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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.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.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.Healthcare maintenance organization in Israel.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, p0.05) compared to the unexposed. The point-precision estimates were generally similar to the primary analysis across fourteen sensitivity analyses.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.

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.

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.

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.

Psychometric network analysis is an alternative theoretically-driven analytic approach that has the potential to conceptualize cognitive impairment in Alzheimer's disease differently than was previously assumed and consequently detect unknown treatment effects. Based on individual participant data, extracted from three double-blind, randomized placebo-controlled clinical trials, psychometric networks were computed on observed Alzheimer's Disease Assessment Scale Cognitive Subscale scores at baseline (N=1,554) and on predicted change scores at 24 weeks of follow-up for participants who received donepezil (N=797) or placebo (N=484). A novel conceptualization of cognitive impairment in Alzheimer's disease was displayed through the baseline network, that had 90% (n=27) positive statistically significant (p0.05) associations, and a most central aspect of ideational praxis. Following 24 weeks, treatment effects emerged via the differences between the change score networks. The donepezil network had more statistically significant (p0.05) positive associations and a higher global strength (n=15; S=1.22; p=0.03), than the placebo network (n=8; S=0.57). This suggests that for those who were treated with donepezil compared with placebo, cognition is a more unified construct. The main aspects of change in cognitive impairment were comprehension of spoken language for the donepezil network and spoken language ability for the placebo network. Comprehension of spoken language apears to be most sensitive to psychopharmaceutical interventions and should therefore be closely monitored. Overall, our psychometric network analysis presents a new conceptualization of cognitive impairment in Alzheimer's disease, points to previously unknown treatment effects and highlights well-defined aspects of cognitive impairment that may translate into future treatment targets.

BackgroundThe association between serum folate deficiency and the risk of dementia in old age is unclear, perhaps owing to small sample sizes, the competing risk of mortality or reverse causation.ObjectiveTo examine the associations between serum folate deficiency and the risks of incident dementia and all-cause mortality in a large national sample of older adults.MethodsA prospective cohort aged 60–75 years (n=27 188) without pre-existing dementia for at least 10 years, was tested for serum concentrations of folate and followed up for dementia or all-cause mortality. Serum folate deficiency was classified as present (FindingsThe presence compared with the absence of serum folate deficiency was associated with higher risks of dementia (HR=1.68; 95% CI 1.32 to 2.13; pConclusionsSerum concentrations of folate may function as a biomarker used to identify those at risk of dementia and mortality; however, reverse causation is likely. Further research is needed to examine the role of serum folate deficiency in dementia aetiology.Clinical implicationsSerum folate deficiency in older adults requires monitoring and treatment for preventative measures and/or as part of implemented therapeutic strategies.

BackgroundMany 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.MethodsThis 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).ResultsThe 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].ConclusionsSixteen 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.

The identification of demographic factors of vulnerability and resilience in communities facing belligerent conflicts is increasingly relevant today. This representative study aims to examine the effect of protracted violence on the level of fear of the overall Israeli-Jewish population, and the role of the conflict on the connection between socio-economic factors and fears. Sixty-six representative samples were identified and surveyed from 2001 to 2019 (n = 37,190) that occurred during (n = 14,362) and between (n = 22,828) seven conflicts and non-conflict periods. Results show that during military conflicts, civilians declared less fears of physical injury comparing routine time; a slow trend of decline in the level of fears over time was observed; during routine periods, fear was associated with female-gender and with the lowest income level group. Ultra-orthodox and Religious respondents had significantly less fear than the secular and traditional respondents. During military conflicts, the results changed significantly, mainly for the lowest income group, women and ultra-orthodox.

BackgroundThere exists substantial evidence of the effects of maternal mental health on birth outcomes. However, the roles of (1) comorbidity between mental and physical health, and (2) familial confounding underlying this association, remain unclear.MethodsThis cohort study included a random sample of 19.5% children born between January 1, 1997, through December 31, 2008, within a health maintenance organization (HMO) in Israel, as well as their parents and siblings born within the cohort years. Outcomes were ICD-9 diagnoses of neonatal adversity (birth complications and congenital anomalies), and exposure was parental mental health diagnosis – all ascertained through the HMO records. Odds ratios (ORs) and their 95% CIs for the associations between the maternal mental health diagnosis and neonatal adversity were calculated using logistic regression, iteratively adjusting for covariates (maternal age, child’s year of birth, socioeconomic status, number of physical health diagnoses). We also examined potential familial confounding using a negative control approach based on paternal exposure.ResultsIn our sample of 74,533 children, 6,674 (9.1%) were born after birth complications and 14,569 (19.9%) with a congenital anomaly. Maternal mental health diagnosis around pregnancy was significantly associated with these measures of neonatal adversity, adjusting for demographic and socioeconomic factors (birth complications: OR=1.3 (1.2-1.4); pcongenital anomalies:OR=1.2 (1.1-1.3); pbirth complications: ORmat=1.3 (1.1-1.4); p < 0.001; ORpat=1.2 (1.1-1.3); p=0.004;congenital anomalies: ORmat=1.2 (1.1-1.3); ppat=1.1 (1.0-1.2); p=0.01).ConclusionsPhysical health comorbidities and familial factors play a role in the associations between maternal mental health and neonatal adversity.

BackgroundTo characterize the association between the protracted biopsychosocial coronavirus disease 2019 (COVID-19) pandemic exposures and incident suicide attempt rates.MethodsData 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.ResultsDespite 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).ConclusionsThe 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.

AIM Substantial research has focused on the examination of factors that contribute to the development of psychiatric problems. However, much less is known about factors early in life that may protect from poor mental health outcomes in midlife. This study aimed to identify the extent to which a set of key perinatal demographic variables and adolescent academic performance were associated with good mental health in mid-adulthood. METHODS In a sample of 525 individuals (aged 34-44, 55.4% male) born and raised in Jerusalem, Israel (STREAM study) we attempted to differentiate those who did and did not report psychiatric symptoms in mid-adulthood. Using χ2 and regression analysis, we explored birth factors (year of birth, sex, birth weight, and number of older siblings, data on parental immigration and socioeconomic status), academic achievement in eighth grade and contemporaneous measures of lifestyle factors, personality traits, and perceived resilience. RESULTS Participants with good mental health were more often male (P = .005) and had better academic performance already at adolescence than participants who reported psychiatric symptoms in midlife (P

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.

BackgroundThere is growing interest in the potential effects of maternal health in pregnancy on the risk for autism spectrum disorder (ASD) in the offspring. Studies to date have examined only a few maternal diagnoses in pregnancy and did not account for the potential effects of co-occurring conditions. This study systematically investigates the associations between maternal diagnoses in pregnancy and the risk of ASD in the offspring, addressing comorbidity and familial confounding.MethodsThe study sample included all children born in Denmark in 1998-2007 (N=653,580) and their mothers. We fitted Cox proportional hazard regression models to estimate the risk of ASD associated with maternal chronic and non-chronic ICD-10 diagnoses. We further examined the evidence for potential familial confounding using discordant sibling and negative control designs.ResultsThe analytic sample included 7,866 ASD cases (1.2%) and 645,714 controls, born to 425,399 mothers. We tested 241 non-chronic, and 90 chronic maternal conditions for an association with ASD. In a multivariable model, adjusting for maternal comorbidities, 15 of the non-chronic and 5 of the chronic diagnoses were significantly associated with ASD after correcting for multiple testing. Pregnancy complications and injuries accounted for a major portion of the non-chronic maternal diagnoses associated with risk of ASD (e.g., diabetes mellitus in pregnancy: HR=1.27, 95%CI: 1.07-1.51; fracture of skull and facial bones: HR=1.61, 95%CI: 1.09-2.38), and maternal psychiatric diagnoses were most strongly associated with ASD among the chronic conditions (e.g., major depressive disorder: HR=1.89, 95%CI: 1.39, 2.56). Results from negative control (timing of diagnosis, before vs. during pregnancy) and sibling analyses provide limited evidence for the role of familial confounding in the observed associations.ConclusionsOur findings highlight the potential relevance of maternal health around pregnancy for offspring long-term neurodevelopmental outcomes and offer insights into the ASD etiology – necessitating further dissection of the mechanisms underlying the observed associations.

Background:Cumulative evidence suggests that health-related risk factors during midlife and old-age are associated with cognitive impairment. However, studies are needed to clarify the association between early-life risk factors and impaired cognitive functioning to increment existing knowledge.Objective:To examine the association between childhood infectious diseases and late-life cognitive functioning in a nationally representative sample of older adults.Participants:Eligible respondents were 2994 community-dwelling individuals aged 65–85.Measurements:Cognitive functioning was assessed using the Mini-Mental State Examination (MMSE). Childhood infectious diseases (i.e. chicken pox, measles, and mumps) were self-reported. The study covariates were age, sex, highest educational level achieved, smoking status, body mass index, and depression. The primary statistical analysis examined the association between the number of childhood infectious diseases and total MMSE scores, accounting for all study covariates. Regression models of progressive complexity were examined for parsimony. The robustness of the primary results was tested in 17 sensitivity analyses.Results:The most parsimonious model was a linear adjusted model (Bayesian Information Criterion = 12646.09). Late-life cognitive functioning significantly improved as the number of childhood infectious diseases increased (β = 0.18; 95% CI = 0.11, 0.26; p < 0.001). This effect was not significantly attenuated in all sensitivity analyses.Conclusion:The current study results are consistent with prior ecological findings indicating that some childhood infectious diseases are associated with better cognitive functioning in old-age. This points to an early-life modifiable risk factor associated with older-life cognitive functioning. Our results may reflect selective mortality and/or beneficial effects via hormetic processes.

This cross-sectional study uses electronic health record data to compare monthly incidence rates of spontaneous abortion in Israel before and during the COVID-19 pandemic.

In our recent paper,1 we presented the results of the equipercentile linking analysis between the Patient Health Questionnaire (PHQ-9) and the Euro-Qol Five Dimentions Three Levels (EQ-5D-3L) in order to increase the clinical interpretability of the PHQ-9 scores and their changes. Our paper was based on the clinical approach to linking that has been applied to various scales in psychiatry.2 3 Drs Franklin and Young made some important comments on our approach and we will try our best to clarify the concerns they raise. Drs Franklin and Young cite the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Good Practices for Outcomes Research Task Force Report for studies mapping non-preference-based measures of health to generic preference-based measures.4 This guideline …

It is biologically plausible that risk of autism spectrum disorder (ASD) is elevated by both short and long interpregnancy intervals (IPI). We conducted a retrospective cohort study of singleton, non-nulliparous live births, 1998-2007 in Denmark, Finland, and Sweden (N = 925,523 births). Optimal IPI was defined as the IPI at which minimum risk was observed. Generalized additive models were used to estimate relative risks (RR) of ASD and 95% Confidence Intervals (CI). Population impact fractions (PIF) for ASD were estimated under scenarios for shifts in the IPI distribution. We observed that the association between ASD (N = 9302) and IPI was U-shaped for all countries. ASD risk was lowest (optimal IPI) at 35 months for all countries combined, and at 30, 33, and 39 months in Denmark, Finland, and Sweden, respectively. Fully adjusted RRs at IPIs of 6, 12, and 60 months were 1.41 (95% CI: 1.08, 1.85), 1.26 (95% CI: 1.02, 1.56), and 1.24 (95% CI: 0.98, 1.58) compared to an IPI of 35 months. Under the most conservative scenario PIFs ranged from 5% (95% CI: 1%-8%) in Denmark to 9% (95% CI: 6%-12%) in Sweden. The minimum ASD risk followed IPIs of 30-39 months across three countries. These results reflect both direct IPI effects and other, closely related social and biological pathways. If our results reflect biologically causal effects, increasing optimal IPIs and reducing their indications, such as unintended pregnancy and delayed age at first pregnancy has the potential to prevent a salient proportion of ASD cases. LAY SUMMARY: Waiting 35 months to conceive again after giving birth resulted in the least risk of autism. Shorter and longer intervals resulted in risks that were up to 50% and 85% higher, respectively. About 5% to 9% of autism cases might be avoided by optimizing birth spacing.

The number needed to treat is often used to measure the efficacy of a binary outcome in randomized clinical trials. There are three different available measures of the number needed to treat. Two of these measures, Furukawa and Leucht’s and Kraemer and Kupfer’s, focus on converting Cohen’s δ index into the number needed to treat, while Laupacis et al.’s measure deals primarily with the number needed to treat’s estimation rather than with a reformulation. Mathematical and numerical analysis of numbers needed to treat and their estimators was conducted. Three novel number needed to treat estimators were introduced to supplement the numbers needed to treat introduced by Laupacis, Furukawa and Leucht, and Kraemer and Kupfer. The analysis showed that Laupacis et al.’s number needed to treat is intrinsically different from Kraemer and Kupfer’s number needed to treat, and that Furukawa and Leucht’s estimator is appropriate to use only for normally distributed outcomes with equal standard deviations. Based on the numerical analysis, the novel numbers needed to treat outperformed the existing ones under correct model specifications. Asymptotic analysis was used to test three different types of confidence intervals to supplement the numbers needed to treat. An R-package to calculate these numbers needed to treat and their confidence intervals has been developed and made available for users online.

Objective Familial recurrence risk is an important population-level measure of the combined genetic and shared familial liability of autism spectrum disorder (ASD). Objectives were to estimate ASD recurrence risk among siblings and cousins by varying degree of relatedness and by sex. Method This is a population-based cohort study of livebirths from 1998 to 2007 in California, Denmark, Finland, Israel, Sweden and Western Australia followed through 2011 to 2015. Subjects were monitored for an ASD diagnosis in their older siblings or cousins (exposure) and for their ASD diagnosis (outcome). The relative recurrence risk was estimated for different sibling and cousin pairs, for each site separately and combined, and by sex. Results During follow-up, 29,998 cases of ASD were observed among the 2,551,918 births used to estimate recurrence in ASD and 33,769 cases of childhood autism (CA) were observed among the 6,110,942 births used to estimate CA recurrence. Compared with the risk in unaffected families, there was an 8.4-fold increase in the risk of ASD following an older sibling with ASD and a 17.4-fold increase in the risk of CA following an older sibling with CA. A 2-fold increase in the risk for cousin recurrence was observed for the 2 disorders. There also was a significant difference in sibling ASD recurrence risk by sex. Conclusion The present estimates of relative recurrence risks for ASD and CA will assist clinicians and families in understanding autism risk in the context of other families in their population. The observed variation by sex underlines the need to deepen the understanding of factors influencing ASD familial risk.

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.Traditional and Simplified Chinese Abstracts by the Asian Society for Traumatic Stress Studies (AsianSTSS) 簡體及繁體中文撮要由亞洲創傷心理研究學會翻譯 Exposure to Genocide and the Risk of Dementia Traditional Chinese 標題: 種族滅絕經歷和患認知障礙症的風險 撮要: 有一種假設, 認為過去曾經歷種族滅絕會 (因為恢復力的關係) 減低患認知障礙症的風險, 但亦有人假設其會 (因為脆弱性的關係) 提升患認知障礙症的風險。兩種假設仍欠缺實證支持, 而本研究旨在測試兩者。我們在2002年9月至2012年1月期間, 透過一註冊處取得51,752名無患認知障礙症的以色列居民資料。樣本於1901至1945年期間出生, 於2012年1月仍在世;我們在2013年1月至2017年10月期間, 對樣本進行患認知障礙症風險的跟進評估。我們把樣本分類為基於政府資料經歷過歐洲的大屠殺及無此經歷兩個類別。我們對人口變量和診斷共變量作調整, 並利用從Cox迴歸模型得出的風險比率(HRs), 量化不同組別患認知障礙症的風險;亦以電腦進行12項敏感度分析。共有10,780名樣本(20.8%)經歷了大屠殺, 5,584名樣本(10.8%)在跟進期被診斷出患認知障礙症。在經歷了大屠殺的組別中, 患有認知障礙症的比率為16.5%, 在無大屠殺經歷的組別則為9.3%。在初級分析中, 經歷了大屠殺的組別其預測出及未調整的認知障礙症HR, 相比無大屠殺經歷的組別為1.77, 95% CI [1.67, 1.87], 而已調整的HR 為 1.21, 95% CI [1.15, 1.28]。敏感度分析得出相似的預測值, 顯著地確認了初級分析的結果, 已調節 HRs = 1.18- 1.28, 所有 ps.001;所有的 HRs的效應量為小。這次研究結果與以下假設吻合:經歷種族滅絕這種極端的逆境會使個人更為脆弱, 提升個人日後患認知障礙症的風險。 Simplified Chinese 标题: 种族灭绝经历和患认知障碍症的风险 撮要: 有一种假设, 认为过去曾经历种族灭绝会 (因为恢复力的关系) 减低患认知障碍症的风险, 但亦有人假设其会 (因为脆弱性的关系) 提升患认知障碍症的风险。两种假设仍欠缺实证支持, 而本研究旨在测试两者。我们在2002年9月至2012年1月期间, 透过一注册处取得51,752名无患认知障碍症的以色列居民资料。样本于1901至1945年期间出生, 于2012年1月仍在世;我们在2013年1月至2017年10月期间, 对样本进行患认知障碍症风险的跟进评估。我们把样本分类为基于政府资料经历过欧洲的大屠杀及无此经历两个类别。我们对人口变量和诊断共变量作调整, 并利用从Cox回归模型得出的风险比率(HRs), 量化不同组别患认知障碍症的风险;亦以计算机进行12项敏感度分析。共有10,780名样本(20.8%)经历了大屠杀, 5,584名样本(10.8%)在跟进期被诊断出患认知障碍症。在经历了大屠杀的组别中, 患有认知障碍症的比率为16.5%, 在无大屠杀经历的组别则为9.3%。在初级分析中, 经历了大屠杀的组别其预测出及未调整的认知障碍症HR, 相比无大屠杀经历的组别为1.77, 95% CI [1.67, 1.87], 而已调整的HR 为 1.21, 95% CI [1.15, 1.28]。敏感度分析得出相似的预测值, 显著地确认了初级分析的结果, 已调节 HRs = 1.18- 1.28, 所有 ps.001;所有的 HRs的效应量为小。这次研究结果与以下假设吻合:经历种族灭绝这种极端的逆境会使个人更为脆弱, 提升个人日后患认知障碍症的风险。.

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.

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.

IMPORTANCEComorbidity between mental and physical health is a frequent problem, resulting in greater morbidity than the sum of the effects of individual diseases. Despite pervasive physiological and behavioral changes during pregnancy, the pattern of comorbidities among pregnant women is not well-understood.OBJECTIVESystematically examine the associations between mental and physical diagnoses around pregnancy.DESIGN, SETTING, PARTICIPANTSPopulation-based sample, containing all children born between January 1st, 1997 and December 31st, 2008 within a health maintenance organization (HMO) in Israel. Cohort children were linked to their mothers’ health information, creating mother-child dyads.MAIN OUTCOMES AND MEASURESThe primary outcome was any ICD-9 mental health diagnosis within the pregnancy period or the preceding 12 months. The secondary outcomes were specific ICD-9 mental health diagnoses. Exposures were all ICD-9 physical (non-mental) health diagnoses received during the exposure period. We used logistic regression to test the risk of physical health diagnoses in pregnant women associated with mental health diagnoses. The covariates for this study included maternal age, birth year, socioeconomic status and total number of ICD-9 diagnoses during the exposure period.RESULTSThe analytical sample included 76,783 mother-child dyads, with 30,084 unique mothers. The mean age at birth was 29.8 years, with 4.4% of mothers diagnosed with a mental health disorder during the pregnancy period. Of the 18 major ICD-9 diagnostic categories, 10 were positively associated with mental health disorders, including ICD categories of e.g., symptoms, signs, and ill-defined conditions (OR=1.69; 95% CI=1.50, 1.89), musculoskeletal (OR=1.33; 95% CI=1.22,1.45) and digestive system diseases (OR=1.25; 95% CI=1.15, 1.37). Comorbidity between mental and physical health diagnoses was higher than that observed between various physical health diagnoses. Associations between physical health diagnoses and specific mental health conditions were consistent with the results of the general mental health and physical health comorbidity.CONCLUSION AND RELEVANCEWe observed that associations between maternal diagnoses and mental health stand out from the general pattern of comorbidity between non-mental health diseases. The high co-occurrence of mental health and physical health diagnoses has implications for diagnoses and management of morbidity among pregnant women, with potential impact on pregnancy and child health outcomes.

BackgroundQuality-adjusted life years (QALYs) are widely used to measure the impact of various diseases on both the quality and quantity of life and in their economic valuations. It will be clinically important and informative if we can estimate QALYs based on measurements of depression severity.ObjectiveTo construct a conversion table from the Patient Health Questionnaire-9 (PHQ-9), the most frequently used depression scale in recent years, to the Euro-Qol Five Dimensions Three Levels (EQ-5D-3L), one of the most commonly used instruments to assess QALYs.MethodsWe obtained individual participant data of randomised controlled trials of internet cognitive-behavioural therapy which had administered depression severity scales and the EQ-5D-3L at baseline and at end of treatment. Scores from depression scales were all converted into the PHQ-9 according to the validated algorithms. We used equipercentile linking to establish correspondences between the PHQ-9 and the EQ-5D-3L.FindingsIndividual-level data from five trials (total N=2457) were available. Subthreshold depression (PHQ-9 scores between 5 and 10) corresponded with EQ-5D-3L index values of 0.9–0.8, mild major depression (10–15) with 0.8–0.7, moderate depression (15–20) with 0.7–0.5 and severe depression (20 or higher) with 0.6–0.0. A five-point improvement in PHQ-9 corresponded approximately with an increase in EQ-5D-3L score by 0.03 and a ten-point improvement by approximately 0.25.Conclusions and Clinical ImplicationsThe conversion table between the PHQ-9 and the EQ-5D-3L scores will enable fine-grained assessment of burden of depression at its various levels of severity and of impacts of its various treatments.

Background: In patients with Alzheimer’s disease, global assessment scales, such as the Clinical Dementia Rating-Sum of Boxes (CDR-SB), the Clinician’s Interview-Based Impression Plus Caregiver Input (CIBI plus), and the Clinical Global Impression (CGI) are commonly used. Objective: To clinically understand and interpret the associations between these scales, we examined the linkages for the total and change scores of CDR-SB, CIBI plus, and CGI. Methods: Individual participant data (N = 2,198) from five pivotal randomized placebo-controlled trials of donepezil were included. Data were collected at baseline and scheduled visits for up to 6 months. Spearman’s correlation coefficients ρ were examined between corresponding total and change scores of simultaneous CDR-SB, CIBI plus, and CGI ratings. To link between the simultaneous ratings, equipercentile linking was used. Results: We found strong evidence that the Spearman’s correlation coefficients between the CDR-SB and CGI, and CDR-SB and CIBI plus total scores were at least adequately correlated (ρ= 0.50 to 0.71, with p < 0.01). The correlation coefficients between the change scores of CDR-SB and CGI were deemed adequate for weeks 6 to 24 (ρ= 0.44 to 0.65); the remaining correlations were smaller in magnitude (ρ= 0.09 to 0.35). Overall, the linkages were in-line with expectations, e.g., CDR-SB range score of 3-4 (= very mild dementia) was linked to a CGI score of 3 (= mildly ill), and an increase of CDR-SB of 1 was linked to a change of 5 (= minimal worsening) in both CGI and CIBI plus. Conclusion: The study findings can be useful for clinicians wishing to compare scores of different scales across patients. They can also help researchers understand results of studies using different scales and can facilitate meta-analyses, to increase statistical power.

Background The current study aims to overcome past methodological limitations and capture adolescents in need of psychiatric care with psychopathological symptoms in a cohort with unrestricted access to mental health professionals. Methods The study source population consisted of a random sample of adolescents aged 16-17 years (N=1,369) assessed by the Israeli Draft Board. An adapted version of the Brief Symptom Inventory was used to identify clinically relevant psychopathological symptoms with scores categorized as severe if they were in the top 10th percentile of symptoms, otherwise not severe. An independent interview with a subsequent referral to a mental health professional was used to categorize adolescents in need of psychiatric care. To examine the association between severe psychopathological symptoms and the need for psychiatric care, logistic regression models were fitted unadjusted and adjusted for age, sex, and intellectual assessment scores. Adjusted classification measures were estimated to examine the utility of severe psychopathological symptoms for clinical prediction of need for psychiatric care. Results Information on 1,283 adolescents was available in the final analytic sample. Logistic regression modeling showed a statistically significant (p Conclusions Severe psychopathological symptoms, although accounting for a fair proportion of treatment seeking, would perhaps be better useful for classification purposes alongside other variables rather than in isolation.

BackgroundThe Mini-Mental State Examination (MMSE), the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) and the Severe Impairment Battery (SIB) are widely used rating scales to assess cognition in Alzheimer’s disease.ObjectiveTo understand the correspondence between these rating scales, we aimed to examine the linkage of MMSE with the ADAS-Cog and SIB total and change scores.MethodsWe used individual-level data on participants with Alzheimer’s disease (n=2925) from five pivotal clinical trials of donepezil. Data were collected at baseline and scheduled visits for up to 6 months. We used equipercentile linking to identify the correspondence between simultaneous measurements of MMSE with ADAS-Cog, and SIB total and change ratings.FindingsSpearman’s correlation coefficients were of strong magnitude between the MMSE total score and the ADAS-Cog (rs from −0.82 to −0.87; pConclusionsThe current results can be used in meta-analyses, data harmonisation and may contribute to increasing statistical power when pooling data from multiple sources.Clinical implicationsThe current study results help clinicians to understand these cognitive rating scale scores.

IMPORTANCE: Many maternal diagnoses in pregnancy have been linked with offspring ASD risk. However, pregnant women receive many other diagnoses, most of which have not been evaluated for an association with offspring ASD. OBJECTIVE: Systematically test the associations between maternal diagnoses around pregnancy, and ASD risk in offspring, filtering out potential false positives and accounting for correlation between maternal diagnoses. DESIGN, SETTING AND PARTICIPANTS: This case-cohort study included children born in Israel from January 1, 1999, through December 31, 2008, and followed up until January 26, 2015. We used information on all ICD-9 codes received by their mothers during pregnancy and the preceding year. ASD risk in children whose mothers experienced each of those conditions during the exposure period was compared with ASD risk in unexposed children. Data were analyzed from December 1, 2019, through April 30, 2020. MAIN OUTCOME AND MEASURES: Hazard ratios (HRs) and 95% confidence intervals (CIs) of ASD risk associated with each maternal ICD-9 code, 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 (1,132 cases, 79,055 controls; median [interquartile range] age at the end of follow up was 11.2 [8.8-13.6]; 48.8% female). Of 822 ICD-9 codes tested, 148 were recorded in at least 10 of each case and control mothers. Of those, 22 maternal diagnoses were nominally significantly associated with offspring ASD, and 16 of those survived subsequent filtering steps (permutation testing, multiple testing correction, multiple regression). Among those 16 diagnoses, we recorded increased risk of ASD associated with certain metabolic (e.g. hypertension (ICD-9 401); HR=2.74(1.92-3.90), P=2.43E-8), genitourinary (e.g. noninflammatory disorders of cervix (ICD-9 622); HR=1.88(1.38-2.57), P=7.06E-5) and psychiatric (depressive disorder (ICD-9 311); HR=2.11(1.32-3.35), P=1.70E-3) diagnoses. Meanwhile, mothers of children with ASD were less likely to attend prenatal care appointment (ICD-9 V22; HR=0.62 (0.54-0.71), P=1.80E-11). CONCLUSIONS AND RELEVANCE: We observed an association between ASD and 16 maternal ICD-9 diagnoses, after rigorous filtering out potential false positive associations. Replication in other cohorts and further research to understand the mechanisms underlying the observed associations with ASD are warranted.

Knowledge is limited regarding the risks of death and dementia in very-late onset schizophrenia-like psychosis (VLOS). This study aims to scrutinize the associations between VLOS with the risks of death and dementia. Based on a prospective Israeli cohort study with national coverage, 94,120 persons without dementia or schizophrenia diagnoses aged 60 to 90 in 2012 were followed-up for the risks of dementia or death from 2013 to 2017. VLOS was classified as present from the age of the first ICD-9 diagnosis during follow-up, otherwise as absent. Hazard ratios (HR) with confidence intervals (95% CI) were computed with survival models to quantify the associations between VLOS and the risks of death and dementia, without and with adjustment for confounding. Nine sensitivity analyses were computed to examine the robustness of the results. The group with VLOS, compared to the group without, had higher death (n = 61, 18.5% vs. n = 7028, 7.5%, respectively) and dementia (n = 64, 19.5% vs. n = 5962, 6.4%, respectively) rates. In the primary analysis, the group with VLOS compared to the group without had increased risks of death (unadjusted HR = 3.10, 95% CI = 2.36, 4.06, P .001; adjusted HR = 2.89, 95% CI = 2.15, 3.89; P .001) and dementia (unadjusted HR = 3.81, 95% CI = 2.90, 4.99, P .001; adjusted HR = 2.67, 95% CI = 1.82, 3.91; P .001). The results remained statistically significant (P .05) in all sensitivity analyses, including among persons without antipsychotic medication. The results may support notions of increased dementia risk and accelerated aging in VLOS, or that VLOS is a prodromal state of dementia.

This study tested the hypothesis that maternal exposure to terror attacks during pregnancy is associated with the risk of schizophrenia in the offspring. A population-based study was conducted of Israeli children born between 1975 and 1995 and that were registered in the Ministry of Interior and followed up in the Ministry of Health from birth to 2015 for the risk of schizophrenia (N = 201,048). The association between maternal exposure to terror attacks during pregnancy and the risk of schizophrenia in the offspring was quantified with relative risks (RR) and their 95% confidence intervals (CI) fitting Cox regression models unadjusted and adjusted for confounders. Sensitivity analyses were performed to test the robustness of the results. The RR of schizophrenia in offspring of mothers exposed to terror attacks during pregnancy compared to offspring of mothers not exposed during pregnancy were estimated unadjusted (RR = 2.51, 95% CI, 1.33, 4.74) and adjusted (RR = 2.53, 95% CI, 1.63, 3.91). In the sensitivity analyses adjusted RRs were estimated using a sibling-based study design (2.85, 95% CI: 1.31–6.21) and propensity matching (2.45, 95% CI: 1.58–3.81). Maternal exposure to terror attacks during pregnancy was associated with an increased risk of schizophrenia in the offspring, possibly indicating a critical period of neurodevelopment that is sensitive to the stress of terror attacks and affected by epigenetic modifications.

Background:Age of onset is considered central to understanding the course of schizophrenia, yet little is known regarding its association with quality of life in general, and specifically among males and females.Aims:To examine the association between the age of schizophrenia onset and quality of life, in general, and among males and females, using data from a national sample and competing statistical models.Methods:Participants with a diagnosis of schizophrenia (N = 1624) completed the Manchester Short Assessment of Quality of Life (MSA-QoL) and were rated on a parallel measure by their professional caregivers (N = 578). Multiple regression analysis models were computed for self-appraised quality of life, and mixed models with random intercepts were used for caregivers. Six competing models were tested for parsimony for each rating source. Three models without adjustment and three models adjusted for confounding variables. Sensitivity analyses were conducted for males and females separately.Results:Age of onset was statistically significantly (P ConclusionsAn earlier age of onset is associated with a better quality of life in schizophrenia which is tentatively explained by social decline. Specific trends in psychiatric symptom severity may account for this association among females while social advantages may account for the particular results found among males.

Objective The role of baseline severity as effect modifier in various psychiatric disorders is a topic of controversy and of clinical import. This study aims to examine whether baseline severity modifies the efficacy of various antidepressants for major depression through individual participant data (IPD) meta‐analysis. Method We identified all placebo‐controlled, double‐blind randomised trials of new generation antidepressants in the acute phase treatment of major depression conducted in Japan and requested their IPD through the public–private partnerships (PPPs) between the relevant academic societies and the pharmaceutical companies. The effect modification by baseline depression severity was examined through six increasingly complex competing mixed‐effects models for repeated measures. Results We identified eleven eligible trials and obtained IPD from six, which compared duloxetine, escitalopram, mirtazapine, paroxetine or bupropion against placebo (total n = 2464). The best‐fitting model revealed that the interaction between baseline severity and treatment was not statistically significant (coefficient = −0.04, 95% confidence interval: −0.16 to 0.08, P = 0.49). Several sensitivity analyses confirmed the robustness of the findings. Conclusion We may expect as much benefit from antidepressant treatments for mild, moderate or severe major depression. Clinical practice guidelines will need to take these findings into consideration.

Summary Background The efficacy of antipsychotics across the initial severity range in patients with acute mania remains unclear. Therefore, we examined the influence of baseline severity on the efficacy of olanzapine. Methods We did an individual participant data meta-analysis of double-blind, randomised controlled trials that compared olanzapine with placebo, identified through searches of the ClinicalStudyDataRequest.com database on Feb 2, 2016. We included patients with acute mania associated with bipolar I disorder. We examined the association between baseline and change scores on the Young Mania Rating Scale (YMRS; range 0–60) up to 3 weeks for olanzapine versus placebo groups using eight increasingly complex competing mixed-effects models for repeated measures. Findings We identified 33 reports, five (15%) of which were eligible and contained data for 939 patients (552 received olanzapine; 387 received placebo). The interaction between baseline severity and treatment was significant (β=0·22, 95% CI 0·05–0·39; p=0·013). The greater the baseline severity, the greater the magnitude of the differences between olanzapine and placebo was expected. The mean estimated YMRS scores were reduced at 3 weeks in both groups, but were greater with olazapine than placebo by 2·56 points for patients with a baseline score of 20–25 (9·26 for olanzapine vs 6·70 for placebo; effect size 0·35, 95% CI 0·11–0·60), by 4·74 points for a baseline score of 25–35 (14·25 vs 9·51; 0·58, 0·34–0·86), and by 8·01 points for a baseline score of 35–60 (21·72 vs 13·71; 0·70, 0·31–1·23). Interpretation Benefits of olanzapine can be expected for patients across the full spectrum of symptom severity who are likely to be treated for acute mania. Less severely ill patients seem to benefit less in terms of olanzapine efficacy, but still experience the same side-effects as more severely ill patients. Thus, clinicians and patients should carefully consider the benefit-to-risk ratio of olanzapine and its additional, prophylactic effect against relapse in the long term. The generalisability of these results to other antipsychotics, trial designs, and medical conditions remains to be established. Funding None.