Faculty Bibliography

Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P<5 x 10(-8)); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 x 10(-6)). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 x 10(-7) for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.

The Genomic Psychiatry Cohort (GPC) is a longitudinal resource designed to provide the necessary population-based sample for large-scale genomic studies, studies focusing on Research Domain Criteria (RDoC) and/or other alternate phenotype constructs, clinical and interventional studies, nested case-control studies, long-term disease course studies, and genomic variant-to-phenotype studies. We provide and will continue to encourage access to the GPC as an international resource. DNA and other biological samples and diagnostic data are available through the National Institute of Mental Health (NIMH) Repository. After appropriate review and approval by an advisory board, investigators are able to collaborate in, propose, and co-lead studies involving cohort participants.

This study investigated psychotherapy trainees' ability to facilitate change in outcomes (e.g., well-being, symptom reduction, and life functioning) specifically related to the phase model. Four different psychotherapist experience levels (beginning practicum, advanced practicum, intern/postdoc, and psychologist) were compared to determine whether there are training differences related to significant change for psychotherapy outcomes according to the phase model. A total of 1,318 clients from a university counseling center, treated by 64 psychotherapists, were included in the analysis for this study. Results indicate that interns/postdocs' clients achieve more significant change than psychologists' and advanced practicum students' clients related to life functioning. In addition, interns/postdocs' clients achieve more significant change related to symptom reduction, when compared with the clients of psychologists. Implications for these results, given the hypotheses of both the phase model and competency models, are discussed.

CONTEXT: In response to national efforts to improve quality of care, policymakers and health care leaders have increasingly turned to quality improvement collaboratives (QICs) as an efficient approach to improving provider practices and patient outcomes through the dissemination of evidence-based practices. This article presents findings from a systematic review of the literature on QICs, focusing on the identification of common components of QICs in health care and exploring, when possible, relations between QIC components and outcomes at the patient or provider level. METHODS: A systematic search of five major health care databases generated 294 unique articles, twenty-four of which met our criteria for inclusion in our final analysis. These articles pertained to either randomized controlled trials or quasi-experimental studies with comparison groups, and they reported the findings from twenty different studies of QICs in health care. We coded the articles to identify the components reported for each collaborative. FINDINGS: We found fourteen crosscutting components as common ingredients in health care QICs (e.g., in-person learning sessions, phone meetings, data reporting, leadership involvement, and training in QI methods). The collaboratives reported included, on average, six to seven of these components. The most common were in-person learning sessions, plan-do-study-act (PDSA) cycles, multidisciplinary QI teams, and data collection for QI. The outcomes data from these studies indicate the greatest impact of QICs at the provider level; patient-level findings were less robust. CONCLUSIONS: Reporting on specific components of the collaborative was imprecise across articles, rendering it impossible to identify active QIC ingredients linked to improved care. Although QICs appear to have some promise in improving the process of care, there is great need for further controlled research examining the core components of these collaboratives related to patient- and provider-level outcomes.

Fifty-six mothers of premature infants who participated in a study to reduce symptoms of posttraumatic stress disorder (PTSD) completed the Brief COPE, a self-report inventory of coping mechanisms, the Stanford Acute Stress Reaction Questionnaire to assess acute stress disorder (ASD) and the Davidson Trauma Scale to assess PTSD. 18 % of mothers had baseline ASD while 30 % of mothers met the criteria for PTSD at the 1-month follow-up. Dysfunctional coping as measured by the Brief COPE was positively associated with elevated risk of PTSD in these mothers (RR = 1.09, 95 % CI 1.02-1.15; p = .008). Maternal education was positively associated with PTSD; each year increase in education was associated with a 17 % increase in the relative risk of PTSD at 1 month follow-up (RR = 1.17, 95 % CI 1.02-1.35; p = .03). Results suggest that dysfunctional coping is an important issue to consider in the development of PTSD in parents of premature infants.

This functional magnetic resonance imaging study shows that children and adults with bipolar disorder (BD), compared with healthy subjects, exhibit impaired memory for emotional faces and abnormal fusiform activation during encoding. Fusiform activation abnormalities in BD were correlated with mania severity and may therefore represent a trait and state BD biomarker.

The data reported in the Technical Comments by Fitz et al., Price et al., Tesseur et al., and Veeraraghavalu et al. replicate and validate our central conclusion that bexarotene stimulates the clearance of soluble beta-amyloid peptides and results in the reversal of behavioral deficits in mouse models of Alzheimer's disease (AD). The basis of the inability to reproduce the drug-stimulated microglial-mediated reduction in plaque burden is unexplained. However, we concluded that plaque burden is functionally unrelated to improved cognition and memory elicited by bexarotene.

OBJECTIVES: Compare reported rates of mood-shifts from major depression to mania/hypomania/mixed-states during antidepressant (AD)-treatment and rates of diagnostic change from major depressive disorder (MDD) to bipolar disorder (BPD). METHODS: Searching computerized literature databases, followed by summary analyses. RESULTS: In 51 reports of patients diagnosed with MDD and treated with an AD, the overall risk of mood-switching was 8.18% (7837/95,786) within 2.39+/-2.99 years of treatment, or 3.42 (95% CI: 3.34-3.50) %/year. Risk was 2.6 (CI: 2.5-2.8) times greater with/without AD-treatment by meta-analysis of 10 controlled trials. Risk increased with time up to 24 months of treatment, with no secular change (1968-2012). Incidence rates were 4.5 (CI: 4.1-4.8)-times greater among juveniles than adults (5.62/1.26 %/year; p<0.0001). In 12 studies the overall rate of new BPD-diagnoses was 3.29% (1928/56,754) within 5.38 years (0.61 [0.58-0.64] %/year), or 5.6-times lower (3.42/0.61) than annualized rates of mood-switching. CONCLUSIONS: AD-treatment was associated with new mania-like responses in 8.18% of patients diagnosed with unipolar MDD. Contributions to mood-switching due to unrecognized BPD versus mood-elevating pharmacological effects, as well as quantitative associations between switching and later diagnosis of BPD not associated with AD-treatment remain uncertain. LIMITATIONS: Rates and definitions of mood-switching with ADs varied greatly, exposure-times rarely were precisely defined, and there was little information on predictive associations between mood-switches and BPD-diagnosis.

BACKGROUND:Women and men have diverse responses to many infectious diseases. These differences are amplified following menopause. However, despite extensive information regarding the effects of sex hormones on immune cells, our knowledge is limited regarding the effects of sex and gender on the function of the mucosal immune system. Sex differences also manifest in the prevalence of gut associated inflammatory and autoimmune disorders, including Crohn's disease, ulcerative colitis and Celiac disease. It is thus hypothesized that a baseline sex-associated difference in immune activation may predispose women to inflammation-associated disease. METHODS:Peripheral blood samples and small intestinal biopsies were obtained from 34 healthy men and women. Immunophenotypic analysis of isolated lymphocytes was performed by flow cytometry. Oligonucleotide analysis was used to study the transcriptional profile in the gut mucosal microenvironment while real-time PCR analysis was utilized to identify differential gene expression in isolated CD4+ T cells. Transcriptional analysis was confirmed by protein expression levels for genes of interest using fluorescent immunohistochemistry. Data was analyzed using the GraphPad software package. RESULTS:Women had higher levels of immune activation and inflammation-associated gene expression in gut mucosal samples. CD4+ and CD8+ T cells had a significantly higher level of immune activation-associated phenotype in peripheral blood as well as in gut associated lymphoid tissue along with higher levels of proliferating T cells. CD4+ T cells that showed upregulation of IL1β as well as the TH17 pathway-associated genes contributed a large part of the inflammatory profile. CONCLUSION/CONCLUSIONS:In this study, we demonstrated an upregulation in gene expression related to immune function in the gut microenvironment of women compared to men, in the absence of disease or pathology. Upon closer investigation, CD4+ T cell activation levels were higher in the LPLs in women than in men. Sex differences in the mucosal immune system may predispose women to inflammation-associated diseases that are exacerbated following menopause. Our study highlights the need for more detailed analysis of the effects of sex differences in immune responses at mucosal effector sites.