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.     

Relationships among hippocampal volumetry, proton magnetic resonance spectroscopy, and verbal memory in temporal lobe epilepsy

PURPOSE: To examine the relationship between hippocampal volumes, 1H magnetic resonance spectroscopy (MRS)-identified hippocampal metabolic function, and verbal memory in patients with unilateral mesial temporal lobe epilepsy (MTLE). METHODS: Hippocampal volumes, 1H MRS-derived hippocampal creatine to N-acetylaspartate (Cr/NAA), and verbal memory assessment were obtained preoperatively in 22 patients (six right, 16 left) with EEG-defined unilateral MTLE. RESULTS: Left hippocampal volume correlated significantly with left hippocampal Cr/NAA (r=-0.549, p < 0.01), whereas right volume correlated significantly with right Cr/NAA (r=-0.478, p < 0.05). Verbal memory correlated significantly with left hippocampal Cr/NAA (r=-0.594, p < 0.01), but not with left hippocampal volume or right hippocampal measures. CONCLUSIONS: Hippocampal volumes and 1H MRS-derived metabolite ratios are statistically related, but share only a small percentage of variance, suggesting separate but related pathophysiologic processes. Left hippocampal Cr/NAA appears to be more sensitive to verbal memory function than volumes.     

Decreased N-acetyl-aspartate levels in anterior cingulate and hippocampus in subjects with post-traumatic stress disorder: a proton magnetic resonance spectroscopy study

The purpose of this study was to investigate the concentration of N-acetyl-aspartate (NAA) in the brain and its relationship with clinical characteristics in patients with post-traumatic stress disorder (PTSD). Proton magnetic resonance spectroscopy was performed in order to measure NAA concentrations in the anterior cingulate cortex (ACC) and bilateral hippocampus in 26 subjects with fire-related PTSD, who were survivors of a subway fire in South Korea, and 25 age- and sex-matched healthy comparison subjects. There were decreased NAA levels in the ACC (t = -3.88, d.f. = 49, P < 0.001) and bilateral hippocampus (right, t = -3.88, d.f. = 49, P < 0.001; left, t = -3.62, d.f. = 49, P < 0.001) in the PTSD group relative to the healthy comparison group. Also, NAA levels of the ACC (r = -0.43, n = 26, P = 0.027) and bilateral hippocampus (right, r = -0.48, n = 26, P = 0.013; left, r = -0.40, n = 26, P = 0.04) were negatively correlated with re-experience symptom scores in subjects with PTSD. In conclusion, our findings suggest that subjects with PTSD had decreased neuronal viabilities in the ACC and bilateral hippocampus, and that these deficits may play an important role in the pathophysiology of PTSD, especially regarding the re-experiencing of traumatic events.     

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 dexamethasone suppression test for Japanese with eating disorders

A one-mg oral overnight dexamethasone suppression test (DST) was conducted on 22 inpatients with eating disorders. To confirm that the dexamethasone tablets had been ingested, we measured the plasma concentrations of dexamethasone the next morning (at 0900 hr after DST). The diagnosis of anorexia nervosa and bulimia was made according to the criteria for DSM-III, respectively. Of the 22 patients with eating disorders, 16 satisfied the criteria for anorexia nervosa and 6 for bulimia. The DST was carried out within 2 weeks of hospitalization on each patient. The subjects were given 1 mg of dexamethasone in the evening (at 2300 hr) and blood samples were collected the following day (at 0900, 1600 and 2100 hr, respectively). The plasma cortisol and dexamethasone levels were concurrently determined by RIA. The criterion for non-suppression was a failure to suppress the plasma cortisol levels below 5.0 micrograms/dl in any one of the three samples. All but one patient with bulimia had ingested the dexamethasone. Thirteen (62%) of 21 patients with eating disorders were nonsuppressors. We found a significant positive correlation between the plasma cortisol levels at 1600 hr or 2100 hr and a decrease in ideal body weight (n = 16, r = 0.613, p less than 0.05; r = 0.75, p less than 0.01, respectively) and a significant inverse relationship between the plasma dexamethasone levels at 0900 hr and the plasma cortisol levels at 1600 hr was recognized (n = 21, r = 0.631, p less than 0.01). These results suggest that the blood dexamethasone levels as well as body weight might contribute to the abnormalities of DST seen in patients with eating disorders.     

The Dexamethasone Suppression Test for Japanese with Eating Disorders

Abstract: A one-mg oral overnight dexamethasone suppression test (DST) was conducted on 22 inpatients with eating disorders. To confirm that the dexamethasone tablets had been ingested, we measumd the plasma concentrations of dexamethasone the next morning (at 0900 hr after DST). The diagnosis of anorexia nervosa and bulimia was made according to the criteria for DSM-III, respectively. Of the 22 patients with eating disorders, 16 satisfied the criteria for anorexia nervosa and 6 for bulimia. The DST was carried out within 2 weeks of hospitalization on each patient. The subjects were given 1 mg of dexamethasone in the evening (at 2300 hr) and blood samples were collected the following day (at 0900, 1600 and 2100 hr, respectively). The plasma cortisol and dexamethasone levels were concurrently determined by RIA. The criterion for non-suppression was a failure to suppress the plasma cortisol levels below 5.0 μg/dl in any one of the three samples. All but one patient with bulimia had ingested the dexamethasone. Thirteen (62%) of 21 patients with eating disorders were nonsuppressors. We found a significant positive correlation between the plasma cortisol levels at 1600 hr or 2100 hr and a decrease in ideal body weight (n = 16, r = 0.613, p < 0.05; r = 0.75, p < 0.01, respectively) and a significant inverse relationship between the plasma dexamethasone levels at 0900 hr and the plasma cortisol levels at 1600 hr was recognized (n = 21, r - 0.631, p < 0.01). These results suggest that the blood dexamethasone levels as well as body weight might contribute to the abnormalities of DST seen in patients with eating disorders.     

Enhanced sensitivity to glucocorticoids in peripheral mononuclear leukocytes in posttraumatic stress disorder.

BACKGROUND: The aim of this study was to determine whether there is increased responsiveness to corticosteroids in posttraumatic stress disorder (PTSD) by examining the differential effects of dexamethasone (DEX) on the inhibition of lysozyme activity. METHODS: 60 mL of blood was withdrawn at 8:00 am, and mononuclear leukocytes were isolated from the blood of 26 men with, and 18 men without, PTSD. An aliquot of live cells was incubated with a series of concentrations of DEX to determine the rate of inhibition of lysozyme activity; a portion of cells was frozen for the determination of glucocorticoid receptors (GR). RESULTS: Subjects with PTSD showed evidence of a greater sensitivity to glucocorticoids as reflected by a significantly lower mean concentration (nmol/L) of dexamethasone at which 50% of lysozyme activity is inhibited (IC(50-DEX)) (PTSD+ = 4.9 +/-.53; PTSD- group = 7.2 +/-.64). The lysozyme IC(50-DEX) was significantly correlated with age at exposure to the first traumatic event in subjects with PTSD (r =.44, n = 26, p =.025). The number of cytosolic glucocorticoid receptors was also correlated with age at exposure to the focal traumatic event (r = -.44, n = 25, p =.03) in PTSD. CONCLUSIONS: This is the first in vitro demonstration of an alteration in target tissue sensitivity to glucocorticoids in PTSD. The lower lysozyme IC(50-DEX) might be related to the risk factor of prior exposure to trauma.     

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.     

Myths of neuropsychology: intelligence, neurometabolism, and cognitive ability

Recently, Dodrill (1999) revised a previously described "Myth of neuropsychology" (1997) to state: "Just as below average performances on neuropsychological tests are found when intelligence is below average, to that same degree above average performances on neuropsychological tests are expected when intellectual abilities are above average." This study addresses the relationship between intellectual and neuropsychological performance in the context of Magnetic Resonance Spectroscopy (MRS) measurements of the neurometabolite N-acetylaspartate (NAA). When subjects were stratified by Full Scale IQ (Average, High Average, Superior) they differed significantly in terms of total neuropsychological performance [F(2,47) = 17.63; p <.001] and the neuronal marker NAA [F(2,47) = 3.25; p <.05]. Regression analysis across groups demonstrated that FSIQ and NAA were independently related to Total z-score [F(1,47) = 29.43; p <.0001] and accounted for over half the variance (r(2) of model =.56). The concurrent relationship of FSIQ and NAA to total neuropsychological performance suggests that the relationship between measures sensitive to intellectual ability and neuropsychological performance is real, and does not reflect arbitrary psychometric or scaling properties of the WAIS-III.     

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.     

Bilateral hippocampal volume reduction in adults with post-traumatic stress disorder: a meta-analysis of structural MRI studies

Over the last decade a significant number of studies have reported smaller hippocampal volume in individuals with symptoms of post-traumatic stress disorder (PTSD) relative to control groups, and in some cases hemispheric asymmetries in this effect have been noted. However these reported asymmetries have not been in a consistent direction, and other well-controlled studies have failed to observe any hippocampal volume difference. This paper reports a systematic review and meta-analysis of studies in which hippocampal volume was estimated from magnetic resonance images in adult patients with PTSD. After applying a variety of selection criteria intended to minimize potential confounds in pooled effect-size estimates, the meta-analysis included 13 studies of adult patients with PTSD that compared the patients to well-matched control groups, for a total of 215 patients and 325 control subjects. The studies varied with respect to participant age, gender distribution, source of trauma, severity of symptoms, duration of disorder, the nature of the control groups, and the methods employed for volumetric quantification. Despite these differences, pooled effect size calculations across the studies indicated significant volume differences in both hemispheres. On average PTSD patients had a 6.9% smaller left hippocampal volume and a 6.6% smaller right hippocampal volume compared with control subjects. These volume differences were smaller when comparing PTSD patients with control subjects exposed to similar levels of trauma, and larger when comparing PTSD patients to control subjects without significant trauma exposure. Such differences are consistent with the notion that exposure to stressful experiences can lead to hippocampal atrophy, although prospective studies would be necessary to unambiguously establish such a relationship.     

Abnormal N-acetylaspartate in hippocampus and anterior cingulate in posttraumatic stress disorder

Magnetic resonance spectroscopic imaging (MRSI) studies suggest hippocampal abnormalities in posttraumatic stress disorder (PTSD), whereas findings of volume deficits in the hippocampus, as revealed with magnetic resonance imaging (MRI), have been inconsistent. Co-morbidities of PTSD, notably alcohol abuse, may have contributed to the inconsistency. The objective was to determine whether volumetric and metabolic abnormalities in the hippocampus and other brain regions are present in PTSD, independent of alcohol abuse. Four groups of subjects, PTSD patients with (n=28) and without (n=27) alcohol abuse and subjects negative for PTSD with (n=23) and without (n=26) alcohol abuse, were enrolled in this observational MRI and MRSI study of structural and metabolic brain abnormalities in PTSD. PTSD was associated with reduced N-acetylaspartate (NAA) in both the left and right hippocampus, though only when normalized to creatine levels in the absence of significant hippocampal volume reduction. Furthermore, PTSD was associated with reduced NAA in the right anterior cingulate cortex regardless of creatine. NAA appears to be a more sensitive marker for neuronal abnormality in PTSD than brain volume. The alteration in the anterior cingulate cortex in PTSD has implications for fear conditioning and extinction.     

Hyperresponsiveness of hypothalamic-pituitary-adrenal axis to combined dexamethasone/corticotropin-releasing hormone challenge in female borderline personality disorder subjects with a history of sustained childhood abuse.

BACKGROUND: High coincidence of childhood abuse, major depressive disorder (MDD), and posttraumatic stress disorder (PTSD) has been reported in patients with borderline personality disorder (BPD). Animals exposed to early trauma show increased stress-induced hypothalamic-pituitary-adrenal (HPA) axis activity due to an enhanced corticotropin-releasing hormone (CRH) drive and glucocorticoid feedback resistance. In humans, PTSD and MDD are associated with decreased and increased resistance to glucocorticoid feedback, respectively, which might reflect persistent changes in neuroendocrine sequelae following childhood abuse. METHODS: We investigated the relationship between childhood abuse and HPA axis function using a combined dexamethasone/CRH (DEX/CRH) test in 39 BPD patients with (n = 24) and without (n = 15) sustained childhood abuse and comorbid PTSD (n = 12) or MDD (n = 11) and 11 healthy control subjects. RESULTS: Chronically abused BPD patients had a significantly enhanced corticotropin (ACTH) and cortisol response to the DEX/CRH challenge compared with nonabused subjects. Comorbid PTSD significantly attenuated the ACTH response. CONCLUSIONS: Hyperresponsiveness of the HPA axis in chronically abused BPD subjects might be due to the enhanced central drive to pituitary ACTH release. Sustained childhood abuse rather than BPD, MDD, or PTSD pathology accounts for this effect. Possibly due to an enhanced efficacy of HPA suppression by dexamethasone, PTSD attenuates the ACTH response to DEX/CRH.     

The dexamethasone suppression test and thyrotropin-releasing hormone stimulation test in posttraumatic stress disorder

Male veterans with posttraumatic stress disorder (PTSD) (n = 11), including 6 with concurrent major depressive disorder (MDD), were compared to veterans with MDD alone (n = 18) and to 28 controls in their response to the dexamethasone suppression test (DST) and thyrotropin-releasing hormone (TRH) stimulation tests. We found higher levels of 4 PM serum cortisol and lower peak thyroid-stimulating hormone (TSH) response to TRH in the MDD patients than in either the PTSD patients or controls, in spite of equivalent levels of depression for MDD and PTSD. DST suppression (cortisol less than 5 mg/dl) occurred in 90% of control, 90% of PTSD, and 78% of MDD subjects, whereas TRH blunting (dTSHmax less than 7 microU/ml) occurred in 28% of control, 27% of PTSD, and 67% of MDD subjects. Rather than blunting, four PTSD patients (36%) and only 10% of the control and MDD subjects had high TSH responses (13-24 microU/ml), which may be linked to high noradrenergic activity, since subclinical hypothyroidism seemed unlikely.     

The ACTH response to dexamethasone in PTSD

OBJECTIVE: Enhanced negative feedback and reduced adrenal output are two different models that have been put forth to explain the paradoxical observations of increased release of corticotropin-releasing factor in the face of low cortisol levels in posttraumatic stress disorder (PTSD). To discriminate between these models, the authors measured levels of adrenocorticopic hormone (ACTH) and cortisol at baseline and in response to dexamethasone in medically healthy subjects with and without PTSD. Under conditions of enhanced negative feedback inhibition, ACTH levels would not be altered relative to cortisol levels, but the ACTH response to dexamethasone would be augmented, in concert with the enhanced cortisol response to dexamethasone. In contrast, under conditions of reduced adrenal output, ACTH levels would be expected to be higher at baseline relative to cortisol levels, but the ACTH response to dexamethasone would be unchanged in PTSD relative to healthy comparison subjects. METHOD: The ACTH and cortisol responses to 0.50 mg of dexamethasone were assessed in 19 subjects (15 men and four women) with PTSD and 19 subjects (14 men and five women) without psychiatric disorder. RESULTS: The ACTH-to-cortisol ratio did not differ between groups before or after dexamethasone, but the subjects with PTSD showed greater suppression of ACTH (as well as cortisol) in response to dexamethasone. CONCLUSIONS: The data support the hypothesis of enhanced cortisol negative feedback inhibition of ACTH secretion at the level of the pituitary in PTSD. Pituitary glucocorticoid receptor binding, rather than low adrenal output, is implicated as a likely mechanism for this effect.     

Salivary cortisol responses to dexamethasone in adolescents with posttraumatic stress disorder

OBJECTIVE: Previous studies of adults with posttraumatic stress disorder (PTSD) have found various abnormalities in the regulation of the hypothalamic-pituitary-adrenal axis, including enhanced suppression of cortisol following low-dose dexamethasone. The purpose of the present study was to investigate salivary cortisol responses to low-dose dexamethasone in adolescents with PTSD. METHOD: Forty-eight adolescents (20 with current PTSD, 9 trauma controls without PTSD, and 19 healthy nontraumatized controls) were enrolled in the study. On day 1, baseline saliva samples were obtained at 8 a.m. and 0.5 mg of dexamethasone was administered at 11 p.m. Cortisol and dexamethasone levels were assessed at 8 a.m. the following day. RESULTS: Adolescents with current PTSD showed no difference in the suppression of salivary cortisol in response to low-dose (0.5 mg) dexamethasone compared to trauma controls without PTSD and nontraumatized controls. More severely affected PTSD subjects with co-occurring major depression showed higher pre- and post-dexamethasone salivary cortisol levels compared to controls. CONCLUSIONS: The present study did not find evidence for enhanced suppression of salivary cortisol at 8 a.m. following low-dose dexamethasone in multiply traumatized adolescents with PTSD. This result differs from findings in adults with PTSD. Further investigations of hypothalamic-pituitary-adrenal axis abnormalities in traumatized children and adolescents are needed.     

Stress sensitivity in metastatic breast cancer: analysis of hypothalamic-pituitary-adrenal axis function

The normal diurnal cortisol cycle has a peak in the morning, decreasing rapidly over the day, with low levels during the night, then rising rapidly again to the morning peak. A pattern of flatter daytime slopes has been associated with more rapid cancer progression in both animals and humans. We studied the relationship between the daytime slopes and other daytime cortisol responses to both pharmacological and psychosocial challenges of hypothalamic-pituitary-adrenal (HPA) axis function as well as DHEA in a sample of 99 women with metastatic breast cancer, in hopes of elucidating the dysregulatory process. We found that the different components of HPA regulation: the daytime cortisol slope, the rise in cortisol from waking to 30 min later, and cortisol response to various challenges, including dexamethasone (DEX) suppression, corticotrophin releasing factor (CRF) activation, and the Trier Social Stress Task, were at best modestly associated. Escape from suppression stimulated by 1mg of DEX administered the night before was moderately but significantly associated with flatter daytime cortisol slopes (r=0.28 to .30 at different times of the post DEX administration day, all p<.01). Daytime cortisol slopes were also moderately but significant associated with the rise in cortisol from waking to 30 min after awakening (r=.29, p=.004, N=96), but not with waking cortisol level (r=-0.13, p=.19). However, we could not detect any association between daytime cortisol slope and activation of cortisol secretion by either CRF infusion or the Trier Social Stress Task. The CRF activation test (following 1.5mg of DEX to assure that the effect was due to exogenous CRF) produced ACTH levels that were correlated (r=0.66, p<.0001, N=74) with serum cortisol levels, indicating adrenal responsiveness to ACTH stimulation. Daytime cortisol slopes were significantly correlated with the slope of DHEA (r=.21, p=.04, N=95). Our general findings suggest that flatter daytime cortisol slopes among metastatic breast cancer patients may be related to disrupted feedback inhibition rather than hypersensitivity in response to stimulation.     

Glucocorticoid feedback sensitivity and adrenocortical responsiveness in posttraumatic stress disorder.

BACKGROUND: Decreased basal cortisol levels have been reported in individuals with posttraumatic stress disorder (PTSD). There is evidence for enhanced negative feedback sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis in PTSD, which could account for this, but other possible mechanisms have not been ruled out. We examined the HPA axis employing a metyrapone-cortisol infusion protocol designed to study negative feedback sensitivity. METHODS: Vietnam combat trauma-exposed subjects met DSM-IV criteria for PTSD. Exclusion criteria included substance abuse and most medications. Endogenous feedback inhibition was removed by blocking cortisol synthesis with oral metyrapone and reintroduced by intravenous infusion of cortisol. In a placebo condition, subjects received oral placebo and normal saline infusion. Serial blood samples drawn over 4 hours were assayed for adrenocorticotrophic hormone (ACTH), cortisol, and 11-deoxycortisol. Selected samples were assayed for cortisol binding globulin (CBG) and dehydroepiandrosterone (DHEA). RESULTS: Basal plasma cortisol was significantly decreased in PTSD subjects (n = 13) compared with control subjects (n = 16). No significant difference in the ACTH response to cortisol infusion following metyrapone was observed; however 11-deoxycortisol was significantly decreased in PTSD subjects. In addition, CBG was significantly increased in PTSD subjects, and DHEA was significantly decreased in both PTSD and combat-exposed control subjects. CONCLUSIONS: These observations suggest decreased adrenocortical responsiveness may be an additional or alternative mechanism accounting for low cortisol in PTSD.     

Proton magnetic resonance spectroscopy of the hippocampus and occipital white matter in PTSD: preliminary results.

OBJECTIVE: Previous proton magnetic resonance spectroscopy (1H-MRS) studies in posttraumatic stress disorder (PTSD) report decreased hippocampal N-acetylaspartate (NAA), an indicator of neuronal integrity. However, other areas of the brain need to be explored. The objective of this study was to investigate the specificity of hippocampal NAA concentration changes in PTSD by also examining a control region, the occipital white matter (OWM). METHODS: Eight patients with PTSD and 5 control subjects underwent single-voxel 1H-MRS of the hippocampi and bilateral OWM. Absolute neurometabolite concentrations were determined. PRELIMINARY RESULTS: Trends toward reduced left hippocampal NAA and creatine (Cre) were found in the PTSD group. PTSD subjects also had reduced bilateral OWM Cre. CONCLUSIONS: The preliminary results of our study in civilians with PTSD replicate previous MRS studies and are consistent with decreased hippocampal neuronal integrity without effects in the OWM. Replication of our findings is needed.     

A.E. Bennett Research Award. Developmental traumatology. Part I: Biological stress systems.

BACKGROUND: This investigation examined the relationship between trauma, psychiatric symptoms and urinary free cortisol (UFC) and catecholamine (epinephrine [EPI], norepinephrine [NE], dopamine [DA]) excretion in prepubertal children with posttraumatic stress disorder (PTSD) secondary to past child maltreatment experiences (n = 18), compared to non-traumatized children with overanxious disorder (OAD) (n = 10) and healthy controls (n = 24). METHODS: Subjects underwent comprehensive psychiatric and clinical assessments and 24 hour urine collection for measurements of UFC and urinary catecholamine excretion. Biological and clinical measures were compared using analyses of variance. RESULTS: Maltreated subjects with PTSD excreted significantly greater concentrations of urinary DA and NE over 24 hours than OAD and control subjects and greater concentrations of 24 hour UFC than control subjects. Post hoc analysis revealed that maltreated subjects with PTSD excreted significantly greater concentrations of urinary EPI than OAD subjects. Childhood PTSD was associated with greater co-morbid psychopathology including depressive and dissociative symptoms, lower global assessment of functioning, and increased incidents of lifetime suicidal ideation and attempts. Urinary catecholamine and UFC concentrations showed positive correlations with duration of the PTSD trauma and severity of PTSD symptoms. CONCLUSIONS: These data suggest that maltreatment experiences are associated with alterations of biological stress systems in maltreated children with PTSD. An improved psychobiological understanding of trauma in childhood may eventually lead to better treatments of childhood PTSD.