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Nausea in the peri-traumatic period is associated with prospective risk for PTSD symptom development

Neuropsychopharmacologyvolume 44pages668673 (2019) | Download Citation


While nausea often develops following exposure to trauma, little is known regarding the relationship between peri-traumatic nausea and prospective risk for developing posttraumatic stress disorder (PTSD). We examined the association between peri-traumatic nausea and PTSD symptom development in three independent cohorts. Participants were recruited from (1) the Emergency Departments (ED) at Grady Memorial Hospital (GMH) in Atlanta, GA, (2) from multiple other ED sites in the TRYUMPH Research Network, and (3) from the ED during evaluation for suspected acute coronary syndrome in the REACH cohort. Administration of IV ondansetron, the most predominant antiemetic used at GMH, was used as a surrogate marker for nausea in the initial GMH cohort; nausea was then directly assessed in the internal validation at GMH, and within the replication TRYUMPH Research Network and REACH cohorts. In the GMH cohort (N = 363), ondansetron administration was associated with increased 1- and 3-month posttrauma PTSD symptoms in adjusted models (all p’s < 0.05). In the GMH internal validation, nausea significantly predicted 1 month (p = 0.009; n = 68) and 3 month (p = 0.029; n = 54) PTSD symptoms. In the TRYUMPH cohort (N = 1846), patient reported nausea in the ED was significantly associated with increased PTSD symptoms (p = 0.009) in adjusted models. In the REACH cohort (N = 758), peri-traumatic nausea was associated with PTSD symptom severity at the 1-month follow-up in adjusted models (p’s ≤ 0.008). The current prospective data from three independent cohorts suggest that peri-traumatic nausea is a prospective predictor of PTSD symptom development. Further studies are needed to determine the mechanistic role of nausea as an intermediate phenotype of PTSD risk.

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  1. 1.

    Gillespie CF, Bradley B, Mercer K, Smith AK, Conneely K, Gapen M, et al. Trauma exposure and stress-related disorders in inner city primary care patients. Gen Hosp Psychiatry. 2009;31:505–14.

  2. 2.

    Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry. 1995;52:1048–60.

  3. 3.

    Koenen KC, Sumner JA, Gilsanz P, Glymour MM, Ratanatharathorn A, Rimm EB, et al. Post-traumatic stress disorder and cardiometabolic disease: improving causal inference to inform practice. Psychol Med. 2017;47:209–25.

  4. 4.

    Kleim B, Ehlers A, Glucksman E. Early predictors of chronic post-traumatic stress disorder in assault survivors. Psychol Med. 2007;37:1457–67.

  5. 5.

    Blevins CA, Weathers FW, Witte TK. Dissociation and posttraumatic stress disorder: a latent profile analysis. J Trauma Stress. 2014;27:388–96.

  6. 6.

    Roitman P, Gilad M, Ankri YL, Shalev AY. Head injury and loss of consciousness raise the likelihood of developing and maintaining PTSD symptoms. J Trauma Stress. 2013;26:727–34.

  7. 7.

    Holbrook TL, Galarneau MR, Dye JL, Quinn K, Dougherty AL. Morphine use after combat injury in Iraq and post-traumatic stress disorder. N Engl J Med. 2010;362:110.

  8. 8.

    Rothbaum BO, Kearns MC, Reiser E, Davis JS, Kerley KA, Rothbaum AO, et al. Early intervention following trauma may mitigate genetic risk for PTSD in civilians: a pilot prospective emergency department study. J Clin Psychiatry. 2014;75:1380–7.

  9. 9.

    Ulirsch JC, Ballina LE, Soward AC, Rossi C, Hauda W, Holbrook D, et al. Pain and somatic symptoms are sequelae of sexual assault: results of a prospective longitudinal study. Eur J Pain (Lond, Engl). 2014;18:559–66.

  10. 10.

    Gillock KL, Zayfert C, Hegel MT, Ferguson RJ. Posttraumatic stress disorder in primary care: prevalence and relationships with physical symptoms and medical utilization. Gen Hosp Psychiatry. 2005;27:392–9.

  11. 11.

    Halpern CT, Tucker CM, Bengtson A, Kupper LL, McLean SA, Martin SL. Somatic symptoms among US adolescent females: associations with sexual and physical violence exposure. Matern Child Health J. 2013;17:1951–60.

  12. 12.

    Stein MB, Lang AJ, Laffaye C, Satz LE, Lenox RJ, Dresselhaus TR. Relationship of sexual assault history to somatic symptoms and health anxiety in women. Gen Hosp Psychiatry. 2004;26:178–83.

  13. 13.

    Escalona R, Achilles G, Waitzkin H, Yager J. PTSD and somatization in women treated at a VA primary care clinic. Psychosomatics. 2004;45:291–6.

  14. 14.

    Bailey BN, Delaney-Black V, Hannigan JH, Ager J, Sokol RJ, Covington CY. Somatic complaints in children and community violence exposure. J Dev Behav Pediatr : JDBP. 2005;26:341.

  15. 15.

    Lowe B, Kroenke K, Spitzer RL, Williams JB, Mussell M, Rose M, et al. Trauma exposure and posttraumatic stress disorder in primary care patients: cross-sectional criterion standard study. J Clin Psychiatry. 2011;72:304–12.

  16. 16.

    Drews T, Franck M, Radtke FM, Weiss B, Krampe H, Brockhaus WR, et al. Postoperative delirium is an independent risk factor for posttraumatic stress disorder in the elderly patient: a prospective observational study. Eur J Anaesthesiol. 2015;32:147–51.

  17. 17.

    Milne RJ, Heel RC. Ondansetron. Therapeutic use as an antiemetic. Drugs. 1991;41:574–95.

  18. 18.

    APA (2000). Diagnostic and Statistical Manual of Mental Disorders.

  19. 19.

    Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry. 1961;4:561–71.

  20. 20.

    Foa EB, Cashman L, Jaycox L, Perry K. The validation of a self- report measure of posttraumatic stress disorder: The Posttraumatic Diagnostic Scale. Psychol Assess. 1997;9:445–51.

  21. 21.

    Bernstein DP, Ahluvalia T, Pogge D, Handelsman L. Validity of the Childhood Trauma Questionnaire in an adolescent psychiatric population. J Am Acad Child Adolesc Psychiatry. 1997;36:340–8.

  22. 22.

    Foa EB, Riggs DS, Dancu CV, Rothbaum BO. Reliability and validity of a brief instrument for assessing post-traumatic stress disorder. J Traum Stress 1993;6:459–73.

  23. 23.

    Linnstaedt SD, Hu J, Liu AY, Soward AC, Bollen KA, Wang HE, et al. Methodology of AA CRASH: a prospective observational study evaluating the incidence and pathogenesis of adverse post-traumatic sequelae in African-Americans experiencing motor vehicle collision. BMJ Open. 2016;6:e012222.

  24. 24.

    Brunet A, Weiss DS, Metzler TJ, Best SR, Neylan TC, Rogers C, et al. The Peritraumatic Distress Inventory: a proposed measure of PTSD criterion A2. Am J Psychiatry. 2001;158:1480–5.

  25. 25.

    Creamer M, Bell R, Failla S. Psychometric properties of the Impact of Event Scale—Revised. Behav Res Ther. 2003;41:1489–96.

  26. 26.

    Sumner JA, Chen Q, Roberts AL, Winning A, Rimm EB, Gilsanz P, et al. Cross-sectional and longitudinal associations of chronic posttraumatic stress disorder with inflammatory and endothelial function markers in women. Biol Psychiatry. 2017;82:875–84.

  27. 27.

    Meli L, Kautz M, Julian J, Edmondson D, Sumner JA. The role of perceived threat during emergency department cardiac evaluation and the age-posttraumatic stress disorder link. J Behav Med. 2018;41:357–63.

  28. 28.

    Bryant RA, Moulds ML, Guthrie RM. Acute Stress Disorder Scale: a self-report measure of acute stress disorder. Psychol Assess. 2000;12:61–68.

  29. 29.

    Eagle KA, Lim MJ, Dabbous OH, Pieper KS, Goldberg RJ, Van de Werf F, et al. A validated prediction model for all forms of acute coronary syndrome: estimating the risk of 6-month postdischarge death in an international registry. J Am Med Assoc. 2004;291:2727–33.

  30. 30.

    Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidemiol. 1994;47:1245–51.

  31. 31.

    Weathers F, Litz B, Herman D, Huska J, Keane T (1993). The PTSD Checklist (PCL): reliability, validity, and diagnostic utility.

  32. 32.

    Verbalis JG, McHale CM, Gardiner TW, Stricker EM. Oxytocin and vasopressin secretion in response to stimuli producing learned taste aversions in rats. Behav Neurosci. 1986;100:466–75.

  33. 33.

    Sweatt JD. Chapter 4—Rodent Behavioral Learning and Memory Models. Mechanisms of Memory. Second Edition. London: Academic Press; 2010. p. 76–103.

  34. 34.

    Fisher LA, Kikkawa DO, Rivier JE, Amara SG, Evans RM, Rosenfeld MG, et al. Stimulation of noradrenergic sympathetic outflow by calcitonin gene-related peptide. Nature. 1983;305:534–6.

  35. 35.

    Carter ME, Han S, Palmiter RD. Parabrachial calcitonin gene-related peptide neurons mediate conditioned taste aversion. J Neurosci. 2015;35:4582–6.

  36. 36.

    Sink KS, Davis M, Walker DL. CGRP antagonist infused into the bed nucleus of the stria terminalis impairs the acquisition and expression of context but not discretely cued fear. Learn Mem. 2013;20:730–9.

  37. 37.

    Stockhorst U, Enck P, Klosterhalfen S. Role of classical conditioning in learning gastrointestinal symptoms. World J Gastroenterol. 2007;13:3430–37.

  38. 38.

    Morrow GR, Hickok JT, Rosenthal SN. Progress in reducing nausea and emesis. Comparisons of ondansetron (Zofran), granisetron (Kytril), and tropisetron (Navoban). Cancer. 1995;76:343–57.

  39. 39.

    Jakab RL, Goldman-Rakic PS. Segregation of serotonin 5-HT2A and 5-HT3 receptors in inhibitory circuits of the primate cerebral cortex. J Comp Neurol. 2000;417:337–48.

  40. 40.

    Park SM, Williams CL. Contribution of serotonin type 3 receptors in the successful extinction of cued or contextual fear conditioned responses: interactions with GABAergic signaling. Rev Neurosci. 2012;23:555–69.

  41. 41.

    Chaouloff F, Berton O, Mormede P. Serotonin and stress. Neuropsychopharmacology. 1999;21(Suppl. 2):28S–32S.

  42. 42.

    Fergusson D, Doucette S, Glass KC, Shapiro S, Healy D, Hebert P, et al. Association between suicide attempts and selective serotonin reuptake inhibitors: systematic review of randomised controlled trials. Br Med J. 2005;330:396.

  43. 43.

    McManis PG, Talley NJ. Nausea and vomiting associated with selective serotonin reuptake inhibitors. CNS Drugs. 1997;8:394–91.

  44. 44.

    Browning M, Reid C, Cowen PJ, Goodwin GM, Harmer CJ. A single dose of citalopram increases fear recognition in healthy subjects. J Psychopharmacol. 2007;21:684–90.

  45. 45.

    Garcia-Leal C, Del-Ben CM, Leal FM, Graeff FG, Guimaraes FS. Escitalopram prolonged fear induced by simulated public speaking and released hypothalamic–pituitary–adrenal axis activation. J Psychopharmacol. 2010;24:683–94.

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We would like to particularly thank Alex Rothbaum, Thomas Crow, and Becky Hinrichs for their support and assistance. All of this work would not have been possible without the support of all the nurses, physicians, associate providers, and staff of the Emergency Care Center at Grady Memorial Hospital, the TRYUMPH Research Network sites, and Columbia University Medical Center. Additionally, we would like to acknowledge the patients and families that agreed to participate in these studies.


This work was supported by the National Institute for Health (R01 MH094757, K.J.R.), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR060852 and R01 AR056328, S.A.M.), the National Institute of Child Health and Human Development (K12 HD085850, V.M.), the National Heart, Lung, and Blood Institute (R01 HL123368, I.M.K.; R01 HL117832; K01 HL130650, J.A.S.) and the Brain and Behavior Research Foundation.

Author information


  1. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA

    • Vasiliki Michopoulos
    • , Jessica Maples-Keller
    • , Elizabeth I. Roger
    • , Barbara O. Rothbaum
    • , Charles F. Gillespie
    •  & Kerry J. Ressler
  2. Yerkes National Primate Research Center, Atlanta, GA, USA

    • Vasiliki Michopoulos
  3. Naval Medical Center San Diego, San Diego, CA, USA

    • Elizabeth I. Roger
  4. Department of Emergency Medicine, Alpert Medical School of Brown University, Providence, RI, USA

    • Francesca L. Beaudoin
  5. Center for Behavioral Cardiovascular Health, Columbia University Medical Center, New York, NY, USA

    • Jennifer A. Sumner
    •  & Ian M. Kronish
  6. Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA, USA

    • Lauren Hudak
  7. Departments of Anesthesiology and Emergency Medicine, University of North Carolina, Chapel Hill, NC, USA

    • Samuel A. McLean
  8. Mclean Hospital, Harvard Medical School, Belmont, MA, USA

    • Kerry J. Ressler


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The authors declare no competing interests.

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Correspondence to Vasiliki Michopoulos.

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