. Most studies were primarily composed of or included only women, and only the study conducted by Blyth et al. (2008) included exclusively men. All but one (Cummings et al., 2003) of the cross-sectional studies reported a statistically significant positive association between frailty and depressive symptomatology that persisted after adjustment for covariates, whether depression was examined as the determinant or consequence of frailty. For example, Hybels et al. (2001) reported that persons with elevated depressive symptoms were over five times as likely to have activities of daily living (ADL) limitations as persons with-out depression (Hybels et al., 2001). Several reports examined factors that influenced the depression–frailty relationship, including social support (Newsom and Schulz, 1996; Cummings et al., 2003), sense of mastery (Jang et al., 2002), religiosity (Cummings et al., 2003), and perceived health (Jang et al., 2006).
A wide range of metrics were used to index frailty, including traditional disability indices (e.g., ADL/instrumental activities of daily living scales) (Mirowsky and Ross, 1992; Davidson et al., 1994; Newsom and Schulz, 1996; Prince et al., 1997; Hybels et al., 2001; Jang et al., 2002; Cummings et al., 2003; Stek et al., 2004), history or fear of falling (Deshpande et al., 2008; Wada et al., 2008), number of medical conditions (Hybels et al., 2001), cognitive functioning (Hajjar et al., 2009), and specific frailty indices (Blyth et al., 2008; Deshpande et al., 2008; Chang et al., 2010; Chen et al., 2010). Three studies incorporated objective measures of physical performance (e.g., chair stands, grip strength) (Newsom and Schulz, 1996; Deshpande et al., 2008; Hajjar et al., 2009). Two-thirds (10 of 16) of studies used the Centers for Epidemiologic Studies–Depression (CES-D) scale to index depressive symptomatology (Mirowsky and Ross, 1992; Davidson et al., 1994; Newsom and Schulz, 1996; Broe et al., 1999; Hybels et al., 2001; Cummings et al., 2003; Jang et al., 2006; Deshpande et al., 2008; Hajjar et al., 2009; Chen et al., 2010). No studies that met the inclusion criteria used diagnostic instruments. One notable exception to the traditional regression approach used by these studies was a report by Hajjar and colleagues (2009) that examined the confluence of depressive symptoms, cognitive status, and slowness using latent variable modeling (Hajjar et al., 2009); they reported that the clustering of these characteristics was consistent with the notion that they describe a common geriatric syndrome.
Table 2 illustrates prospective studies in which depression was studied as a risk factor for onset of frailty, and in which frailty was examined as a risk factor for onset or persistence of depressive symptoms. As shown by the top portion of Table 2, all studies reported a positive association between frailty with onset or worsening of depressive symptomatology at follow-up (Kennedy et al., 1991; Ormel et al., 2002; Taylor and Lynch, 2004; Yang & George, 2005; Han, 2006; Atkinson et al., 2007; Schieman & Plickert, 2007; Gayman et al., 2008; Chang et al., 2009). For example, Yang and George (2005) reported that onset and persistence of frailty were stronger predictors of depressive symptoms than recovery from frailty over 6 years (Yang & George, 2005). As displayed in the lower portion of Table 2, most studies reported a significant positive association between depression and risk of frailty onset, at least in bivariate analyses (Buchner, 1996; Strawbridge et al., 1998; Vaillant, 1998; Rantanen et al., 2000; Sarkisian et al., 2000; Mehta et al., 2002; Avlund, 2006; Barry et al., 2009). For example, Strawbridge et al. (1998) reported that persons with repeatedly elevated depressive symptoms were 3.2 times more likely to be frail at follow-up than those with no history of depression (Strawbridge et al., 1998). However, studies were mixed as to whether depression was an independent risk factor for onset of frailty after accounting for overall health status (Hebert et al., 1999; Ormel et al., 2002; Avlund et al., 2006; Gayman et al., 2008; Xue et al., 2008). For example, Avlund and colleagues reported that depressive symptoms were not significantly predictive of tiredness at 5-year follow-up after accounting for comorbidity, physical performance measures, and psychological factors, despite being significantly associated with tiredness at baseline (Avlund et al., 2006). Hebert and colleagues did not find a significant association between depression and onset of frailty over 3 years in even bivariate analyses in their study of adults 75 years and older (Hebert et al., 1999). Similarly, in 2007, Xue and colleagues reported that depression was not associated with onset of frailty but did predict frailty-free mortality over a 3-year period.
Three studies explicitly examined the bidirectional relationship between depression and frailty (Ormel et al., 2002; Taylor and Lynch, 2004; Gayman et al., 2008). In 2002, Ormel and colleagues reported that frailty was a stronger predictor of increasing depressive symptoms than baseline depression was of increasing frailty. Similarly, Gayman et al. (2008) found that although frailty was significantly associated with worsening of depression, depressive symptoms were only weakly predictive of functional decline over a 3-year period. In contrast, Chang et al. (2009) found that incident frailty was strongly associated with depressive symptoms at the time of frailty onset, but that frailty did not predict development of new depressive symptoms 6 months later.
As with the cross-sectional studies, a wide range of indices were used to measure frailty status, although four utilized specific syndrome criteria outlined by Fried et al. (2001) (Ostir et al., 2004; Woods et al., 2005; Xue et al., 2008; Park-Lee et al., 2009). Approximately 60% (14 of 23) of studies used the CES-D to index depressive symptomatology; no studies that met the inclusion criteria used diagnostic instruments. Six studies did not report the racial/ethnic composition of the sample; of the remainder, most did not include large samples of racial/ethnic minorities. No-table exceptions were the reports by Schieman and Plickert (2007), Yang and George (2005), Ostir et al.(2004), Gayman et al. (2008), Rantanen et al. (2000), and Taylor and Lynch (2004), which all used cohorts in which at least 40% of the sample was not White. There was some indication of heterogeneity in the association between depression and frailty across racial/ethnic groups; Schieman and Plickert (2007) reported that depressive symptoms were strongly associated with greater functional decline among Whites but not among Blacks.
The primary findings from this review are as follows: (i) most studies report a positive, and potentially bidirectional, association between depressive symptoms and frailty status; (ii) few studies have examined the potential overlap between depression in late life and frailty, instead of treating them as independent geriatric syndromes; (iii) existing research is limited by the methods used to assess depression; (iv) no studies evaluated the role of medications to treat depression; and (v) few studies have included enough men or racial/ethnic minorities to examine variation in the depression–frailty relationship across these groups.
The results of this review have implications for both the construct validity and measurement of geriatric syndromes. These results underscore the relevance of considering the consequences of a narrowing between psychological and physical aspects of health—the notion that “mental health becomes health” (Katz, 1996; Schnittker, 2005)—for clinical care. In line with the notion that frailty reflects psychological and social elements of health above and beyond the burden of chronic medical conditions, the correspondence between self-rated health and burden of chronic physical conditions declines with age, whereas the correlation between self-rated health and depressive symptoms increases with age (Schnittker, 2005). Similarly, geriatric failure-to-thrive, although primarily characterized by nutritive and functional decline, also reflects an integration of physical, functional, social, and psychological aspects of health (Rocchiccioli & Sanford, 2009). Despite the 20 years since the Institute of Medicine report stating that geriatric failure-to-thrive is “often accompanied by dehydration, depressive symptoms, impaired immune function, and low cholesterol” (emphasis added) (Committee on a National Research Agenda on Aging, 1991), empirical investigations of the potential overlap in depressive symptomatology and geriatric frailty syndromes remain scant. Consistent with a developmental approach to examining the etiology and consequences of psychopathology, research efforts must reflect the protean nature of the relationship between mental and physical aspects of health, both within individuals over the life course and across population groups.
The next implication for research concerns efforts to measure frailty and related geriatric syndromes in later life. As this review illustrates, there is wide variation in the metrics used to operationalize frailty, and these measurement differences probably hamper efforts to develop prevention and intervention programs because of ambiguity about the clinical target. The conceptual development of frailty as a syndrome may be informed by the prior empirical work in psychiatry on alternate presentations of depression in later life (e.g., depression without sadness, vegetative depression). Latent variable approaches, which explicitly account for measurement error in ways that simple sum scores cannot, have been successfully employed to assess depression in later life and frailty (Gallo et al., 1994; Bandeen-Roche et al., 2006); this approach is well suited to investigating potential construct overlap between depression and frailty but has not yet been applied to this measurement problem. There is also a clear need to understand and explicitly assess how the behavioral signs of psychopathology (i.e., sleeping disturbances) interrelate with symptoms of frailty and related geriatric syndromes (i.e., fatigue), both from diagnostic and clinical care standpoints (Simon et al., 1999; Dowrick et al., 2005).
The limitations of the measurement of depression in these studies must be considered. None of the studies reviewed used diagnostic instruments to assess depression syndrome, instead assessing only recent depressive symptoms; as a result, there is probably substantial heterogeneity within cases of depression identified in these reports (Mezuk & Eaton, 2010). The most commonly used scale, the CES-D, has not been extensively validated against clinical diagnosis, particularly among older adults (Eaton et al., 2007; Fiske & O’Riley, 2008), and there is evidence that the underlying factor structure of this scale differs across racial/ethnic groups (Guarnacia et al., 1989). Because instruments such as the CES-D make no effort to separate symptoms attributable to medical illness or medication side effects from those due to psychopathology, they may be particularly inappropriate for examining the relationship between depression and geriatric syndromes that are characterized by non-specific physical complaints (e.g., fatigue, weakness). This measurement strategy hampers efforts to examine depression as a risk factor for frailty and associated geriatric conditions. Measurement error in depression may produce spurious findings as to the natural history, predictors, and consequences of thiscondition in later life and may have contributed to disparate findings across studies reviewed here.
The apparent link between depression and frailty begs the question of the role that psychotropic medications may play in this relationship. No studies included in this review considered the impact of medications used to treat depression (e.g., antidepressants) in the study design or the analytic strategy. Antidepressants have been associated with many of same outcomes as frailty, including osteoporosis (Mezuk et al., 2008), falls (Ensrud et al., 2002), and fracture (Takkouche et al., 2007), and studies are needed to determine whether these agents potentially mediate the observed associations between depression and frailty. This research also has clear implications for efforts to treat depression in later life; although selective serotonin reuptake inhibitors are considered a first-line therapy for treating depression among older adults, there is a paucity of effectiveness data on these medications in this age group (Mottram et al., 2006). Most trials are of short duration, and therefore, it is difficult to identify the potential complications from prolonged use or the role of polypharmacy (Fialova & Onder, 2009). Antidepressant classes may also confer differential fracture risk (Gagne et al., 2011). Frailty may contribute to withdrawal from pharmacotherapy (Katz et al., 1994), which emphasizes the need to explore multimodal, non-pharmacological interventions for depressed, frail adults (Schulz & Williamson, 1993; Fairhall et al., 2008), or at least more focused targeting of antidepressant medications that reflects the patient’s needs in a holistic manner (Mezuk & Golden, 2009).
Variation in study design may have contributed to differences in findings across studies. Few studies had meaningful numbers of men or racial/ethnic minorities to permit evaluation of whether the associations between depression and frailty vary across these groups; there is reason to believe that these relationships may differ because the burden of depression is lower among men and racial/ethnic minorities relative to women and non-Hispanic Whites, respectively (Breslau et al., 2006; Needham & Hill, 2010). Also, most studies focused on adults 65 years and older, precluding an investigation of how depressive episodes earlier in the life course may have contributed to frailty risk; studies that included younger adults would address this issue. Finally, some studies examined worsening or persistence of depressive symptoms, rather than onset of new symptoms, as an outcome, and thus, it is unclear whether frailty should be thought of as a potential prognostic, rather than etiologic, factor for late-life depression.
This review provides support for the bidirectional relationship between depression and frailty. Understanding the extent to which depression and frailty reflect plieotropic effects of common risk factors, or are simply variants in expression of the same underlying pathology, is paramount. If depression and frailty are overlapping syndromes, as opposed to etiologically distinct aspects of health, this has implications for the development of tools to appropriately measure and track changes in symptomatology over time. Shifting the paradigm for conceptualizing and measuring depression and frailty is also likely to significantly impact approaches to prevention and intervention. The plieotropic risk model acknowledges that interventions targeted at specific pre-clinical signs or symptoms will be inefficient and calls for comprehensive efforts to reduce morbidity and mortality in later life. Furthering understanding of these relationships may have important implications for the development of public health and clinical care interventions to reduce disability in later life.
B. Mezuk is supported by the VCU Building Interdis-ciplinary Research Careers in Women’s Health (BIRCWH) Program (K12-HD055881). This project was also supported by award number UL1RR031990 from the National Center for Research Resources and NIH Roadmap for Medical Research, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
Supporting information may be found in the online version of this article.
Conflict of interest None declared.