Adrenocortical responsiveness to infusions of physiological doses of ACTH is not altered in posttraumatic stress disorder

Early studies of posttraumatic stress disorder (PTSD) reported that abnormal function of the hypothalamic-pituitary-adrenocortical (HPA) system was associated with the disorder. However, subsequent studies attempting to identify a specific aspect of HPA dysfunction that characterizes PTSD have been marked by considerable inconsistency of results. A facet of HPA regulation that has been considered but not definitively investigated is the possibility that the responsiveness of the adrenal cortex to physiological concentrations of ACTH is diminished in PTSD. Relationships between PTSD and the adrenal androgen dehydroepiandrosterone (DHEA) have also been postulated. In this study we investigated the magnitude and time course of changes in concentrations of plasma cortisol and DHEA in response to bolus infusions of physiological doses of ACTH 1-24 in PTSD patients and control subjects. We found no evidence for PTSD-related alterations in cortisol or DHEA secretion in response to stimulation by low doses of ACTH and conclude that adrenocortical responsiveness is normal in PTSD. Results from this and other studies suggest that the occurrence of defects in HPA function in PTSD may be specific responses to particular combinations of trauma type, genetic susceptibility, and individual history

Adrenocortical responsiveness to infusions of physiological doses of ACTH is not altered in posttraumatic stress disorder

Early studies of posttraumatic stress disorder (PTSD) reported that abnormal function of the hypothalamic–pituitary–adrenocortical (HPA) system was associated with the disorder. However, subsequent studies attempting to identify a specifi c aspect of HPA dysfunction that characterizes PTSD have been marked by considerable inconsistency of results. A facet of HPA regulation that has been considered but not defi nitively investigated is the possibility that the responsiveness of the adrenal cortex to physiological concentrations of adrenocorticotropin (ACTH) is diminished in PTSD. Relationships between PTSD and the adrenal androgen dehydroepiandrosterone (DHEA) have also been postulated. In this study we investigated the magnitude and time course of changes in concentrations of plasma cortisol and DHEA in response to bolus infusions of physiological doses of ACTH1–24 in PTSD patients and control subjects. We found no evidence for PTSD-related alterations in cortisol or DHEA secretion in response to stimulation by low doses of ACTH and conclude that adrenocortical responsiveness is normal in PTSD. Results from this and other studies suggest that the occurrence of defects in HPA function in PTSD may be specifi c responses to particular combinations of trauma type, genetic susceptibility, and individual history.

Neurocognitive performance in family-based and case-control studies of schizophrenia.

BackgroundNeurocognitive deficits in schizophrenia (SZ) are established and the Consortium on the Genetics of Schizophrenia (COGS) investigated such measures as endophenotypes in family-based (COGS-1) and case-control (COGS-2) studies. By requiring family participation, family-based sampling may result in samples that vary demographically and perform better on neurocognitive measures.MethodsThe Penn computerized neurocognitive battery (CNB) evaluates accuracy and speed of performance for several domains and was administered across sites in COGS-1 and COGS-2. Most tests were included in both studies. COGS-1 included 328 patients with SZ and 497 healthy comparison subjects (HCS) and COGS-2 included 1195 patients and 1009 HCS.ResultsDemographically, COGS-1 participants were younger, more educated, with more educated parents and higher estimated IQ compared to COGS-2 participants. After controlling for demographics, the two samples produced very similar performance profiles compared to their respective controls. As expected, performance was better and with smaller effect sizes compared to controls in COGS-1 relative to COGS-2. Better performance was most pronounced for spatial processing while emotion identification had large effect sizes for both accuracy and speed in both samples. Performance was positively correlated with functioning and negatively with negative and positive symptoms in both samples, but correlations were attenuated in COGS-2, especially with positive symptoms.ConclusionsPatients ascertained through family-based design have more favorable demographics and better performance on some neurocognitive domains. Thus, studies that use case-control ascertainment may tap into populations with more severe forms of illness that are exposed to less favorable factors compared to those ascertained with family-based designs

Neurocognitive performance in family-based and case-control studies of schizophrenia.

BackgroundNeurocognitive deficits in schizophrenia (SZ) are established and the Consortium on the Genetics of Schizophrenia (COGS) investigated such measures as endophenotypes in family-based (COGS-1) and case-control (COGS-2) studies. By requiring family participation, family-based sampling may result in samples that vary demographically and perform better on neurocognitive measures.MethodsThe Penn computerized neurocognitive battery (CNB) evaluates accuracy and speed of performance for several domains and was administered across sites in COGS-1 and COGS-2. Most tests were included in both studies. COGS-1 included 328 patients with SZ and 497 healthy comparison subjects (HCS) and COGS-2 included 1195 patients and 1009 HCS.ResultsDemographically, COGS-1 participants were younger, more educated, with more educated parents and higher estimated IQ compared to COGS-2 participants. After controlling for demographics, the two samples produced very similar performance profiles compared to their respective controls. As expected, performance was better and with smaller effect sizes compared to controls in COGS-1 relative to COGS-2. Better performance was most pronounced for spatial processing while emotion identification had large effect sizes for both accuracy and speed in both samples. Performance was positively correlated with functioning and negatively with negative and positive symptoms in both samples, but correlations were attenuated in COGS-2, especially with positive symptoms.ConclusionsPatients ascertained through family-based design have more favorable demographics and better performance on some neurocognitive domains. Thus, studies that use case-control ascertainment may tap into populations with more severe forms of illness that are exposed to less favorable factors compared to those ascertained with family-based designs

Robust differences in antisaccade performance exist between COGS schizophrenia cases and controls regardless of recruitment strategies.

The impaired ability to make correct antisaccades (i.e., antisaccade performance) is well documented among schizophrenia subjects, and researchers have successfully demonstrated that antisaccade performance is a valid schizophrenia endophenotype that is useful for genetic studies. However, it is unclear how the ascertainment biases that unavoidably result from recruitment differences in schizophrenia subjects identified in family versus case-control studies may influence patient-control differences in antisaccade performance. To assess the impact of ascertainment bias, researchers from the Consortium on the Genetics of Schizophrenia (COGS) compared antisaccade performance and antisaccade metrics (latency and gain) in schizophrenia and control subjects from COGS-1, a family-based schizophrenia study, to schizophrenia and control subjects from COGS-2, a corresponding case-control study. COGS-2 schizophrenia subjects were substantially older; had lower education status, worse psychosocial function, and more severe symptoms; and were three times more likely to be a member of a multiplex family than COGS-1 schizophrenia subjects. Despite these variations, which were likely the result of ascertainment differences (as described in the introduction to this special issue), the effect sizes of the control-schizophrenia differences in antisaccade performance were similar in both studies (Cohen's d effect size of 1.06 and 1.01 in COGS-1 and COGS-2, respectively). This suggests that, in addition to the robust, state-independent schizophrenia-related deficits described in endophenotype studies, group differences in antisaccade performance do not vary based on subject ascertainment and recruitment factors

The Consortium on the Genetics of Endophenotypes in Schizophrenia: Model Recruitment, Assessment, and Endophenotyping Methods for a Multisite Collaboration

Background: The Consortium on the Genetics of Schizophrenia (COGS) is an ongoing, National Institute of Mental Health–funded, 7-site collaboration investigating the occurrence and genetic architecture of quantitative endophenotypes related to schizophrenia. The purpose of this article is to provide a description of the COGS structure and methods, including participant recruitment and assessment. Methods: The hypothesis-driven recruitment strategy ascertains families that include a proband with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of schizophrenia, and at least one unaffected full sibling available for genotyping and endophenotyping, along with parents available for genotyping and (optional depending on age) endophenotyping. The family structure is selected to provide contrast in quantitative endophenotypic traits and thus to maximize the power of the planned genetic analyses. Probands are recruited from many sources including clinician referrals, local National Alliance for the Mentally Ill chapters, and advertising via the media. All participants undergo a standardized protocol that includes clinical characterization, a blood draw for genotyping, and endophenotype assessments (P50 suppression, prepulse inhibition, antisaccade performance, continuous performance tasks, letter-number span, verbal memory, and a computerized neurocognitive battery). Investigators participate in weekly teleconferences to coordinate and evaluate recruitment, clinical assessment, endophenotyping, and continuous quality control of data gathering and analyses. Data integrity is maintained through use of a highly quality-assured, centralized web-based database. Results: As of February 2006, 355 families have been enrolled and 688 participants have been endophenotyped, including schizophrenia probands (n = 154, M:F = 110:44), first-degree biological relatives (n = 343, M:F = 151:192), and community comparison subjects (n = 191, M:F = 81:110). Discussion: Successful multisite genetics collaborations must institute standardized methodological criteria for assessment and recruitment that are clearly defined, well communicated, and uniformly applied. In parallel, studies utilizing endophenotypes require strict adherence to criteria for cross-site data acquisition, equipment calibration and testing and software equivalence, and continuous quality assurance for many measures obtained across sites. This report describes methods and presents the structure of the COGS as a model of multisite endophenotype genetic studies. It also provides demographic information after the first 2 years of data collection on a sample for whom the behavioral data and genetics of endophenotype performance will be fully characterized in future articles. Some issues discussed in the reviews that follow reflect the challenges of evaluating endophenotypes in studies of the genetic architecture of endophenotypes in schizophrenia

Posttraumatic Stress Disorder Screening Status is Associated with Increased VA Medical and Surgical Utilization in Women

BACKGROUND: Women with posttraumatic stress disorder (PTSD) report poor health, but associations with health care utilization are understudied. OBJECTIVE: To determine associations between medical/surgical utilization and PTSD in female Veterans Affairs (VA) patients. DESIGN: Prospective comparison of utilization rates between women screening positive or negative for PTSD on a mailed survey. SUBJECTS: Women receiving care at an urban VA medical center between October 1996 and January 2000. MEASUREMENTS: Survey responses, including a validated screen for PTSD (PCL-C), and VA utilization data through September 2002. RESULTS: Two thousand five hundred and seventy-eight (2,578) women (78% of those eligible) completed the PCL-C; 858 (33%) of them screened positive for PTSD (PTSD+). In unadjusted models, PTSD+ women had higher rates of medical/surgical hospitalizations and surgical inpatient procedures. Among women ages 35 to 49, mean days hospitalized/100 patients/year was 43.4 (95% CI 26 to 61) for PTSD+ women versus 17.0 (16 to 18) for PTSD negative (PTSD–) women. More PTSD+ women underwent surgical procedures (P<.001). Mean annual outpatient visits were significantly higher among PTSD+ women, including: emergency department (ED) (1.1 [1.0 to 1.2] vs 0.6 [0.5 to 0.6]), primary care (3.2 [3.0 to 3.4] vs 2.2 [2.1 to 2.3]), medical/surgical subspecialists (2.1 [1.9 to 2.3] vs 1.5 [1.4 to 1.6]), ancillary services (4.1 [3.7 to 4.5] vs 2.4 [2.2 to 2.6]), and diagnostic tests (5.6 [5.1 to 6.1] vs 3.7 [3.4 to 4.0]). In multivariate models adjusted for demographics, smoking, service access, and medical comorbidities, PTSD+ women had greater likelihood of medical/surgical hospitalization (OR=1.37 [1.04 to 1.79]) and of being among the top quartile of patients for visits to the ED, primary care, ancillary services, and diagnostic testing. CONCLUSIONS: Female veterans who screen PTSD+ receive more VA medical/surgical services. Appropriateness of that care deserves further study