Reduction of plasma glutathione in psychosis associated with schizophrenia and bipolar disorder in translational psychiatry.

The establishment of mechanism-driven peripheral markers is important for translational psychiatry. Many groups, including ours, have addressed molecular alterations in peripheral tissues in association with symptomatic changes in major illnesses. Oxidative stress is implicated in the pathophysiology of schizophrenia (SZ) and bipolar disorder (BP) through studies of patient peripheral tissues and animal models. Although the relationship between peripheral changes and brain pathology remain elusive, oxidative stress may bridge such translational efforts. Nonetheless, the molecular substrates of oxidative stress are not well defined in mental conditions. Glutathione (GSH) is a non-enzymatic antioxidant that eliminates free radicals, and has been suggested to have a role in SZ. We performed a cross-sectional study of 48 healthy controls (CON), 52 SZ patients and 62 BP patients to compare the levels of peripheral GSH by a biochemical enzyme assay. We show a significant reduction of plasma GSH in both SZ and BP patients compared with CON. We evaluated possible influences of clinical characteristics on the level of GSH in SZ and BP. A decrease in GSH level correlated with Positive and Negative Syndrome Scale (PANSS) total and positive scores for SZ and correlated with the PANSS general for BP. Taken together, we provide evidence that SZ and BP display a common molecular signature in the reduction of peripheral GSH in the psychosis dimension.

Mental health and psychosocial support in humanitarian settings: a public mental health perspective.

AIMS: To discuss the potential usefulness of a public health approach for 'mental health and psychosocial support' (MHPSS) interventions in humanitarian settings. METHODS: Building on public mental health terminology in accordance with recent literature on this topic and considering existing international consensus guidelines on MHPSS interventions in humanitarian settings, this paper reflects on the relevance of the language of promotion and prevention for supporting the rationale, design and evaluation of interventions, with a particular focus on populations affected by disasters and conflicts in low- and middle-income countries. RESULTS: A public mental health approach and associated terminology can form a useful framework in the design and evaluation of MHPSS interventions, and may contribute to reducing a divisive split between 'mental health' and 'psychosocial' practice in the humanitarian field. Many of the most commonly implemented MHPSS interventions in humanitarian settings can be described in terms of promotion and prevention terminology. CONCLUSIONS: The use of a common terminology across health, protection, education, nutrition and other relevant sectors providing humanitarian interventions has the potential to allow for integration of MHPSS activities in one overall framework, with diverse humanitarian practitioners working to achieve a common goal.

Epigenetic and genetic variation at SKA2 predict suicidal behavior and post-traumatic stress disorder.

Traumatic stress results in hypothalamic pituitary adrenal (HPA) axis abnormalities and an increased risk to both suicidal behaviors and post-traumatic stress disorder (PTSD). Previous work out of our laboratory identified SKA2 DNA methylation associations with suicidal behavior in the blood and brain of multiple cohorts. Interaction of SKA2 with stress predicted suicidal behavior with ~80% accuracy. SKA2 is hypothesized to reduce the ability to suppress cortisol following stress, which is of potentially high relevance in traumatized populations. Our objective was to investigate the interaction of SKA2 and trauma exposure on HPA axis function, suicide attempt and PTSD. SKA2 DNA methylation at Illumina HM450 probe cg13989295 was assessed for association with suicidal behavior and PTSD metrics in the context of Child Trauma Questionnaire (CTQ) scores in 421 blood and 61 saliva samples from the Grady Trauma Project (GTP) cohort. Dexamethasone suppression test (DST) data were evaluated for a subset of 209 GTP subjects. SKA2 methylation interacted with CTQ scores to predict lifetime suicide attempt in saliva and blood with areas under the receiver operator characteristic curve (AUCs) of 0.76 and 0.73 (95% confidence interval (CI): 0.6-0.92, P = 0.003, and CI: 0.65-0.78, P < 0.0001) and to mediate the suppression of cortisol following DST (ß = 0.5 ± 0.19, F = 1.51, degrees of freedom (df) = 12/167, P = 0.0096). Cumulatively, the data suggest that epigenetic variation at SKA2 mediates vulnerability to suicidal behaviors and PTSD through dysregulation of the HPA axis in response to stress.

A population-based study of the risk of schizophrenia and bipolar disorder associated with parent-child separation during development.

BACKGROUND: There is growing interest in the role of childhood adversities, including parental death and separation, in the etiology of psychotic disorders. However, few studies have used prospectively collected data to specifically investigate parental separation across development, or assessed the importance of duration of separation, and family characteristics. METHOD: We measured three types of separation not due to death: maternal, paternal, and from both parents, across the ages of 1-15 years among a cohort of 985 058 individuals born in Denmark 1971-1991 and followed to 2011. Associations with narrowly and broadly defined schizophrenia and bipolar disorder in the psychiatric register were assessed in terms of separation occurrence, age of separation, and number of years separated. Interactions with parental history of mental disorder were assessed. RESULTS: Each type of separation was associated with all three outcomes, adjusting for age, sex, birth period, calendar year, family history of mental disorder, urbanicity at birth and parental age. Number of years of paternal separation was positively associated with both schizophrenia and bipolar disorder. Associations between separation from both parents and schizophrenia were stronger when separation occurred at later ages, while those with bipolar disorder remained stable across development. The first occurrence of paternal separation appeared to increase risk more when it occurred earlier in childhood. Associations differed according to parental history of mental disorder, although in no situation was separation protective. CONCLUSIONS: Effects of parental separation may differ by type, developmental timing and family characteristics. These findings highlight the importance of considering such factors in studies of childhood adversity.

Smoking quit success genotype score predicts quit success and distinct patterns of developmental involvement with common addictive substances.

Genotype scores that predict relevant clinical outcomes may detect other disease features and help direct prevention efforts. We report data that validate a previously established v1.0 smoking cessation quit success genotype score and describe striking differences in the score in individuals who display differing developmental trajectories of use of common addictive substances. In a cessation study, v1.0 genotype scores predicted ability to quit with P=0.00056 and area under receiver-operating characteristic curve 0.66. About 43% vs 13% quit in the upper vs lower genotype score terciles. Latent class growth analyses of a developmentally assessed sample identified three latent classes based on substance use. Higher v1.0 scores were associated with (a) higher probabilities of participant membership in a latent class that displayed low use of common addictive substances during adolescence (P=0.0004) and (b) lower probabilities of membership in a class that reported escalating use (P=0.001). These results indicate that: (a) we have identified genetic predictors of smoking cessation success, (b) genetic influences on quit success overlap with those that influence the rate at which addictive substance use is taken up during adolescence and (c) individuals at genetic risk for both escalating use of addictive substances and poor abilities to quit may provide especially urgent focus for prevention efforts.

Concordance between personality disorder assessment methods.

BACKGROUND: Studies have criticized the low level of agreement between the various methods of personality disorder (PD) assessment. This is an important issue for research and clinical purposes. METHOD: Seven hundred and forty-two participants in the Hopkins Epidemiology of Personality Disorders Study (HEPS) were assessed on two occasions using the Personality Disorder Schedule (PDS) and the International Personality Disorder Examination (IPDE). The concordance between the two diagnostic methods for all DSM-IV PDs was assessed using standard methods and also two item response analytic approaches designed to take account of measurement error: a latent trait-based approach and a generalized estimating equations (GEE)-based approach, with post-hoc adjustment. RESULTS: Raw criteria counts, using the intraclass correlation coefficient (ICC), κ and odds ratio (OR), showed poor concordance. The more refined statistical methods showed a moderate to moderately high level of concordance between the methods for most PDs studied. Overall, the PDS produced lower prevalences of traits but higher precision of measurement than the IPDE. Specific criteria within each PD showed varying endorsement thresholds and precision for ascertaining the disorder. CONCLUSIONS: Concordance in the raw measurement of the individual PD criteria between the two clinical methods is lacking. However, based on two statistical methods that adjust for differential endorsement thresholds and measurement error in the assessments, we deduce that the PD constructs themselves can be measured with a moderate degree of confidence regardless of the clinical approach used. This may suggest that the individual criteria for each PD are, in and of themselves, less specific for diagnosis, but as a group the criteria for each PD usefully identify specific PD constructs.

The effect of social networks and social support on common mental disorders following specific life events.

OBJECTIVE: This study examined the association between life events and common mental disorders while accounting for social networks and social supports. METHOD: Participants included 1920 adults in the Baltimore Epidemiologic Catchment Area Cohort who were interviewed in 1993-1996, of whom 1071 were re-interviewed in 2004-2005. Generalized estimating equations were used to analyze the data. RESULTS: Social support from friends, spouse or relatives was associated with significantly reduced odds of panic disorder and psychological distress, after experiencing specific life events. Social networks or social support had no significant stress-buffering effect. Social networks and social support had almost no direct or buffering effect on major depressive disorder, and no effect on generalized anxiety disorder and alcohol abuse or dependence disorder. CONCLUSION: The significant association between social support and psychological distress, rather than diagnosable mental disorders, highlights the importance of social support, especially when the severity of a mental health related problem is low.

Arsenic levels in wipe samples collected from play structures constructed with CCA-treated wood: impact on exposure estimates.

Lumber treated with chromated copper arsenate (CCA) has been used in residential outdoor wood structures and playgrounds. The U.S. EPA has conducted a probabilistic assessment of children's exposure to arsenic from CCA-treated structures using the Stochastic Human Exposure and Dose Simulation model for the wood preservative scenario (SHEDS-Wood). The EPA assessment relied on data from an experimental study using adult volunteers and designed to measure arsenic in maximum hand and wipe loadings. Analyses using arsenic handloading data from a study of children playing on CCA-treated play structures in Edmonton, Canada, indicate that the maximum handloading values significantly overestimate the exposure that occurs during actual play. The objective of our paper is to assess whether the dislodgeable arsenic residues from structures in the Edmonton study are comparable to those observed in other studies and whether they support the conclusion that the values derived by EPA using modeled maximum loading values overestimate hand exposures. We compared dislodgeable arsenic residue data from structures in the playgrounds in the Edmonton study to levels observed in studies used in EPA's assessment. Our analysis showed that the dislodgeable arsenic levels in the Edmonton playground structures are similar to those in the studies used by EPA. Hence, the exposure estimates derived using the handloading data from children playing on CCA-treated structures are more representative of children's actual exposures than the overestimates derived by EPA using modeled maximum values. Handloading data from children playing on CCA-treated structures should be used to reduce the uncertainty of modeled estimates derived using the SHEDS-Wood model.

Restless Legs Syndrome and the five-factor model of personality: results from a community sample.

OBJECTIVE: To examine personality characteristics as potential mediators of the association between Restless Legs Syndrome (RLS) and psychiatric disorders. METHOD: Revised NEO Personality Inventory traits are compared in respondents with (n=42) versus without (n=982) a diagnosis of RLS in a general population sample. RESULTS: RLS was associated with higher neuroticism after adjusting for potential confounders, including current psychopathology. Further analysis showed that the association between RLS and neuroticism contributes to, but does not fully explain, the relationship between RLS and either panic disorder or major depression. CONCLUSIONS: Neuroticism may mediate part of the relationship between RLS and depression or panic, but the mechanisms of these associations need further exploration.

Depression and osteoporosis: epidemiology and potential mediating pathways.

INTRODUCTION: There have been numerous studies examining the association between depression and bone mineral density (BMD), but the underlying nature of this relationship remains unclear. Independent of this association, there is a growing body of evidence that depression impacts the risk for fracture in older adults. This article reviews the current epidemiological evidence regarding comorbidity of depression, low bone mineral density, and fracture. METHODS: A review of the literature on depression, depressive symptoms, low BMD, osteoporosis, and fracture using electronic databases. RESULTS: We reviewed 20 studies of the association between depression and BMD and five reports of the relationship between depression and fractures. Potential mediating mechanisms (both physiological and behavioral) are discussed, as well as potential confounding influences (e.g., medication use). CONCLUSIONS: Most studies support the finding that depression is associated with increased risk for both low BMD and fractures, but variation in study design, sample composition, and exposure measurement make comparisons across studies difficult. Researchers should be aware of potential confounders, such as medication use, that may influence results. Future research should focus on identifying mediating pathways and targets for intervention in the relationships between depression, low BMD, and fracture.

Prevalence and incidence of depressive disorder: the Baltimore ECA follow-up, 1981-2004.

OBJECTIVE: To describe trends in prevalence and incidence of depressive disorder in a cohort from Eastern Baltimore. METHOD: Twenty-three-year-old longitudinal cohort, the Baltimore Epidemiologic Catchment Area Follow-up. Participants were selected probabilistically from the household population in 1981, and interviewed in 1981, 1993, and 2004. Diagnoses were made via the Diagnostic Interview Schedule according to successive editions of the American Psychiatric Association Diagnostic and Statistical Manual. RESULTS: Older age, lower education, non-White race, and cognitive impairment are independent predictors of attrition due to death and loss of contact, but depressive disorder is not related to attrition. Prevalence rates rise for females between 1981, 1993, and 2004. Incidence rates in the period 1993-2004 are lower than the period 1981-1993, suggesting the rise in prevalence is due to increasing chronicity. CONCLUSION: There has been a rise in the prevalence of depression in the prior quarter century among middle-aged females.

How migraines impact cognitive function: findings from the Baltimore ECA.

OBJECTIVE: To examine the cross-sectional and longitudinal relationship between migraine headaches and cognitive functioning. METHODS: The data were from Waves III (1993 through 1996) and IV (2004 through 2005) of the Baltimore Epidemiologic Catchment Area Study. Migraine headaches were diagnosed according to modified criteria of the International Headache Society. Scores on the immediate and delayed recall tests and the Mini-Mental State Examination (MMSE) were compared for migraineurs (n = 204) vs nonmigraineurs (n = 1,244). The longitudinal association between migraine and cognitive changes was assessed by generalized estimating equations. RESULTS: Migraineurs scored lower on tests of immediate and delayed memory at baseline, but declined by less over time than nonmigraineurs. These associations were specific to migraineurs with aura, who declined by 1.26 (p < 0.01) and 1.47 (p < 0.01) words less on the immediate and delayed recall tests over the 12 years of follow-up. The effects of migraine, specifically with aura, on the MMSE were restricted to those older than 50 years. Among those younger than 50 years, migraineurs with aura declined at the same rate on the MMSE as nonmigraineurs. However, among those older than 50 years, migraineurs with aura declined by 0.99 points (p < 0.01) less over the follow-up. CONCLUSIONS: Migraineurs, specifically those with aura, exhibited less decline on cognitive tests over time vs nonmigraineurs. For the Mini-Mental State Examination, these effects were only apparent among those who were older than 50 years.

Indicators of fetal growth and bipolar disorder: a Danish national register-based study.

BACKGROUND: Several studies have found an association between indicators of fetal growth and/or obstetric complications and schizophrenia but only a few studies have investigated the possible association between these factors and bipolar disorder. Furthermore, the results of these studies have been contradictory. The aim of this study was to investigate whether the risk of bipolar disorder is associated with exposure to indicators of fetal growth. METHOD: A national population nested case-control study based on Danish longitudinal register databases was carried out. Conditional logistic regression was used, controlling for potential confounding factors such as parental age at birth, socio-economic indicators and psychiatric history. We identified 196 cases, and each case was time-, age- and sex-matched with 25 normal population-based controls. All cases were between the ages of 12 and 26 years at the time of diagnosis, were born between 1973 and 1983 and were admitted and diagnosed between 1987 and 1999. RESULTS: During the study period 1973-1983, none of the individual variables available for analyses (birthweight, birth length, gestational age and number of previous pregnancies in the mother) was associated with receiving a diagnosis of bipolar disorder. CONCLUSIONS: None of the indicators of fetal growth under study could be identified as risk factors for bipolar disorder, suggesting that the etiologies of schizophrenia and bipolar disorder, at least in part, are different.

Minor depression as a predictor of the first onset of major depressive disorder over a 15-year follow-up.

OBJECTIVE: To study the relationship of minor depression to first onset of major depressive disorder (MDD) among 1634 individuals over a 15-year follow-up using the Baltimore Epidemiologic Catchment Area cohort. METHOD: Logistic regression analyses were conducted with minor depression alone and also adjusting for anxiety, sociodemographic, and medical variables, with MDD as the outcome variable. Also, among those with minor depression, depressive symptom categories were studied with both logistic regression and population attributable risk (PAR) to determine if they predicted MDD. RESULTS: Individuals with a history of minor depression had an odds ratio of more than 5 of having a first lifetime episode of MDD (adjusted OR: 5.37, 95% CI: 2.87, 10.06). Suicidal ideation, appetite/weight issues, and sleep difficulty had the highest PARs. CONCLUSION: Minor depression strongly predicts MDD. Clinical and public health interventions for individuals with minor depression can potentially impact the pathway leading to MDD.

The gluten connection: the association between schizophrenia and celiac disease.

OBJECTIVE: Schizophrenia affects roughly 1% of the population and is considered one of the top 10 causes of disability worldwide. Given the immense cost to society, successful treatment options are imperative. Based on initial findings, gluten withdrawal may serve as a safe and economical alternative for the reduction of symptoms in a subset of patients. METHOD: A review of the literature relevant to the association between schizophrenia and celiac disease (gluten intolerance) was conducted. RESULTS: A drastic reduction, if not full remission, of schizophrenic symptoms after initiation of gluten withdrawal has been noted in a variety of studies. However, this occurs only in a subset of schizophrenic patients. CONCLUSION: Large-scale epidemiological studies and clinical trials are needed to confirm the association between gluten and schizophrenia, and address the underlying mechanisms by which this association occurs.

Personal characteristics associated with consistency of recall of depressed or anhedonic mood in the 13-year follow-up of the Baltimore Epidemiologic Catchment Area survey.

OBJECTIVE: Our study addressed two primary questions: (1) How reliable is long-term recall of lifetime history of episodes of depressed mood? (2) What characteristics are associated with consistent recall of this history? METHOD: Psychiatric symptoms were assessed in a population-based longitudinal survey of 1498 persons twice, in 1981 and 1994. Respondents whose reports of history of depressed affect were discordant after a 13-year follow-up interval were compared with those whose reports were concordant. RESULTS: Absence of a reported history of episode of depressed mood was more consistently recalled than presence of such an episode. The kappa of reported lifetime history of episode of depressed mood was 0.32. Several personal characteristics predicted consistency of recall. CONCLUSION: If assessment of past episodes of depressed mood is used as guide for identifying cases at risk for depression, account must be taken of the personal factors that might influence recall.

Depressive disorder as a long-term antecedent risk factor for incident back pain: a 13-year follow-up study from the Baltimore Epidemiological Catchment Area sample.

BACKGROUND: The co-occurrence of affective distress and back pain is well documented but the relationship between them is less certain. This study examines the relationship between lifetime occurrence of depressive disorder and incident back pain reported over a 13-year period. METHOD: The Baltimore Epidemiologic Catchment Area Study is a prospective study of a household-residing cohort, selected probabilistically from East Baltimore in 1981. Between 1982-3 (wave 2) and again between 1993-6 (wave 3), a follow-up study of the original cohort was conducted. Questions on depressive disorder and back pain were drawn from the Diagnostic Interview Schedule. Logistic regression analyses were used to evaluate whether depressive disorder acts as a risk factor for incident back pain. RESULTS: In cross-sectional analyses, lifetime occurrence of depressive disorder was a significant correlate of lifetime prevalence of back pain at wave 1 (OR = 1.6, P = 0.01). During the 13-year follow-up, across three data collection points, there was an increase in the risk for incident back pain when depressive disorder was present at baseline (OR = 1.9, 95% CI 1.03, 3.4). However, during the short-term follow-up period of 1 year, between baseline and wave 2, depressive disorder at baseline was unrelated to first-ever reports of back pain. Lifetime depressive disorder in both waves 1 (baseline) and 2 (1 year later) was associated with a more than three times greater risk for a first-ever report of back pain during the 12 to 13 year follow-up period, in comparison to those who did not have depressive disorder at waves 1 or 2 (OR = 3.4, 95% CI 1.4, 7.8). Back pain at wave 1 was not significantly associated with an increased risk for depression in the longitudinal analysis (OR = 0.8, 95% CI 0.5, 1.4). CONCLUSIONS: Depressive disorder appears to be a risk factor for incident back pain independent of other characteristics often associated with back pain. Back pain is not a short-term consequence of depressive disorder but emerges over periods longer than 1 year. Moreover, in this study the alternative pathway of back pain as a risk factor for depressive disorder could not be supported.

Socioeconomic inequalities in depression: a meta-analysis.

Low socioeconomic status (SES) is generally associated with high psychiatric morbidity, more disability, and poorer access to health care. Among psychiatric disorders, depression exhibits a more controversial association with SES. The authors carried out a meta-analysis to evaluate the magnitude, shape, and modifiers of such an association. The search found 51 prevalence studies, five incidence studies, and four persistence studies meeting the criteria. A random effects model was applied to the odds ratio of the lowest SES group compared with the highest, and meta-regression was used to assess the dose-response relation and the influence of covariates. Results indicated that low-SES individuals had higher odds of being depressed (odds ratio = 1.81, p < 0.001), but the odds of a new episode (odds ratio = 1.24, p = 0.004) were lower than the odds of persisting depression (odds ratio = 2.06, p < 0.001). A dose-response relation was observed for education and income. Socioeconomic inequality in depression is heterogeneous and varies according to the way psychiatric disorder is measured, to the definition and measurement of SES, and to contextual features such as region and time. Nonetheless, the authors found compelling evidence for socioeconomic inequality in depression. Strategies for tackling inequality in depression are needed, especially in relation to the course of the disorder.