Paradoxical Effect of Anti-inflammatory Drugs on IL-6 MRNA Expression in Patients with PTSD During Treatment

Overview

Journal J Neural Transm (Vienna)

Specialties Neurology
Physiology

Date 2024 Apr 13

PMID 38613673

Authors

Cosima Rhein

Isabella Apelt

Franziska Werner

Eva Schaflein

Werner Adler

Martin Reichel

Caterina Schug

Eva Morawa

Yesim Erim

Affiliations

Soon will be listed here.

Abstract

The pathophysiology of posttraumatic stress disorder (PTSD) is associated with the activation of the innate immune system, including cytokines like interleukin 6 (IL-6). However, the role of IL-6 in the etiology and treatment of PTSD still remains elusive. We conducted a prospective controlled trial to investigate the development of IL-6 during psychosomatic treatment in individuals with PTSD in comparison with individuals without PTSD. We assessed IL-6 mRNA expression before and after 2 months of psychosomatic treatment in individuals with and without PTSD. Severities of PTSD and depressive symptoms were assessed in parallel. Linear mixed regression was applied for statistical analysis, including the factors diagnosis PTSD and pre-post treatment after subgrouping for intake of anti-inflammatory drugs. The development of IL-6 mRNA expression during treatment was affected by the use of anti-inflammatory drugs. In the subgroup without intake of anti-inflammatory drugs, no significant statistical treatment effect in individuals with and without PTSD emerged. In the subgroup of individuals taking anti-inflammatory drugs, a significant interaction effect of the factors pre-post treatment and diagnosis PTSD was observed. Whereas IL-6 mRNA expression in individuals without PTSD decreased according to amelioration of symptoms, IL-6 mRNA expression in individuals with PTSD increased significantly during treatment, in opposite direction to symptom severity. Anti-inflammatory drugs might affect IL-6 mRNA expression in individuals with PTSD in a paradoxical way. This study offers a further piece of evidence that IL-6 could be involved in the pathophysiology of PTSD and PTSD-specific immunologic molecular mechanisms.

References

Dennis P, Weinberg J, Calhoun P, Watkins L, Sherwood A, Dennis M . An investigation of vago-regulatory and health-behavior accounts for increased inflammation in posttraumatic stress disorder. J Psychosom Res. 2016; 83:33-9. PMC: 4813329. DOI: 10.1016/j.jpsychores.2016.02.008. View

Langgartner D, Lowry C, Reber S . Old Friends, immunoregulation, and stress resilience. Pflugers Arch. 2018; 471(2):237-269. PMC: 6334733. DOI: 10.1007/s00424-018-2228-7. View

Hori H, Yoshida F, Itoh M, Lin M, Niwa M, Ino K . Proinflammatory status-stratified blood transcriptome profiling of civilian women with PTSD. Psychoneuroendocrinology. 2019; 111:104491. DOI: 10.1016/j.psyneuen.2019.104491. View

Boscarino J . Posttraumatic stress disorder and physical illness: results from clinical and epidemiologic studies. Ann N Y Acad Sci. 2005; 1032:141-53. DOI: 10.1196/annals.1314.011. View

Kimerling R . An investigation of sex differences in nonpsychiatric morbidity associated with posttraumatic stress disorder. J Am Med Womens Assoc (1972). 2004; 59(1):43-7. View

Rhein C, Hepp T, Kraus O, von Majewski K, Lieb M, Rohleder N . Interleukin-6 secretion upon acute psychosocial stress as a potential predictor of psychotherapy outcome in posttraumatic stress disorder. J Neural Transm (Vienna). 2021; 128(9):1301-1310. DOI: 10.1007/s00702-021-02346-8. View

Toft H, Bramness J, Tilden T, Bolstad I, Lien L . Persistent level of mental distress in PTSD patients is not reflected in cytokine levels 1 year after the treatment. Acta Neuropsychiatr. 2021; 33(5):254-260. DOI: 10.1017/neu.2021.11. View

Tucker P, Beebe K, Burgin C, Wyatt D, Parker D, Masters B . Paroxetine treatment of depression with posttraumatic stress disorder: effects on autonomic reactivity and cortisol secretion. J Clin Psychopharmacol. 2004; 24(2):131-40. DOI: 10.1097/01.jcp.0000116649.91923.cb. View

Passos I, Vasconcelos-Moreno M, Costa L, Kunz M, Brietzke E, Quevedo J . Inflammatory markers in post-traumatic stress disorder: a systematic review, meta-analysis, and meta-regression. Lancet Psychiatry. 2015; 2(11):1002-12. DOI: 10.1016/S2215-0366(15)00309-0. View

10.

Gola H, Engler H, Sommershof A, Adenauer H, Kolassa S, Schedlowski M . Posttraumatic stress disorder is associated with an enhanced spontaneous production of pro-inflammatory cytokines by peripheral blood mononuclear cells. BMC Psychiatry. 2013; 13:40. PMC: 3574862. DOI: 10.1186/1471-244X-13-40. View

11.

Toft H, Lien L, Neupane S, Abebe D, Tilden T, Wampold B . Cytokine concentrations are related to level of mental distress in inpatients not using anti-inflammatory drugs. Acta Neuropsychiatr. 2019; 32(1):23-31. DOI: 10.1017/neu.2019.36. View

12.

Dahl J, Ormstad H, Aass H, Sandvik L, Malt U, Andreassen O . Recovery from major depressive disorder episode after non-pharmacological treatment is associated with normalized cytokine levels. Acta Psychiatr Scand. 2016; 134(1):40-7. DOI: 10.1111/acps.12576. View

13.

Jergovic M, Bendelja K, Savic Mlakar A, Vojvoda V, Aberle N, Jovanovic T . Circulating levels of hormones, lipids, and immune mediators in post-traumatic stress disorder - a 3-month follow-up study. Front Psychiatry. 2015; 6:49. PMC: 4396135. DOI: 10.3389/fpsyt.2015.00049. View

14.

Koenen K, Ratanatharathorn A, Ng L, McLaughlin K, Bromet E, Stein D . Posttraumatic stress disorder in the World Mental Health Surveys. Psychol Med. 2017; 47(13):2260-2274. PMC: 6034513. DOI: 10.1017/S0033291717000708. View

15.

Toft H, Bramness J, Lien L, Abebe D, Wampold B, Tilden T . PTSD patients show increasing cytokine levels during treatment despite reduced psychological distress. Neuropsychiatr Dis Treat. 2018; 14:2367-2378. PMC: 6149900. DOI: 10.2147/NDT.S173659. View

16.

Toft H, Bramness J, Lien L . Levels of Peripheral Circulating IL-6 and IL-10 Decrease Over Time Despite High Depression Burden in PTSD Patients. Neuropsychiatr Dis Treat. 2022; 18:737-747. PMC: 8995001. DOI: 10.2147/NDT.S357797. View

17.

Tucker P, Ruwe W, Masters B, Parker D, Hossain A, Trautman R . Neuroimmune and cortisol changes in selective serotonin reuptake inhibitor and placebo treatment of chronic posttraumatic stress disorder. Biol Psychiatry. 2004; 56(2):121-8. DOI: 10.1016/j.biopsych.2004.03.009. View

18.

Raison C, Miller A . When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. Am J Psychiatry. 2003; 160(9):1554-65. DOI: 10.1176/appi.ajp.160.9.1554. View

19.

Rytila-Manninen M, Frojd S, Haravuori H, Lindberg N, Marttunen M, Kettunen K . Psychometric properties of the Symptom Checklist-90 in adolescent psychiatric inpatients and age- and gender-matched community youth. Child Adolesc Psychiatry Ment Health. 2016; 10:23. PMC: 4946097. DOI: 10.1186/s13034-016-0111-x. View

20.

Tsuboi I, Tanaka H, Nakao M, Shichijo S, Itoh K . Nonsteroidal anti-inflammatory drugs differentially regulate cytokine production in human lymphocytes: up-regulation of TNF, IFN-gamma and IL-2, in contrast to down-regulation of IL-6 production. Cytokine. 1995; 7(4):372-9. DOI: 10.1006/cyto.1995.0047. View