Is cognition integral to psychopathology? A population-based cohort study.

BACKGROUND: Lower cognitive functioning has been documented across psychiatric disorders and hypothesized to be a core deficit of mental disorders. Situating psychopathology and cognition as part of a unitary construct is therefore important to understanding the etiology of psychiatric disorders. The current study aims to test competing structural models of psychopathology and cognition in a large national cohort of adolescents. METHODS: The analytic sample consisted of 1189 participants aged 16-17 years, screened by the Israeli Draft Board. Psychopathology was assessed using a modified version of the Brief Symptom Inventory, and cognition was assessed based on four standardized test scores ((1) mathematical reasoning, concentration, and concept manipulation; (2) visual-spatial problem-solving skills and nonverbal abstract reasoning; (3) verbal understanding; (4) categorization and verbal abstraction). Confirmatory factor analysis was implemented to compare competing structural models of psychopathology with and without cognition. Sensitivity analyses examined the models in different subpopulations. RESULTS: Confirmatory factor analysis indicated a better model fit of psychopathological symptoms without cognition (RMSEA = 0.037; TLI = 0.991; CFI = 0.992) than with cognition (RMSEA = 0.04-0.042; TLI = 0.987-0.988; CFI = 0.988-0.989). Sensitivity analyses supported the robustness of these results with a single exception. Among participants with low cognitive abilities (N = 139), models that integrated psychopathological symptoms with cognition had a better fit compared to models of psychopathology without cognition. CONCLUSIONS: The current study suggests that cognition and psychopathology are, generally, independent constructs. However, within low cognitive abilities, cognition was integral to the structure of psychopathology. Our results point toward an increased vulnerability to psychopathology in individuals with low cognitive abilities and may provide valuable information for clinicians.

Attempted suicide rates before and during the COVID-19 pandemic: interrupted time series analysis of a nationally representative sample.

BACKGROUND: To characterize the association between the protracted biopsychosocial coronavirus disease 2019 (COVID-19) pandemic exposures and incident suicide attempt rates. METHODS: Data were from a nationally representative cohort based on electronic health records from January 2013 to February 2021 (N = 852 233), with an interrupted time series study design. For the primary analysis, the effect of COVID-19 pandemic on incident suicide attempts warranting in-patient hospital treatment was quantified by fitting a Poisson regression and modeling the relative risk (RR) and the corresponding 95% confidence intervals (CIs). Scenarios were forecast to predict attempted suicide rates at 10 months after social mitigation strategies. Fourteen sensitivity analyses were performed to test the robustness of the results. RESULTS: Despite the increasing trend in the unexposed interval, the interval exposed to the COVID-19 pandemic was statistically significant (p < 0.001) associated with a reduced RR of incident attempted suicide (RR = 0.63, 95% CI 0.52-0.78). Consistent with the primary analysis, sensitivity analysis of sociodemographic groups and methodological factors were statistically significant (p < 0.05). No effect modification was identified for COVID-19 lockdown intervals or COVID-19 illness status. All three forecast scenarios at 10 months projected a suicide attempt rate increase from 12.49 (7.42-21.01) to 21.38 (12.71-35.99). CONCLUSIONS: The interval exposed to the protracted mass social trauma of the COVID-19 pandemic was associated with a lower suicide attempt rate compared to the unexposed interval. However, this trend is likely to reverse 10 months after lifting social mitigation policies, underscoring the need for enhanced implementation of public health policy for suicide prevention.

Increased incident rates of antidepressant use during the COVID-19 pandemic: interrupted time-series analysis of a nationally representative sample.

BACKGROUND: The COVID-19 pandemic has been associated with increased levels of depression and anxiety with implications for the use of antidepressant medications. METHODS: The incident rate of antidepressant fills before and during the COVID-19 pandemic were compared using interrupted time-series analysis followed by comprehensive sensitivity analyses on data derived from electronic medical records from a large health management organization providing nationwide services to 14% of the Israeli population. The dataset covered the period from 1 January 2013 to 1 February 2021, with 1 March 2020 onwards defined as the period of the COVID-19 pandemic. Forecasting analysis was implemented to test the effect of the vaccine roll-out and easing of social restrictions on antidepressant use. RESULTS: The sample consisted of 852 233 persons with a total antidepressant incident fill count of 139 535.4 (total cumulative rate per 100 000 = 16 372.91, 95% CI 16 287.19-16 459.01). We calculated the proportion of antidepressant prescription fills for the COVID-19 period, and the counterfactual proportion for the same period, assuming COVID-19 had not occurred. The difference in these proportions was significant [Cohen's h = 10-3 (0.16), 95% CI 10-3 ( - 0.71 to 1.03)]. The pandemic was associated with a significant increase in the slope of the incident rate of antidepressant fills (slope change = 0.01, 95% CI 0.00-0.03; p = 0.04) and a monthly increase of 2% compared to the counterfactual (the estimated rate assuming no pandemic occurred). The increased rate was more pronounced in women, and was not modified by lockdown on/off periods, socioeconomic or SARS-CoV-2 status. The rate of observed antidepressant fills was similar to that forecasted under the assumption of ongoing COVID-19 distress. CONCLUSION: These findings underscore the toll of the pandemic on mental health and inform mental health policy and service delivery during and after implementing COVID-19 attenuation strategies.

Maternal rheumatoid arthritis and risk of autism in the offspring.

BACKGROUND: Maternal Rheumatoid Arthritis (RA) is suggested to increase the risk of Autism Spectrum Disorder (ASD) in the offspring, mainly through inflammation/autoimmunity, but the association is unclear. A prospective population-based cohort study was implemented to examine the association between maternal RA and offspring ASD. METHODS: We included all children born alive in Sweden from 1995 to 2015, followed up through 2017. Diagnoses of ASD and RA were clinically ascertained from National Patient Register. We quantified the association by hazard ratios (HR) and two-sided 95% confidence intervals (CI), from Cox regression after detailed adjustment for potential confounders. We examined RA serostatus, etiological subgroups and the timing of exposure. To closer examine the underlying mechanism for the association, we included a negative control group for RA, arthralgia, with similar symptomology as RA but free from inflammation/autoimmunity. RESULTS: Of 3629 children born to mothers with RA, 70 (1.94%) were diagnosed with ASD, compared to 28 892 (1.92%) of 1 503 908 children born to mothers without RA. Maternal RA before delivery was associated with an increased risk of offspring ASD (HR = 1.43, 95% CI 1.11-1.84), especially for seronegative RA (HR = 1.61, 95% CI 1.12-2.30). No similar association was observed for paternal RA, maternal sisters with RA, or RA diagnosed after delivery. Maternal arthralgia displayed as high risks for offspring ASD as did maternal RA (HR = 1.41, 95% CI 1.24-1.60). CONCLUSIONS: In Sweden, maternal RA before delivery was associated with an increased risk of offspring ASD. The comparable association between maternal arthralgia and ASD risk suggests other pathways of risk than autoimmunity/inflammation, acting jointly or independently of RA.

Opioid Exposure and the Risk of Dementia: A National Cohort Study.

OBJECTIVES: To examine the association between prescription opioid use and the risk of dementia in old-age, since existing studies of the association are few, and the evidence is inconsistent. DESIGN: Prospective national cohort study (N = 91,307, aged 60 years and over), without a dementia diagnosis for ten years, followed-up for incident dementia from January 2013 to October 2017. MEASUREMENTS: Opioid exposure was based on opioid purchases classified from Anatomical Therapeutic Chemical Classification system codes (N02A), and classified as exposed if the purchase period covered at least 60 days within a 120-day interval; otherwise, unexposed. SETTING: Healthcare maintenance organization in Israel. RESULTS: During follow-up, 2,849 (3.1%) persons were opioid exposed (mean age 73.94 ± 6.71 years), and 5,298 (5.8 %) persons developed dementia (mean age 78.07 ± 6.54 years). Cox regression models were fitted to quantify the risk of incident dementia with Hazard Ratios (HR) and their associated 95% Confidence Intervals (CI). The opioid exposed group aged 75+ to 80 years were at an increased risk of incident dementia (Adjusted HR = 1.39, 95% CI = 1.01, 1.92, Z-statistic = 2.02, p <0.05) compared to the unexposed. The point-precision estimates were generally similar to the primary analysis across fourteen sensitivity analyses. CONCLUSION: Policymakers, caregivers, patients, and clinicians may wish to consider that opioid exposure aged 75-80 is linked with an increased dementia risk to balance the potential benefits and adverse side effects of opioid use in old age.

Linkage of Young Mania Rating Scale to Clinical Global Impression Scale to Enhance Utility in Clinical Practice and Research Trials.

INTRODUCTION: The Young Mania Rating Scale (YMRS) is the gold standard to assess manic symptoms of bipolar disorder, yet the clinical meaning of scores is unknown. To clinically understand and interpret YMRS scores, we examined linkages between the total and change scores of YMRS with the Clinical Global Impression (CGI) ratings. METHODS: Individual participant data (N=2,988) from eight randomized, double-blind, placebo-controlled trials were included. Data were collected at baseline and subsequent visits. Spearman's correlation coefficients ρ were computed, and equipercentile linking was implemented. RESULTS: A YMRS score of 6 points corresponded approximately to 'borderline mentally ill,' 12 points to 'mildly ill,' 20 points to 'moderately ill,' 30 points to 'markedly ill,' 40 points to 'severely ill,' and 52 points to 'among the most extremely ill' patients on the CGI-S. A reduction of CGI-S by one point as well as 'minimally improved' on the CGI-I corresponded approximately to an absolute decrease of 4 to 8 YMRS points or a 21% to 29% reduction of YMRS baseline score whereas a reduction of CGI-S by two points and 'much improved' on the CGI-I corresponded to an absolute decrease of 10 to 15 points or a 42% to 53% reduction of YMRS baseline score. DISCUSSION: The current study findings offer clinicians meaningful cutoff values to interpret YMRS scores. Moreover, these values contribute to the definition of treatment targets, response, remission, and entry criteria in mania trials.

The number needed to treat adjusted for explanatory variables in regression and survival analysis: Theory and application.

The number needed to treat (NNT) is an efficacy index commonly used in randomized clinical trials. The NNT is the average number of treated patients for each undesirable patient outcome, for example, death, prevented by the treatment. We introduce a systematic theoretically-based framework to model and estimate the conditional and the harmonic mean NNT in the presence of explanatory variables, in various models with dichotomous and nondichotomous outcomes. The conditional NNT is illustrated in a series of four primary examples; logistic regression, linear regression, Kaplan-Meier estimation, and Cox regression models. Also, we establish and prove mathematically the exact relationship between the conditional and the harmonic mean NNT in the presence of explanatory variables. We introduce four different methods to calculate asymptotically-correct confidence intervals for both indices. Finally, we implemented a simulation study to provide numerical demonstrations of the aforementioned theoretical results and the four examples. Numerical analysis showed that the parametric estimators of the NNT with nonparametric bootstrap-based confidence intervals outperformed other examined combinations in most settings. An R package and a web application have been developed and made available online to calculate the conditional and the harmonic mean NNTs with their corresponding confidence intervals.

Effect size quantification for interrupted time series analysis: implementation in R and analysis for Covid-19 research.

BACKGROUND: Interrupted time series (ITS) analysis is a time series regression model that aims to evaluate the effect of an intervention on an outcome of interest. ITS analysis is a quasi-experimental study design instrumental in situations where natural experiments occur, gaining popularity, particularly due to the Covid-19 pandemic. However, challenges, including the lack of a control group, have impeded the quantification of the effect size in ITS. The current paper proposes a method and develops a user-friendly R package to quantify the effect size of an ITS regression model for continuous and count outcomes, with or without seasonal adjustment. RESULTS: The effect size presented in this work, together with its corresponding 95% confidence interval (CI) and P-value, is based on the ITS model-based fitted values and the predicted counterfactual (the exposed period had the intervention not occurred) values. A user-friendly R package to fit an ITS and estimate the effect size was developed and accompanies this paper. To illustrate, we implemented a nation population-based ITS study from January 2001 to May 2021 covering the all-cause mortality of Israel (n = 9,350 thousand) to quantify the effect size of Covid-19 exposure on mortality rates. In the period unexposed to the Covid-19 pandemic, the mortality rate decreased over time and was expected to continue decreasing had Covid-19 not occurred. In contrast, the period exposed to the Covid-19 pandemic was associated with an increased all-cause mortality rate (relative risk = 1.11, 95% CI = 1.04, 1.18, P < 0.001). CONCLUSION: For the first time, the effect size in ITS: was quantified, can be estimated by end-users with an R package we developed, and was demonstrated with data showing an increase in mortality following the Covid-19 pandemic. ITS effect size reporting can assist public health policy makers in assessing the magnitude of the entire intervention effect using a single, readily understood measure.

Maternal health around pregnancy and autism risk: a diagnosis-wide, population-based study.

BACKGROUND: Many studies have reported an increased risk of autism spectrum disorder (ASD) associated with some maternal diagnoses in pregnancy. However, such associations have not been studied systematically, accounting for comorbidity between maternal disorders. Therefore our aim was to comprehensively test the associations between maternal diagnoses around pregnancy and ASD risk in offspring. METHODS: This exploratory case-cohort study included children born in Israel from 1997 to 2008, and followed up until 2015. We used information on all ICD-9 codes received by their mothers during pregnancy and the preceding year. ASD risk associated with each of those conditions was calculated using Cox proportional hazards regression, adjusted for the confounders (birth year, maternal age, socioeconomic status and number of ICD-9 diagnoses during the exposure period). RESULTS: The analytic sample consisted of 80 187 individuals (1132 cases, 79 055 controls), with 822 unique ICD-9 codes recorded in their mothers. After extensive quality control, 22 maternal diagnoses were nominally significantly associated with offspring ASD, with 16 of those surviving subsequent filtering steps (permutation testing, multiple testing correction, multiple regression). Among those, we recorded an increased risk of ASD associated with metabolic [e.g. hypertension; HR = 2.74 (1.92-3.90), p = 2.43 × 10-8], genitourinary [e.g. non-inflammatory disorders of cervix; HR = 1.88 (1.38-2.57), p = 7.06 × 10-5] and psychiatric [depressive disorder; HR = 2.11 (1.32-3.35), p = 1.70 × 10-3] diagnoses. Meanwhile, mothers of children with ASD were less likely to attend prenatal care appointment [HR = 0.62 (0.54-0.71), p = 1.80 × 10-11]. CONCLUSIONS: Sixteen maternal diagnoses were associated with ASD in the offspring, after rigorous filtering of potential false-positive associations. Replication in other cohorts and further research to understand the mechanisms underlying the observed associations with ASD are warranted.

Ethnic group and social support contribution to posttraumatic growth after sudden spousal loss among Jewish, Muslim, and Druze widows in Israel.

This study aimed to examine the contribution of ethnic group status and social support to posttraumatic growth (PTG) among widows after sudden spousal loss. Participants included 184 widows from three ethnic groups: 59 (32.3%) Jewish, 58 (31.7%) Muslim, and 66 (36%) Druze. Information was gathered via a demographic questionnaire, PTG Inventory, and Multidimensional Scale of Perceived Social Support. Analysis of covariance was used to test ethnic group status differences in social support, controlling for demographic variables. Hierarchical linear models were used to assess groups differences in the study outcome variables. The results showed that the PTG total score was higher for Jewish widows than for Muslim and Druze widows, with a null difference between the latter two, and social support contributed to increased PTG among Jewish widows more than among Muslim and Druze widows, with no significant association between social support and PTG among Druze widows. The highest PTG levels were observed among widows from modern individualistic cultural backgrounds, compared with traditional collectivist, cultural backgrounds after sudden spousal death. The social support system may be a pathway to enhance PTG among widows in traditional collectivist societies.

Exposure to Antidepressant Medication and the Risk of Incident Dementia.

OBJECTIVE: To test competing hypotheses that monotherapeutic antidepressant exposure is associated with an increased versus a decreased risk of dementia. METHODS: A prospective national matched cohort study from Israel (N = 71,515) without dementia (2002-2012) aged 60 and over were followed up for incident dementia from May 2013 to October 2017. Exposure to antidepressant monotherapy was classified with Anatomical Therapeutic Chemical Codes (N06A) from January 1, 2013 to December 31, 2016. The association between antidepressant monotherapy and the risk of incident dementia was quantified with hazard ratios (HR) and their 95% confidence intervals (CI) obtained from Cox regression models unadjusted and adjusted for 42 covariates. The robustness of the results was tested with 24 sensitivity analyses: 19 analyses restricted to subsamples with plausible differential dementia risks (e.g., anxiety and depression), and 5 analyses across and within antidepressant drug classes. RESULTS: In the primary analysis, the risk of incident dementia for the group exposed to antidepressant monotherapy compared to the group unexposed to antidepressants was estimated with an unadjusted HR = 4.09 (df = 1, 95% Wald CI = 3.64, 4.60) and an adjusted HR = 3.43 (df = 1, 95% Wald CI = 3.04, 3.88). Across the 24 sensitivity analyses the estimated adjusted HR values ranged from 1.99 to 5.47. CONCLUSION: In this study, monotherapeutic antidepressant exposure in old age was associated with increased incident dementia. Clinicians, caregivers, and patients may wish to consider this potentially negative consequence of antidepressant exposure and aim to balance the costs and benefits of treatment.

Efficient two-step multivariate random effects meta-analysis of individual participant data for longitudinal clinical trials using mixed effects models.

BACKGROUND: Mixed effects models have been widely applied in clinical trials that involve longitudinal repeated measurements, which possibly contain missing outcome data. In meta-analysis of individual participant data (IPD) based on these longitudinal studies, joint synthesis of the regression coefficient parameters can improve efficiency, especially for explorations of effect modifiers that are useful to predict the response or lack of response to particular treatments. METHODS: In this article, we provide a valid and efficient two-step method for IPD meta-analyses using the mixed effects models that adequately addresses the between-studies heterogeneity using random effects models. The two-step method overcomes the practical difficulties of computations and modellings of the heterogeneity in the one-step method, and enables valid inference without loss of efficiency. We also show the two-step method can effectively circumvent the modellings of the between-studies heterogeneity of the variance-covariance parameters and provide valid and efficient estimators for the regression coefficient parameters, which are the primary objects of interests in the longitudinal studies. In addition, these methods can be easily implemented using standard statistical packages, and enable synthesis of IPD from different sources (e.g., from different platforms of clinical trial data sharing systems). RESULTS: To assess the proposed method, we conducted simulation studies and also applied the method to an IPD meta-analysis of clinical trials for new generation antidepressants. Through the numerical studies, the validity and efficiency of the proposed method were demonstrated. CONCLUSIONS: The two-step approach is an effective method for IPD meta-analyses of longitudinal clinical trials using mixed effects models. It can also effectively circumvent the modellings of the between-studies heterogeneity of the variance-covariance parameters, and enable efficient inferences for the regression coefficient parameters.

Exposure to Genocide and the Risk of Dementia.

Competing hypotheses stating that past genocide exposure reduces (owing to resilience) versus increases (owing to vulnerabilities) the risk of dementia are yet to receive empirical support. This study tested these competing hypotheses. Registry data were extracted on 51,752 Israeli residents without dementia from September 2002 to January 2012; individuals were born between 1901 and 1945, alive on January 2012, and followed-up for the risk of dementia between January 2013 and October 2017. Groups were classified as exposed to the European Holocaust, based on government recognition, or unexposed. Hazard ratios (HRs) from Cox regression models were used to quantify the risk of dementia between the groups, adjusting for demographic and diagnostic covariates; additionally, 12 sensitivity analyses were computed. In total 10,780 participants (20.8%) were exposed to the Holocaust and 5,584 (10.8%) were diagnosed with dementia during follow-up. Dementia rates were 16.5% in the Holocaust-exposed group and 9.3% in the unexposed group. In the primary analysis, the estimated unadjusted HR of dementia for the exposed compared to the unexposed group was 1.77, 95% CI [1.67, 1.87], and the adjusted HR was 1.21, 95% CI [1.15, 1.28]. Sensitivity analyses significantly replicated the primary results with similar point estimates, adjusted HRs = 1.18-1.28, all ps < .001; all HRs had a small effect size. The current study results are consistent with the hypothesis that exposure to the extreme adversities of genocide heightens vulnerability to the risk of dementia in later life.

Spanish Abstracts by Asociación Chilena de Estrés Traumático (ACET) Exposición al Genocidio y el Riesgo de Demencia EXPOSICIÓN A GENOCIDIOS Y RIESGO DE DEMENCIA Existen hipótesis contradictorias que indican que la exposición pasada al genocidio, por un lado, reduce (debido a la resiliencia), y por otro, aumenta (debido a las vulnerabilidades) el riesgo de demencia, aún no han recibido apoyo empírico. Este estudio puso a prueba estas hipótesis en competencia. Los datos fueron tomados de un registro de 51,752 residentes israelíes, sin demencia, desde Septiembre del 2002 hasta Enero del 2012; los individuos nacieron entre 1901 y 1945, y se encontraban vivos a Enero del 2012, y con un seguimiento de riesgo de demencia entre Enero del 2013 y Octubre de 2017. Los grupos fueron clasificados como expuestos al Holocausto Europeo, basado en el reconocimiento del gobierno, o no expuestos. Se utilizaron cocientes de riesgos instantáneos (Hazard Ratio, HR en delante de acuerdo con su sigla en inglés) de modelos de regresión de Cox para cuantificar el riesgo de demencia entre los grupos, ajustándolo a las covariables demográficas y diagnósticas. Adicionalmente, se computaron 12 análisis de sensibilidad. Un total de 10,780 participantes (20.8%) fueron expuestos al Holocausto y 5,584 (10.8%) fueron diagnosticados con demencia durante el seguimiento. Las tasas de demencia fueron del 16.5% en el grupo expuesto al Holocausto y el 9.3% en el grupo no expuesto. En el análisis primario, el HR estimado no ajustado de demencia fue de 1.77, IC del 95% [1.67, 1.87], para el grupo expuesto en comparación con el grupo no expuesto, y el HR ajustada fue de 1.21, IC del 95% [1.15, 1.28]. Los análisis de sensibilidad replicaron significativamente los resultados primarios con estimaciones puntuales similares, HR ajustadas = 1.18-1.28, todos los ps <.001; todos los HR tuvieron un tamaño efecto pequeño. Los resultados del presente estudio son consistentes con la hipótesis de que la exposición a las adversidades extremas como el genocidio aumenta la vulnerabilidad para el riesgo de demencia en edad avanzada.

A randomized, double-blind, placebo- and risperidone-controlled study on valnoctamide for acute mania.

OBJECTIVES: Mood stabilizers administered for bipolar disorder during pregnancy, such as valproic acid, can increase the risk of congenital anomalies in offspring. Valnoctamide is a valproic acid derivative associated with a decreased risk for congenital abnormalities in animals. The present study evaluated the efficacy and safety of valnoctamide monotherapy, compared to placebo, in the treatment of patients in an acute manic episode. METHODS: A 3-week, double-blind, randomized, placebo- and risperidone-controlled, parallel group trial was conducted on 173 patients in an acute manic episode. Patients were randomized to receive valnoctamide 1500 mg/d (n=71), risperidone 6 mg/d (n=32), or matching placebo (n=70). The primary outcome measure was the change in Young Mania Rating Scale (YMRS) scores. RESULTS: Valnoctamide did not differ significantly from placebo on any of the study endpoints (YMRS, Positive and Negative Syndrome Scale, and the Clinical Global Impression Scale for Bipolar Disorder [CGI-BP] scales; all P>.60). Mixed models for repeated measures showed that risperidone produced significantly more improvement than placebo in the overall bipolar disorder CGI-BP severity scale (P=.036), and the CGI-BP severity scale for mania (P=.021). The Kaplan-Meier survival curve revealed higher all-cause discontinuation rates (mainly due to lack of efficacy) in the valnoctamide group compared to the other study groups (P=.026). Patients with higher valnoctamide plasma levels had a numerically higher YMRS response, but this was not statistically significant. CONCLUSIONS: Valnoctamide was well tolerated at 1500 mg/d but lacked efficacy in the treatment of symptoms in patients with acute mania. Possible differences between the biological mechanisms of action of valproic acid and valnoctamide are discussed.

Holocaust exposure and subsequent suicide risk: a population-based study.

OBJECTIVES: To examine the association between the extent of genocide exposure and subsequent suicide risk among Holocaust survivors. METHODS: Persons born in Holocaust-exposed European countries during the years 1922-1945 that immigrated to Israel by 1965 were identified in the Population Registry (N = 209,429), and followed up for suicide (1950-2014). They were divided into three groups based on likely exposure to Nazi persecution: those who immigrated before (indirect; n = 20,229; 10%), during (partial direct; n = 17,189; 8%), and after (full direct; n = 172,061; 82%) World War II. Groups were contrasted for suicide risk, accounting for the extent of genocide in their respective countries of origin, high (>70%) or lower levels (<50%). Cox model survival analyses were computed examining calendar year at suicide. Sensitivity analyses were recomputed for two additional suicide-associated variables (age and years since immigration) for each exposure group. All analyses were adjusted for confounders. RESULTS: Survival analysis showed that compared to the indirect exposure group, the partial direct exposure group from countries with high genocide level had a statistically significant (P < .05) increased suicide risk for the main outcome (calendar year: HR 1.78, 95% CI 1.09, 2.90). This effect significantly (P < .05) replicated in two sensitivity analyses for countries with higher relative levels of genocide (age: HR 1.77, 95% CI 1.09, 2.89; years since immigration: HR 1.85, 95% CI 1.14, 3.02). The full direct exposure group was not at significant suicide risk compared to the indirect exposure group. Suicide associations for groups from countries with relative lower level of genocide were not statistically significant. DISCUSSION: This study partly converges with findings identifying Holocaust survivors (full direct exposure) as a resilient group. A tentative mechanism for higher vulnerability to suicide risk of the partial direct exposure group from countries with higher genocide exposure includes protracted guilt feelings, having directly witnessed atrocities and escaped death.

Initial Severity Effects on Residual Symptoms in Response and Remission: A STAR*D Study During and After Failed Citalopram Treatment.

The effects of initial severity on the time to and course of residual symptoms based on response or remission periods, and during and after failed response to citalopram in major depressive disorder are unknown. STAR*D data during and after failed citalopram treatment were reanalyzed to examine the effect of initial severity on the time to and course of residual symptoms using the Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR). During and after failed citalopram treatment, Cox regression and Generalized Estimating Equation models were computed to examine mild and moderate residual symptoms during (1) response based on at least a 50% QIDS-SR reduction, as well as (2) remission based on a QIDS-SR score below 6. Generally, initial severity significantly (P < 0.05) increased the time to and course of residual symptoms at the time of response and remission. The course of select mild and moderate residual symptoms was significantly (P < 0.05) more likely to persist in the presence of initial severity during response than remission (eg, energy) across treatment levels. It is concluded that initial severity is a predictor of the time to and course of residual symptoms. The presence of residual symptoms is more likely during response than remission, thereby directing their definition as a treatment target.

Study of resilience and environmental adversity in midlife health (STREAM).

PURPOSE: The Jerusalem study of resilience and environmental adversity in midlife health (STREAM) was established to examine the prevalence of common mental and physical health issues in mid-adulthood in the inner city of Jerusalem, and to examine their association with lifespan psychosocial factors of vulnerability and resilience. METHOD: Participants were 811 randomly selected individuals from 7000 individuals who were born and grew up in inner-Jerusalem. Participants were 34-44 years old during first wave of STREAM assessment. Initial telephone surveys took place in 2007-2008 and participants were followed-up for a second survey 1 year later. Upon funding, a new wave is planned for 2017-2018. Survey topics comprised common health problems (e.g., type 2 diabetes/migraine), health markers (e.g., BMI), and psychiatric vulnerabilities (e.g., anxiety, post-traumatic stress, depressive symptoms, psychosis). Other measures included socioeconomic status, creativity, life style behavior (e.g., smoking, exercise), social contact and adaptation to change. Survey data were retrospectively merged with data of national registry sources that included adverse psychosocial factors, psychiatric and social measures assessed across all developmental stages through midlife. This includes data available on birth factors, school achievement and adjustment, cognitive and behavioral functioning during young adulthood, psychiatric hospitalizations, immigration and socioeconomic status. RESULTS: Results on health outcomes of the first STREAM wave indicate that prevalence rates of health problems are comparable to recent World Mental Health Surveys. CONCLUSIONS: Apart from measures on adverse psychosocial factors, STREAM provides a cohort to examine resilience to developing health problems and having a poor health and functional outcome.

Shortening the Alzheimer's disease assessment scale cognitive subscale.

BACKGROUND: A short yet reliable cognitive measure is needed that separates treatment and placebo for treatment trials for Alzheimer's disease. Hence, we aimed to shorten the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog) and test its use as an efficacy measure. METHODS: Secondary data analysis of participant-level data from five pivotal clinical trials of donepezil compared with placebo for Alzheimer's disease (N = 2,198). Across all five trials, cognition was appraised using the original 11-item ADAS-Cog. Statistical analysis consisted of sample characterization, item response theory (IRT) to identify an ADAS-Cog short version, and mixed models for repeated-measures analysis to examine the effect sizes of ADAS-Cog change on the original and short versions in the placebo versus donepezil groups. RESULTS: Based on IRT, a short ADAS-Cog was developed with seven items and two response options. The original and short ADAS-Cog correlated at baseline and at weeks 12 and 24 at 0.7. Effect sizes based on mixed modeling showed that the short and original ADAS-Cog separated placebo and donepezil comparably (ADAS-Cog original ES = 0.33, 95% CI = 0.29, 0.40, ADAS-Cog short ES = 0.25, 95% CI =0.23, 0.34). CONCLUSIONS: IRT identified a short ADAS-cog version that separated donepezil and placebo, suggesting its clinical potential for assessment and treatment monitoring.

Evaluating the seven-item Center for Epidemiologic Studies depression scale short-form: a longitudinal U.S. community study.

PURPOSE: The current study aims to examine the potential use of the seven-item Center for Epidemiologic Studies depression scale (CES-D) short form (CES-D-SF). METHODS: Data were examined from the National Longitudinal Survey of Youth 1979. Participants responded to the 20-item CES-D (n = 8,858) in 1992, and to the 7-item CES-D-SF in 1994 (n = 8,500) and from 1998 to 2010 if aged 40 (n = 7,972) or 50 (n = 1,574) or over. Variables examined in 1979 were race, SES, and sex and in 1981 cognitive functioning. The CES-D-SF was examined for internal and test-retest reliability, unidimensionality with confirmatory factor analysis, and a cutoff score with receiver operator curve characteristics. Survival analysis was used to examine time period of first CES-D-SF suspected major depression episode, multinomial regression to examine the chronicity of CES-D-SF suspected major depression, and the course of depression with a Generalized Estimating Equation model. RESULTS: Compared to the CES-D, the CES-D-SF had higher internal consistency, and better unidimensionality based on confirmatory factor analysis. A CES-D-SF cutoff score ≥8 had acceptable specificity (0.97, 95% CI 0.96, 0.97) and modest sensitivity (0.69, 95% CI 0.67, 0.71) with the standard CES-D cutoff score of 16. Female sex and lower cognitive functioning were significantly (p < 0.05) associated with more CES-D-SF suspected depression that was more chronic based on a multinomial regression model, and occurred at a younger age based on a Cox regression model. CONCLUSIONS: The seven-item CES-D-SF has acceptable psychometric properties, is associated with exposures documented to be associated with an increased likelihood of depression, and may be used to screen for suspected major depressive disorder in US community studies.