Cited by 296Stress Responses and CortisolTryptophan and brain disordersAnxiety, Depression, Psychometrics, Treatment, Cognitive Processes

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Clinical anxiety, cortisol and interleukin-6: Evidence for specificity in emotion–biology relationships

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O’Donovan, Aoife, Hughes, Brian M., Slavich, George M., Lynch, Lydia, Cronin, Marie-Therese, O’Farrelly, Cliona, Malone, Kevin M.·2010·Brain, Behavior, and Immunity

DOI 10.1016/j.bbi.2010.03.003PMC PMC4361085

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Abstract

Anxiety confers increased risk for inflammatory diseases, and elevated inflammatory activity in anxious individuals may contribute to this increased risk. One complication, however, is that anxiety could be associated with inflammatory activity either through a specific anxiety pathway or through a more general negative emotionality pathway. To investigate, we measured levels of the stress hormone cortisol, the pro-inflammatory cytokine interleukin-6 (IL-6), and the systemic inflammatory marker C-reactive protein (CRP), as well as depression and neuroticism, in clinically anxious and non-anxious adults. Compared with non-anxious participants, clinically anxious participants exhibited significantly lower levels of morning cortisol and significantly higher levels of IL-6, independent of age, sex, and depressive symptoms. These group differences were robust when controlling for neuroticism. Conversely, the groups had equivalent levels of CRP in all analyses. Results are indicative of anxiety-specific effects on inflammatory activity, and highlight a pathway by which anxiety may increase risk for inflammatory diseases.

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Is there any association of anxiety-depressive symptoms with vascular endothelial function or systemic inflammation?
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The incidence and risk of osteoporosis in patients with anxiety disorder
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Effects of self-expressive writing as a therapeutic method to relieve stress among university students
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“There is ample evidence to demonstrate that depression, anxiety, and stress in general have clear-cut relationships with the cortisol system, with stress and depression being a hypercortisolaemic state (O’Donovan et al., 2010).”
Background
C-Reactive Protein (CRP): A Potent Inflammation Biomarker in Psychiatric Disorders
Orsolini, L., Pompili, S., & Volpe, U. (2023) · Advances in experimental medicine and biology · doi:10.1007/978-981-19-7376-5_7 · Cited by 19
Psychiatric Symptoms, Salivary Cortisol and Cytokine Levels in Young Marijuana Users
Cloak, C., Alicata, D., Ernst, T., & Chang, L. (2015) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-015-9606-0 · Cited by 17
“Our findings of modest elevation in IL-6, which others have observed in anxious adults (O’Donovan et al. 2010), further support this interpretation.”
Result
Exercise for the Management of Anxiety and Stress-Related Disorders
Herring, M. P. (2018) · Exercise-Based Interventions for Mental Illness · doi:10.1016/b978-0-12-812605-9.00002-2 · Cited by 15
The critical role of physical frailty and function on depressive symptoms among community-dwelling older adults in China: A cross-sectional study
Wang, Q., Song, D., Lin, Q., Tao, A., Zhang, Y., Li, X., & Qiu, X. (2023) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2023.1134427 · Cited by 15
Context is complex: Challenges and opportunities addressing contextual factors in manual therapy mechanisms research
Keter, D. L., Esteves, J. E., Loghmani, M. T., Rossettini, G., & Cook, C. E. (2025) · International journal of osteopathic medicine · doi:10.1016/j.ijosm.2025.100750 · Cited by 17
A szorongás és a diabetes közti kapcsolat
Hargittay, C., Gonda, X., Márkus, B., Sipkovits, Z., Vörös, K., Kalabay, L., Rihmer, Z., & Torzsa, P. (2021) · Orvosi Hetilap · doi:10.1556/650.2021.32169 · Cited by 14
“A C-re-aktív proteint vizsgálva nem találtak szignifikáns eltérést a két csoport között [38].”
Symptoms of anxiety but not depression before start of taxane-based chemotherapy are associated with peripheral neuropathy: a multicenter study in women with breast cancer
Verhoeff-Jahja, R., ter Kuile, M. M., Weijl, N. I., Oosterkamp, R., Balen, M. C., Portielje, J. E. A., Kroep, J. R., & Hinnen, C. (2022) · Supportive Care in Cancer · doi:10.1007/s00520-022-07093-4 · Cited by 14
Dyadic Cross-Sectional Associations Between Negative Mood, Marital Idealization, and Relationship Quality
Gana, K., Saada, Y., Broc, G., Koleck, M., & Cazauvieilh, C. (2016) · The Journal of Psychology · doi:10.1080/00223980.2016.1211982 · Cited by 14
“For instance, O’Donovan et al. (2010) found that HADS-A scores were significantly correlated with neuroticism (r D .28, p D .04).”
Background
Causal association between psycho-psychological factors, such as stress, anxiety, depression, and irritable bowel syndrome: Mendelian randomization
Diao, Z., Xu, W., Guo, D., Zhang, J., Zhang, R., Liu, F., Hu, Y., & Ma, Y. (2023) · Medicine · doi:10.1097/md.0000000000034802 · Cited by 13
“[60,61] Inflammatory factors such as Interleukin-1 (IL-1), C-reactive protein, and IL-6 are significantly increased in the peripheral blood of patients with anxiety and depression,[62,63] suggesting that anxiety and depression may induce inflammation.”
Background
Antagonism of the brain P2X7 ion channel attenuates repeated social defeat induced microglia reactivity, monocyte recruitment and anxiety-like behavior in male mice
Biltz, R. G., Swanson, S. P., Draime, N., Davis, A. C., Yin, W., Goodman, E. J., Gallagher, N. R., Bhattacharya, A., Sheridan, J. F., & Godbout, J. P. (2023) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2023.10.011 · Cited by 14
Increased telomerase activity in major depressive disorder with melancholic features: Possible role of pro-inflammatory cytokines and the brain-derived neurotrophic factor
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Psychological Profile, Salivary Cortisol, C-Reactive Protein, and Perceived Health of Grandmothers With Childrearing Responsibility
Ross, M. E., Kang, D.-H., & Cron, S. G. (2014) · Journal of Family Issues · doi:10.1177/0192513x14540157 · Cited by 13
“Similarly, CRP levels did not show a difference between clinically anxious and nonanxious adults (O’Donovan et al., 2010).”
Background
Longitudinal associations between salivary cortisol to C-reactive protein ratios and psychological well-being in Chinese adults
Fong, T. C. T., Ho, R., & Yau, J. C. Y. (2022) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2022.105824 · Cited by 11
Effect of type of disease-modifying antirheumatic drugs on depression and anxiety of patients with rheumatoid arthritis in Saudi Arabia: a cross-sectional study
Baghdadi, L. R., Alhassan, M. K., Alotaibi, F. H., Alsuwaida, A. A., Shehadah, A. E., & AlZahrani, M. T. (2023) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2023.1184720 · Cited by 11
“IL-6 is associated and mostly elevated in patients with depression and anxiety (3, 4).”
Background
Effect of Chinese herbal compound Naofucong (脑复聪) on the inflammatory process induced by high glucose in BV-2 cells
Jing, G., Zhang, M., Ji, C., Zuo, P., Liu, Y., & Gu, B. (2016) · Chinese Journal of Integrative Medicine · doi:10.1007/s11655-016-2256-0 · Cited by 12
“A large number of clinical and animal experiments have confirmed the main role IL-6 played in cognitive decline.((21-24)) Cytokines, particularly higher peripheral IL-6, is related to brain inflammation that might adversely affect learning and memory through processes related to neurodegeneration and structural remode…”
Background
Associations between asthma trigger reports, mental health conditions, and asthma morbidity among world trade center rescue and recovery workers
Morales-Raveendran, E., Goodman, E., West, E., Cone, J. E., Katz, C. L., Weiss, J. J., Feldman, J. M., Harrison, D. J., Markowitz, S. B., Federman, A. D., et al. (2018) · Journal of Asthma · doi:10.1080/02770903.2018.1502300 · Cited by 11
“Changes in the HPA axis can also lead to low levels of cortisol (which helps with reducing inflammation) [42].”
Background
Interaction effect of the serum interleukin-6 level and anxiety on the 12-week pharmacotherapeutic responses of patients with depressive disorders
Choi, W., Kang, H., Kim, J., Kim, H. K., Kang, H., Lee, J., Kim, S., Stewart, R. J., & Kim, J.-M. (2022) · Journal of Affective Disorders · doi:10.1016/j.jad.2022.04.048 · Cited by 12
Effects of short-term preoperative intranasal dexmedetomidine plus conventional treatment on delirium following cardiac surgery in patients with sleep disorders
Fang, J., Yang, J. M., Zhai, M., Zhang, Q., Zhang, M., & Xie, Y. (2024) · Perioperative Medicine · doi:10.1186/s13741-024-00371-1 · Cited by 10
“It is hypothesised that the connection between anxiety and delirium might be associated with shared central neuroinflammatory pathways implicated in their development (Inouye et al. 2014; Vasunilashorm et al. 2015; Furtado and Katz-man 2015; O’Donovan et al. 2010).”
Background
Ancient roots – Modern applications: Mindfulness as a novel intervention for cardiovascular disease
Zieff, G. H. (2017) · Medical Hypotheses · doi:10.1016/j.mehy.2017.08.001 · Cited by 10
Effects of statins on anxiety and depression in patients with asthma-chronic obstructive pulmonary disease overlap syndrome
Yeh, J., Syue, S.-H., Lin, C., Hsu, C. Y., Shae, Z., & Kao, C. (2019) · Journal of Affective Disorders · doi:10.1016/j.jad.2019.05.002 · Cited by 10
The Effects of Peer Support on Depression, Anxiety, and Stress Among Patients Receiving Hemodialysis
Irajpour, A., Hashemi, M. S., Abazari, P., Shahidi, S., & Fayazi, M. (2019) · Iranian Red Crescent Medical Journal · doi:10.5812/ircmj.66321 · Cited by 10
“Moreover, the levels of inflammatory factors among anxious patients are high, and therefore, they are at risk for malnutrition, impaired immune function, and early death (22).”
Background
Treatment of Heart Failure Patients with Anxiolytics Is Associated with Adverse Outcomes, with and without Depression
Zwas, D. R., Keren, A., Amir, O., & Gotsman, I. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9123967 · Cited by 10
“Clinically anxious individuals have also been found to have higher levels of IL-6 [35] and lower levels of morning cortisol, even in the absence of depression [35].”
Background
TLR7 and IL-6 differentially regulate the effects of rotarod exercise on the transcriptomic profile and neurogenesis to influence anxiety and memory
Hung, Y.-F., & Hsueh, Y. (2021) · iScience · doi:10.1016/j.isci.2021.102384 · Cited by 10
The Potential Roles of Astrocytes and Microglia in the Spinal Cord and Brain After Spinal Cord Injury
Fiorin, F. D. S., & Santo, C. C. D. E. (2025) · Neuroglia · doi:10.3390/neuroglia6010012 · Cited by 9
Do Anxiety and Depression Levels Affect the Inflammation Response in Patients Hospitalized for COVID-19
Kahve, A. C., Kaya, H., Okuyucu, M., Göka, E., Barun, S., & Hacımusalar, Y. (2021) · Psychiatry Investigation · doi:10.30773/pi.2021.0029 · Cited by 9
Non-invasive diagnosis and monitoring tool of children’s mental health: A point-of-care immunosensor for IL-6 quantification in saliva samples
Cruz, A., Vieira, M., Mesquita, A. R., Sampaio, A., Pinto, I. M., Soares, I., & Freitas, P. P. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.919551 · Cited by 9
“IL-6 an inflammatory cytokine is associated with the presence of mental health problems, such as depression or anxiety (O’Donovan et al., 2010; Trapero and Cauli, 2014; Raposa et al., 2015; de Baumont et al., 2019; Müller et al., 2019; Niraula et al., 2019), or internalization and externalization behaviors (Slopen et…”
Background
Prenatal mood and anxiety disorders and associated cytokine changes
Mancuso, R. A., Ross, K. M., Accortt, E. E., Coussons‐Read, M. E., Okun, M. L., Irwin, J. L., Carroll, J., Hobel, C. J., & Schetter, C. D. (2023) · Journal of Affective Disorders · doi:10.1016/j.jad.2023.12.014 · Cited by 9
Anxiety: An overlooked confounder in the characterisation of chronic stress-related conditions?
Viljoen, M., Benecke, R. M., Martin, L. I., Adams, R. C. M., Seedat, S., & Smith, C. (2020) · PLoS ONE · doi:10.1371/journal.pone.0230053 · Cited by 9
“Furthermore, in terms of the pro-inflammatory phenotype shift that is linked to HPAaxis dysregulation, upregulation of inflammatory markers such as interleukin -6 (IL-6) has been reported in the context of trauma [15,16,17], with similar findings in anxiety related research [18,19].”
Result
Depression, Anxiety, and Resilience
Kutcher, A. M., Byon, H. D., & Howie‐Esquivel, J. (2023) · The Journal of Cardiovascular Nursing · doi:10.1097/jcn.0000000000001049 · Cited by 8
Gut microbiota connects the brain and the heart: potential mechanisms and clinical implications
Zhang, Y., Huang, K., Duan, J., Zhao, R., & Yang, L. (2024) · Psychopharmacology · doi:10.1007/s00213-024-06552-6 · Cited by 9
IL-6 and Inflammatory Diseases
Kamimura, D., Arima, Y., Hirano, T., Ogura, H., & Murakami, M. (2013) · Springer eBooks · doi:10.1007/978-4-431-54442-5_2 · Cited by 9
Chronic Inflammation Mediates the Association between Cortisol and Hyperglycemia: Findings from the Cross-Sectional Population-Based KORA Age Study
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LQFM212, a piperazine derivative, exhibits potential antioxidant effect as well as ameliorates LPS-induced behavioral, inflammatory and oxidative changes
Moreira, L. K. D. S., Turones, L. C., Campos, H. M., Martins, A. N., Thomaz, D. V., Gil, E. D. S., Ghedini, P. C., da Rocha, F. F., Menegatti, R., Fajemiroye, J. O., et al. (2022) · Life Sciences · doi:10.1016/j.lfs.2022.121199 · Cited by 9
Potential Neuroimmunological Targets in the Treatment of Anxiety Disorders
Hou, R. H., Tang, Z., & Baldwin, D. S. (2013) · Modern trends in psychiatry · doi:10.1159/000351965 · Cited by 7
Transgenerational Social Stress Alters Immune–Behavior Associations and the Response to Vaccination
Hicks-Nelson, A., Beamer, G., Gurel, K., Cooper, R., & Nephew, B. C. (2017) · Brain Sciences · doi:10.3390/brainsci7070089 · Cited by 7
“While there is a negative association between IL-6 and self grooming in the control F1 juveniles, this relati nship may be either gen rally disrupted in CSS anim ls and/or transitioning to a positive association whe high ba al levels of IL-6 mediate anxiety associated i creased levels of self grooming, as IL-6 has bee…”
Background
Attachment and dream emotions: The mediating role of trait anxiety and depression
Sándor, P., Horváth, K., Bódizs, R., & Thege, B. K. (2018) · Current Psychology · doi:10.1007/s12144-018-9890-y · Cited by 8
Predicting the course of anxiety disorders: The role of biological parameters
Bosman, R. C., van Balkom, A. J. L. M., Rhebergen, D., van Hemert, A. M., Schoevers, R. A., Penninx, B. W. J. H., & Batelaan, N. M. (2020) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2020.109924 · Cited by 8
Perfectionistic cognitions, Interleukin-6, and C-Reactive protein: A test of the perfectionism diathesis stress model
Molnar, D. S., Moore, J., O’Leary, D. D., MacNeil, A. J., & Wade, T. J. (2021) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2021.100211 · Cited by 12
Inflammatory markers changes following acceptance-based behavioral psychotherapy in generalized anxiety disorder patients: Evidence from a randomized controlled trial
Gandarela, L., de A. Sampaio, T. P., Marçal, L., Burdmann, E. A., Neto, F. L., & Bernik, M. A. (2024) · Brain, Behavior, & Immunity - Health · doi:10.1016/j.bbih.2024.100779 · Cited by 6
“…animal models (Schrott and Crnic, 1996; Yang et al., 2016; De Miranda et al., 2011), healthy volunteers with anxious symptoms (Maes et al., 1998; Pitsavos et al., 2006; O ’ Donovan et al., 2010), and anxiety disorders (Vogelzangs et al., 2013; Belem da Silva et al., 2017; Renna et al., 2018).”
Background
Sex-specific regulation of microglial MyD88 in HMGB1-Induced anxiety phenotype in mice
Rawls, A., Dziabis, J. E., Nguyen, D. M., Anbarci, D. N., Clark, M., Zhang, G., Dzirasa, K., & Bilbo, S. D. (2025) · Neurobiology of Stress · doi:10.1016/j.ynstr.2025.100721 · Cited by 8

Authors: O’Donovan, A., Hughes, B. M., Slavich, G. M., Lynch, L., Cronin, M.-T., O’Farrelly, C., & Malone, K. M.
Affiliations: University College Dublin (IE)
Ollscoil na Gaillimhe – University of Galway (IE)
University of California, San Francisco (US)
St. Vincent's University Hospital (IE)
Trinity College Dublin (IE)
ORCID: O’Donovan, Aoife
Hughes, Brian M.
Slavich, George M.
Lynch, Lydia
O’Farrelly, Cliona
Malone, Kevin M.
Venue: Brain, Behavior, and Immunity
Publisher: Elsevier BV
Published: 2010-10
Volume: 24
Issue: 7
Pages: 1074-1077
ISSN: 0889-1591 (ISSN-L)
DOI: 10.1016/j.bbi.2010.03.003
PMC: PMC4361085
OpenAlex: W2010803460
Cited by: 296
References: 30
Citations by year: 2026: 12 · 2025: 20 · 2024: 15 · 2023: 18 · 2022: 21 · 2021: 27 · 2020: 23 · 2019: 23 · 2018: 28 · 2017: 12 · 2016: 21 · 2015: 12 · 2014: 22 · 2013: 13 · 2012: 16
FWCI: 5.81
Type: journal article
Language: en
Open access: green
hdl.handle.net
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Brain Behavior and Immunity (publishedVersion)
PubMed (publishedVersion)
ARAN (University of Galway Research Repository) (Ollscoil na Gaillimhe – University of Galway) (acceptedVersion, cc-by-nc-nd)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Arrow@dit (Dublin Institute of Technology) (submittedVersion)
ARAN (University of Galway Research Repository) (Ollscoil na Gaillimhe – University of Galway) (submittedVersion, cc-by-nc-nd)
eScholarship (California Digital Library) (submittedVersion)
University of Galway Research Repository (submittedVersion, cc-by-nc)
Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
Lenus, The Irish Health Repository (Dr Steevens Hospital Library) (submittedVersion)
Research Repository UCD (University College Dublin) (cc-by-nc)
Funders: National Institute of Mental Health (T32MH019925)
Topics: Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
Keywords: clinical anxiety, cortisol, interleukin-6, C-reactive protein, inflammation, neuroticism, depression, inflammatory diseases, stress hormones, inflammatory cytokines
MeSH terms: Adult, Anxiety, C-Reactive Protein, Depression, Female, Humans, Hydrocortisone, Male, Neurotic Disorders, Personality Inventory, Surveys and Questionnaires, Saliva, Interleukin-6

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Clinical anxiety, cortisol and interleukin-6: Evidence for specificity in emotion–biology relationships

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