The Natural History of Neuroendocrine Changes in Pediatric Posttraumatic Stress Disorder (PTSD) After Motor Vehicle Accidents: Progressive Divergence of Noradrenaline and Cortisol Concentrations Over Time Panagiota Pervanidou, Gerasimos Kolaitis, Stella Charitaki, Christina Lazaropoulou, Ioannis Papassotiriou, Peter Hindmarsh, Chrysa Bakoula, John Tsiantis, and George P. Chrousos Background: The hypothalamic-pituitary-adrenal axis and the catecholaminergic system are involved in the pathophysiology of post- traumatic stress disorder (PTSD). This was a prospective and longitudinal study of neuroendocrine physiology in children with PTSD following a motor vehicle accident (MVA). Methods: Sixty children aged 7–18 were studied immediately after an MVA and 1 and 6 months later. Fasting morning plasma catechol- amine and serum cortisol concentrations were measured. Salivary cortisol concentrations were measured serially five times daily to examine circadian variation in all three assessments. Values were compared between those who did (PTSD) or did not develop PTSD (non-PTSD) after the trauma and a control group at months 1 and 6. Results: Twenty-three of the children had PTSD at the 1-month and 9 children at the 6-month evaluations. 1) Plasma noradrenaline concentrations were higher in the PTSD group than in the other two groups at both months 1 and 6 (p = .001 and p = .001, respectively). Additionally, the PTSD patients presented with significantly higher salivary cortisol concentrations at 18.00 (p = .03) and 21.00 (p = .04) at month 1.2) Eight children suffering from PTSD at both months 1 and 6 had significantly elevated plasma noradrenaline concentrations at month 6 compared with those at month 1 and at baseline and to the other two groups (within subjects: p  .001; between subjects: p = .005). The initially elevated evening salivary cortisol concentrations in this group normalized at month 6. Conclusions: This progressive divergence of noradrenaline and cortisol concentrations over time might underlie the natural history and pathophysiology of PTSD. Key Words: Childhood, development, motor vehicle accidents, plasma catecholamines, PTSD, salivary cortisol P osttraumatic stress disorder (PTSD) develops after expo- sure to events that involve a threat to the physical integrity of the individual or others and evokes intense fear, helplessness, or horror. Symptoms include reexperience of the initial trauma, avoidance of stimuli associated with the trauma, and symptoms of excessive arousal. By definition, PTSD lasts over 4 weeks (1). Motor vehicle accidents (MVAs) are major stressors and causes of PTSD. Thirty to 80% of children may exhibit full PTSD symptomatology after MVAs (2,3). In adults with PTSD, 24-hour urinary catecholamine excretion and/or plasma catecholamine concentrations are higher than those of control subjects (4–9). In the majority of studies, these patients have elevated basal cerebrospinal fluid (CSF) corticotropin- releasing hormone (CRH) concentrations (10), while variable findings have been reported regarding cortisol concentrations in the periphery (11): low or normal 24-hour urinary excretion of free cortisol and low or normal plasma and salivary cortisol concentrations (11–17). In cases of PTSD and comorbid major depression, high urinary cortisol concentrations have been re- ported (18). Children with PTSD have increased urinary catecholamine excretion. However, unlike adults, their plasma, salivary, and urinary cortisol concentrations are usually normal or high. A recent report (19) on PTSD development after the impact of an acute stressor such as an MVA showed increased initial cortisol secretion after the trauma, and a second report (20) of pediatric PTSD shortly after the trauma showed high salivary cortisol concentrations. In contrast to these findings, adolescents with PTSD 5 years after the trauma demonstrated low cortisol levels after the dexamethasone suppression test (21). Finally, variable cortisol levels were reported in maltreated children with or without a clinical diagnosis (22,23). These findings raise two hypotheses: first, acute stressors and chronic repeated trauma, such as child maltreatment, may alter neuroendocrine mechanisms differentially, resulting in diverse cortisol secretory patterns. Second, low cortisol, a frequent finding in adult studies, may either reflect previous psychopa- thology, and thus vulnerability to PTSD, when found immedi- ately after the accident or it may be the neuroendocrine end stage of the natural history of the disorder, months or years after the trauma. We hypothesized that a healthy young population, screened for psychopathology and concurrent use of alcohol or drugs, after the impact of a single acute stressor such as a car accident may be an ideal population for an observational study regarding the longitudinal neuroendocrine profile of the disorder. We investigated the changes in the two major neuroendocrine axes From the First Department of Pediatrics (PP, CB, GPC) and the Department of Child Psychiatry (GK, SC, JT), Athens University Medical School, Aghia Sophia Children’s Hospital; the Department of Clinical Biochemistry (CL, IP), Aghia Sophia Children’s Hospital, Athens, Greece; and the London Center for Pediatric Endocrinology (PH), Great Ormond Street Hospital, London, United Kingdom. Address reprint requests to Panagiota Pervanidou, M.D., First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children’s Hospital, 26 Charavgis str., 152 32 Chalandri, Athens, Greece; e-mail: ppervanid@med.uoa.gr. Received August 8, 2006; revised February 2, 2007; accepted February 5, 2007. BIOL PSYCHIATRY 2007;62:1095–1102 0006-3223/07/$32.00 doi:10.1016/j.biopsych.2007.02.008 © 2007 Society of Biological Psychiatry