Biomedical frailty in affective disorders; prospective associations in the LifeLines cohort study.

Biomedical frailty is a vulnerability state characterized by poor resolution of homeostasis after a stressor, placing persons at risk of iatrogenic damage, dependency and death (Morley et al, 2013).
Biomedical frailty is increasingly recognized as an important construct for risk stratification at a population level (Hoogendijk et al, 2019) as well as in clinical care to prevent further decline and iatrogenic damage (Morley et al, 2013; Clegg et al, 2015). Nonetheless, knowledge on its course in the population as well as interactions with mental health remain sparse.

While operationalization of frailty widely differs between research groups (Collard & Oude Voshaar, 2012; Dent et al, 2016), the most dominant biomedical operationalizations of this concept are 1) the deficit accumulation model (Frailty Index), stating that the proportion of ageing-related deficits reflects biological age on top of chronological age (Minitski et al, 2001; Kulminski et al, 2007), and 2) the Fried Frailty Phenotype, which mark an underlying physiologic state of multisystem and energy dysregulation
(Fried et al, 2001). Surplus of the deficit accumulation model is that it can easily be studied in existing datasets that might not have set out to measure frailty per se, as explained below.

Deficits in health can be symptoms, signs, diseases, disabilities or laboratory, radiographic or electrocardiographic abnormalities (Mitnitski et al, 2001). As stated above, the Frailty Index (FI) is expressed as a ratio of deficits present to the total number of deficits considered. While not every FI considers the same deficits, or even the same number of deficits, results based on the FI have been consistent between studies (Searle et al, 2008):

•  The frailer the person is (the higher the deficit count) the more vulnerable they are to adverse outcomes like death, institutionalization and worsening health status. Moreover, the FI   has been shown to be a better predictor of adverse outcomes than chronological age (Romero-Ortuno & Kenny, 2012) and other indices of biological age (Mitnitski et al, 2016).
•  The frailty index is most strongly associated with adverse health outcomes when at least 30 variables are included.
•  Older persons accumulate deficits at an average rate of about 0.03/year.
•  The frailty index also shows a consistent, sub-maximal limit at about 2/3 of the deficits that are considered.

Collectively, these findings suggest that frailty is a real phenomenon, which is a property of a biologically complex system that can be measured in many ways (Jazwinski & Kim, 2019).

Constructing a valid Frailty Index in Lifelines enables us to study the prevalence of frailty in a large cohort and its change over time. Of particular interest is the possibility to study frailty among specific patient groups as chronic somatic diseases generally shorten life-expectancy, but the different diseases and disease clusters probably at different rates.
Furthermore, epidemiological studies consistently show a strong and reciprocal association between depression and physical frailty (Soyal et al, 2017). This strong association, however, may partly be explained by confounding as diagnostic criteria for depressive disorders and physical frailty partly overlap (Mezuk et al, 2013; Mezuk et al, 2012; Lohman et al, 2016). Moreover, most studies thus far rely on self-reported depressive symptom severity scales (Soyal et al, 2017). In these cases, depressive symptom scales may yield elevated scores due to criterion contamination (Pincus et al, 009). In other words, items like “I am no more worried about my health than usual” or “I felt like everything I did was an effort” should be interpreted as indicative of depression in somatically healthy persons, but may describe an accurate report of a patients with a chronic somatic disease or biomedical frailty. In clinical practice, overlapping criteria places older persons are at risk of misdiagnosis as well as inappropriate treatment (Lohman et al, 2017; Collard et al, 2017). Therefore, better understanding of the association between frailty and depressive disorders is needed. 
Moreover, while accumulating data have shown the association between depression and frailty (Soyal et al, 2017), thus far, no or limited data is available on the association between frailty and other clusters of affective disorders, i.e. one study with respect to somatic symptom disorders (psychiatric classification of functional syndromes) (Arts et al, 2019) and none about the association between anxiety disorders and frailty. This is remarkably, as pure affective disorders are rare: comorbidity between affective disorders is high (40-70%) (Löwe et al, 2008; Kohlmann et al, 2016) and diagnostic stability over time limited (Scholten et al, 2016). Moreover, comorbidity between affective disorders increases the disease burden more than can be explained by the sum of the4 individual disorders (Kohlman et al, 2016). Therefore, the absence of data on the association between frailty and affective disorders may unnecessarily contribute to the neglect of frailty in geriatric psychiatry.

The first objective of the present proposal is to construct a FI in LifeLines to describe the level of frailty at baseline and over time (at 5-year follow-up) in the general population as well as among patients suffering from specific chronic diseases and/or disease clusters.
The second objective is to examine its association with affective disorders, including depressive disorder, anxiety disorders and functional somatic syndromes.