Cortisol response to acute trauma and risk of posttraumatic stress disorder

This study sought to characterize the variability of the acute cortisol response following trauma and its relationship to posttraumatic stress disorder (PTSD). Forty eight participants were recruited within 24h of a traumatic accident requiring hospital admission. A saliva sample was collected at 08.00 h and 16.00 h 2 days, 1 month and 6 months after hospital admission, together with 24-h urine collection. Participants completed a dexamethasone suppression test (0.5mg DEX at 21.00 h) at each follow up, together with self-report questionnaires. The Clinician Administered PTSD Scale (CAPS) was administered at 1 and 6 months to identify PTSD. Prevalence of PTSD was 27% at 1 month and 21% at 6 months. PTSD symptoms at 6 months were negatively correlated with salivary cortisol at 08.00 h on day 2 (r=-0.36, p=0.04), but positively correlated with 16.00 h cortisols (r=0.41, p=0.03). A lower rise in cortisol at 08.00 h on day 2 was associated with an increase in risk of PTSD at both 1 month (OR=1.411 (1.017, 1.957)) and 6 months (OR=1.411 (1.066, 1.866)). At 1 month, 70% of participants with PTSD suppressed cortisol to more than 90% of pre-dex levels compared with 25% without PTSD (χ(2)=6.77, p=0.034). Urinary cortisol excretion was not different between groups at any time point. The findings support a hypothesis that sensitization of the HPA axis and enhanced suppression of cortisol following the dexamethasone suppression test are established early in the disease process.     

Increased adrenocorticotropin suppression following dexamethasone administration in sexually abused adolescents with posttraumatic stress disorder

Evidence suggests that individuals with posttraumatic stress disorder (PTSD) have an enhanced sensitization of the hypothalamic–pituitary–adrenocortical (HPA) axis. However, few studies in adolescents have been performed. Fourteen sexually abused adolescent inpatients with DSM-IV PTSD (12 female, two male; mean±SD age, 16.2±1.9 years) were compared with 14 adolescent hospitalized controls (11 female, three male; mean age, 15.7±2.0 years). All subjects underwent a standard dexamethasone suppression test (DST, 1 mg given orally at 2300 h) five days after admission. Baseline blood samples were obtained at 0800 h, and the following day, adrenocorticotropin (ACTH) and cortisol levels were measured at 0800, 1600, and 2300 h. Clinical assessment included the Impact of Event Scale, Stanford Acute Stress Reaction Questionnaire, Beck Depression Inventory, and Coping Inventory for Stressful Situations. Post-DST ACTH levels were significantly lower in PTSD than in control adolescents (at 0800 h: P<0.005; at 1600 h: P<0.001; at 2300 h: P<0.05). In patients, post-DST cortisol levels were reduced but not significantly. No correlations were found between ACTH and cortisol levels and time elapsed since trauma. These results demonstrate that sexually abused adolescents with PTSD show ACTH hypersuppression to DST suggesting enhanced glucocorticoid receptor sensitivity in the pituitary.     

Altered cortisol awakening response in posttraumatic stress disorder

An altered function of the hypothalamic-pituitary-adrenal axis is assumed to be characteristic for Posttraumatic Stress Disorder (PTSD), although there is inconsistent empirical evidence. Only few studies examined the awakening cortisol response and a daytime profile in PTSD. Salivary cortisol levels were measured at seven intervals from awakening until 8 PM in trauma-exposed subjects with (N=29) and without PTSD (N=19) and in 15 non-exposed controls. While the three groups did not differ with respect to their first cortisol level immediately after awakening, the expected cortisol increase to awakening 15-60 min later was significantly lower in PTSD patients compared to non-PTSD subjects and healthy controls. This effect remained stable when trauma-exposed subjects with comorbid major depression were excluded from the analysis. A significant negative correlation between the overall cortisol secretion (AUC(G)) and overall PTSD symptomatology and hyper-arousal symptoms was found. The findings are discussed in light of the hypothesis of a counterregulation of hyper-arousal symptoms and chronic stress in PTSD.     

Increased beclomethasone-induced vasoconstriction in women with posttraumatic stress disorder

It has been hypothesized that patients with posttraumatic stress disorder (PTSD) show increased glucocorticoid sensitivity. The study tested beclomethasone-induced vasoconstriction (BIV), a measure of peripheral glucocorticoid sensitivity, in women with PTSD. A case-control design was employed in 33 PTSD patients and 33 healthy controls. BIV was tested using beclomethasone dipropionate (1-100 micro g/ml). Vasoconstriction was assessed after 15-18 h. Waking and afternoon salivary cortisol concentrations were measured. BIV ratings were significantly increased in PTSD at beclomethasone concentrations from 10-100 micro g/ml. Salivary cortisol concentrations did not differ between groups or correlate with BIV. Preliminary evidence has been found for increased peripheral glucocorticoid sensitivity in PTSD. Further study is required to replicate this finding and assess its relationship to the pathophysiology of the disorder.     

Enhanced cortisol suppression in response to dexamethasone administration in traumatized veterans with and without posttraumatic stress disorder

BACKGROUND: While enhanced cortisol suppression in response to dexamethasone is one of the most consistent biological findings in posttraumatic stress disorder (PTSD), the relative contribution of trauma exposure to this finding remains unclear. METHODS: Assessment of diurnal salivary cortisol levels and 1600 h salivary cortisol before and after oral administration of 0.5mg dexamethasone in veterans with PTSD, veterans without PTSD (trauma controls) and healthy controls. Assessment of 1600 h plasma cortisol, ACTH and corticotrophin binding globulin (CBG) in response to dexamethasone in PTSD patients and trauma controls. RESULTS: Both PTSD patients and trauma controls demonstrated significantly more salivary cortisol suppression compared to healthy controls. Salivary cortisol, plasma cortisol and ACTH suppression as well as CBG levels did not differ between PTSD patients and trauma controls. PTSD patients showed a reduced awakening cortisol response (ACR) compared to healthy controls that correlated significantly with PTSD symptoms. No significant differences were observed in ACR between PTSD patients and trauma controls. CONCLUSIONS: These data suggest that enhanced cortisol suppression to dexamethasone is related to trauma exposure and not specifically to PTSD. The correlation between the ACR and PTSD severity suggests that a flattened ACR may be a result of clinical symptoms.     

A combined dexamethasone/corticotropin-releasing hormone test in patients with chronic PTSD--first preliminary results

BACKGROUND: Reports about alterations of hypothalamic-pituitary-adrenocortical (HPA) function in patients with chronic posttraumatic stress disorder (PTSD) are inconsistent and controversial. More refined laboratory tests and subgrouping of PTSD patients might help to decrease variance of findings. METHODS: 14 subjects with chronic PTSD and 14 healthy controls were examined between 13:00 and 17:00 using a modified combined dexamethasone/CRH test (0.5 mg dexamethasone at 23:00, 100 microg CRH at 15:00). Plasma adenocorticotropic hormone (ACTH), cortisol and blood pressure were measured every 15 min from 14:45 until 17:00. RESULTS: No significant differences between patients and controls were found in the analyses of ACTH and cortisol levels, but a significantly elevated systolic and diastolic blood pressure in PTSD. Severity of depressive symptoms had no influence. However, explorative analyses showed that patients with a history of childhood traumatization had significantly higher post-dexamethasone-ACTH levels and a significantly lower diastolic blood pressure in comparison to patients without early trauma. CONCLUSIONS: In this first pilot study in a typical clinical sample of patients with chronic PTSD we found effects of severe adverse events in childhood on HPA axis regulation. Maybe, childhood traumatization could influence HPA axis findings in PTSD. Further research is needed, especially dose-response studies with different doses of dexamethasone in dexamethasone/CRH tests in PTSD.     

Increased cortisol in women with intimate partner violence-related posttraumatic stress disorder

BACKGROUND: Alterations of hypothalamic-pituitary-adrenal (HPA) axis function and sympathetic-adrenal activity have been proposed as key factors in biological models of posttraumatic stress disorder (PTSD). METHODS: We examined neuroendocrine function in female survivors of intimate partner violence (IPV) with lifetime (current or remitted) PTSD (n=29) and in women who were exposed to IPV but never developed PTSD (n=20). Salivary cortisol was collected as a marker of HPA axis function at 1, 4, 9, and 11 h after awakening. Platelet epinephrine and norepinephrine were assayed as markers of sympathetic-adrenal activation. RESULTS: Women with lifetime PTSD had significantly higher cortisol levels across the day compared to abuse-exposed participants without PTSD, after controlling for age, depression, severity, and latency of abuse. There were no significant group differences in levels of platelet catecholamines. CONCLUSIONS: Elevated cortisol levels may be a biomarker of IPV-related lifetime PTSD, reflecting long-lasting changes associated with trauma-exposure or possibly a reflection of risk for PTSD in women.     

Elevated cortisol in healthy female adolescent offspring of mothers with posttraumatic stress disorder

Offspring with maternal PTSD are at increased risk of developing PTSD themselves. Alterations in the hypothalamic-pituitary-adrenal (HPA) axis may play a role and have been noted in offspring, although evidence is mostly from adult offspring with PTSD symptoms themselves. The present study of adolescent girls (N = 472) and their mothers (n = 18 with lifetime PTSD versus n = 454 with no PTSD) sought to determine whether healthy, non-affected offspring of mothers with PTSD would exhibit altered HPA axis function. Saliva samples were collected from the adolescent girls at waking, 30 min after waking, and 8 pm on 3 consecutive days. Offspring whose mothers were diagnosed with PTSD demonstrated higher cortisol awakening response (CAR; Cohen’s d = 0.58) and greater total cortisol output (Cohen’s d = 0.62). In this preliminary study, higher cortisol levels during adolescence among offspring of mothers with PTSD may index a vulnerability in these at-risk youth.     

HPA- and HPT-axis alterations in chronic posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) has been associated with dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis as well as of the hypothalamus-pituitary-thyroid (HPT) axis. Findings have not been consistent and may depend on methodological issues like controlling for relevant variables. This study examines the levels of six HPA and HPT-axis related hormones in civilian PTSD patients without psychotropic medication. In a cross sectional study, 39 chronic PTSD patients and 44 healthy volunteers were included. Psychometric instruments included SCID, SI-PTSD, IES-R and BDI. The plasma hormones levels assessed were cortisol, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEA-S), prolactin, thyrotropin (TSH), and free thyroxin (fT4). Results showed that patients had significantly lower plasma cortisol, prolactin and TSH levels compared to the comparison group. The difference between TSH levels in patients and comparison subjects only emerged after controlling for relevant background variables. Furthermore, the severity of PTSD symptoms was negatively related to cortisol levels. Secondary analyses revealed no statistically significant effect of comorbid depression (26% of patients) on any of the hormone levels. Complex feedback mechanisms are likely to result in altered levels of stress related hormones in PTSD, and results depend on controlling for relevant variables. Further research with longitudinal designs is needed to find out whether these lower hormone levels are preexisting risk factors or consequence of trauma and whether these alterations are deleterious or adaptive.     

Women's posttraumatic stress symptoms and autism spectrum disorder in their children

Maternal posttraumatic stress disorder (PTSD) may be associated with autism spectrum disorder (ASD) in offspring through multiple pathways: maternal stress may affect the fetus; ASD in children may increase risk of PTSD in mothers; and the two disorders may share genetic risk. Understanding whether maternal PTSD is associated with child's ASD is important for clinicians treating children with ASD, as PTSD in parents is associated with poorer family functioning. We examined the association of maternal PTSD with offspring ASD in a large US cohort (N ASD cases = 413, N controls = 42,868). Mother's PTSD symptoms were strongly associated with child's ASD (RR 4–5 PTSD symptoms = 1.98, 95% CI = 1.39, 2.81; RR 6–7 symptoms = 2.89, 95% CI = 2.00, 4.18). Clinicians treating persons with ASD should be aware of elevated risk of PTSD in the mother. Genetic studies should investigate PTSD risk alleles in relation to ASD.     

Cortisol suppression by dexamethasone reduces exaggerated fear responses in posttraumatic stress disorder

PTSD symptoms are associated with heightened fear responses in laboratory fear conditioning paradigms. This study examined the effects of dexamethasone administration on hypothalamic-pituitary-adrenal (HPA) function and fear-potentiated startle (FPS) in trauma-exposed individuals with and without PTSD. We used an established fear discrimination procedure, in which one visual stimulus (CS+, danger cue) was paired with aversive airblasts to the throat (unconditioned stimulus, US), and another stimulus (CS-, safety cue) was presented without airblasts. In addition to FPS, the dexamethasone suppression test (DST) was performed. The study sample (N=100) was recruited from a highly traumatized civilian population in Atlanta, GA. Half of the subjects (n=54, 16 PTSD, 38 controls) underwent conditioning at baseline and the other half (n=46, 17 PTSD, 29 controls) after DST, in a cross-sectional design. We found a significant interaction effect of diagnostic group and dexamethasone treatment. Under baseline conditions, subjects with PTSD showed more than twice as much fear-potentiated startle to the danger cue compared to traumatized controls, F(1,53)=8.08, p=0.006. However, there was no group difference in subjects tested after dexamethasone suppression. Furthermore, there was a significant treatment effect in PTSD subjects but not in controls, with dexamethasone reducing fear-potentiated startle to the CS+, F(1,32)=4.00, p=0.05. There was also a positive correlation between PTSD subjects' FPS and cortisol levels, r=0.46, p=0.01. These results suggest that transient suppression of HPA function via dexamethasone suppression may reduce exaggerated fear in patients with PTSD.     

The relevance of differential response to trauma in an animal model of posttraumatic stress disorder.

BACKGROUND: Posttraumatic stress disorder affects 20%-30% of those exposed. Clinical studies employ stringent inclusion-exclusion criteria, yet animal studies include the entire exposed population as the study population. We examined the effect of grouping prestressed rats according to magnitude of response on the statistical analysis of results. METHOD: Response magnitude to predator exposure was assessed and used to group the animals into "diagnostic" groups. Two extremes were studied (clearly "maladapted" and clearly "well adapted" rats) using arbitrarily selected cutoff behavioral criteria (CBC). The data for the middle group were discarded for reasons of clarity. Hypothalamic-pituitary-adrenal axis and heart-rate variability were analyzed for the entire exposed population and then according to the CBC. RESULTS: A single 10-min exposure to a predator caused fear-related behaviors in only 25.3% of exposed rats. Compared with control subjects and well-adapted exposed rats, maladapted rats exhibited significantly higher plasma corticosterone and corticotropin concentrations, increased sympathetic activity, diminished vagal tone, and increased sympathovagal balance. These differences surfaced only when data were analyzed according to CBC.Animals respond to stress heterogeneously, resembling humans. Overlooking this heterogeneity may obscure the results of data analysis. CONCLUSIONS: Animals can be divided into distinct groups according to magnitude of response and be studied accordingly.     

Variation in SLC1A1 is related to combat-related posttraumatic stress disorder

Candidate gene studies have yet to investigate the glutamate system, the primary excitatory neurotransmitter of the HPA-axis related to PTSD risk. We investigated 13 SNPs in the glutamate transporter gene (SLC1A1) in relation to PTSD among combat-exposed veterans. Participants (n = 418) completed a diagnostic interview and provided a blood sample for DNA isolation and genotyping. A subset of participants (n = 391) had severity and combat exposure data available. In the primary logistic regression gender and rs10739062 were significant predictors of PTSD diagnosis (OR = 0.50; OR = 1.43). In the linear regression analysis, combat exposure was the only significant predictor (β = 0.16) of severity. A computed genetic risk sum score was significant in relation to PTSD diagnosis (OR = 1.15) and severity scores (β = 0.14) above and beyond the effects of combat exposure. This study provides preliminary support for the relationship of glutamate transporter polymorphisms to PTSD risk and the need for further genetic studies within this system.     

Self-mutilative behaviors in male veterans with posttraumatic stress disorder

Self-mutilative behaviors (SMB) were examined in a sample of male veterans with posttraumatic stress disorder (PTSD). The primary objective was to determine the prevalence of SMB and any physical, cognitive, or affective antecedents and correlates for these behaviors. Participants included 509 male veterans with PTSD and levels of PTSD, depression, alcohol use, hostility, and impulsivity were evaluated to determine if these variables were related to SMB. Antecedents and sequelae of SMB were also examined to generate hypotheses regarding the functions of these behaviors. A second type of habit behavior, body-focused repetitive behaviors (BFRB), was also examined as part of the study. Findings indicated that veterans who engaged in either type of habit behavior were younger than those who did not engage in SMB or BFRB. Veterans reporting SMB also reported higher levels of PTSD, depression, hostility, and impulsivity compared to the BFRB and no-habit groups. Examination of habit antecedents and sequelae showed support for the automatic-positive reinforcement function of SMB. These findings are discussed in the context of research and treatment involving male veterans with PTSD who engage in SMB.     

Blunted pituitary-adrenocortical stress response in adult rats following neonatal dexamethasone treatment

Glucocorticoids have a prominent impact on the maturation of the stress-related neuroendocrine system and on the postnatal establishment of adaptive behaviour. The present study aimed at investigating the stress responsiveness of the hypothalamo-pituitary-adrenocortical (HPA) axis in young and adult rats after neonatal treatment with the synthetic glucocorticoid agonist, dexamethasone. Newborn male Wistar rats were injected s.c. with 1 microg/g dexamethasone on postnatal days 1, 3 and 5. Circulating adrenocorticotropic hormone (ACTH) and corticosterone concentrations were measured in the resting state and following a 30-min cold stress at the age of 10 days, as well as after a 30-min restraint stress at the age of 14 weeks. Also in adults, pituitary and adrenocortical hormone responsiveness was evaluated after i.v. administration of 2 microg/kg corticotropin releasing hormone (CRH). In addition, glucocorticoid (GR) and mineralocorticoid receptor (MR) binding capacities were assessed in the pituitaries of adult rats. The results showed that at day 10 basal ACTH concentration was elevated while the cold stress-evoked ACTH response was attenuated in the dexamethasone-treated rats. As adults, treated rats showed a suppressed elevation of both ACTH and corticosterone plasma concentrations in response to restraint, while basal hormonal concentrations were not altered. There was no difference in the magnitude of the CRH-induced elevation of ACTH and corticosterone concentrations initially; however, the dexamethasone-treated animals showed a prolonged secretion of both hormones. These animals also showed a selective decrease in pituitary GR binding capacity. Neonatal dexamethasone treatment strongly suppressed body weight gain, and adrenal and thymus weights in the early phase of postnatal development. By adulthood, the body and adrenal weights were normalized while thymus weight was greater than in controls. These findings indicate that neonatal dexamethasone treatment permanently alters HPA axis activity by reducing stress responses to cold and restraint probably through supra-pituitary actions, and by decreasing the effectiveness of feedback through a diminished GR binding in the pituitary.     

Prevalence and features of panic disorder and comparison to posttraumatic stress disorder in VA primary care

Objective

Although panic disorder (PD) is a highly prevalent condition in both community and community primary care settings, little is known about PD in veteran populations, especially in comparison to posttraumatic stress disorder (PTSD). The present study investigated prevalence, comorbidity, physical and mental health impairment, and health care utilization of veterans with PD and PTSD.

Method

A total of 884 veterans participated in a cross-sectional investigation in primary care clinics in four Veteran Affairs Medical Centers (VAMCs). Participants completed diagnostic interviews and self-report questionnaires, and a chart review was completed to assess their VAMC health care utilization.

Results

A large number of veterans (8.3%) met the diagnostic criteria for PD and reported significantly more severe physical health impairment (pain, general health), mental health impairment (emotional well-being, role limitations) and social functioning than veterans without PD. Veterans with PD also had increased health care utilization for mental health. Further, PD was highly comorbid with PTSD, with similar symptoms across all measures.

Conclusions

These findings demonstrate the high prevalence and severe impairment associated with PD in veterans and highlight the need for improved recognition, assessment and specialized treatments for PD in VAMCs and other care settings.     

Basal and dexamethasone suppressed salivary cortisol concentrations in a community sample of patients with posttraumatic stress disorder

Background

Posttraumatic stress disorder (PTSD) has been associated with lower concentrations of cortisol and enhanced suppression of cortisol by dexamethasone, although discrepancies exist among reports. The objective of the study was to determine the pattern of cortisol responses in patients seeking treatment for PTSD resulting from a variety of traumatic experiences and to test whether cortisol responses are significantly related to childhood trauma, severity of symptoms, or length of time since trauma.

Methods

Salivary cortisol was measured at 8 am, 4 pm, and 10 pm on 2 consecutive days before and after a 10 pm dose of .5 mg dexamethasone in 17 psychotropic medication and substance-free subjects with PTSD and 17 matched control subjects.

Results

Repeated-measures analysis of variance (ANOVA) of the baseline salivary cortisol concentrations demonstrated a significant effect for group with higher concentrations in the PTSD group but no significant differences in responses to dexamethasone. The presence of childhood abuse did not significantly affect salivary cortisol concentrations, and there was no correlation between predexamethasone cortisol and either the severity of PTSD symptoms or the time since the index trauma.

Conclusions

Neither low basal concentrations nor enhanced suppression of cortisol are consistent markers of a PTSD diagnosis.     

Melatonin, cortisol and ACTH in patients with major depressive disorder and healthy humans with special reference to the outcome of the dexamethasone suppression test

The 24 hr profiles of melatonin and cortisol in serum, morning levels of ACTH in plasma, and the dexamethasone suppression test (DST) were investigated in 32 acutely ill patients with a RDC diagnosis of major depressive disorder, 24 patients with a history of longlasting unipolar or bipolar major depressive disorder studied in remission, and 33 healthy subjects. A significant decrease in maximum nocturnal melatonin level (MTmax) was found in the acutely ill depressed patients with abnormal DST compared to both those with normal DSTs and the healthy subjects. The MTmax levels were unaltered when these patients were reinvestigated in remission. A decrease of MTmax was also seen in the group of unipolar and bipolar patients studied in remission. Low nocturnal melatonin is proposed to be a trait marker for major depressive disorder and depressive states with abnormalities in the hypothalamic--pituitary--adrenal (HPA) axis. A significant decrease of ACTH levels at 0800 hr after dexamethasone administration the preceding evening was found in the healthy subjects, the unipolar--bipolar patients in remission, and the acutely ill depressed patients with normal DSTs, but was not found in the acutely ill depressed patients with abnormal DSTs. These findings support the hypothesis that pituitary ACTH regulation is altered in depressed patients with abnormal DST. Morning plasma ACTH before the administration of dexamethasone did not significantly differ between the acutely ill depressed patients with abnormal DSTs, normal DSTs, the patients with unipolar--bipolar disease in remission, or the healthy subjects. Thus, the abnormalities in the HPA axis in depresséd patients are proposed to be due to a hypersecretion of corticotrophin releasing factor (CRF) with a subsequent stimulus-induced pituitary desensitization. A significant decrease of melatonin after dexamethasone was seen at 0800 hr in the unipolar--bipolar patients in remission as well as in the healthy subjects, at 1600 hr and 2200 hr in the acutely ill depressed patients in remission, but not at 0800 hr in the acutely ill depressed patients in relapse. A significant regression was found between MTmax levels and the degree of non-suppression of cortisol at 0800 hr in the DST in the acutely ill depressed patients both in relapse and in remission. Melatonin thus is proposed to be an inhibiting factor for CRF during depression. A trend to a phase-advance of cortisol nadir and melatonin peak was seen in the acutely ill depressed patients with abnormal DST, possibly indicating an involvement of the suprachiasmatic nuclei in the hypothalamus.