The Relationship Between C-Reactive Protein and Depression is Partially Moderated by Sexual Identity Among Bisexuals

Abstract

Sexual minorities (SM) are at increased risk for inflammation and experience higher rates of depression at younger ages relative to heterosexuals. In this analysis, we aimed to delineate the relationship between C-reactive protein (CRP) and severity of depressive symptoms and to determine if this relationship is moderated by sexual identity. Data came from National Health and Nutrition Survey (NHANES), 2015–2016. Survey weighted regression analysis was used to assess the relationship between CRP and depressive symptoms. Broadly, elevated CRP was predictive of more depressive symptoms among women but not among men. The relationship between CRP and depression was moderated by sexual identity for bisexual women and men but no other sexual minority subgroups. This analysis demonstrates that CRP is predictive of depression symptom severity, and that this relationship was moderated by sexual identity among bisexual individuals. Future research should focus on better characterizing the relationship between stigma and discrimination, inflammation, and depression in bisexuals, and work to decrease experiences of stigma and other psychosocial stressors in both clinical and community settings.

Introduction

Depression is a complex, multi-symptom illness and is responsible for significant morbidity and disability (Briley & Lépine, 2011). In 2019, 18.5% of adults in the United States experienced some form of depressive symptoms (Villarroel & Terlizzi, 2020), with 7.2% reporting a major depressive episode in the preceding 12 months (Brody & Gu, 2020). And, during the period 2015 through 2018, 13.2% off U.S. adults reported taking antidepressant medications in the past 30 days (Brody & Gu, 2020). These rates of depressive symptoms and medication use, however, differ based on demographic differences. For example, women are more likely to develop depression and seek treatment than men (Kessler, 2003). These differences are highlighted even further when examining differences between heterosexuals and sexual minorities. Sexual minority (SM) men and women are each more likely to experience depressive symptoms than their heterosexual peers, while also experiencing more severe depressive symptoms from a younger age. Even within the population of sexual minorities we observe stark differences, with bisexuals more likely than other sexual minorities to experience severe depression (Plöderl & Tremblay, 2015). Where less research exists, however, is in understanding how the depression may differentially impact systemic inflammation between these populations. This is key to reducing health disparities, as persistently elevated inflammation has been associated with a host of chronic diseases (Costello et al., 2013; Howren et al., 2009; Mirza et al., 2012; Noble et al., 2010), and sexual minorities are already at increased risk of elevated inflammation, regardless of other comorbidities (E. Morgan, D’Aquila, et al., 2019; Ethan Morgan et al., 2021; E. Morgan, Taylor, et al., 2019). To develop a better understanding of said differences, and how they may impact overall health disparities between heterosexuals and SMs, we aim to examine both sex and SM differences in the link between depression and systemic inflammation.

The number adults in the United States who identify as lesbian, gay, bisexual, or a different sexual identity has doubled over the past decade and continues to grow, now standing at nearly 7% of the U.S. population (N > 11 million; [Gallup, 2022; Newport, 2018]). Sexual minorities experience greater risk of poor health outcomes across a host of conditions, including, obesity, asthma, diabetes, cardiovascular disease, and some cancers, and have earlier onset of many of these chronic diseases (Bostwick et al., 2010; Bradford et al., 2013; Caceres et al., 2017; Corte et al., 2013; Dilley et al., 2010; Institute of Medicine, 2011; Mayer et al., 2008; Sherman et al., 2022). Minority stress theory (Meyer, 2003) posits that both distal (e.g., discrimination, stigma) and proximal stressors (e.g., concealment, internalized homonegativity) contribute to disparities in mental and physical health (Blosnich et al., 2013; Boehmer et al., 2012; Frost et al., 2015; Gamarel et al., 2016; Garrido-Hernansaiz et al., 2016; Jackson et al., 2016; LeBlanc et al., 2015; Lee et al., 2016; Lick et al., 2013; H. Liu et al., 2016; Patterson et al., 2018; Wight et al., 2012). Although these pathways are supported in studies of sexual minorities, data on stress biology within this context are remarkably limited; there are a few studies examining cortisol and/or immunity among those living with HIV, but very little work has examined systemic inflammation differences among subgroups of sexual minorities (Burack et al., 1993; Cole et al., 2003; Cole et al., 1996; Everett et al., 2014; Flentje et al., 2018; Hatzenbuehler & McLaughlin, 2014; Hatzenbuehler et al., 2013; Juster et al., 2015; Juster et al., 2013; Manigault et al., 2018; Mays et al., 2018; Parra et al., 2016).

In this analysis, we utilize an expanded Biopsychosocial Minority Stress Framework (L. M. Christian et al., 2021). This model expands on earlier minority stress frameworks to account for biologic function as a result of persistent exposure to stressors. The effects of said stressors on the immune system have demonstrated that the body responds in a complex manner better described as immune dysregulation, with complementary up-regulation of inflammatory processes (Blair et al., 2015; L. M. Christian et al., 2016; L. M. Christian et al., 2013; Lisa M Christian et al., 2018; L.M. Christian et al., 2016; Gillespie et al., 2016). These inflammatory processes are typically quantified via the measurement of C-reactive protein, a nonspecific biomarker of systemic inflammation. C-reactive protein itself has been associated with increased risk for a variety of chronic diseases (e.g., asthma, cardiovascular diseases, some cancers), while simultaneously appearing to be elevated among SMs as compared to heterosexuals (Everett et al., 2014; Hatzenbuehler et al., 2013; Luan & Yao, 2018; E. Morgan, D’Aquila, et al., 2019; E. Morgan, Taylor, et al., 2019).

Elevated systemic inflammation may also play a key role in depression pathogenesis. Inflammation, particularly CRP (Felger et al., 2020; Köhler-Forsberg et al., 2017), has been associated with the development of depression and with the severity of depressive symptoms (Khandaker et al., 2020; Köhler-Forsberg et al., 2017; Y. Liu et al., 2014; Mac Giollabhui et al., 2020; Valkanova et al., 2013; Wium-Andersen et al., 2013). This relationship represents one potential biologic pathway that could be a key contributor to observed depression disparities among SMs. Sexual minorities experience high levels of stigma, discrimination, and other psychosocial stressors related to their sexual identity (Baptiste-Roberts et al., 2017; Scheer & Pachankis, 2019; Schulman & Erickson-Schroth, 2019). These repeated experiences of stress and stigma lead to chronically elevated levels of systemic inflammation which may (Meyer, 2003), in turn, partially explain extant depression-related health disparities.

Inflammation may also be a potential driver of depression disparities observed between men and women. There are social, psychological, and biological factors that contribute to sex differences in relationship between inflammation and depression, and this may partially explain sex-related depression disparities (Derry et al., 2015; Suarez et al., 2015). However, current research on sex differences in the relationship between inflammation and depression is inconclusive, let alone sex differences moderated by sexual minority status. Some studies have found no gender differences in this relationship (Zalli et al., 2016), while others suggest that inflammation is associated with development of depression and depression symptom severity among women but not men (Köhler-Forsberg et al., 2017; Matthews et al., 2010; Niles et al., 2018). Still further work has demonstrated the exact opposite relationship, namely that systemic inflammation was associated with depression in men but not women, particularly after controlling for BMI and tobacco use (Y. Liu et al., 2014; Song et al., 2015; Vetter et al., 2013).

Although past work has explored sex differences in the link between inflammation and depression (Köhler-Forsberg et al., 2017; Matthews et al., 2010; Niles et al., 2018), there is a dearth of literature that examines differences in this relationship among SMs. It is possible inflammation is also a key factor that contributes to depression inequities in this population. To address these gaps in the literature, we analyzed data from the 2015–2016 National Health and Nutrition Survey (NHANES) to delineate the relationship between systemic inflammation, as measured by CRP, and depressive symptom severity. Given that current research suggests sex differences in this relationship, we stratified all results according to sex assigned at birth, while simultaneously assessing whether any moderation effect is present according to sexual identity. Our main hypothesis for this analysis as that those with higher CRP will report a greater number of depressive symptoms among both men and women, with stronger effects observed among women relative to men. Secondarily, we hypothesized that this association would differ not only based on sex but that there would be significant moderation of CRP based on sexual identity, with the strongest relationship present among bisexual individuals.

Methods

Study population

Data from the National Health and Nutrition Examination Survey (NHANES) were used for this analysis. NHANES is a nationally representative, cross-sectional survey of non-institutionalized individuals that combines data from questionnaires, physical exams, and laboratory results to assess the health and nutritional status of children and adults in the United States (Centers for Disease Control and Prevention [CDC] & National Center for Health Statistics [NCHS], 2016). All survey data are collected by trained interviewers using the Computer-Assisted Personal Interview System (CAPI). Interviews took place in the participant’s home. Participants could select the language of the interviewer, and interviews were conducted in English or Spanish, otherwise an interpreter was used. Physical exam and laboratory data were collected in a mobile examination center by trained professionals (CDC & NCHS, 2016).

NHANES uses a complex, multistage sampling design to ensure generalizability. To achieve a representative study population, NHANES oversamples Non-Hispanic Asian, Hispanics, non-Hispanic Black, older, and low-income individuals. Survey weights, which are applied to the data to ensure non-biased estimates of survey results, are provided by NHANES as part of the publicly available dataset. All data used in this analysis are publicly available and are exempt from institutional review board approval.

The data used in this analysis were limited to NHANES data from 2015–2016. These years were selected as they provided publicly available information on sexual identity. Additionally, the analytic sample was limited to those over the age of 18, as relevant data on those younger than 18 years old is not publicly available. Those whose depression questionnaires were incomplete (n = 498) were not able to have total depression scores calculated and are thus not included in subsequent analyses. Additionally, those that did not answer the sexual identity question (n = 1,430) were excluded from the main analyses. Listwise deletion was employed in all models as alternative methods for imputing sexual identity are unreliable, particularly given that sexual minority groups are relatively small (Office of the Chief Statistician of the United States, 2022). The total analytic sample included 3,413 individuals.

Demographic data

Demographic information including age, gender, race, and ethnicity were all self-reported by participants. Age was recorded as the age in years at the time of the interview and operationalized as a continuous variable (mean age = 37.7 years, standard deviation [SD] = 12.3). To prevent identification of participants, all persons ages 80 and over were grouped into a single category. Gender (NHANES refers to biological sex as gender, not to be confused with current gender identity which NHANES does not assess) was reported as male (n = 1,648, 48.3%) or female (n = 1,765, 51.7%) and operationalized as a binary variable. NHANES combines race and ethnicity as a single variable, provided predefined: non-Hispanic White (n = 1,035, 30.3%), non-Hispanic Black (n = 765, 22.4%), Hispanic (n = 1,051, 30.8%), non-Hispanic Asian (n = 411, 12.0%), and a different race or ethnicity (n = 151, 4.4%), which included multiracial identities and those identifying as a different race or ethnicity. NHANES differentiates between Mexican American and other Hispanic individuals; however, for this analysis, these two categories were combined. Race and ethnicity was operationalized as a categorical variable in this analysis (reference = non-Hispanic White). Sexual identity was assessed by asking participants “Which of the following best represents how you think of yourself?” and options included “heterosexual,” “gay or lesbian,” “bisexual,” “something else,” “I don’t know the answer,” and “don’t know.” The latter three were combined into one category entitled “other,” with the variable operationalized as a categorical variable (reference = heterosexual). Overall, 2,993 identified as heterosexual (87.7%), 67 as gay or lesbian (2.0%), 119 as bisexual (3.5%), and 234 as a different sexual identity (6.9%).

Other variables

Alcohol use was assessed using a single measure, “In the past 12 months, on those days that drank alcoholic beverages, on the average, how many drinks did have?” with a range of values from 0 to 15 (mean = 2.9, SD = 2.4). Marijuana use was operationalized as a dichotomous variable; substance use was operationalized as those that have ever used marijuana in their lifetime (n = 1,711, n = 50.2%) and those who have never used marijuana (reference; n = 1,702, 48.8%). Other substance use was assessed as any lifetime use of cocaine, heroin, or methamphetamines (n = 538, 15.8%) or no lifetime use of any of these substances (reference; n = 2,875, 84.2%). Tobacco use was operationalized as those that have used at least 100 cigarettes in their lifetime (n = 1,262, 37.0%) and those who have not (reference; n = 2,151, 63.0%). Health insurance status was operationalized as those who have any type of insurance coverage at the time of interview (reference; e.g., private, Medicaid, Medicare, TRICARE, etc.; n = 2,621, 77.0%) and those who are uninsured (n = 792, 23.0%).

The Patient Health Questionnaire (PHQ-9) was used to assess severity of depressive symptoms (Kroenke et al., 2001). The PHQ-9 is a 9-item questionnaire that assesses how often individuals have experienced depressive symptoms consistent with the DSM-IV diagnostic criteria for depression in the preceding two-week period. Items in this measure are assessed as: “Over the last 2 wks, how often have you been bothered by the following problems …” with each item focusing on different aspects such as, “little interest or pleasure in doing things,” “feeling down, depressed, or hopeless?” or “trouble falling or staying asleep, or sleeping too much?.” Response options for each item include not at all (0), several days (1), more than half of the days (2), and nearly every day (3). Severity of depressive symptoms was operationalized by calculating a PHQ-9 total score, which consisted of summarizing the scores from each item in the questionnaire (alpha = 0.84, potential and observed range = 0–27), with higher scores indicating more severe depressive symptoms (Kroenke et al., 2001).

Examination and laboratory data

C-reactive protein was assessed by NHANES staff using the Synchron High Sensitivity C-reactive Protein (Hs-CRP) reagent, which uses the highly sensitive Near Infrared Particle Immunoassay rate methodology (Beckman Coulter, Brea, CA). Body mass index was calculated using standard methods as weight in kilograms divided by height in meters (Weir & Jan, 2021).

Statistical analysis

Participant characteristics were described using means, standard deviations, and proportions, as appropriate. Bivariate analyses were subsequently conducted using Pearson’s correlation, ANOVA, and Student’s t-test, where appropriate. Next, a weighted multivariable linear regression model was constructed to assess the association between CRP and depressive symptoms. The model was stratified by gender, and interaction terms between CRP and sexual identity were included to assess effect moderation by sexual identity. Models were adjusted for demographic characteristics and other known confounders, including age, race, education, BMI, insurance status, tobacco use, marijuana use, other substance use, and alcohol use. The model was weighted to account for the complex sampling design of NHANES. Standard model diagnostics were assessed with no irregularities noted (e.g., no multicollinearity, etc.). All analyses were completed in Stata 18.0.

Results

There was a total of 3,413 participants in the analytic sample; Table 1 presents demographic characteristics.  Among the sample as a whole, mean PHQ-9 score was 3.3 (SD = 4.2), indicating minimal depression. Total PHQ-9 score differed significantly by gender (t = −5.59, p-value < 0.001), with mean score among males 2.9 (SD = 4.1) and among females 3.6 (SD = 4.4), each falling within the range indicating minimal depression. Total PHQ-9 score also differed significantly based on sexual identity (F = 15.92, p-value < 0.001), with mean score among heterosexuals of 3.2 (SD = 4.1), among gay and lesbian individuals of 4.6 (SD = 5.4), among bisexuals of 5.6 (SD = 5.6), and among those identifying as a different sexual identity of 3.0 (SD = 4.4). Here, both gay/lesbian individuals and bisexuals each had mean scores indicating mild depression, while heterosexuals and those identifying as a different sexual identity had mean scores indicating minimal depression. Mean CRP among the entire sample was 4.09 (SD = 8.00), indicating levels of systemic inflammation associated with greater risk for chronic comorbid conditions. This did differ significantly based on gender (t = −7.22, p-value < 0.001), with mean CRP among males of 3.29 mg/L (SD = 6.8) and among females of 5.0 mg/L (SD = 8.8). C-reactive protein did not differ significantly based on sexual identity, with mean CRP among heterosexuals of 4.1 mg/L (SD = 7.9), among gay and lesbian individuals of 3.4 mg/L (SD = 5.1), among bisexuals of 5.2 mg/L (SD = 14.0), and among those identifying as a different sexual identity of 3.6 mg/L (SD = 5.9).

Table 1. Demographic characteristics of participants in the analytic sample, NHANES 2015–2016 (N = 3,413).

Variable	n (%)	Mean (SD)
Age (years)	–	37.8 (12.3)
Sex
Male	1,648 (48.3)	–
Female	1,765 (51.7)	–
Race
Non-Hispanic White	1,035 (30.3)
Non-Hispanic Black	765 (22.4)
Non-Hispanic Asian	411 (12.0)
Hispanic	1,051 (30.8)
Different race or ethnicity	151 (4.4)
Education
Less than high school	695 (20.4)
High school/GED	796 (23.3)
Some college	1,055 (30.9)
College graduate or above	867 (25.4)
Sexual orientation
Heterosexual	2,993 (87.7)	–
Gay/lesbian	67 (2.0)	–
Bisexual	119 (3.5)	–
Different identity	234 (6.9)	–
PHQ-9 Score (depression)	–	3.3 (4.2)
CRP	–	4.1 (8.0)
BMI	–	29.5 (7.4)
Health Insurance (any)	2,621 (77.0)	–
Tobacco use, at least 100 lifetime cigarettes	1,262 (37.0)
Alcohol use^a	–	3.0 (2.5)
Drug use^b
Marijuana, ever	1,711 (50.2)	–
Other drugs^c	538 (15.8)	–
Tobacco use, at least 100 lifetime cigarettes	1262 (37.0)	–

Abbreviations: SD = standard deviation; NH = non-Hispanic; PHQ-9 = Patient Health Questionnaire 9; BMI = body-mass index; CRP = C-reactive protein.

^a Number of times drank any alcohol in the past 12 months.

^b Ever used in lifetime.

^c Other drugs includes cocaine, methamphetamine, and heroin.

Other bivariate analyses suggest that total depression score was significantly associated with race/ethnicity (F = 9.94, p-value < 0.001), education (F = 17.35, p-value < 0.001), sexual identity (F = 15.92, p-value < 0.001), CRP (r = 0.12, p-value < 0.001), BMI (r = 0.10, p-value < 0.001), having smoked more than 100 lifetime cigarettes (t = −10.29, p-value < 0.001), ever having used marijuana (t = −9.23, p-value < 0.001), other substance use (t = −6.73, p-value < 0.001), and number of alcohol drinks per day (r = 0.11, p-value < 0.001). No association was observed between total depression score and age (r = 0.03, p-value = 0.07) nor insurance status (t = −1.32, p-value = 0.1865). For brevity, post hoc tests of ANOVAs are not reported here.

Weighted multivariable linear regression models assessed the relationship between CRP and depressive symptoms, stratified by gender (Table 2).  As a reminder, our main hypothesis for this analysis was that those with higher CRP would report a greater number of depressive symptoms among both men and women, with stronger effects observed among women relative to men. Secondarily, we hypothesized that this association would differ not only based on sex but that there would be significant moderation of CRP based on sexual identity, with the strongest relationship present among bisexual individuals. The first model examined this relationship among males where our hypotheses were not supported, no significant association was observed between CRP and number of depressive symptoms. We did observe that both smoking at least 100 cigarettes in one’s lifetime (Coef. = 0.83; 95% CI: 0.10, 1.56; p-value = 0.028) and number of alcoholic drinks per day in the past 12 months (Coef. = 0.24; 95% CI: 0.05, 0.44; p-value = 0.017) were each associated with more depressive symptoms among males. Conversely, compared to those with less than a high school education, those with some college education reported fewer depressive symptoms (Coef. = −1.06; 95% CI: −2.03, −0.008; p-value = 0.035). Our hypothesis regarding moderation by sexual identity was only partially supported among bisexual males (model without interaction, R² = 0.0805; model with interaction, R² = 0.0824). Linear combination of the main effects and interaction terms suggests that, relative to heterosexual males, higher CRP was associated with a greater number of depressive symptoms (Coef. = 2.00; 95% CI: 0.14, 3.86; p-value = 0.037).

Table 2. Results of weighted multivariable linear regressions examining the association between depressive symptoms and CRP with interaction terms between CRP and sexual orientation by biological sex, NHANES, 2015–2016.

	Males			Females
	(n = 1,180)			(n = 1,109)
Variable	Coefficient	95% CI	p-value	Coefficient	95% CI	p-value
Age	0.006	−0.03, 0.05	0.756	−0.009	−0.03, 0.01	0.329
Race
Non-Hispanic White	Ref	–	–	Ref	–	–
Non-Hispanic Black	0.07	−0.61, 0.75	0.838	0.25	−0.83, 1.32	0.633
Non-Hispanic Asian	−0.56	−1.33, 0.21	0.140	−0.24	−0.97, 0.49	0.496
Hispanic	−0.14	−0.83, 0.56	0.682	0.55	−0.69, 1.79	0.363
Different race/ethnicity	0.65	−0.88, 2.19	0.379	1.80	−0.72, 4.32	0.148
Education
Less than high school	Ref	–	–	Ref	–	–
High school/GED	−0.98	−2.51, 0.56	0.194	−1.33	−2.62, −0.04	0.044
Some college	−1.06	−2.03, −0.08	0.035	−1.82	−3.10, −0.55	0.008
≥ College graduate	−0.78	−2.19, 0.62	0.253	−1.92	−3.31, −0.53	0.010
Sexual orientation
Heterosexual	Ref	–	–	Ref	–	–
Gay/lesbian	1.89	−0.29, 4.07	0.085	0.87	−1.40, 3.13	0.429
Bisexual	1.77	−0.64, 4.19	0.139	2.24	0.52, 3.95	0.014
Different identity	−0.15	−1.19, 0.89	0.763	1.39	−2.02, 4.80	0.399
CRP	0.05	−0.007, 0.10	0.083	0.05	0.01, 0.08	0.012
CRP × sexual orientation
Heterosexual	Ref	–	–	Ref	–	–
Gay/lesbian	0.005	−0.34, 0.35	0.977	0.06	−0.27, 0.39	0.688
Bisexual	0.22	−0.51, 0.96	0.523	−0.17	−0.27, −0.07	0.002
Different identity	−0.09	−0.17, −0.02	0.014	0.17	−0.09, 0.44	0.187
BMI	−0.03	−0.08, 0.01	0.118	0.06	0.02, 0.10	0.008
Insurance status (any)
Yes	Ref	–	–	Ref	–	–
None	0.21	−0.70, 1.13	0.623	0.60	−0.46, 1.63	0.253
Tobacco Use^a
None	Ref	–	–	Ref	–	–
Yes	0.83	0.10, 1.56	0.028	1.44	0.76, 2.11	< 0.001
Marijuana Use^b
None	Ref	–	–	Ref	–	–
Yes	0.50	−0.18, 1.19	0.136	0.41	−0.38, 1.20	0.288
Other substance use^b^,^c
None	Ref	–	–	Ref	–	–
At least one substance	−0.35	−1.09, 0.39	0.325	0.87	−0.35, 2.09	0.150
Alcohol use^d	0.24	0.05, 0.44	0.017	0.20	0.01, 0.39	0.039

Abbreviations: CI = confidence interval, CRP = C-reactive protein, NH = non-Hispanic, GED = general education development, BMI = body-mass index.

^a At least 100 lifetime cigarettes.

^b Ever used in lifetime.

^c Other drugs includes cocaine, methamphetamine, and heroin.

^d Number of times drank any alcohol in the past 12 months.

The bolded values are statistically significant.

The second model in Table 2 examined the relationship between CRP and depressive symptoms among females. Here, our hypotheses were supported; namely, we observed that elevated CRP was associated with a greater number of depressive symptoms (Coef. = 0.05; 95% CI: 0.01, 0.08; p-value = 0.012). The main effect of sexual identity suggests that, compared to heterosexual women, bisexual women (Coef. = 2.24; 95% CI: 0.52, 3.95; p-value = 0.014) reported more depressive symptoms. Our moderation hypothesis among women was also partially supported by combination of the main effects and interaction terms, that is, that significant moderation of CRP by sexual identity was observed only among bisexuals (model without interaction, R² = 0.1455; model with interaction, R² = 0.1523). Relative to heterosexual females, as CRP increased among bisexual females, a greater number of depressive symptoms were reported (Coef. = 2.07; 95% CI: 0.41, 3.73; p-value = 0.018). Compared to those with less than high school education, those with high school education or GED (Coef. = −1.33; 95% CI: −2.62, −0.04; p-value = 0.044), some college (Coef. = −1.82; 95% CI: −3.10, −0.55; p-value = 0.008), and those who were at least a college graduate (Coef. = −1.92; 95% CI: −3.31, −0.53; p-value = 0.010) each reported fewer depressive symptoms. BMI was positively associated with depressive symptoms (Coef. = 0.06; 95% CI: 0.02, 0.10; p-value = 0.008). Again, as with males, we observed that both smoking at least 100 cigarettes in one’s lifetime (Coef. = 1.43; 95% CI: 0.76, 2.11; p-value < 0.001) and number of alcoholic drinks per day in the past 12 months (Coef. = 0.20; 95% CI: 0.01, 0.39; p-value = 0.039) were each associated with more depressive symptoms.

Discussion

This analysis used data from NHANES, a nationally representative survey, to assess the relationship between CRP and depression, including differences between males and females and potential moderation based on sexual identity. Our main hypothesis was partially supported; we observed that only women, but not men, with higher CRP reported a greater number of depressive symptoms. Our secondary hypothesis was also only partially supported. We did indeed see significant moderation of CRP based on sexual identity but only among bisexuals, not among other subgroups of sexual minorities. Other key findings include an association between both tobacco and alcohol use and a greater number of depressive symptoms, findings that were consistent across both males and females. These findings support past research suggesting inflammation contributes to depression primarily among women while simultaneously contributing to a growing body of literature highlighting health disparities among bisexuals.

Our study is among the first to examine the effect of sexual identity on the relationship between inflammation and depression, particularly as this relationship differs between males and females. We found that the association between CRP and depressive symptoms severity is moderated by sexual identity among both bisexual women and bisexual men. Our finding is not surprising given the extant research on health disparities within the bisexual community, often as a result of their stigmatized identities among both heterosexuals and the broader community of sexual minorities. Bisexual individuals experience stigma that is unique to their sexual identity and that is different from other SM (i.e., biphobia; (Feinstein & Dyar, 2017)), such as being frequently stereotyped as promiscuous and indecisive. Bisexuality is also often not acknowledged as a “legitimate” sexual identity, with bisexual individuals experiencing discrimination and exclusion from both heterosexual and gay/lesbian communities. These experiences of stigma and discrimination can lead to repeated and prolonged activation of biological stress responses (e.g., sympathetic nervous system, hypothalamic-pituitary-adrenal axis), resulting in sustained elevated systemic inflammation (Lagraauw et al., 2015; Osborne et al., 2020). This is one potential mechanism that could explain differences in the relationship between CRP and depression among bisexuals relative to their peers, particularly as this translates to disparities in physical health. Bisexuals have repeatedly been shown to have worse mental and physical health outcomes compared to other SM (Dyar et al., 2019; Ross et al., 2018). For example, bisexual women are more likely to report poorer general health than lesbian women (Fredriksen-Goldsen et al., 2010), and bisexual women are at elevated risk for depression, anxiety, PTSD, and substance-use disorder compared to lesbian and heterosexual women (Shearer et al., 2016). Meanwhile, bisexual men often report a higher rate of diabetes and get tested for HIV at lower rates than gay men (Karen I. Fredriksen-Goldsen et al., 2013). Taken together, our work here and this past body of work highlight the need for tailored behavioral interventions aimed at reducing stress and stigma among bisexuals or, perhaps, even biomedical interventions that may serve to reduce systemic inflammation and, potentially, health disparities as well.

Our findings also augment extant literature that demonstrates inflammation is linked with depression in certain populations. Past work has noted consistent associations between CRP and the development of depression (Valkanova et al., 2013; Wium-Andersen et al., 2013), depressive symptom severity (Köhler-Forsberg et al., 2017; Zalli et al., 2016), suicidality (Courtet et al., 2015), and response to depression treatment (Chamberlain et al., 2019; Chang et al., 2012). Additionally, treatment of depression has been associated with a decrease in inflammatory biomarkers, and the use of anti-inflammatory medication decreases depressive symptoms among those with treatment-resistant depression (Köhler et al., 2014). Our work here adds to this by highlighting key differences between men and women with regard to these relationships, namely, that inflammation may only impact depressive symptoms among women and not among men. As noted in the preceding paragraph, however, even the findings among women may be driven in particular by bisexual women. Taken together, this indicates inflammation may be a key driver in the clinical course of depression and that CRP, which is inexpensive and easy to test, may be a useful tool in the clinical management of depression in certain populations (Köhler-Forsberg et al., 2017). Future research should investigate not only the utility of CRP in clinical decision making related to depression management but should also assess the longitudinal, and potentially bidirectional, relationship between inflammation and depression to better identify specific populations at risk of more severe development of depression.

Our study has several limitations which need to be considered when interpreting our results. NHANES is a cross-sectional survey, which limits the ability to assess the temporality between CRP and depressive symptoms among sexual minorities. We were also limited to one biological marker of inflammation, CRP, as it was the only marker available in the data set. This limits the scope of our interpretation because CRP is a nonspecific biomarker of inflammation; thus, elevated CRP levels may be indicative of other acute illnesses rather than specific to depression. NHANES is also limited as 2015–2016 was the last year in which sexual-identity information was publicly available, limiting analysis and study of more recent data sets. Lastly, NHANES does not differentiate between gender identity and sex assigned at birth, which means we were unable to include transgender and gender-nonconforming individuals in our analysis.

Even in light of these limitations, we noted several key findings with regard to the relationship between inflammation and depression. First, we observed that elevated CRP is associated with more severe depressive symptoms among women but not men. Next, we noted that this relationship was moderated by sexual identity among bisexual women and men but not among other sexual minority subgroups. This may be because of bisexual-specific stressors leading to repeated and prolonged activation of physiological stress responses and, in turn, chronically elevated systemic inflammation. Future research should focus on better characterizing the relationship between stigma and discrimination, inflammation, and depression among bisexuals, and work to decrease experiences of stigma and other psychosocial stressors in both clinical and community settings.

Statement of ethics

Ethical approval was not required as this study was based on publicly available data.

Author contributions

EM conceived of the manuscript. JS procured the data, led analyses of the data, and co-led writing of the manuscript. EM assisted with the analyses of the data and co-led the writing of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Conflict of interest statement

The authors have no conflicts of interest to declare.

Data availability statement

The data that support the findings of this study are openly available from the Centers for Disease Control and Prevention at www.cdc.gov/nchs/nhanes/index.htm.

Additional information

Notes on contributors

Jessica P. Sherman

Dr. Sherman completed her PhD at Ohio State University in 2023, her dissertation focused on internalized HIV stigma among women living with HIV. Prior to this she was a nurse providing care the LGBTQ+ community.

Ethan Morgan

Dr. Ethan Morgan is an Assistant Professor of Epidemiology in Center for Healthy Aging, Self-Management and Complex Care in the College of Nursing as well as the Infectious Disease Institute at The Ohio State University. The overarching goal of his research is to improve the health of SM populations. In particular, he focuses on examining the etiology of elevated inflammation among SMs in terms of stress and stigma, chronic disease risk, and substance use. In brief, this work has suggested that SMs experience elevated systemic inflammation (regardless of their infectious disease status) and may be at particularly high risk for a host of inflammation-associated health outcomes from a much younger age than their heterosexual counterparts.