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Clinical anxiety, cortisol and interleukin-6: Evidence for specificity in emotion–biology relationships
Open accessAbstract
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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“and some studies have failed to find an association between depression and inflammation.[7][8][9]”
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“However, there is wide variability in the levels of inflammation observed in depressed individuals, and some studies have failed to find an association between depression and inflammation.[7][8][9]”
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“High levels of CRP and IL-6 were also reported in individuals with anxiety disorders [6, 7].”
From Interleukin-6 Induced by Social Stress Promotes a Unique Transcriptional Signature in the Monocytes That Facilitate Anxiety (2019) · cites this paper as [7]
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BackgroundTransformational Teaching: Theoretical Underpinnings, Basic Principles, and Core Methods
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Childhood trauma associated with short leukocyte telomere length in posttraumatic stress disorder
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InfluentialSelf-citationAn Integrative Approach to Neuroinflammation in Psychiatric disorders and Neuropathic Pain
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A neuroimmunological perspective on anxiety disorders
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“When compared with non-anxious participants, clinically anxious participants exhibited significantly higher levels of IL-6, independent of depressive symptoms that indicate an anxiety-specific effect on inflammatory activity and highlights a pathway by which anxiety may increase risk for inflammatory diseases (O’Donov…”
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Potential contribution of oxidative stress and inflammation to anxiety and hypertension
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Effects of SSRIs on Peripheral Inflammatory Cytokines in Patients with Generalized Anxiety Disorder
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BackgroundAre Anxiety Disorders Associated with Accelerated Aging? A Focus on Neuroprogression
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BackgroundThe cytokine profile of women with severe anxiety and depression during pregnancy
Leff, P., Mancilla‐Herrera, I., Flores‐Ramos, M., Takashima, M. F. S., Coronel, F., Cruz-Fuentes, C. S., Molina, A., Hernández-Ruiz, J., Silva-Aguilera, F. S., Farfán-Labonne, B. E., et al. (2019) · BMC Psychiatry · doi:10.1186/s12888-019-2087-6 · Cited by 90
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“…and all of these disorders have been linked with elevated inflammation in physically healthy individuals (Hoge et al., 2009; Miller et al., 2002; O’Donovan et al., 2010, 2011b), and in some but not all samples of patients with CVD (Ferketich et al., 2005; von Kanel et al., 2010; Whooley et al.,…”
Self-citationFerguson, B. J., Marler, S., Altstein, L. L., Lee, E. B., Mazurek, M. O., McLaughlin, A., Macklin, E. A., McDonnell, E., Davis, D. J., Belenchia, A. M., et al. (2016) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2016.05.009 · Cited by 89
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EPIGENETIC VARIATION AT SKA2 PREDICTS SUICIDE PHENOTYPES AND INTERNALIZING PSYCHOPATHOLOGY
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BackgroundPopulation differences in proinflammatory biology: Japanese have healthier profiles than Americans
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The Association Between Obesity and Low Back Pain and Disability Is Affected by Mood Disorders
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“27 Adipose tissue, particularly when deposited in an androgenic distribution around the torso rather than evenly distributed throughout the body, is considered a metabolically active organ.”
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Oxidative Imbalance and Anxiety Disorders
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Aging faster: worry and rumination in late life are associated with greater brain age
Karim, H. T., Ly, M. J., Yu, G. Z., Krafty, R. T., Tudorascu, D., Aizenstein, H. J., & Andreescu, C. (2021) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2021.01.009 · Cited by 76
“…include molecular aging markers (e.g., shortened telomeres [Okereke et al., 2012]) and increased stress response including chronic in fl ammatory stress, increased hypothalamic-pituitary-adrenocortical activity and excessive autonomic responses (O'Donovan et al., 2010, 2013; Perna et al., 2016).”
Yin, W., Gallagher, N. R., Sawicki, C. M., McKim, D. B., Godbout, J. P., & Sheridan, J. F. (2019) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2019.01.015 · Cited by 68
Satyanarayanan, S. K., Chien, Y.-C., Chang, J. P., Huang, S., Guu, T., Su, H., & Su, K. (2019) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2019.03.003 · Cited by 68
Chen, P., Chen, F., Chen, G., Zhong, S., Gong, J., Zhong, H., Ye, T., Tang, G., Wang, J., Luo, Z., et al. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.07.004 · Cited by 66
Niles, A. N., Smirnova, M., Lin, J. E., & O’Donovan, A. (2018) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2018.05.035 · Cited by 69
“…et al., 2003; Penninx et al., 2003; Tayefi et al., 2017; Toker et al., 2005; Vogelzangs et al., 2012) and only a few published studies have reported no association between depression and inflammation (Duivis et al., 2013; Liukkonen et al., 2011; O’Donovan et al., 2010; Vogelzangs et al., 2013).”
BackgroundResultInfluentialSelf-citationVagotomy and insights into the microbiota-gut-brain axis
Liu, Y., & Forsythe, P. (2021) · Neuroscience Research · doi:10.1016/j.neures.2021.04.001 · Cited by 67
O’Connor, T. G., Moynihan, J. A., & Caserta, M. T. (2013) · Journal of Child Psychology and Psychiatry · doi:10.1111/jcpp.12187 · Cited by 68
“An abundance of research in adults associates multiple markers of neuro-inflammation with psychiatric symptoms (Dantzer, O’Connor, Lawson, & Kelley, 2011; Howren, Lamkin, & Suls, 2009; O’Connor, Lawson et al., 2009; O’Donovan et al., 2010).”
BackgroundLopez, R. B., Denny, B. T., & Fagundes, C. P. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.10.019 · Cited by 64
“counterparts, even when controlling for age, sex, and depressive symptoms (O’Donovan et al., 2010).”
Lin, J. E., Neylan, T. C., Epel, E., & O’Donovan, A. (2016) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2015.11.015 · Cited by 63
“We analyzed both the presence and the number of childhood adversities and adulthood traumas, because the number of adverse experiences can increase risk for inflammation and for the development of physical and mental disorders (Coker et al., 2005; McLaughlin et al., 2010; O’Donovan et al., 2012).”
InfluentialSelf-citationEffects of maternal breathing rate, psychiatric status, and cortisol on fetal heart rate
Monk, C. E., Fifer, W. P., Myers, M. M., Bagiella, E., Duong, J., Chen, I. S., Leotti, L. A., & Altincatal, A. (2010) · Developmental Psychobiology · doi:10.1002/dev.20513 · Cited by 63
“…(Wadhwa, 2005; Weinstock, 2005), as it is a major effector of psychosocial stress, and anxiety and depression are associated with variation in salivary cortisol levels (Heaney, Phillips, & Carroll, 2010; O’Donovan et al., 2010; Veen et al., 2010), even during pregnancy (Evans, Myers, & Monk, 2008).”
BackgroundUdina, M., Moreno-España, J., Navinés, R., Giménez, M. D., Langohr, K., Gratacòs, M., Capuron, L., de la Torre, R., Sola, R. L., & Martín‐Santos, R. (2013) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2013.03.007 · Cited by 64
“…has been poorly evaluated in previous biological and genetic studies of CHC, some studies have reported an association between anxiety and alterations of the inflammatory pathway such as elevations of plasma IL-6 or tumour necrosis factor alpha (TNF-alpha) concentrations (O’Donovan et al., 2010).”
Platero, J. L., Cuerda‐Ballester, M., Valle, V. I.-D., Sancho, D., López‐Rodriguez, M. M., Drehmer, E., & Ortí, J. E. D. L. R. (2020) · Nutrients · doi:10.3390/nu12020305 · Cited by 61
“Thus, the most anxious individuals have higher levels of IL-6, regardless of their age or gender [10].”
BackgroundBratek, A., Zawada, K., Beil-Gawełczyk, J., Beil, S., Sozańska, E., Krysta, K., Barczyk, A., Krupka-Matuszczyk, I., & Pierzchała, W. (2014) · Journal of Neural Transmission · doi:10.1007/s00702-014-1171-9 · Cited by 62
“The effect of interleukin 6 (IL-6) has been most exhaustively described (Słu _ zewska et al. 1995; Alesci et al. 2005; O’Donovan et al. 2010) but among the proinflammatory mediators investigated so far are also interleukin-1 beta (IL-1b), tumor necrosis factor alpha (TNF-a) and C-reactive protein (CRP) (Ford and Erlin…”
BackgroundThe role of Th17 cells in the pathophysiology of pregnancy and perinatal mood and anxiety disorders
Osborne, L. M., Brar, A., & Klein, S. L. (2018) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2018.11.015 · Cited by 62
“O’Donovan and colleagues, in the only study to address sex differences, found that IL-6 was elevated in individuals with clinically significant anxiety regardless of sex, age, or depressive symptoms (O’Donovan et al., 2010).”
BackgroundGriñán‐Ferré, C., Palomera‐Ávalos, V., Puigoriol‐Illamola, D., Camins, A., Porquet, D., Plá, V., Aguado, F., & Pallàs, M. (2016) · Experimental Gerontology · doi:10.1016/j.exger.2016.03.014 · Cited by 60
Santo, C. C. D. E., Fiorin, F. D. S., Ilha, J., Duarte, M. M. M. F., Duarte, T., & Santos, A. R. S. (2019) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2019.01.012 · Cited by 61
Role of negative affects in pathophysiology and clinical expression of irritable bowel syndrome
Muscatello, M. R. A. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i24.7570 · Cited by 61
Hanns, L., Radziszewska, A., Suffield, L., Josephs, F., Chaplin, H., Peckham, H., Sen, D., Christie, D., de Carvalho, L. A., & Ioannou, Y. (2019) · Arthritis Care & Research · doi:10.1002/acr.24006 · Cited by 58
Therapeutic psychological and biological responses to mindfulness‐based art therapy
Beerse, M. E., Lith, T. V., & Stanwood, G. D. (2020) · Stress and Health · doi:10.1002/smi.2937 · Cited by 59
The impact of tocilizumab on anxiety and depression in patients with rheumatoid arthritis
Tiosano, S., Yavne, Y., Watad, ., Langevitz, P., Lidar, M., Feld, J., Tishler, M., Aamar, S., Elkayam, O., Balbir‐Gurman, A., et al. (2020) · European Journal of Clinical Investigation · doi:10.1111/eci.13268 · Cited by 57
Psychosocial effects of the COVID-19 pandemic on staff in a dental teaching hospital
Mahendran, K., Patel, S. S., & Sproat, C. (2020) · BDJ · doi:10.1038/s41415-020-1792-3 · Cited by 56
Renna, M. E. (2021) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2021.100397 · Cited by 65
“However, more broadly, heightened anxiety and depressive symptoms can also correspond to inflammation among physically healthy adults and those with chronic health conditions (Duivis et al., 2011; Kiecolt-Glaser et al., 2015; Pierce et al., 2017; O'Donovan et al., 2010; Whooley et al., 2007; Powell et al., 2013).”
BackgroundShorter telomere length in peripheral blood leukocytes is associated with childhood autism
Li, Z., Tang, J., Li, H., Chen, S., Hé, Y., Liao, Y., Wei, Z., Wan, G., Xiang, X., Xia, K., et al. (2014) · Scientific Reports · doi:10.1038/srep07073 · Cited by 54
Ma, J., Li, C., Zhang, W., Zhou, L., Shu, S., Wang, S., Wang, D., & Chai, X. (2021) · BMC Anesthesiology · doi:10.1186/s12871-021-01271-3 · Cited by 55
“Similarly, the pathway was also involved in the process of anxiety [46, 47], therefore, resulting from the increased release of inflammatory cytokines in central nervous system, the POA could be a good predictor for the POD.”
BackgroundA short Mindfulness retreat can improve biological markers of stress and inflammation
Gardi, C., Fazia, T., Stringa, B., & Giommi, F. (2021) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2021.105579 · Cited by 59
“Many human and animal studies have shown that physiological pathways involving inflammatory and stress responses likely play an important role in the etiology of anxiety and other psychiatric disorders (O‟Donovan et al., 2010; Sominsky et al., 2013).”
BackgroundPerić, I., Stanisavljević, A., Gass, P., & Filipović, D. (2017) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-017-0807-9 · Cited by 51
“We focused on the proinflammatory cytokine IL-1β and IL-6 in our study because of previous studies indicating increased serum IL-1β and IL-6 concentrations in depressed patients [66, 67] and clinically anxious individuals [68], as well as in animal models of depression [69].”
BackgroundSu, S., Sun, M.-T., Wen, M.-J., Lin, C.-J., Chen, Y.-C., & Hung, Y. (2011) · The International Journal of Psychiatry in Medicine · doi:10.2190/pm.42.3.a · Cited by 50
Matura, L. A., Ventetuolo, C. E., Palevsky, H. I., Lederer, D. J., Horn, E. M., Mathai, S. C., Pinder, D., Archer-Chicko, C. L., Bagiella, E., Roberts, K. E., et al. (2015) · Annals of the American Thoracic Society · doi:10.1513/annalsats.201410-463oc · Cited by 48
Liu, Y., Mian, M. F., Neufeld, K. M., & Forsythe, P. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.04.014 · Cited by 49
The Psychological Impact of Hemodialysis on Patients with Chronic Renal Failure
Wang, L., & Che, C. (2012) · InTech eBooks · doi:10.5772/36832 · Cited by 46
“O'Donovan et al. (2010) reported that clinically anxious participants exhibited significantly lower levels of morning cortisol and significantly higher levels of IL-6, compared with non-anxious participants.”
Labrenz, F., Ferri, F., Wrede, K. H., Forsting, M., Schedlowski, M., Engler, H., Elsenbruch, S., Benson, S., & Costantini, M. (2018) · NeuroImage · doi:10.1016/j.neuroimage.2018.09.056 · Cited by 46
Expectations of Racism and Carotid Intima-Media Thickness in African American Women
Lewis, T. T., Lampert, R. J., Charles, D., & Katz, S. D. (2019) · Psychosomatic Medicine · doi:10.1097/psy.0000000000000684 · Cited by 43
Beerse, M. E., Van Lith, T., Pickett, S. M., & Stanwood, G. D. (2020) · Experimental Biology and Medicine · doi:10.1177/1535370219883634 · Cited by 45
Telomere length – A cellular aging marker for depression and Post-traumatic Stress Disorder
Zhang, L., Hu, X., Li, X., Li, H., Smerin, S. E., Russell, D. W., & Ursano, R. J. (2014) · Medical Hypotheses · doi:10.1016/j.mehy.2014.04.033 · Cited by 43
Anxiolytic properties of N -acetylcysteine in mice
Santos, P. C. D., Herrmann, A. P., Benvenutti, R., Noetzold, G., Giongo, F. K., Gama, C. S., Piato, Â., & Elisabetsky, E. (2016) · Behavioural Brain Research · doi:10.1016/j.bbr.2016.10.010 · Cited by 47
Mun, C. J., Letzen, J. E., Nance, S., Smith, M. T., Khanuja, H. S., Sterling, R. S., Bicket, M. C., Haythornthwaite, J. A., Jamison, R. N., Edwards, R. R., et al. (2019) · Journal of Pain · doi:10.1016/j.jpain.2019.11.003 · Cited by 43
Association of Quality of Life, Anxiety, and Depression with Left Atrial Ablation Outcomes
Efremidis, M., Letsas, Κ. P., Lioni, L., Γιαννόπουλος, Γ., Korantzopoulos, P. G., Vlachos, K. G., Dimopoulos, N. P., Karlis, D., Bouras, G., Sideris, A., et al. (2014) · Pacing and Clinical Electrophysiology · doi:10.1111/pace.12420 · Cited by 42
Comorbidity of Anxiety and Hypertension: Common Risk Factors and Potential Mechanisms
Qiu, T., Jiang, Z., Chen, X., Dai, Y., & Zhao, H. (2023) · International Journal of Hypertension · doi:10.1155/2023/9619388 · Cited by 69
Wang, L., Wu, M.-S., Hsu, H.-J., Wu, I., Sun, C., Chou, C., Lee, C., Tsai, C., Tsai, Y.-C., & Chen, C. (2012) · The International Journal of Psychiatry in Medicine · doi:10.2190/pm.44.2.b · Cited by 41
“reported that clinically anxious participants among the community samples exhibited significantly higher levels of IL-6, compared to participants that were not anxious [17].”
BackgroundRévész, D., Verhoeven, J. E., Milaneschi, Y., & Penninx, B. W. J. H. (2016) · Psychological Medicine · doi:10.1017/s0033291716000891 · Cited by 39
“Some evidence points towards a higher sympathetic drive combined with lower vagal state among depressed persons, but the findings are inconsistent and possibly more complex due to antidepressant medication use in patients (Kemp et al. 2010; Penninx et al. 2013).”
BackgroundResultAlshogran, O. Y., Khalil, A. A., Oweis, A. O., Altawalbeh, S. M., & Alqudah, M. A. Y. (2018) · General Hospital Psychiatry · doi:10.1016/j.genhosppsych.2018.04.003 · Cited by 37
Metadata
- 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
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2010-10
- Volume
- 24
- Issue
- 7
- Pages
- 1074-1077
- ISSN
- 0889-1591 (ISSN-L)
- 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
- 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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