Enhanced effects of cortisol administration on episodic and working memory in aging veterans with PTSD.

Though both glucocorticoid alterations and memory impairments have been noted in posttraumatic stress disorder (PTSD), it is not clear if these phenomena are causally linked. As there is emerging evidence that these domains become further altered in PTSD with increasing age, it is of interest to examine these relationships in an older cohort. Aging (mean age, 62.7+/-8.9; range, 52-81) combat veterans with (n=13) and without (n=17) PTSD received an intravenous bolus of 17.5 mg hydrocortisone (cortisol), a naturally occurring glucocorticoid, or placebo in a randomized, double-blind manner, on two mornings approximately 1-2 weeks apart. Neuropsychological testing to evaluate episodic and working memory performance was performed 75 min later. Cortisol enhanced episodic memory performance in both groups of subjects, but enhanced elements of working memory performance only in the PTSD+ group. The preferential effect of cortisol administration on working memory in PTSD may be related to the superimposition of PTSD and age, as cortisol had impairing effects on this task in a previously studied, younger cohort. The findings suggest that there may be opportunities for developing therapeutic strategies using glucocorticoids in the treatment of aging combat veterans.

Hippocampal volume in aging combat veterans with and without post-traumatic stress disorder: relation to risk and resilience factors.

OBJECTIVE: To examine whether there are post-traumatic stress disorder (PTSD) related differences in hippocampal volume in middle-aged and elderly veterans and to examine the relationship of neuroendocrine activity, memory performance, and measures of risk and resilience for PTSD to hippocampal volume in this cohort. METHODS: Seventeen veterans with chronic PTSD and 16 veterans without chronic PTSD received an MRI scan followed by neuroendocrine assessment (24-h urinary cortisol excretion and the lysozyme IC(50-DEX), a measure of glucocorticoid receptor (GR) responsiveness), and cognitive testing. RESULTS: Veterans with PTSD did not differ from those without PTSD in hippocampal volume, but they did show significantly lower urinary cortisol levels, and poorer memory performance on the Wechsler Logical Memory test and Digit Span test. Smaller left hippocampal volumes were observed in veterans who developed PTSD in response to their first reported traumatic exposure, compared to veterans who had first experienced a traumatic event to which they did not develop PTSD, prior to experiencing a subsequent event that led to PTSD. In contrast, the two neuroendocrine measures were associated with risk factors related to early trauma exposure. CONCLUSION: Although hippocampal volume was not found to differ between subjects with and without PTSD, smaller hippocampal volumes in PTSD may be associated with specific risk and resilience factors. These may be distinct from vulnerability markers associated with increased responsiveness to glucocorticoids and/or other neuroendocrine measures that have been observed in combat-related PTSD.

Longitudinal assessment of cognitive performance in Holocaust survivors with and without PTSD.

BACKGROUND: There are currently no longitudinal studies of cognitive performance in older patients with Posttraumatic Stress Disorder (PTSD). It is therefore unclear whether relationships between memory and symptoms differ over time among older persons with and without PTSD. METHODS: Twenty-eight Holocaust survivors and nineteen comparison subjects were evaluated 5 years after they had received a memory assessment including paired-associates learning and the California Verbal Learning Test (CVLT). RESULTS: While Holocaust survivors with PTSD showed a diminution in symptom severity (t = 2.99, df = 12, p = .011), they still manifested a decline in paired associates learning, suggesting an acceleration in age-related memory impairment (related word pairs: t = 2.87, df = 13, p = .013; unrelated word pairs: t = 2.06, df = 13, p = .060). The survivors with PTSD showed improvements on several CVLT measures over time. These improvements correlated with symptom improvements, such that group differences at the follow-up were no longer detected. CONCLUSIONS: The discrepancy in the pattern of performance on these two tests of memory following symptom improvement suggests possible differentiation between of aspects of memory functions associated with aging and trauma exposure and those associated with the severity of PTSD symptoms. Performance on the CVLT appeared related to clinical symptom severity while paired associate learning worsened over time in Holocaust survivors with PTSD, consistent with earlier cross-sectional findings.

The relationship between hippocampal volume and declarative memory in a population of combat veterans with and without PTSD.

Both reduced hippocampal volume and cognitive alterations have been found in posttraumatic stress disorder (PTSD). The purpose of this article was to examine the relationship between hippocampal volume, combat exposure, symptom severity, and memory performance in a sample of combat veterans with and without a history of PTSD. Subjects were 33 male veteran volunteers (16 PTSD+, 17 PTSD-) who underwent an MRI and neuropsychological testing with the California Verbal Learning Test (CVLT), a measure of declarative memory. Relationships between hippocampal volume (i.e., right + left hippocampal volume/whole brain volume) and performance on the CVLT were determined using partial correlational analysis controlled for age and Wechsler Adult Intelligence Scale, Third Edition (WAIS-III) vocabulary scores. Percent hippocampal volume for the entire sample was positively associated with several aspects of memory performance as reflected by the CVLT. In the PTSD+ group, CVLT performance was negatively correlated with lifetime, but not current CAPS symptoms. CVLT performance appears to be strongly correlated with hippocampal volume in a group of trauma survivors with and without PTSD. Insofar as CVLT performance in the PTSD group was negatively associated with worst episode, but not to current PTSD symptoms, memory performance in combat veterans may reflect some aspect of risk related to the magnitude of the psychological response to trauma, rather than current symptoms that may be interfering with cognitive performance. It will be of interest to study cognitive abilities that may relate to the likelihood of specific PTSD symptoms and to track changes in CVLT performance and hippocampal volume over time in persons with and without a history of trauma exposure.

Are adult offspring reliable informants about parental PTSD? A validation study.

We developed a short questionnaire--Parental PTSD Questionnaire--(PPQ), designed to assess the presence of posttraumatic stress disorder (PTSD) symptoms in parents. Fifty-eight adult offspring of Holocaust survivors (23 men and 35 women) completed the questionnaire about a parent who was independently evaluated by a trained clinician using the Clinician Administered PTSD Scale (CAPS). Only 5.2% of the offspring reported, "not knowing" if their parent had experienced 10 or fewer symptoms, while 56.9% provided estimates for all 17 items. There were no significant differences between lifetime frequencies of the individual symptoms as endorsed on the PPQ compared to the CAPS when subjects with completed PPQs were compared with CAPS. Interrater reliability between offspring and clinician was highly significant for each of the items when evaluated separately so as to include data for subjects who endorsed not knowing if a certain symptom had been present. Further studies are warranted to examine the psychometric properties of this measure.

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.

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 muM 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 x Condition interaction reflected that SER altered the lysozyme IC(50-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 IC(50-DEX) suggest that this medication may target a biologic alteration associated with PTSD pathophysiology.

Learning and memory in aging combat veterans with PTSD.

The California Verbal Learning Test (CVLT) was administered to examine learning and memory performance in aging combat veterans with (n = 30) and without PTSD (n = 20), and veterans unexposed to combat (n = 15). Combat veterans with PTSD (PTSD+) showed many impairments compared to non-exposed veterans, but only long-delay free recall consistently discriminated the PTSD+ group from combat-exposed subjects without PTSD (PTSD-), when data were corrected for subscale scores on the WAIS (Vocabulary, Block Design). Alterations in total learning were associated with PTSD when controlling for substance abuse and depression. Two contrast measures, proactive interference and recognition hits, distinguished combat from noncombat veterans, and may be related to trauma exposure. Impairments in total learning are similar to what has been observed in Holocaust survivors. However, increased severity of rapid forgetting may be a specific alteration in older combat veterans, likely reflecting aspects of both combat exposure and aging.

Relationship between cortisol and age-related memory impairments in Holocaust survivors with PTSD.

RATIONALE: Holocaust survivors with PTSD appear to show an accelerated aging effect as evidenced by their performance on tests of explicit memory, and also show more exaggerated patterns on age-related alterations in cortisol release over the diurnal cycle than Holocaust survivors without PTSD and nonexposed subjects. To investigate the implications of age-related HPA axis alterations on cognition, we examined correlations between parameters reflecting circadian cortisol release and implicit and explicit memory performance. METHODS: Nineteen Holocaust survivors with PTSD (7 men, 12 women), 16 Holocaust survivors without PTSD (7 men, 9 women), and 28 non-exposed healthy comparison subjects (13 men, 15 women) collected salivary samples at six times over the diurnal cycle, and were tested with Paired Associates and Word Stem Completion Tests. RESULTS: Negative correlations were observed between several measures of salivary cortisol concentrations and explicit memory in Holocaust survivors with PTSD after adjusting for IQ, years of education and current age reflecting poorer performance in association with higher cortisol levels. This relationship was absent in Holocaust survivors without PTSD and in demographically-comparable subjects who were not exposed to the Holocaust or other extremely traumatic events. CONCLUSION: The significantly different relationship between cortisol and memory performance in these groups suggests that the neuropsychological impairments observed in Holocaust survivors with PTSD may reflect an interaction of PTSD and aging effects.

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.

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 micromol/l of TPM to evaluate the effects of DEX to inhibit lysozyme activity and the effect of TPM on it. ANCOVA compared the IC(50) for lysozyme inhibition under conditions of DEX only and TPM+DEX. TPM affected lysozyme IC(50) 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 IC(50) 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.