Dorcas J. Dobie

Screening for post-traumatic stress disorder in female Veteran’s Affairs patients: validation of the PTSD checklist

We evaluated the screening validity of a self-report measure for post traumatic stress disorder (PTSD), the PTSD Checklist (PCL), in female Veterans Affairs (VA) patients. All women seen for care at the VA Puget Sound Health Care system from October 1996-January 1999 (n=2,545) were invited to participate in a research interview. Participants (n=282) completed the 17-item PCL, followed by a gold standard diagnostic interview for PTSD, the Clinician Administered PTSD Scale (CAPS). Thirty-six percent of the participants (n=100) met CAPS diagnostic criteria for current PTSD. Receiver Operating Characteristic (ROC) analysis was used to evaluate the screening performance of the PCL. The area under the ROC curve was 0.86 (95% CI 0.82-0.90). A PCL score of 38 optimized the performance of the PCL as a screening test (sensitivity 0.79, specificity 0.79). The PCL performed well as a screening measure for the detection of PTSD in female VA patients.

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.

Genome-Wide Linkage Analyses of 12 Endophenotypes for Schizophrenia From the Consortium on the Genetics of Schizophrenia

OBJECTIVE The Consortium on the Genetics of Schizophrenia has undertaken a large multisite study to characterize 12 neurophysiological and neurocognitive endophenotypic measures as a step toward understanding the complex genetic basis of schizophrenia. The authors previously demonstrated the heritability of these endophenotypes; in the present study, genetic linkage was evaluated. METHOD Each family consisted of a proband with schizophrenia, at least one unaffected sibling, and both parents. A total of 1,286 participants from 296 families were genotyped in two phases, and 1,004 individuals were also assessed for the endophenotypes. Linkage analyses of the 6,055 single-nucleotide polymorphisms that were successfully assayed, 5,760 of which were common to both phases, were conducted using both variance components and pedigree-wide regression methods. RESULTS Linkage analyses of the 12 endophenotypes collectively identified one region meeting genome-wide significance criteria, with a LOD (log of odds) score of 4.0 on chromosome 3p14 for the antisaccade task, and another region on 1p36 nearly meeting genome-wide significance, with a LOD score of 3.5 for emotion recognition. Chromosomal regions meeting genome-wide suggestive criteria with LOD scores >2.2 were identified for spatial processing (2p25 and 16q23), sensorimotor dexterity (2q24 and 2q32), prepulse inhibition (5p15), the California Verbal Learning Test (8q24), the degraded-stimulus Continuous Performance Test (10q26), face memory (10q26 and 12p12), and the Letter-Number Span (14q23). CONCLUSIONS Twelve regions meeting genome-wide significant and suggestive criteria for previously identified heritable, schizophrenia-related endophenotypes were observed, and several genes of potential neurobiological interest were identified. Replication and further genomic studies are needed to assess the biological significance of these results.

Inhibition of the P50 cerebral evoked response to repeated auditory stimuli: Results from the Consortium on Genetics of Schizophrenia

Inhibition of the P50 evoked electroencephalographic response to the second of paired auditory stimuli has been frequently examined as a neurophysiological deficit in schizophrenia. The Consortium on the Genetics of Schizophrenia (COGS), a 7-site study funded by the National Institute of Mental Health, examined this endophenotype in recordings from 181 probands with schizophrenia, 429 of their first degree relatives, and 333 community comparison control subjects. Most probands were treated with second generation antipsychotic medications. Highly significant differences in P50 inhibition, measured as either the ratio of amplitudes or their difference in response to the two stimuli, were found between the probands and the community comparison sample. There were no differences between the COGS sites for these findings. For the ratio parameter, an admixture analysis found that nearly 40% of the relatives demonstrated deficiencies in P50 inhibition that are comparable to the deficit found in the probands. These results indicate that P50 auditory evoked potentials can be recorded across multiple sites and reliably demonstrate a physiological abnormality in schizophrenia. The appearance of the physiological abnormality in a substantial proportion of clinically unaffected first degree relatives is consistent with the hypothesis that deficits in cerebral inhibition are a familial neurobiological risk factor for the illness.

Successful multi-site measurement of antisaccade performance deficits in schizophrenia

The antisaccade task is a promising schizophrenia endophenotype; it is stable over time and reflects neurophysiological deficits present in both schizophrenia subjects and their first-degree relatives. Meaningful genetic research requires large sample sizes that are best ascertained using multi-site study designs. To establish the criterion validity of the antisaccade task in a multi-site design, the Consortium on the Genetics of Schizophrenia (COGS) examined whether seven sites could detect previously reported antisaccade deficits in schizophrenia subjects. Investigators presented 3 blocks of 20 antisaccade stimuli to 143 schizophrenia subjects and 195 comparison subjects. Frequent collaborator communication, standardized training, and ongoing quality assurance optimized testing uniformity. Data were discarded from only 1.2% of subjects due to poor quality, reflecting the high fidelity of data collection and scoring methods. All sites detected a significant difference in the proportion of correct antisaccades between schizophrenia and comparison subjects (p<.02 at all sites); group differences in gain and latency were less robust. Regression analyses to adjust for the effects of group, site, age, gender, smoking, and parental education on the proportion of correct antisaccades revealed a significant effect of group, site, and age but no effect of gender, smoking, or parental education, and no group-by-site interactions. Intraclass correlations between proportion of correct antisaccades across the blocks of stimuli ranged from 0.87 to 0.93, demonstrating good within-session reliability at sites. These results confirm previous findings of antisaccade deficits in schizophrenia subjects and support the use of the antisaccade task as a potential schizophrenia endophenotype in multi-site genetic studies.

Effects of estrogen replacement on choline acetyltransferase and trkA mRNA expression in the basal forebrain of aged rats

The effects of one week of estrogen replacement on choline acetyltransferase (ChAT) and trkA mRNA expression are examined in young and aged rodents to determine whether estrogen continues to affect cholinergic neurons in aging brain. Significant increases in ChAT and trkA are observed in the nucleus basalis of Meynert (nBM) of both age groups. ChAT expression is also increased in the HDB without changes in trkA expression. Results indicate modulation of ChAT expression by estrogen is retained in the aged rodent brain and suggests the possibility that changes in ChAT expression may be dissociated from concurrent alterations in trkA.

Frequency of Mastalgia Among Women Veterans

AbstractOBJECTIVE: To determine the prevalence and frequency of mastalgia and its association with psychiatric conditions and unexplained pain syndromes. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional mailed survey completed by 1,219 female veterans enrolled at the VA Puget Sound Health Care System in 1998. MEASUREMENTS: Breast pain in the past year, unrelated to pregnancy, was categorized as infrequent (≤ monthly) or frequent (≥ weekly) mastalgia. Surveys assessed posttraumatic stress disorder (PTSD), depression, panic disorder, and alcohol misuse with validated screening tests, as well as self-reported past-year chronic pelvic pain, fibromyalgia, and irritable bowel syndrome. RESULTS: The response rate was 63%. Fifty-five percent of the respondents reported past-year mastalgia. Of these, 15% reported frequent mastalgia. Compared to women without mastalgia, women reporting frequent mastalgia were more likely to screen positive for PTSD (odds ratio [OR] 5.2, 95% confidence interval [CI] 3.2 to 8.4), major depression (OR 4.2, 2.6 to 6.9), panic disorder (OR 7.1, 3.9 to 12.8), eating disorder (OR 2.6, 1.5 to 4.7), alcohol misuse (OR 1.8, 1.1 to 2.8), or domestic violence (OR 3.1, 1.9 to 5.0), and to report fibromyalgia (OR 3.9, 2.1 to 7.4), chronic pelvic pain (OR 5.4, 2.7 to 10.5), or irritable bowel syndrome (OR 2.8, 1.6 to 4.8). Women with infrequent mastalgia were also more likely than women without mastalgia to screen positive for PTSD, depression, or panic disorder, or report pelvic pain or irritable bowel syndrome, although associations were weaker than with frequent mastalgia. CONCLUSIONS: Like other unexplained pain syndromes, frequent mastalgia is strongly associated with PTSD and other psychiatric conditions. Clinicians seeing patients with frequent mastalgia should inquire about anxiety, depression, alcohol misuse, and trauma history.

Cerebrospinal Fluid Epinephrine in Alzheimer’s Disease and Normal Aging

Central nervous system (CNS) adrenergic systems are involved in regulation of behavior and blood pressure. The effects of Alzheimers disease (AD) and normal aging on resting CNS adrenergic activity were estimated by measuring cerebrospinal fluid (CSF) epinephrine (EPI) concentrations in 74 persons with AD, 42 cognitively normal healthy older persons, and 54 healthy young persons. The responsiveness of CSF EPI to the alpha-2 adrenergic antagonist yohimbine and the alpha-2 adrenergic agonist clonidine was measured in smaller subject groups. Resting CSF EPI was higher in AD than in older or young subjects, and increased with dementia severity in AD subjects. There was no relationship between resting CSF EPI and blood pressure. CSF EPI increased following yohimbine in AD and older subjects but not in young subjects. CSF EPI was unaffected by clonidine in all subject groups. The agitation increase following yohimbine was substantially greater in AD subjects than in older or young subjects. CNS adrenergic activity seems increased in AD, may further increase as AD progresses, and may be involved in the pathophysiology of agitation.

Characteristics of Deployed Operation Iraqi Freedom Military Personnel Who Seek Mental Health Care

INTRODUCTION This study reports on the feasibility of using validated mental health screening instruments for deployed Operation Iraqi Freedom military personnel. METHODS For a 3-month period in 2005, all service members (N=296) who initially presented to the U.S. Military Hospital Kuwait mental health clinic completed an intake questionnaire that gathered demographic information and contained validated instruments to screen for mental disorders and functional impairment. RESULTS A total of 19% of the sample subjects screened positive for post-traumatic stress disorder-related symptoms, 35% for a major depressive disorder, and 11% for severe misuse of alcohol. Significant levels of distress and functional impairment were reported by 58% of the sample. Women represented a disproportionately high percentage of those presenting for care (27%). CONCLUSIONS Screening instruments were well accepted and useful in detecting psychopathological conditions and functional impairment. Female service members might represent a high-risk group. These results are useful for those caring for service members during or after deployment.

Hypothalamic-pituitary-adrenocortical axis responses to physostigmine : Effects of Alzheimer's disease and gender

We asked whether hypothalamic-pituitary-adrenocortical (HPA) axis responses to a cholinergic stimulus are blunted in patients with Alzheimers disease (AD) of mild to moderate severity. Such a finding would be consistent with a central cholinergic deficiency early in the course of AD. To address this question, we measured the plasma adrenocorticotropic hormone (ACTH), beta-endorphin-like immunoreactivity (beta E-LI), and cortisol responses to the cholinesterase inhibitor physostigmine in 10 healthy normal older subjects (age = 71 +/- 2 years) and 11 outpatients with probable AD (age = 72 +/- 2 years; Mini Mental State Exam score = 19 +/- 2). Cortisol concentrations were higher in AD subjects throughout the study, but AD and normal older subjects had similar robust ACTH, beta E-LI, and cortisol responses to physostigmine. In all subjects combined, women had greater ACTH, beta E-LI, and cortisol responses to physostigmine than did men. Plasma physostigmine concentrations did not differ between groups. These results suggest that female gender enhances the magnitude of HPA axis responses to cholinergic stimulation in older humans; however, the HPA axis response to physostigmine does not appear to reflect central cholinergic deficiency in the early stages of AD.