Ren-Kui Yang

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 METHODS 60 mL of blood was withdrawn at 8:00 am, and mononuclear leukocytes were isolated from the blood of 26 men with, and 18 men without, PTSD.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.

Plasma norepinephrine and 3-methoxy-4-hydroxyphenylglycol concentrations and severity of depression in combat posttraumatic stress disorder and major depressive disorder.

BACKGROUND Catecholamines are thought to play a significant role in the pathophysiology of posttraumatic stress disorder (PTSD), but findings in PTSD have been discrepant. METHODS To obtain more information about catecholamine activity in PTSD, we sampled plasma norepinephrine (NE) and 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations over a 24-hour period in men with PTSD (n = 15) and major depressive disorder (MDD) (n = 12), and nonpsychiatric comparison subjects (n = 13), under unstimulated conditions. Chronobiological analyses were performed to determine possible changes in the circadian and ultradian release of these hormones. RESULTS Significant group differences were present for mean plasma NE levels (p = .03), but not MHPG. NE levels were significantly associated with severity of depression in the PTSD group (p = .002). Therefore, PTSD subjects were further subdivided into those with and without a comorbid secondary depression. Increased NE levels were only present in PTSD subjects who did not have a secondary depression. This study also found no significant group differences on any of the chronobiological parameters. CONCLUSIONS The results clarify that increased NE levels in PTSD may be confined to the subgroup of subjects who do not have comorbid depression, and as such, may help resolve some of the discrepancies in the literature regarding basal catecholamine activity.

Clinical correlates of DHEA associated with post‐traumatic stress disorder

Objective:  Increased plasma dehydroepiandrosterone (DHEA) and dehydroepiandrosterone‐sulfate (DHEAS) have been demonstrated in post‐traumatic stress disorder (PTSD), but the documented beneficial effects of these steroids in enhancing mood and cognition, as well as neuroprotection, suggest their presence in PTSD may be associated with defensive rather than maladaptive effects.

Alterations in cortisol negative feedback inhibition as examined using the ACTH response to cortisol administration in PTSD.

OBJECTIVE Studies using the dexamethasone suppression test (DST) have demonstrated an enhanced negative feedback inhibition at the pituitary in PTSD, but have not provided information about central feedback effects, since dexamethasone (DEX) does not penetrate the brain well. The authors therefore examined the change in ACTH and cortisol before and after cortisol administration, which acts at central feedback sites in addition to peripheral targets. METHOD Blood was obtained from 31 male veterans (18 with PTSD) before, and 8, 40 and 95 min following injection of 17.5 mg cortisol and placebo. RESULTS A greater decline in ACTH was observed after cortisol injection in PTSD. CONCLUSIONS Central as well as peripheral negative feedback inhibition may be altered in PTSD.

Predictors of Cortisol and 3-Methoxy-4-Hydroxyphenylglycol Responses in the Acute Aftermath of Rape

BACKGROUND Prospective studies of trauma survivors can provide information about the relationship between rape characteristics and the development of subsequent symptoms. METHODS The present study examined the relationship of prior assault, rape severity, posttraumatic stress disorder (PTSD) symptoms following rape, and subsequent PTSD diagnosis, to the acute cortisol and 3-methoxy-4-hydroxyphenylglycol (MHPG) response to this traumatic event in 20 women. RESULTS Women with a history of prior physical or sexual assault showed a significantly attenuated cortisol response to the acute stress of rape compared to women without such a history. MHPG appeared to be associated with injury-related rape characteristics, and symptoms of active avoidance, but not prior history. PTSD status at the 3-month follow-up was predicted by both a prior history of assault and high injury rape, but was not directly predicted by either cortisol or MHPG levels. MHPG and cortisol were not correlated in the sample as a whole, but were correlated among individuals who did not subsequently develop PTSD (p = .04) CONCLUSIONS The results suggest that different neuroendocrine systems may mediate different components of the response to traumatic stress.

CSF Somatostatin in alzheimer's disease, depressed patients, and control subjects ☆

The widespread use of the NINCDS criteria for Alzheimer’s disease (McKhann et al. 1984) has substantially improved diagnostic accuracy; however, the degree of misdiagnosis is still in the range of lo%-20% (Barclay et al. 1986). Thus, continuing investigations seek a readily accessible antemortem marker of Alzheimer’s disease. A logical point of initiation in a search for an antemortem biological marker is with the neurochemical changes that have been consistently reported in postmortem examinations of Alzheimer’s brains. Although a number of neurotransmitters have been reported to be decreased in some subgroups of Alzheimer’s patients, the most consistent abnormalities appear to involve acetylcholine (Perry 1987) and the neuropeptide somatostatin (Rossor et al. 1980; Davies and Terry 198 1). Cerebrospinal fluid (CSF) concentrations of somatostatin have been reported to be reduced

Relationship between dexamethasone-inhibited lysozyme activity in peripheral mononuclear leukocytes and the cortisol and glucocorticoid receptor response to dexamethasone

The assessment of lysozyme activity in mononuclear leukocytes (MNLs) following the in vitro administration of dexamethasone (DEX) provides a measure of peripheral glucocorticoid sensitivity. The goal of the present study was to determine the relationship between the IC(50) of lysozyme activity following such challenge, and the cortisol response to oral administration of 0.50 mg DEX in 18 healthy subjects. The results demonstrated a robust association between the IC(50) and both cortisol decline and percent suppression of cortisol in response to low-dose DEX. However, this measure was uncorrelated with pre or post DEX cortisol levels or GR number. The high correlation between the inhibitory effect of DEX on lysozyme synthesis and two measures reflecting cortisol suppression in response to oral DEX reflects the similarities of GC responsiveness in both in vivo and in vitro models, and suggests that the in vitro assessment of lysozyme activity in MNLs may be useful in the study of neuropsychiatric or other clinical disorder.

Correlations post-mortem between ventricular CSF and cortical tissue concentrations of MHPG, 5-HIAA and HVA in Alzheimer's disease

Alzheimer’s disease, characterized by plagues and tangles in hippocampal and cortical areas, is also associated with reduced choline acetylase and choline esterase, noradrenergic cell loss in the locus ceruleus and serotonergic impairment. We confirm the reported cholinergic, noradrenergic and serotonergic deficits in Alzheimer’s brain tissue. Furthermore, we find that concentrations of the norepinephrine metabolite , MHPG , of the serotonin metabolite, 5-HIAA and of the dopamine metabolite, HVA in most cerebral cortical regions correlate significantly with concentration of these substances in ventricular CSF post-mortem. Brains from 13 subjects (eight Alzheimer’s disease; two multi-infarct dementia control; one normal control and two other non-AD dementia) were divided into ten Brodman areas and a corresponding sample of ventricular CSF was also obtained at autopsy. All samples were assayed for amine metabolite concentration by HPLC with electrochemical detection. Regression analysis of tissue and CSF values of MHPG, 5-HIAA and HVA of all 13 subjects are shown in the table below. These data suggest that post-mortem ventricular CSF concentrations of MHPG , 5-HIAA and HVA are meaningful indicators of their concentrations in cortical tissue.

Effect of sertraline on glucocorticoid sensitivity of mononuclear leukocytes in post-traumatic stress disorder

This study examined the effects of sertraline (SER) on glucocorticoid sensitivity in mononuclear leukocytes (MNL) from eight subjects with current post-traumatic stress disorder (PTSD) and nine comparison subjects. In all, 60 ml of blood was withdrawn by venipuncture at 0800, and MNL were isolated from blood and divided into two portions: the first contained live cells incubated with a series of concentrations of dexamethasone (DEX); the second contained cells incubated with similar concentrations of DEX+2 μM SER. Group difference in the concentrations of DEX required to inhibit lysozyme activity by 50% were evaluated under conditions of DEX-only and DEX+SER using analysis of covariance (ANCOVA). A significant Group × Condition interaction reflected that SER altered the lysozyme IC50-DEX in the direction of decreasing sensitivity to glucocorticoids in PTSD while having no uniform effect in cells from comparison subjects. The data provide support for the idea that glucocorticoid receptors might be more responsive to antidepressants in PTSD than in persons without PTSD. Insofar as increased sensitivity to glucocorticoids has been linked with PTSD, the actions of SER on the lysozyme IC50-DEX suggest that this medication may target a biologic alteration associated with PTSD pathophysiology.

Effect of topiramate on glucocorticoid receptor mediated action.

This study examined the effects of topiramate (TPM) on glucocorticoid receptors (GRs) in mononuclear leukocytes of nine men and four women with chronic and recurring post-traumatic stress disorder (PTSD) and a group of comparison subjects (nine men, four women). A measure of 60 ml of blood was withdrawn by venipuncture at 0800 and mononuclear leukocytes were isolated. The cells were incubated with a series of concentrations of dexamethasone (DEX) without or with 50 μmol/l of TPM to evaluate the effects of DEX to inhibit lysozyme activity and the effect of TPM on it. ANCOVA compared the IC50 for lysozyme inhibition under conditions of DEX only and TPM+DEX. TPM affected lysozyme IC50 in the direction of increasing the sensitivity of the receptor in the sample as a whole. This effect was more pronounced in the mononuclear leukocytes from participants in the PTSD group, particularly in cells from subjects whose pretreatment lysozyme IC50 was relatively higher (eg, reflecting decreased glucococorticoid receptor responsiveness), compared to the rest of the sample. In conclusion, further investigation of the actions of TPM on GR and other neuroendocrine systems may prove useful in understanding some of the other established clinical effects of this agent.