The Association Between Anemia and Depressive Symptoms in Non-White Male Adults: National Health and Nutrition Examination Survey (2005–2018)

Background: The relationship between anemia and depression remains controversial. This study aimed to investigate the association between hemoglobin (Hb) levels and depressive symptoms. Study Design: A cross-sectional study. Methods: This study was conducted using National Health and Nutrition Examination Survey data from 2005–2018. Hb levels were obtained from laboratory files, and depressive symptoms were assessed using the Patient Health Questionnaire (PHQ-9). Multivariable logistic regression analysis and smoothing plots were performed to examine the relationship between anemia and depression, including potential nonlinear associations. Results: The study included 6008 male adults. Multivariable analysis revealed that anemia was associated with an increased odds ratio for mild (OR=1.49, 95% CI: 1.06, 2.10) and moderate (OR=2.05, 95% CI: 1.14-3.70) anemia. Additionally, each additional g/dL of Hb was significantly inversely associated with developing depression (OR=0.91, 95% CI: 0.85, 0.96). A nonlinear relationship was detected between Hb and depression, with an inflection point at 15 g/dL. Below this threshold, there was a significantly negative association between Hb and depression (OR=0.88, 95% CI: 0.79, 0.98); no significant relationship was observed above it (OR=1.05, 95% CI: 0.84, 1.31). Conclusion: Anemia was positively associated with depression in non-White American men. A nonlinear relationship between Hb and depression was detected, and it had a saturation effect. A significant negative correlation with depression was observed when the Hb level was below 15 g/dL.

reported controversial outcomes in this regard.Yi et al 25 discovered a link between lower serum ferritin levels and depressive symptoms in middle-aged Japanese men, while other studies conducted on Korean populations demonstrated no association in this respect. 26,27Due to the presence of nonspecific symptoms, men with depression often face challenges in obtaining an accurate diagnosis 28,29 and are frequently overlooked. 30Furthermore, men with depression are more likely to commit suicide. 31A metaanalysis has also concluded that depression in men should not be disregarded. 32Similarly, men with anemia may also be at risk of being overlooked, as their symptoms may be less apparent.Consequently, the potential association between anemia and depression in men may be easily missed.Therefore, it is crucial to explore the link between anemia and depression in men.González et al 33 found that non-white individuals experience significantly higher depression chronicity and lower depression care use and guidelines.In addition, research has shown that non-white individuals are often underdiagnosed or undertreated for depression due to factors, including socioeconomic disparities, access to appropriate care, and patientphysician relationships. 34Consequently, non-white males have been selected as the primary population of interest for this study.
However, research investigating the association between Hb levels and depression among non-white male adults in the United States is currently limited.Therefore, this study has attempted to examine the relationship between Hb levels and depression, specifically within this population.

Study Population
The National Health and Nutrition Examination Survey (NHANES) is a cross-sectional study of the Centers for Disease Control and Prevention conducted by the National Center for Health Statistics (NCHS) that provides nationally representative estimates of the US population.An analysis was performed based on NHANES data from 2005 to 2018.All NHANES data and information are publicly available at https://www.cdc.gov/nchs/nhanes/index.htm.
In accordance with the research objective and due to a limited number of participants with severe anemia and from other races, NHANES participants were excluded from our study based on the exclusion criteria; they included (1) PHQ-9, anemia, and other covariates with missing data, (2) non-Hispanic White and other races, (3) females, and (4) participants diagnosed with severe anemia.Finally, 6008 participants were included in the study.

Ascertainment of Depression and Anemia
The Patient Health Questionnaire-9 (PHQ-9) depression scale was used for the diagnosis of depression and was administered during a face-to-face mobile examination center (MEC) interview to assess depression symptoms over the last two weeks.The scale has nine items, and each item is scored from 0 (not at all) to 3 (nearly every day).Total scores range from 0 to 27, and adults with scores of 0-4 are considered to have no symptoms of depression, while those with scores of ≥ 5 are considered to have depression symptoms. 35he amount of Hb (g/dL) was obtained from the laboratory file.Anemia was defined based on the World Health Organization's (WHO's) cutoff points for Hb.The Hb in male participants (15 years of age and older) was defined as no anemia, mild, and moderate anemia according to Hb levels ≥ 13 g/dL, 11-12.9g/dL, and 8-10.9 g/dL, respectively. 36

Covariates
The covariates considered known or potential influences on the association between anemia and depression were chosen through a review of the literature and input from healthcare experts.Sociodemographic variables, lifestyle habits, socioeconomic status indicators, medical history, and dietary patterns were among the covariates chosen for inclusion in the study.Specifically, these variables comprised age, ethnicity, education, citizenship, smoking status, marital status, family size, family income to poverty ratio, alcohol consumption, body mass index (BMI, kg/ m 2 ), hypertension (HTN), hyperlipidemia, and asthma, as well as intake of fruits, vegetables, grains, dairy products, meat, and eggs.
The study utilized various criteria to categorize participants.The family income to poverty ratio (PIR) was calculated by dividing the family income by the survey year-specific poverty guidelines, accounting for variations in family size and geographic location. 37PIR was employed to establish low (PIR < 1.3) and mildhigh (PIR ≥ 1.3) categories.The WHO classification was used to divide participants into underweight ( < 18.5 kg/m 2 ), normal weight (18.5-24.9kg/m 2 ), overweight (25.0-29.9kg/m 2 ), and obese ( ≥ 30 kg/m 2 ) groups based on their BMI 38 .HTN was defined as having a systolic blood pressure ≥ 140 mm Hg and/or diastolic blood pressure ≥ 90 mm Hg 39 .Hyperlipidemia was characterized as an elevated cholesterol level (total cholesterol ≥ 200 mg/ dL [5.18 mmol/L], triglyceride level ( ≥ 150 mg/dL), lowdensity lipoprotein ≥ 130 mg/dL [3.37 mmol/L], highdensity lipoprotein < 40 mg/dL [1.04 mmol/L], or the use of cholesterol-lowering agents. 40Asthma was ascertained through the question, "Ever been told you have asthma or use anti-asthmatic drugs".

Statistical Analyses
The information was recorded in a database using Excel and analyzed by a statistical package of the survey in R software.Continuous variables were expressed as means with their standard errors.Categorical variables were presented as proportions and frequencies.Weighted univariable and multivariable logistic regressions were performed to examine the association between anemia and depression.We built three sets of models, adjusting for different covariates, to verify the stability of the results.The crude model controlled for no variables.Model one controlled for age, ethnicity, education, citizenship, total number of people in the family, marital status, and family income-to-poverty ratio.Model II controlled for all variables in Model I plus smoking, drinking, BMI, HTN, hyperlipidemia, and asthma.Confounding factors were selected based on prior literature and a significance level of P < 0.05.If nonlinearity was found between anemia and depression, two-piecewise logistic regression models were constructed on both sides of the inflection point.Finally, a subgroup analysis of the association between anemia and depression was performed in terms of age, ethnicity, education, and PIR.The P values were two-sided, and a P value ≤ 0.05 was considered statistically significant.

Baseline Characteristics of Participants
A total of 6008 male individuals from NHANES (2005-2018) were included in this study, with 34.92% Mexican Americans, 46.01%non-Hispanic Blacks, and 19.07%other Hispanics.There were 1152 (19.17%) individuals with depression.The baseline characteristics of the study participants based on anemia are presented in Table 1.Among all participants, the distribution of education, family income to poverty ratio, hyperlipidemia, and egg intake showed no significant differences by anemia level (P > 0.05).Comparing different groups (Table 1), the distribution of anemia was significantly different by age, ethnicity, citizenship, smoking, marital status, total number of people in the family, drinking, BMI, HTN, asthma, depression, fruit, vegetables, grains, dairy, and meat intake (all P ≤ 0.05).

Association Between Anemia and Depression
Three models were constructed using the binary logistic regression model to investigate the association between anemia and depression (Table 3).In the unadjusted model and Model I, which minimally adjusted for several variables, each 1 g/L increment in Hb was significantly inversely associated with developing depression (nonadjusted: OR = 0.92, 95% CI: 0.87, 0.97; model I: OR = 0.92, 95% CI: 0.86, 0.98).Furthermore, Model II, which fully adjusted for all variables, revealed the inverse relationship between Hb and depression (OR = 0.91, 95% CI: 0.85, 0.96).The results were statistically significant.Consistent results were also found when Hb was converted from a continuous variable to a categorical variable, including normal, mild, and moderate anemia (Table 3).The results of the crude model without adjusting for any factors showed that mild and moderate anemia were positively associated with depression (mild: OR = 1.56, 95% CI: 1.16, 2.09; moderate: OR = 1.95, 95% CI: 1.14, 3.32).In the minimally adjusted model I, there was a positive relationship between anemia and depression (mild: OR = 1.51, 95% CI: 1.09, 2.10; moderate: OR = 1.98, 95% CI: 1.09, 3.62).Model II, adjusted for all variables, still demonstrated a positive connection between anemia and depression (mild: OR = 1.49, 95% CI: 1.06, 2.10; moderate: OR = 2.05, 95% CI: 1.14, 3.70).The association between anemia and depression in the three models and the increasing trend of the effect sizes in different groups were statistically significant.

Nonlinear Link Between Anemia and Depression
Based on the results (Figure 1), the association between Hb and the risk of depression was nonlinear.The inflection point for Hb was 15 g/dL.When Hb was on the left side of this inflection point ( ≤ 15 g/dL), a significantly negative association was found between Hb and depression (OR = 0.88, 95% CI: 0.79, 0.98, P = 0.018).However, when Hb was on the right side of this inflection point ( > 15 g/ dL), no relationship was observed between anemia and depression (OR = 1.05, 95% CI: 0.84, 1.31, P = 0.687).
The analysis represented a significant association between mild anemia and depression among individuals with less than high school education (OR = 1.73, 95% CI: 1.10, 2.74), more than high school education (OR = 1.53, 95% CI: 1.02, 2.30), and mild-high family income (OR = 1.65, 95% CI: 1.16, 2.34).In addition, the results showed that none of the interactions were observed based on the analyzed variables (P for interaction > 0.05 for all covariates, Table 4).

Discussion
Our study findings confirmed that anemia was significantly associated with vulnerability to depression, and a significant relationship was identified between Hb level and depression.Additionally, a nonlinear relationship was observed between Hb and depression.This study provides valuable insights, as this specific population's health concerns may often be overlooked.These findings indicate that prioritizing and addressing the health problems of these specific subgroups are critical for reducing barriers to mental health care and depression burden.Further, our research can provide reference data that can inform government policies aimed at preventing and controlling anemia and depression in this population.
Anemia is probably associated with greater fatigue, leading to a worse quality of life and decreased emotional wellbeing 41 .To assess the potential relationship between anemia and depression, a multivariable analysis was conducted to adjust for covariates.The results revealed that each additional g/dL of Hb was inversely associated with developing depression (OR = 0.91).Categorizing Hb levels, a positive relationship was found between anemia and depression.The OR for mild and moderate anemia was 1.49 and 2.05, respectively.This positive effect was also evident in subgroup analyses based on various factors.Several potential reasons may explain the observed relationship between anemia and depression.People with anemia may experience reduced physical function or oxygen delivery to the brain, 8 as well as alterations in neurotransmitter systems, 9,10 all of which potentially contribute to an increased risk of depression.Furthermore, anemia can cause changes in the hippocampus, corpus striatum, and monoamine levels that may lead to depression. 11Several meta-analyses have indicated a significant association between anemia and depression.One meta-analysis of older adults represented that anemia was associated with worse cognitive function and depression symptoms, 42 while another meta-analysis in adults reported a significant correlation between low Hb levels and depression (OR/RR = 1.43). 15Hence, anemia might be related to vulnerability to depression.However, a Korean study demonstrated no significant association between anemia and depression in men. 27he reasons for these discrepant findings may reflect differences in the study design (e.g., cross-sectional vs. cohort), variations in depression screening criteria, or the unique sociodemographic characteristics of the Korean population (e.g., distinct economic levels, living environments, cultural backgrounds, and lifestyles).
In the present study, a significantly increasing trend effect size was observed between mild-to-moderate anemia and depression among subjects in the fully adjusted model (P for trend = 0.003).Meanwhile, when Hb was ≤ 15 g/dL, a significantly negative association was identified between Hb level and depression (OR = 0.88).This result is consistent with the findings of a crosssectional analysis in which depression was independently associated with lower Hb levels (β = -0.074;P = 0.05). 43To some extent, anemia might affect the brain and mood; thus, correcting anemia may be beneficial in improving the oxygen supply to brain tissue and reducing the risk of cognitive dysfunction and depression symptoms. 8,9,44ur findings revealed no significant association between anemia and depression when Hb was > 15 g/dL (OR = 1.05, 95% CI: 0.84, 1.31).Vulser et al 24 also reported no association between depression status and high Hb levels ( > 16 g/dL in men).Similarly, Lever-van Milligen  Anemia and depressive symptoms et al 18 noted that the association between higher Hb ( > 16.1 g/dL in men) and increased depression severity did not reach a significance level after adjusting for sociodemographics, disease indicators, and lifestyle.However, further academic research is needed to understand the lack of association when Hb is at a high level.
Our study has some limitations.Firstly, the crosssectional nature of the study precluded us from definitively  establishing a causal relationship between anemia and depression.Secondly, the extent of generalization is limited as the majority of participants were Mexican, Black, and Hispanic-American men without severe anemia.Thirdly, reporting bias may have been reported by some participants who had hidden sensitive information during the survey.Lastly, some uncontrolled variables affecting the results may not have been considered confounders due to missing data or sample size.Future research could improve upon the limitations of our study using longitudinal designs to establish causal links, including broader ranges of populations and disease severity, reducing reporting bias through a variety of methods, and considering more potential confounders.These improvements could strengthen the validity of future findings and provide more reliable insights into the relationship between anemia and depression.

Conclusion
Overall, the present study, to the best of our knowledge, is the first to report a significant association between anemia and depression in non-White American men.The results showed that the relationship between mild or moderate anemia and depression was statistically significant, with a trend of increasing effect sizes.Additionally, a nonlinear association was observed between Hb and depression.Our findings highlight the importance of continuous screening for these diseases and the need for a comprehensive approach to healthcare that addresses both physical and mental health concerns.Such a conclusion would suggest that further research is necessary to explore intervention strategies, confirm their causal relationship, and evaluate the possible mechanisms through large-scale, multicenter longitudinal follow-up studies.
• The present study is the first to report a significant association between anemia and depression in non-White American men.• The relationship between mild or moderate anemia and depression was statistically significant, with a trend of increasing effect sizes.• A nonlinear association was observed between hemoglobin (Hb) and depression, with an inflection point of 15 g/dL.• A significant negative association was found between Hb and depression for levels of 15 g/dL or below, while no relationship was observed for levels above 15 g/dL. Highlights

Figure 1 .
Figure 1.The nonlinear relationship between anemia and depression
Note.Ce: Cup equivalents; oe: Ounce equivalents; NHANES: National Health and Nutrition Examination Survey, SE: standard deviation Anemia and depressive symptoms (

Table 2 .
The results of the univariate analysis of depression

Table 3 .
Multivariable analysis of the association between anemia and depression Note.CI: Confidence interval; OR: Odds ratio; BMI: Body mass index.Model I was adjusted for age, ethnicity, education, citizenship, total number of people in the family, marital status, and family income to poverty ratio.Model II was adjusted for age, ethnicity, education, citizenship, total number of people in the family, marital status, family income to poverty ratio, smoking, drinking, BMI, hypertension, hyperlipidemia, asthma, fruit, vegetables, grains, dairy, meat, and eggs intake.

Table 4 .
Subgroup analyses of the association between anemia and depression