Is PTSD-Phenotype Associated with HPA-Axis Sensitivity?: The Endocannabinoid System in Modulating Stress Response in Rats.

Endocannabinoids play a role in adaptation to stress and regulate the release of glucocorticoids in stressed and unstressed conditions. We recently found that basal corticosterone pulsatility may significantly impact the vulnerability for developing post-traumatic-stress-disorder (PTSD), suggesting that the endocannabinoid system may contribute to its development. To examine this, we exposed rats to predator scent stress (PSS). Behavioral reactions were recorded seven days post-PSS. Cerebrospinal fluid (CSF) was collected from anesthetized rats shortly after PSS exposure to determine the levels of 2-arachidonoyl glycerol (2-AG) and anandamide (AEA). To correlate between endocannabinoids and corticosterone levels, rats were placed in metabolic cages for urine collection. To assess the levels of endocannabinoids in specific brain regions, rats' brains were harvested one day after behavioral analysis for staining and fluorescence quantification. Moreover, 2-AG was elevated in the CSF of PTSD-phenotype rats as compared with other groups and was inversely correlated with corticosterone urinary secretion. Eight days post-PSS exposure, hippocampal and hypothalamic 2-AG levels and hippocampal AEA levels were significantly more reduced in the PTSD-phenotype group compared to other groups. We posit that maladaptation to stress, which is propagated by an abnormal activation of endocannabinoids, mediates the subsequent stress-induced behavioral disruption, which, later, reduces neuronal the expression of endocannabinoids, contributing to PTSD symptomology.

The 24-hour urinary cortisol in post-traumatic stress disorder: A meta-analysis.

OBJECTIVE: Previous studies found inconsistent results on the relationship between post-traumatic stress disorder (PTSD) and concentrations of 24-hour (24-h) urinary cortisol. This study performed a systematic review and meta-analysis to summarize previous findings on this relationship. METHODS: We searched in the databases of Web of Science, PubMed, Embase, and Psyc-ARTICLES for articles published before September 2018. We used the random-effects model with restricted maximum-likelihood estimator to synthesize the effect sizes by calculating the standardized mean difference (SMD) and assessing its significance. RESULTS: Six hundred and nineteen articles were identified from the preceding databases and 20 of them were included in the meta-analysis. Lower concentrations of 24-h urinary cortisol were observed in patients with PTSD when compared with the controls (SMD = -0.49, 95%CI [-0.91; -0.07], p = 0.02). Subgroup analysis revealed that the concentrations of 24-h urinary cortisol were lower in PTSD patients than in the controls for studies that included female participants or studies that included participants from the United States of America. CONCLUSIONS: Overall, decreased levels of 24-h urinary cortisol were linked with the pathophysiology of PTSD. Nonetheless, more studies should be conducted to validate the molecular underpinnings of urine cortisol degeneration in PTSD.

Effect of current and lifetime posttraumatic stress disorder on 24-h urinary catecholamines and cortisol: results from the Mind Your Heart Study.

Posttraumatic stress disorder (PTSD) is associated with an increased risk of cardiovascular disease and several other chronic illnesses. Alterations in the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis in PTSD might contribute to these associations but findings regarding SNS and HPA activity in PTSD are heterogeneous. We measured 24-h urinary catecholamines and cortisol in a large cohort of adult outpatients recruited from 2 Veterans Affairs medical centers. 24-h urinary norepinephrine, epinephrine, dopamine and cortisol were measured by tandem mass spectrometry. Lifetime and current PTSD were assessed with the Clinician Administered PTSD Scale using DSM-IV-TR criteria. Out of 613 participants, 199 (32.5%) had current PTSD, 100 (16.3%) had lifetime but not current PTSD, and 314 (51.2%) never had PTSD. Patients with current PTSD had significantly higher norepinephrine secretion compared to those without PTSD. Patients in the lifetime PTSD group exhibited lower cortisol values compared to those without PTSD. Participants who never had PTSD showed the lowest norepinephrine and the highest cortisol values. All results remained stable when controlling for potentially confounding variables. This study provides evidence for increased norepinephrine secretion and decreased cortisol in PTSD. Future longitudinal studies are needed to determine whether these changes contribute to adverse health outcomes in patients with PTSD.

Association of in vivo κ-opioid receptor availability and the transdiagnostic dimensional expression of trauma-related psychopathology.

IMPORTANCE: Exposure to trauma increases the risk for developing threat (ie, fear) symptoms, such as reexperiencing and hyperarousal symptoms, and loss (ie, dysphoria) symptoms, such as emotional numbing and depressive symptoms. While preclinical data have implicated the activated dynorphin/κ-opioid receptor (KOR) system in relation to these symptoms, the role of the KOR system in mediating these phenotypes in humans is unknown. Elucidation of molecular targets implicated in threat and loss symptoms is important because it can help inform the development of novel, mechanism-based treatments for trauma-related psychopathology. OBJECTIVE: To use the newly developed [11C]LY2795050 radiotracer and high-resolution positron emission tomography to evaluate the relation between in vivo KOR availability in an amygdala-anterior cingulate cortex-ventral striatal neural circuit and the severity of threat and loss symptoms. We additionally evaluated the role of 24-hour urinary cortisol levels in mediating this association. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional positron emission tomography study under resting conditions was conducted at an academic medical center. Thirty-five individuals representing a broad transdiagnostic and dimensional spectrum of trauma-related psychopathology, ranging from nontrauma-exposed psychiatrically healthy adults to trauma-exposed adults with severe trauma-related psychopathology (ie, posttraumatic stress disorder, major depressive disorder, and/or generalized anxiety disorder). MAIN OUTCOMES AND MEASURES: [11C]LY2795050 volume of distribution values in amygdala-anterior cingulate cortex-ventral striatal neural circuit; composite measures of threat (ie, reexperiencing, avoidance, and hyperarousal symptoms) and loss (ie, emotional numbing, major depressive disorder, and generalized anxiety disorder symptoms) symptoms as assessed using the Clinician-Administered PTSD Scale, Hamilton Depression Rating Scale, and Hamilton Rating Scale for Anxiety; and 24-hour urinary cortisol levels. RESULTS: [11C]LY2795050 volume of distribution values in an amygdala-anterior cingulate cortex-ventral striatal neural circuit were negatively associated with severity of loss (r = -0.39; 95% CI, -0.08 to -0.66), but not threat (r = -0.03; 95% CI, -0.30 to 0.27), symptoms; this association was most pronounced for dysphoria symptoms (r = -0.45; 95% CI, -0.10 to -0.70). Path analysis revealed that lower [11C]LY2795050 volume of distribution values in this circuit was directly associated with greater severity of loss symptoms and indirectly mediated by 24-hour urinary cortisol levels. CONCLUSIONS AND RELEVANCE: Results of this study suggest that KOR availability in an amygdala-anterior cingulate cortex-ventral striatal neural circuit mediates the phenotypic expression of trauma-related loss (ie, dysphoria) symptoms. They further suggest that an activated corticotropin-releasing factor/hypothalamic-pituitary-adrenal axis system, as assessed by 24-hour urinary cortisol levels, may indirectly mediate this association. These results may help inform the development of more targeted, mechanism-based transdiagnostic treatments for loss (ie, dysphoric) symptoms.

Using novel methods to examine stress among HIV-positive African American men who have sex with men and women.

Biomarker composites (BCs) that objectively quantify psychosocial stress independent of self report could help to identify those at greatest risk for negative health outcomes and elucidate mechanisms of stress-related processes. Here, BCs are examined in the context of existing disease progression among HIV-positive African American men who have sex with men and women (MSMW) with high stress histories, including childhood sexual abuse. Participants (N = 99) collected 12-h overnight and morning urine samples for assay of cortisol and catecholamines (primary BC) and neopterin (an indicator of HIV disease progression). Data on cumulative psychosocial trauma history (severity, types, frequency, age at first incident), posttraumatic stress disorder (PTSD) symptoms, sexual risk behaviors, and a secondary BC consisting of routine health indicators (heart rate, blood pressure, body mass index, waist-to-hip ratio) were also collected. Lifetime trauma exposure was highly pervasive and significantly greater among those meeting a standard cutoff for PTSD caseness (24 %). After controlling for HIV factors (neopterin levels and years with disease), PTSD was a significant (p < .05) predictor of the primary, but not secondary BC. Those with PTSD also had significantly more sexual partners, sex without a condom, and exchange sex for money or drugs than those without PTSD. Specific trauma characteristics predicted PTSD severity and caseness independently and uniquely in regression models (p's < .05-.001). A primary BC appears sensitive to cumulative trauma burden and PTSD in HIV-positive African American MSMW, providing support for the use of BCs to quantify psychosocial stress and inform novel methods for examining mechanisms of stress influenced health behaviors and disease outcomes in at-risk populations.

The relationship between urinary melatonin metabolite excretion and posttraumatic symptoms following traumatic injury.

BACKGROUND: Associations between 24-hour urinary 6-sulphatoxy melatonin excretion and symptoms of posttraumatic stress disorder were assessed 2 days, 1 month and 6 months after traumatic injury requiring hospitalisation. METHODS: Forty-eight participants were recruited following an admission to hospital for an acute traumatic injury. They completed assessments 48h after the accident, 1 month and 6 months later. A 24-hour urine collection was initiated the morning before questionnaires were administered. PTSD symptoms and caseness was determined using the Impact of Event Scale (IES-R) and the Clinician Administered PTSD Scale respectively. Urinary 6-sulphatoxy melatonin was assayed by radioimmunoassay. RESULTS: Mean age of participants was 34 years (SD=12.72) and 75% were males. Ten (27%) participants met the criteria for PTSD 1 month post trauma and 6 (21%) met the criteria for PTSD at 6 months. Four of the six (67%) participants with PTSD at 6 months were also positive for major depression. Significant negative correlations were found between 6-sulphatoxy melatonin excretion at day 2 and all subscales and total score of the IES-R at the six month assessment. Controlling for depression, every one unit decrease in 6-sulphatoxy melatonin excretion was associated with a 13% increase in PTSD risk at six months (OR=1.13, 95% CI 1.00-1.27). However, this association was lost when self-reported pain, gender and employment was added to the model (OR=1.11, 0.93-1.32). CONCLUSION: This study provides preliminary data suggesting disrupted melatonin levels in the first 48h following trauma may place individuals at increased risk of PTSD.

Cortisol metabolic predictors of response to psychotherapy for symptoms of PTSD in survivors of the World Trade Center attacks on September 11, 2001.

BACKGROUND: A proportion of subjects with symptoms of posttraumatic stress disorder (PTSD) are unresponsive to specialized psychotherapy, but a biological basis for this has not been described. To observe whether differences in cortisol or its metabolites predict or correlate with response to therapy for PTSD symptoms, cortisol and its metabolites were measured from urine samples at pre-treatment, at the conclusion of psychotherapy, and at 3-month follow-up. METHODS: 28 survivors of the World Trade Center attacks on September 11, 2001 seeking psychological treatment for PTSD symptoms received four sessions of either exposure therapy or supportive counseling, followed by up to 10 sessions of prolonged exposure in a specialized PTSD treatment program at a private hospital serving the New York City metropolitan area. 24-h mean integrated cortisol excretion was assessed by radioimmunoassay (RIA); urinary free cortisol and metabolites cortisone, 5alpha-tetrahydrocortisol (5alpha-THF), 5beta-tetrahydrocortisol, and tetrahydrocortisone were assessed by gas chromatography-mass spectrometry (GC-MS); and indices of enzyme activity for 5alpha- and 5beta-reductase and for the 11beta-hydroxysteroid dehydrogenases were derived from the metabolite and glucocorticoid measures. RESULTS: 5alpha-Reductase activity was significantly lower at pre-treatment among non-responders, whereas there were no significant pre-treatment differences between responders and non-responders in any other hormone or metabolite level. In repeated measures analyses across the three time points, 5alpha-reductase activity, as well as 5alpha-THF and total glucocorticoids, significantly differed between responders and non-responders. For urinary cortisol measured by RIA, there was a significant groupxtime interaction indicating that, although not different at pre-treatment, urinary cortisol levels declined over time in the non-responder group, such that by follow-up, lowered cortisol significantly distinguished non-responders from responders. Indices of 5alpha-reductase activity, including 5alpha-THF and total glucocorticoids, were significantly negatively correlated with avoidance symptom severity at pre-treatment. At follow-up, indices of 5alpha-reductase activity were significantly negatively correlated with severity of all three PTSD symptom clusters and with total PTSD severity scores. CONCLUSION: Lower 5alpha-reductase activity is associated with avoidance severity and predicts non-responsiveness to psychological treatment for PTSD symptomatology. Relatively diminished 5alpha-reductase activity may mark a state of primary vulnerability, perhaps via attenuated peripheral catabolism of cortisol resulting in the suppression of hypothalamic-pituitary-adrenal axis responsiveness. Lower cortisol levels appear later in the progression to chronic, treatment-resistant PTSD.

Symptom severity predicts degree of T cell activation in adult women following childhood maltreatment.

Although depression is often associated with a reduction in cellular immune responses, other types of emotional disturbance and psychopathology can activate certain aspects of immunity. Activation markers on T cells, in particular, have been found to be elevated in post-traumatic stress states. However, little is known about the relationship between the severity of PTSD symptoms and the degree of change in T cell phenotypes, or about the potential role of neuroendocrine factors in mediating the association. Twenty-four women with a history of sexual trauma during childhood, including 11 who met diagnostic criteria for PTSD, were compared to 12 age-matched, healthy women without a history of maltreatment. The women provided fasted blood samples for enumeration of cell subsets by immunofluorescence and 24-h urine samples for analysis of catecholamine and cortisol levels. The percent of T cells expressing CD45RA, an early activation marker, was higher in the PTSD diagnosed women, and the levels correlated positively with intrusive symptoms and negatively with avoidant symptoms. These alterations in cell surface markers did not appear to be mediated by norepinephrine (NE) or cortisol, making them a distinctive and independent biomarker of arousal and disturbance in PTSD.

Adult sexual abuse is associated with elevated neurohormone levels among women with PTSD due to childhood sexual abuse.

Posttraumatic stress disorder (PTSD) has been associated with reduced, similar, or increased urinary cortisol levels. The authors identified a factor that might contribute to such variability when they obtained 24-hour urinary neurohormone profiles on 69 women with PTSD due to childhood sexual abuse. Half (n = 35) had subsequently experienced adult sexual abuse (ASA) while the other half (n = 34) had not. The ASA group had significantly elevated urinary cortisol, norepinephrine and dopamine levels in comparison to the non-ASA group. Neither a history of childhood or adult physical abuse nor other variables contributed to this finding. The results suggest that the psychobiological consequences of exposure to the same traumatic event may differ as a result of an interaction between age and the composite history of trauma exposure.

Hypothalamic-pituitary-adrenal axis function in dissociative disorders, post-traumatic stress disorder, and healthy volunteers.

BACKGROUND: This study investigated basal and stress-induced hypothalamic-pituitary-adrenal (HPA)-axis alterations in dissociative disorders (DDs). METHODS: Forty-six subjects with DD without lifetime post-traumatic stress disorder (PTSD), 35 subjects with PTSD, and 58 healthy comparison (HC) subjects, free of current major depression, were studied as inpatients. After a 24-hour urine collection and hourly blood sampling for ambient cortisol determination, a low-dose dexamethasone suppression test was administered, followed by the Trier Social Stress Test. RESULTS: The DD group had significantly elevated urinary cortisol compared with the HC group, which was more pronounced in the absence of lifetime major depression, whereas the PTSD and HC groups did not differ. The DD group demonstrated significantly greater resistance to, and faster escape from, dexamethasone suppression compared with the HC group, whereas the PTSD and HC groups did not differ. The three groups did not differ in cortisol stress reactivity, but both psychiatric groups demonstrated a significant inverse correlation between dissociation severity and cortisol reactivity, after controlling for all other symptomatology. The PTSD subgroup with comorbid DD tended to have blunted stress reactivity compared with the HC group. CONCLUSIONS: The study demonstrates a distinct pattern of HPA-axis dysregulation in DDs, emphasizing the importance of further study of stress-response systems in dissociative psychopathology.

Overnight urinary cortisol release in women with borderline personality disorder depends on comorbid PTSD and depressive psychopathology.

Free cortisol was investigated in BPD patients and healthy controls. A positive association was found between cortisol and depression scores, while the number of PTSD symptoms was negatively correlated with cortisol release. These findings suggest that alterations in cortisol release in BPD are strongly associated with the severity of psychopathology.

Clinical correlates of 24-h cortisol and norepinephrine excretion among subjects seeking treatment following the world trade center attacks on 9/11.

UNLABELLED: Whereas trauma-associated arousal has been linked fairly consistently with elevations in both glucocorticoids and catecholamines, neuroendocrine correlates of hyperarousal in the context of posttraumatic stress disorder (PTSD) have been more variable. Further, neuroendocrine predictors of the development of PTSD following trauma have been related to prior exposure, and data from several laboratories suggests that hyperarousal may develop in a neuroendocrine milieu of relatively diminished basal glucocorticoid secretion. METHODS: In this article we examined 24-h cortisol and norepinephrine excretion in 42 treatment-seeking survivors of the 9/11 World Trade Center (WTC) attacks, 32 of whom met criteria for PTSD, and 15 of whom met criteria for major depression, at the time of evaluation; 14 of the 15 subjects meeting criteria for major depression also suffered from PTSD. RESULTS: PTSD subjects' 24-h cortisol excretion (46.3 +/- 20.0 microL/dL) was lower than that of the non-PTSD cohort (72.2 +/- 22.4 microL/dL; t = 3.18, df = 37, P = 0.003), and 24-h urinary cortisol was negatively correlated with the experience of the WTC attacks as a Criterion-A event (r = -0.427, P = 0.007), and with self-rated avoidance (r = -0.466, P = 0.003) and total score (r = -0.398, P = 0.012) on the PTSD Symptom Scale (PSS). In contrast, 24-h norepinephrine excretion was not associated with the development of PTSD or with PTSD-related symptoms, but was negatively correlated with days since 9/11 at the time of evaluation (r = -0.393, P = 0.015). DISCUSSION: The latter finding suggests a relationship of norepinephrine to a dimension of stress-related arousal not captured by the symptom-rating scales chosen for this study to reflect symptoms related to PTSD and other neuropsychiatric disorders, but instead, of one to that of the sudden multidimensional life disruption suffered by the WTC survivors that applied for treatment. These data also confirm, in a naturalistic sample, the previously observed negative association of urinary cortisol excretion with development of PTSD in the aftermath of severe trauma exposure.

Cortisol production rate in posttraumatic stress disorder.

CONTEXT: Several authors have reported the unsuspected finding of low cortisol levels (urinary, salivary, and serum) in patients with posttraumatic stress disorder (PTSD). OBJECTIVE: Our objective was to assess concentrations of cortisol and its predominant metabolites, cortisol production rate (CPR), and glucocorticoid receptor (GR) binding characteristics in PTSD compared with normal subjects. DESIGN: Matched PTSD patients and control subjects had CPR determined by a stable isotope dilution technique after infusion of deuterated cortisol. Serum cortisol, urinary cortisol, and its metabolites were measured by gas chromatography/mass spectrometry. GR binding capacity (R(o)) and ligand binding affinity (K(d)) were measured in mononuclear leukocytes. SETTING: All subjects were tested during a 40-h admission in an inpatient clinical research center. PATIENTS AND PARTICIPANTS: Ten patients with PTSD were matched by age and gender with 10 controls. OUTCOME MEASURES: Statistical comparison was conducted for various measures of cortisol in PTSD patients and normal subjects. RESULTS: No statistical difference was found in mean level or circadian pattern of cortisol secretion using serum or salivary immunoassay detection methods. Although in the normal range, urinary cortisol by immunoassay showed statistically lower values over a 24-h period in PTSD patients compared with controls. This finding was not confirmed by gas chromatography/mass spectrometry determination of cortisol or its metabolites. CPR was not statistically different between these groups. GR also showed no alteration in R(o) or K(d) between the groups. CONCLUSION: The data indicate that PTSD in the chronic and unprovoked state is not characterized by an acute biological stress response.

Gender-specific association of alexithymia and norepinephrine/cortisol ratios. A preliminary report.

OBJECTIVE: Alexithymia and posttraumatic stress disorder (PTSD) might share a neuroendocrine pattern characterized by increased urinary norepinephrine (N) and decreased cortisol (C) levels, resulting in a high N/C ratio, at least among male alcoholics. We aimed to explore if this association can also be found in other populations. METHODS: Twenty-four-hour urine samples were obtained from 12 major depressive disorder (MDD) patients and 23 healthy controls (HC) and tested for N and free C. Participants completed the 20-item Toronto Alexithymia Scale (TAS) and the Symptom Check List (SCL). RESULTS: Controlling for depression, the neuroendocrine parameters did not differ between the MDD and HC participants nor between women and men. The TAS was not associated with N, C or the N/C ratio in the MDD and HC participants nor in females alone. However, in men, the N/C ratio correlated significantly with the TAS (r = .80). CONCLUSIONS: Our preliminary findings indicate that alexithymia is associated with an increased noradrenergic activity and a decreased basal activity of the hypothalamic-pituitary-adrenal (HPA) axis among men. This gender difference may reflect divergent underlying neurobiological processes of alexithymia in men and women.

Initial urinary epinephrine and cortisol levels predict acute PTSD symptoms in child trauma victims.

BACKGROUND: Previous research examining biological correlates of posttraumatic stress disorder (PTSD) in children has suggested that children with chronic PTSD have altered levels of catecholamines and cortisol compared to similarly traumatized children who do not meet diagnostic criteria. The present study extended these findings by examining whether urinary hormone levels collected soon after a trauma were related to subsequent acute PTSD symptoms in child trauma victims. METHODS: Initial 12-h urine samples were collected from 82 children aged 8-18 admitted to a Level 1 trauma center. Collection was begun immediately upon admission, and samples were assayed for levels of catecholamines and cortisol. PTSD and depressive symptomatology were assessed 6 weeks following the accident. RESULTS: Initial urinary cortisol levels were significantly correlated with subsequent acute PTSD symptoms (r=0.31). After removing the variance associated with demographic variables and depressive symptoms, urinary cortisol and epinephrine levels continued to predict a significant percentage (7-10%) of the variance in 6-week PTSD symptoms. Examination of boys and girls separately suggested that significance was primarily driven by the strength of the relationships between hormone levels and acute PTSD symptoms in boys. CONCLUSIONS: The present findings suggest that high initial urinary cortisol and epinephrine levels immediately following a traumatic event may be associated with increased risk for the development of subsequent acute PTSD symptoms, especially in boys.

Urinary dopamine and turn bias in traumatized women with and without PTSD symptoms.

Turning biases are known to occur in the direction of the brain hemisphere with decreased dopamine (DA). Although elevations in urinary DA have been shown in posttraumatic stress disorder (PTSD), evidence for dysregulation of dopaminergic activity in the brain is lacking. Turn bias and urinary DA levels were examined in mothers of childhood cancer survivors. As expected, cancer trauma mothers with PTSD symptoms (n=14) had higher urinary DA levels than trauma mothers without PTSD symptoms (n=7) and controls (n=8) (P=0.01). Groups were also significantly different in prevalence of left turn bias (P=0.03). All controls (100%) showed a left turn bias compared to 75 and 37.5% prevalence among trauma mothers with and without PTSD, respectively. Urinary DA levels and turn bias rates were not correlated. Results lend support for further exploration of DA in traumatized groups with and without PTSD.

Urinary cortisol and catecholamines in mothers of child cancer survivors with and without PTSD.

Reduced cortisol coupled with elevated catecholamines has been reported for patients with post-traumatic stress disorder (PTSD) precipitated by war and other traumas considered to be "outside the range of usual experiences". It is unclear whether these neuroendocrine abnormalities also occur in PTSD precipitated by more commonly experienced traumas associated with life-threatening illness. Overnight (12-h) urinary cortisol, norepinephrine (NE) and epinephrine (E) were measured in 21 mothers of pediatric cancer survivors with (n = 14) and without PTSD symptoms (n = 7) and in control mothers of healthy children (n = 8). Mothers meeting subthreshold and full PTSD criteria were combined to form the PTSD symptoms group. The PTSD group showed lower total urinary cortisol and a trend for higher total urinary NE than the non-PTSD group, who in turn were no different from controls. There were no significant group effects for E. Cortisol (but not NE) effects remained after controlling for symptoms of co-morbid depression. The finding of reduced cortisol in illness-related PTSD demonstrates neuroendocrine dysregulation similar to that found previously in other types of trauma (e.g., war-related). Future longitudinal studies with repeated urinary collection procedures will be necessary to clarify measurement issues and establish the time course and health implications of the neuroendocrine perturbations.