The association between handgrip strength and depression in cancer survivors: a cross-section study

Background The association between handgrip strength and depression in cancer survivors was unknown. We aim to examine the associations of handgrip strength and depression in cancer survivors by using public data (National Health and Nutrition Examination Survey). We combined two waves of the data of the National Health and Nutrition Examination Survey during 2011-2014 to explore this important issue. The variable of handgrip strength was extracted by the maximum value of each hand. The depressive symptom was assessed by the Patient Health Questionnaire (PHQ-9) with the cut-off >=10 points indicating depressive symptoms. Other characteristics and health-related variables were evaluated. Multivariable logistic regression models were adopted to explore the associations between handgrip strength or low handgrip strength and depressive symptoms by adjusting for potential confounding factors.


Introduction
The number of cancer survivors is increasing thanks to the variety of multiple advances of technology and medicine and the aging society 1 . Meanwhile, cancer survivors were often suffering depression symptoms, with an estimated gure of 20%, as compared to 5% in the general population 2 . A metaanalysis reported that the prevalence of major depression and minor depression was 15% and 20%, respectively 3 . Cancer patients with depression could have an increased risk of adverse outcomes, such as poor adherence to medical treatment 4 , lower survival time 5 , even more likely to suicide 6 , bringing tremendous attention to clinicians and society. Therefore, early identi cation of risk and corresponding management for depression among cancer patients was essential.
Several factors, serious illness, female gender, social deprivation, and other health-related factors, are associated with depression 7 . Apart from these abovementioned factors, functional limitations such as low handgrip strength are becoming the hotpot topic for the researcher to explore with depression 8- 10 . A previous study indicated that muscle mass could in uence depression by secreting myokines 11 and muscle mass as the main component of organ to maintain the function of physical activity. Apparently, regular physical activity was associated with decreased risk of depression 12 . Handgrip strength, as an indicator of the function of muscle mass, can be easily obtained by dynamometer, widely applied in different settings. In addition, handgrip also used a parameter to assess the nutritional status of patients.
The association between handgrip and depression has been widely explored among community-dwelling older adults, with the results being that older adults with high handgrip strength had a lower risk of depression symptom 13,14 . Furthermore, in a recent meta-analysis, handgrip strength was associated with depression (Pooling OR = 0.85,95%CI:0.80,0.89), indicating handgrip strength as a protective factor for depression 15 . However, most of the including studies for meta-analysis were conducted among community or nursing home settings where participants were relatively healthy. In contrast, the association between handgrip strength and depression among cancer patients was unknown.
Therefore, the aim of this present study was to explore the association between handgrip strength and depression among cancer patients and examine the association of low handgrip strength based on the de nition of sarcopenia with depression by using the public internet database of the National Health and Nutrition Examination Survey.

Methods
Study design and participants.
This cross-sectional study of National Health and Nutrition Examination Survey (NHANES) was to explore the overall picture of nutrition, health, and risk factors among residents in various states across the USA (Centers for Disease Control and Prevention-http://www.cdc.gov/nchs/nhanes.htm). This survey is based on national-scale adopting multistage and clustered sample methods with the gure of being 5000 participants each year. Voluntary participants were asked to nish physical examination and this study was approved by Health Statistics Research Ethics Review Board from national center. All the participants have signed the written consent.
In this present study, data including handgrip strength, depression, sleep disorder, cancer type, baseline characteristics, and other health-related variables were extracted from NHANES ranging from 2011 to 2012 and 2013 to 2014, aggregating for nal analysis.

Cancer diagnosis
Cancer patients was con rmed by asking about the question (Have you even been told by the doctor that you had been diagnosed with any type of cancer). We selected the patients whose answer is "YES."

Handgrip strength
The detail of muscle strength measurement was depicted in NHANES Procedure Manual. Brie y, those participants who are able to nish the test obeyed the standard procedure. Investigators explained the detailed information and asked participants to squeeze the dynamometer as hard as possible for three times, recording the maximum value as the participant's nal handgrip strength. In our present study, the de nition of low handgrip strength was <27kg for males and <16kg for females 16 .

Depressive symptoms
According to the Questionnaire Instruments, Patient Health Questionnaire (PHQ-9) was used to assess the depressive symptoms of participants, consisting of 9-items with each item ranging from 0 to 3 points 17 . The total points of PHQ-9 ranged from 0 to 27. We categorized participants into depression and nondepression, with the cut-off being 10 points based on the previous study, which was reported good sensitivity (88%) and speci city (88%) for identifying major depression 18 .

Covariates de nition
We extracted demographic characteristics including age, gender, education, race, marital status, and smoking. Of which, the race was de ned as Non-Hispanic Black, Non-Hispanic White, and others; marital status was classi ed as married, widowed or divorced, and others. Regarding of education, four categories including less than 12 grades, high school, some college, and college graduated above were con rmed. Other covariates such as BMI, cancer diagnosis, sleep disorder, history of stroke, and history of Congestive Heart Failure (CHF) were also extracted. In addition, Leisure-time physical activity was assessed by Global Physical Activity Questionnaire 19 . The detailed calculation method was reported the previous study. In brief, we combined the vigorous and moderate intensities of physical activity each week, and we de ned it as inactive and physical activity, respectively, with the cut-off of zero min/week.

Statistical analysis
Continuous variables including age, BMI, Depression score were present as means and SD, and categorical variables including diagnosis, gender, race, education, marital status, sleep disorder, and other health-related variables were displayed as frequency (%). Comparisons for low handgrip strength versus normal handgrip strength and depression versus non-depression were conducted by Student's-test and chi-squared test or Fisher's Exact Test and Mann-Whitney tests, for appropriate. In addition, the generalized additive model (GAM) analysis was used to detect whether there is a non-linear relationship between handgrip strength and depression 20 . Before performing multivariable logistic regression analysis, we used Least Absolute Shrinkage and Selection Operator (LASSO) regression to select variables for the nal regression model. The results indicated that these variables (age, race, education, marital status, sleep disorder, history of stroke, polypharmacy, BMI, handgrip strength) were selected. Finally, Multivariable logistic regression analysis was adopted to identify the independent association between handgrip strength and depression after controlling for potential confounding factors including age, race, education, marital status, sleep disorder, history of stroke, polypharmacy, BMI. We also categorized handgrip strength into low handgrip and normal handgrip according to the sarcopenia of the revised European consensus on de nition and diagnosis, with the cut-off value being <16kg for females and <27kg for males. The association between low handgrip strength and depression was also detected by multivariable logistic regression analysis with adjustment of the same variables. Unadjusted subgroup analysis between low handgrip strength and depression was performed in terms of different variables( inactive versus active, >=65 versus <65, sleep disorder, congestive heart failure, polypharmacy, history of stroke, marital status, race, and education.) All the statistics were conducted by software packages R and Empowerstats, with the signi cant P-value being <0.05.  Overall, cancer patients with low handgrip strength were more likely older, had poor sleep, and were less likely to participate in physical activity. In addition, the proportions of depression and polypharmacy were higher in cancer patients with low handgrip strength as compared to those with normal handgrip strength. Those patients who suffered a history of stroke or congestive heart failure tended to have low handgrip strength. (Table 1)

Univariate Analysis For The Factors Related To Depression
The results of univariate analysis showed that female, low handgrip strength, sleep disorder, stroke, and polypharmacy were associated with depression. In addition, cancer patients who were not married were more likely to have a risk of depression. Other related variables with depression were displayed in Table 2.

Non-linear Relationship Analyses
The generalized additive model (GAM) analysis was adopted to detect whether there is a non-linear relationship between handgrip strength and depression and the results suggested the association between handgrip strength and the risk of depression was negative, meaning that with the increase of handgrip strength, the possibility of depression was decreased. (Shown in Fig. 1)

Subgroup analysis between low handgrip strength and depression in terms of different variables.
The subgroup analysis showed that the association between low handgrip strength and depression among cancer patients was almost unchanged in various stratum, indicating that this was reliable and stable ( Fig. 2)

Discussion
This present study showed that cancer patients with low handgrip strength had an increased risk of depression as compared to those with normal handgrip strength, implying cancer patients need to take measures such as resistance training and nutritional program to improve handgrip strength, eventually reducing the risk of depression among cancer patients.
To the best of our knowledge, this is the rst study to explore the association between handgrip strength and depression among cancer survivors. Many studies had examined the association between handgrip and depression among the community-dwelling population. In a cross-sectional study consisting of 24,109 Chinese adults (41. 5 ± 11.9 years), the authors found that participants with higher handgrip strength were associated with lower risk of depression and this association was particular in female 21 . Furthermore, another prospective cohort study conducted in rural Chinese populations, reporting the reversely association between handgrip and depression 22 . Our study was in line with these abovementioned previous studies. However, most of these studies were performed among relatively healthy people. Only a few studies focused on hospitalized patients. A study in 2020 was reported this association among participants suffering from different chronic diseases with inconsistent results 23 . The results found that those participants with high strength tertile had decreased depression both among people with no disease or metabolic diseases; however, this association was not observed in patients with arthritis diseases, which need more study for further exploration. Our study focused on a special population, cancer survivors, which are prevalent of suffering from depression 24 . Additionally, co-morbid depression had an adverse impact for treatment and recovery for cancer patients. Therefore, early prevention and treatment for depression were essential for cancer survivors.
Prior studies mainly focused on other aspects of risk factors for depression, which consisting of social factors (family, social support, stressful life event), characteristic of cancer (type of cancer, recurrence, prognosis), cancer treatment (radiotherapy, chemotherapy, treatment burden), individual characteristics (age, gender, marital status) and psychological response to diagnosis. To the best of our knowledge, no study explores the handgrip strength, a modi able parameter, with the association of depression.
Obviously, handgrip strength had many merits, simple, convenient, and not time-consuming, compared to these abovementioned factors, which were widely used in clinical settings and other primary community healthcare 25  Therefore, cancer patients with low handgrip strength, hardly participating in physical activity would not gain the bene cial effect for reducing depression producing by exercise. Third, some studies reported that a muscle-brain crosstalk can be medicated by myokines and metabolites, which were secreted by muscle, playing a role in regulating hippocampal function that was closely related to depression 11,30 .
Although there were some possible reasons for the association between low handgrip strength and depression, future studies were warranted to explore this underlying mechanism.
This study possessed strengths and drawbacks. First, based on our knowledge, this is the rst study to examine the association of handgrip strength and depression among cancer survivors, which was a fundamental issue for the prevention and management of depression among oncology Patients. Second, our study suggests that by using a simple and convenient dynamometer to measure handgrip strength, clinicians can identify the high-risk group of depression. Given the characteristic of modi cation of handgrip strength, appropriate and personalized exercise and nutritional programs are bene cial for reducing the risk of depression. Third, our study used comprehensive statistical analysis such as Lasso regression, by using shrinkage, to better select variables for minimizing multicollinearity. However, some drawbacks need to be mentioned. First, the feature of cross-section study limited the ability to identify a completely causal association, which needs more prospective cohort study for further exploration.
Secondly, the NHANES study database did not provide some other important information about cancer treatment (radiotherapy and chemotherapy), length of time of rst cancer diagnosis, and advanced disease stages, which might overestimate or underestimate the association between low handgrip strength and depression. Our study indicated that cancer survivors with low handgrip strength had an about 2.1-fold risk of depression, implying that clinicians need to perform corresponding interventions (physical activity and nutrition) to improving handgrip strength with the bene t for reducing depression.