Anger expression and social anxiety are associated with dissociable neuroendocrine and inflammatory biomarker patterns: preliminary evidence from a cross-sectional study

Introduction

Psychological stress engages two major biological systems: the hypothalamic-pituitary-adrenal (HPA) axis and the immune-inflammatory response, and growing evidence suggests that these pathways jointly shape risk for stress-related psychopathology [1]. Anger expression style and social anxiety are frequently observed in psychiatric outpatients, but whether they preferentially engage one or the other of these pathways is still poorly characterised. Clarifying these links is particularly relevant for social anxiety disorder, which often follows a chronic and treatment-resistant course.

Aims

In a clinical outpatient sample, we examined whether (1) anger-out is associated with altered HPA axis activity (cortisol; cortisol/dehydroepiandrosterone sulfate (DHEA-S) ratio); (2) anger-in and social anxiety each independently predict elevated interleukin-6 (IL-6); and (3) social anxiety shows a selective association with inflammatory markers but not with HPA indices.

Methods

We enrolled 88 adult psychiatric outpatients (mean age 35.6 years; 55.7% female) at a university-affiliated clinic. Fasting morning serum samples, drawn before 10:00, were assayed for cortisol, DHEA-S, IL-6, and C-reactive protein (CRP). Participants completed the State-Trait Anger Expression Inventory–Korean (STAXI-K; n=61) and the Liebowitz Social Anxiety Scale (LSAS; n=63) [4]. Hierarchical multiple regression was performed in R 4.5.2, with age, sex, and body mass index (BMI) as covariates. The cortisol/DHEA-S ratio was log-transformed, in line with recommendations for analysing hormone ratios [2]. IL-6 values below the limit of detection (LOD=1.50 pg/mL; 22.7%) were handled by LOD/√2 substitution; CRP (>48.9% below LOD) was treated dichotomously as detectable vs. undetectable. For LSAS subscale analyses, a Bonferroni-corrected threshold of α=.007 was applied.

Results

After covariate adjustment, anger-out predicted lower cortisol (B=−.403, 95% CI [−.744, −.061], β=−.311, p=.022, ΔR²=.079) and a lower log cortisol/DHEA-S ratio (B=−.038, β=−.278, p=.037, ΔR²=.062). Anger-in was associated with higher log IL-6 (B=.037, β=.294, p=.033, ΔR²=.068). Total LSAS also predicted higher log IL-6 (B=.007, β=.400, p=.001, ΔR²=.141), with the assertiveness subscale showing the strongest effect (ΔR²=.173, p<.001) and surviving Bonferroni correction. In contrast, LSAS was not significantly related to cortisol, the cortisol/DHEA-S ratio, DHEA-S, or the triglyceride/low-density lipoprotein cholesterol (TG/LDL) ratio (all ΔR²≤.017, p>.29). Logistic regression further showed that anger-in (OR=1.25, 95% CI [1.052, 1.554], p=.021) and LSAS (OR=1.05, 95% CI [1.019, 1.102], p=.012) independently increased the odds of detectable IL-6 elevation.

Outcome	Predictor	B	β	p	ΔR²
Cortisol	Anger-out	−.403	−.311	.022	.079
Cort/DHEA-S	Anger-out	−.038	−.278	.037	.062
Log IL-6	Anger-in	.037	.294	.033	.068
Log IL-6	LSAS total	.007	.400	.001	.141
Log IL-6	LSAS assertiveness	.052	—	<.001	.173

All models were adjusted for age, sex, and BMI.

Conclusions

In this psychiatric outpatient sample, externalised anger was linked to HPA axis hypoactivity, whereas suppressed anger and social anxiety were associated with elevated IL-6 without parallel HPA involvement. The selective inflammatory signal seen in social anxiety—most prominent for assertiveness-related anxiety—is consistent with a distinct allostatic mechanism, though IL-6 is increasingly recognised as a marker of multiple immunometabolic processes rather than inflammation alone [3]. Limitations include the cross-sectional, single-centre design, the heterogeneous outpatient sample, and the modest size of the subsamples completing each questionnaire. The findings should therefore be regarded as hypothesis-generating, and replication in larger, prospective, and diagnostically stratified samples is warranted before clinical translation.

References

1. Slavich, G.M., Irwin, M.R., 2014. From stress to inflammation and major depressive disorder: a social signal transduction theory of depression. Psychol. Bull. 140 (3), 774–815.
2. Sollberger, S., Ehlert, U., 2016. How to use and interpret hormone ratios. Psychoneuroendocrinology 63, 385–397.
3. Del Giudice, M., Gangestad, S.W., 2018. Rethinking IL-6 and CRP: why they are more than inflammatory biomarkers, and why it matters. Brain Behav. Immun. 70, 61–75.
4. Liebowitz, M.R., 1987. Social phobia. Mod. Probl. Pharmacopsychiatry 22, 141–173.