The cortisol and glucocorticoid receptor response to low dose dexamethasone administration in aging combat veterans and holocaust survivors with and without posttraumatic stress disorder.

BACKGROUND: Because alterations in cortisol negative feedback inhibition associated with aging are generally opposite of those observed in posttraumatic stress disorder (PTSD), we examined the cortisol and glucocorticoid receptor (GR) response to dexamethasone (DEX) in older trauma survivors.METHODS: Twenty-three Holocaust survivors (9 men, 14 women), 27 combat veterans (all male), and 10 comparison subjects (7 men, 3 women) provided samples for plasma or salivary cortisol and glucocorticoid receptor determination in mononuclear leukocytes at 8:00 AM on the day of, and following, 0.5 mg of DEX at 11:00 PM.RESULTS: Greater percent suppression of cortisol and lymphocyte GR was observed in older trauma survivors with PTSD compared to survivors without PTSD and comparison subjects. There was a significant main effect of depression in the direction of reduced suppression following DEX, consistent with the effects of DEX in major depressive disorder patients. Responses to DEX were uncorrelated with PTSD symptom severity, but cortisol suppression was associated with years elapsed since the most recent, but not focal, traumatic event.CONCLUSIONS: The response to DEX is generally similar in older and younger trauma survivors, but the findings suggest that age, symptom severity, and lifetime trauma exposure characteristics may influence this response.     

Thyroid hormone alterations among women with posttraumatic stress disorder due to childhood sexual abuse.

BACKGROUND: Research on thyroid activity among male combat veterans with posttraumatic stress disorder (PTSD) has consistently shown elevations in total triiodothyronine (TT3) and inconsistent elevations of other thyroid variables. This study is the first large scale investigation of thyroid function in women with PTSD. METHODS: Thyroid function was measured in 63 women with PTSD due to childhood sexual abuse (PTSD-CSA) in comparison with a community sample of 42 women without current PTSD-CSA. Clinical measures included the Clinician Administered PTSD Scale (CAPS), the Evaluation of Lifetime Stressors, the Trauma Assessment for Adults and the Beck Depression Inventory. RESULTS: Women with PTSD-CSA showed significant elevations in Total T3 and the TT3/free thyroxine (TT3/FT4) ratio, the FT3/TT3 ratio, and modest reductions in thyroid stimulating hormone relative to our community sample. These findings could not be explained by the influence of prior trauma, lifetime PTSD or depressive symptoms. CONCLUSIONS: Altered thyroid activity, especially elevated Total T3 levels, was found in women with PTSD associated with childhood sexual abuse.     

Grey matter reduction associated with posttraumatic stress disorder and traumatic stress

In recent decades, many imaging studies have reported brain structural alterations in posttraumatic stress disorder (PTSD). However, due to differences in the selection of control subjects, it is difficult to conclude whether the observed alterations were related to disease or traumatic stress. The present study was to provide a quantitative voxelwise meta-analysis of grey matter (GM) changes in PTSD relative to either trauma-exposed controls without PTSD (TEC) or non-traumatised healthy controls (HC) separately and to conduct a systematic review of voxel-based morphometry (VBM) studies that compared trauma-exposed individuals with HC to explore the effect of traumatic stress. GM reduction was identified in the medial prefrontal cortex in PTSD compared to both TEC and HC. Additional GM reduction was also observed in PTSD in the left hippocampus, left middle temporal gyrus and right superior frontal gyrus compared with TEC. Additionally, GM decreased in the left occipital cortex in PTSD compared with HC. The present study delimited the significant differences among VBM results in PTSD research when different control groups were chosen.     

Cerebellar volumes in pediatric maltreatment-related posttraumatic stress disorder.

BACKGROUND: The results of previous studies suggest structural brain differences in pediatric maltreatment-related posttraumatic stress disorder (PTSD) However, posterior fossa volumes were not examined, despite the consensus that the cerebellum is important in emotional and cognitive development. We investigated the relationship between structural volumes of the cerebellum hemispheres, vermis, brainstem, and clinical variables in pediatric maltreatment-related PTSD. METHODS: Fifty-eight psychotropic-na?ve maltreated children and adolescents with DSM-IV PTSD were compared with two groups of pediatric subjects who had no DSM-IV criteria A trauma histories: 1) 13 with pediatric generalized anxiety disorder, and 2) 98 healthy non-abused children and adolescents. Subjects underwent a comprehensive psychiatric assessment and an anatomical magnetic resonance image brain scan. RESULTS: Unadjusted means of the left, right, and total cerebellum were smaller in the PTSD group. The group differences remained significant in the left cerebellum, right cerebellum, and total cerebellum in the analyses adjusted for cerebral volume, sociodemographic, and IQ variables. Cerebellar volumes positively correlated with age of onset of the trauma that lead to PTSD and negatively correlated with the duration of the trauma that lead to PTSD. Cerebellar volumes were larger in boys versus girls, but there was no group x gender interaction. There were significant positive correlations between IQ measures and volumetric variables. CONCLUSIONS: The results support cerebellar volume differences in maltreated children and adolescents with PTSD. Further studies are warranted.     

Rumination in posttraumatic stress disorder

Recent studies have shown that rumination is a powerful predictor of persistent posttraumatic stress disorder (PTSD). However, to date, the mechanisms by which rumination maintains PTSD symptoms are little understood. Two studies of assault survivors, a cross-sectional (N = 81) and a 6-month prospective longitudinal study (N = 73), examined several facets of ruminative thinking to establish which aspects of rumination provide the link to PTSD. The current investigation showed that rumination is not only used as a strategy to cope with intrusive memories but it also triggers such memories. Certain characteristics of rumination, such as compulsion to continue ruminating, occurrence of unproductive thoughts, and "why" and "what if" type questions, as well as negative emotions before and after rumination, were significantly associated with PTSD, concurrently and prospectively. These characteristics explained significantly more variance in PTSD severity than the mere presence of rumination, thereby indicating that not all ways of ruminative thinking are equally maladaptive.     

Hippocampal function in posttraumatic stress disorder

Recent studies have reported memory deficits and reduced hippocampal volumes in posttraumatic stress disorder (PTSD). The goal of the current research was to use functional neuroimaging and a validated explicit memory paradigm to examine hippocampal function in PTSD. We used positron emission tomography (PET) and a word-stem completion task to study regional cerebral blood flow (rCBF) in the hippocampus in 16 firefighters: 8 with PTSD (PTSD group) and 8 without PTSD (Control group). During PET scanning, participants viewed three-letter word stems on a computer screen and completed each stem with a word they had previously encoded either deeply (High Recall condition) or shallowly (Low Recall condition). Relative to the Control group, the PTSD group exhibited significantly smaller rCBF increases in the left hippocampus in the High vs Low Recall comparison. However, this finding reflected relatively elevated rCBF in the Low Recall condition in the PTSD group. Collapsing across High and Low Recall conditions, (1) the PTSD group had higher rCBF in bilateral hippocampus and left amygdala than the Control group, and (2) within the PTSD group, symptom severity was positively associated with rCBF in hippocampus and parahippocampal gyrus. The groups did not significantly differ with regard to accuracy scores on the word-stem completion task. The PTSD group had significantly smaller right (and a trend for smaller left) hippocampal volumes than the Control group. The results suggest an abnormal rCBF response in the hippocampus during explicit recollection of nonemotional material in firefighters with PTSD, and that this abnormal response appears to be driven by relatively elevated hippocampal rCBF in the comparison condition.     

Segmented hippocampal volume in children and adolescents with posttraumatic stress disorder.

BACKGROUND: Although many studies of adults with posttraumatic stress disorder (PTSD) have reported smaller hippocampal volume compared with control subjects, comparable studies of children and adolescents have failed to replicate these findings or have noted opposite trends suggesting a larger hippocampus. We therefore performed a secondary analysis combining data from prior studies to examine the hypothesis that hippocampus would be larger in pediatric subjects with PTSD compared with non-maltreated control subjects. We also hypothesized that differences in PTSD subjects would be observed between boys and girls. METHODS: Sixty-one subjects (31 boys, 30 girls) with maltreatment-related PTSD and 122 control subjects matched on age and gender underwent magnetic resonance imaging. RESULTS: As hypothesized, we observed a significantly larger hippocampus controlling for cerebral volume in PTSD subjects compared with control subjects. Segmented hippocampal white-matter volume was greater in PTSD subjects but not gray-matter volume. Hippocampal volume was positively related to age of trauma onset and level of psychopathology, particularly externalizing behavior. No interactions with group were observed for age or gender. CONCLUSIONS: Future longitudinal studies with trauma control subjects and neuropsychological measures are indicated to further elucidate the relationship between hippocampus and behavioral abnormalities in young PTSD subjects.     

Pituitary volumes in pediatric maltreatment-related posttraumatic stress disorder.

BACKGROUND: Previous findings suggest that corticotrophin-releasing hormone (CRH) is elevated in adults with posttraumatic stress disorder (PTSD), maltreated children, and children with maltreatment-related PTSD. METHODS: Magnetic resonance imaging was used to measure pituitary volumes in 61 medication-na?ve maltreated subjects with PTSD (31 male and 30 female subjects) and 121 nontraumatized healthy comparison subjects (62 male and 59 female subjects). RESULTS: Overall, no differences were seen between PTSD and control subjects in pituitary volumes. There was a significant age-by-group effect for PTSD subjects to have greater differences in pituitary volume with age than control subjects. Post hoc analyses revealed that pituitary volumes were significantly larger in pubertal and postpubertal maltreated subjects with PTSD than control subjects but were similar in prepubertal maltreated subjects with PTSD and control subjects. Pituitary volumes were larger in the PTSD subjects with history of suicidal ideation. CONCLUSIONS: These findings may suggest developmental alterations in pituitary volume in maltreatment-related pediatric PTSD. This finding may be associated with stress-related differences in CRH and may be more pronounced in pediatric patients with PTSD comorbid with suicidal ideation.     

Diurnal salivary cortisol in pediatric posttraumatic stress disorder.

BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the pathophysiology of posttraumatic stress disorder (PTSD). Additional information on basal cortisol levels in children exposed to trauma and experiencing PTSD symptoms may contribute to the understanding of the role of this axis in PTSD. METHODS: Fifty-one children (30 boys and 21 girls, mean age 10.7 years) with a history of exposure to trauma and PTSD symptoms were compared with 31 age- and gender-matched healthy control subjects. Salivary cortisol was obtained from participants during home measurements and was collected four times a day (prebreakfast, prelunch, predinner, and prebed) for up to 3 consecutive days. RESULTS: The clinical group demonstrated significantly elevated cortisol levels when compared with the control group. In addition, exploratory analyses revealed that girls with PTSD symptoms had significantly elevated cortisol levels when compared with boys with PTSD symptoms. CONCLUSIONS: The physiologic response of children with history of trauma and with PTSD symptoms may be characterized by heightened adrenal activity.     

Resting regional cerebral perfusion in recent posttraumatic stress disorder.

BACKGROUND: Brain imaging research in posttraumatic stress disorder has been largely performed on patients with chronic disease, often heavily medicated, with current or past alcohol and substance abuse. Additionally, virtually only activation brain imaging paradigms have been done in posttraumatic stress disorder, whereas in other mental disorders both resting and activation studies have been performed. METHODS: Twenty-eight (11 posttraumatic stress disorder) trauma survivors underwent resting state hexamethylpropyleneamineoxime single photon emission computed tomography and magnetic resonance imaging 6 months after trauma. Eleven nontraumatized subjects served as healthy controls. RESULTS: Regional cerebral blood flow in the cerebellum was higher in posttraumatic stress disorder than in both control groups. Regional cerebral blood flow in right precentral, superior temporal, and fusiform gyri in posttraumatic stress disorder was higher than in healthy controls. Cerebellar and extrastriate regional cerebral blood flow were positively correlated with continuous measures of depression and posttraumatic stress disorder. Cortisol level in posttraumatic stress disorder was negatively correlated with medial temporal lobe perfusion. Anterior cingulate perfusion and cortisol level were positively correlated in posttraumatic stress disorder and negatively correlated in trauma survivors without posttraumatic stress disorder. CONCLUSIONS: Recent posttraumatic stress disorder is accompanied by elevated regional cerebral blood flow, particularly in the cerebellum. This warrants attention because the cerebellum is often used as a reference region in regional cerebral blood flow studies. The inverse correlation between plasma cortisol and medial temporal lobe perfusion may herald hippocampal damage.     

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.     

Mitogenic response and steroid sensitivity in MS lymphocytes

Objectives - We investigated mitogenic response and steroid sensitivity in multiple sclerosis (MS) lymphocytes to establish if MS lymphocytes were less steroid responsive. Material and methods - We compared mitogenic response to phytohaemagglutinin (PHA) and inhibition by dexamethasone (DEX) in circulating lymphocytes from both MS patients and healthy subjects. Results - We found a range of responses in each group but no significant differences between the two groups, nor in patients with and without enhancement on magnetic resonance imaging. The mid-inhibitory concentration of DEX in response to 1 μg/ml PHA was significantly lower than that for 2.5 μg/ml PHA in the patients. The mid-inhibitory concentrations of DEX in response to 2.5 μg/ml PHA negatively correlated with endogenous serum Cortisol concentrations. Conclusion - These data imply a spectrum of glucocorticoid response that is similar in normal and MS lymphocytes and can partly explain why response to steroid therapy is variable.     

Neuroimmune and cortisol changes in selective serotonin reuptake inhibitor and placebo treatment of chronic posttraumatic stress disorder.

BACKGROUND: To explore relations between neuroimmune and neuroendocrine systems relative to posttraumatic stress disorder (PTSD) treatment, cortisol and cytokine changes in response to selective serotonin reuptake inhibitor (SSRI) and placebo treatment of chronic PTSD were assessed prospectively. METHODS: Baseline measures of PTSD, depression, salivary 8 am and 4 pm cortisol, and serum interleukin-1beta (IL-1beta; pro-inflammatory) and soluble interleukin-2 receptors (IL-2R; cell-mediated immunity) were obtained for 58 PTSD and 21 control subjects. The PTSD subjects participated in a 10-week, double-blind treatment with citalopram (n = 19), sertraline (n = 18), or placebo (n = 7). RESULTS: At baseline, PTSD subjects had significantly greater PTSD, depression, and IL-1beta and lower IL-2R levels than control subjects, with no group differences found for am or pm cortisol levels. Both SSRI groups' IL-1beta correlated negatively with IL-2R; neither cytokine correlated with cortisol levels. Treatment significantly lowered PTSD, depression, and IL-1beta levels and increased IL-2R for all groups to control subject levels. After treatment, both SSRI groups' IL-1beta correlated with an end cortisol measure (one negatively, one positively). CONCLUSIONS: Our results support a complex relationship between neuroimmune and neuroendocrine systems with PTSD treatment. Implications of normalization of cytokine levels with effective SSRI treatment and placebo are discussed.     

Latent typologies of posttraumatic stress disorder in World Trade Center responders

Posttraumatic stress disorder (PTSD) is a debilitating and often chronic psychiatric disorder. Following the 9/11/2001 World Trade Center (WTC) attacks, thousands of individuals were involved in rescue, recovery and clean-up efforts. While a growing body of literature has documented the prevalence and correlates of PTSD in WTC responders, no study has evaluated predominant typologies of PTSD in this population. Participants were 4352 WTC responders with probable WTC-related DSM-IV PTSD. Latent class analyses were conducted to identify predominant typologies of PTSD symptoms and associated correlates. A 3-class solution provided the optimal representation of latent PTSD symptom typologies. The first class, labeled “High-Symptom (n = 1,973, 45.3%),” was characterized by high probabilities of all PTSD symptoms. The second class, “Dysphoric (n = 1,371, 31.5%),” exhibited relatively high probabilities of emotional numbing and dysphoric arousal (e.g., sleep disturbance). The third class, “Threat (n = 1,008, 23.2%),” was characterized by high probabilities of re-experiencing, avoidance and anxious arousal (e.g., hypervigilance). Compared to the Threat class, the Dysphoric class reported a greater number of life stressors after 9/11/2001 (OR = 1.06). The High-Symptom class was more likely than the Threat class to have a positive psychiatric history before 9/11/2001 (OR = 1.7) and reported a greater number of life stressors after 9/11/2001 (OR = 1.1). The High-Symptom class was more likely than the Dysphoric class, which was more likely than the Threat class, to screen positive for depression (83% > 74% > 53%, respectively), and to report greater functional impairment (High-Symptom > Dysphoric [Cohen d = 0.19], Dysphoric > Threat [Cohen d = 0.24]). These results may help inform assessment, risk stratification, and treatment approaches for PTSD in WTC and disaster responders.     

Learning and memory in Holocaust survivors with posttraumatic stress disorder.

BACKGROUND: Impairments in explicit memory have been observed in Holocaust survivors with posttraumatic stress disorder. METHODS: To evaluate which memory components are preferentially affected, the California Verbal Learning Test was administered to Holocaust survivors with (n = 36) and without (n = 26) posttraumatic stress disorder, and subjects not exposed to the Holocaust (n = 40). RESULTS: Posttraumatic stress disorder subjects showed impairments in learning and short-term and delayed retention compared to nonexposed subjects; survivors without posttraumatic stress disorder did not. Impairments in learning, but not retention, were retained after controlling for intelligence quotient. Older age was associated with poorer learning and memory performance in the posttraumatic stress disorder group only. CONCLUSIONS: The most robust impairment observed in posttraumatic stress disorder was in verbal learning, which may be a risk factor for or consequence of chronic posttraumatic stress disorder. The negative association between performance and age may reflect accelerated cognitive decline in posttraumatic stress disorder.     

Circuits and systems in stress. II. Applications to neurobiology and treatment in posttraumatic stress disorder

This paper follows the preclinical work on the effects of stress on neurobiological and neuroendocrine systems and provides a comprehensive working model for understanding the pathophysiology of posttraumatic stress disorder (PTSD). Studies of the neurobiology of PTSD in clinical populations are reviewed. Specific brain areas that play an important role in a variety of types of memory are also preferentially affected by stress, including hippocampus, amygdala, medial prefrontal cortex, and cingulate. This review indicates the involvement of these brain systems in the stress response, and in learning and memory. Affected systems in the neural circuitry of PTSD are reviewed (hypothalamic-pituitary-adrenal axis (HPA-axis), catecholaminergic and serotonergic systems, endogenous benzodiazepines, neuropeptides, hypothalamic-pituitary-thyroid axis (HPT-axis), and neuro-immunological alterations) as well as changes found with structural and functional neuroimaging methods. Converging evidence has emphasized the role of early-life trauma in the development of PTSD and other trauma-related disorders. Current and new targets for systems that play a role in the neural circuitry of PTSD are discussed. This material provides a basis for understanding the psychopathology of stress-related disorders, in particular PTSD.     

Neopterin production in posttraumatic stress disorder before and after pharmacotherapy

Post-traumatic stress disorder (PTSD) has been associated with decreased neopterin levels. In the present study, we evaluated whether this low neopterin levels would normalize following pharmacotherapy with sertraline in PTSD. Fourteen patients with PTSD and 14 controls were enrolled in the study. A clinical evaluation and measurements of neopterin levels before and after sertraline treatment were performed. In addition, all patients were assessed with the Clinician Administered PTSD Scale (CAPS). The mean neopterin levels were significantly lower in the patient group than control group at baseline and were negatively correlated with the duration of illness, or severity of illness. Sertraline treatment decreased the symptoms of PTSD; however this was not accompanied by a significant increase in neopterin production. In conclusion, our results reveal that the failure for neopterin to normalize through symptom alleviation suggests that either neopterin may be a trait marker of the illness, or that more sustained treatment is necessary to elevate the neopterin production. Received: 30 September 2002 / Accepted: 12 December 2002 Correspondence to Dr. Murad Atmaca     

Neopterin levels and dexamethasone suppression test in posttraumatic stress disorder

Neopterin has recently gained growing importance as an immunological marker in psychiatric disorders. In the present study, we aimed to evaluate whether the dexamethasone suppression test (DST) and neopterin were associated with posttraumatic stress disorder (PTSD). Fourteen patients with PTSD and 14 controls were enrolled in the study. A clinical evaluation and measurements of cortisol and neopterin levels before and after DST were performed. Additionally, all patients were assessed by Clinician Administered PTSD Scale (CAPS). There was a significantly higher DST nonsuppression in the patient group than control group. There were positive correlations between the duration of illness and CAPS, basal cortisol or postdexamethasone cortisol levels in the patient group. The mean neopterin levels for both before and after DST were significantly lower in the patient group than control group. In conclusion, our results suggest that not only the patients with PTSD have considerable DST nonsuppression but also PTSD may be associated with neopterin. Received: 13 February 2002 / Accepted: 13 June 2002     

Hypocortisolism and increased glucocorticoid sensitivity of pro-Inflammatory cytokine production in Bosnian war refugees with posttraumatic stress disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with dysregulation of the hypothalamus pituitary adrenal (HPA) axis. Alterations include various responses to HPA axis stimulation, different basal hormone levels, and changes in glucocorticoid receptor (GR) numbers on lymphocytes. The functional significance of these latter changes remains elusive. METHODS: Twelve Bosnian war refugees with PTSD and 13 control subjects were studied. On 2 consecutive days, they collected saliva samples after awakening and at 11, 15, and 20 hours. Glucocorticoid (GC) sensitivity was measured by dexamethasone (DEX) inhibition of lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) production in whole blood. RESULTS: The PTSD patients showed no cortisol response after awakening and had lower daytime cortisol levels (F = 14.57, p <.001). Less DEX was required for cytokine suppression in PTSD patients (IL-6: t = -2.82, p =.01; TNF-alpha: t = 5.03, p <.001), reflecting higher GC sensitivity of pro-inflammatory cytokine production. The LPS-stimulated production of IL-6, but not TNF-alpha, was markedly increased in patients (IL-6: F = 10.01, p <.004; TNF-alpha: F =.89, p =.34). CONCLUSIONS: In refugees with PTSD, hypocortisolism is associated with increased GC sensitivity of immunologic tissues. Whether this pattern reflects an adaptive mechanism and whether this is sufficient to protect from detrimental effects of low cortisol remains to be investigated.