Childhood infectious diseases and old age cognitive functioning: a nationally representative sample of community-dwelling older adults.

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 (ß = 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.

Systematic analysis of the number needed to treat.

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.

Initial severity of major depression and efficacy of new generation antidepressants: individual participant data meta-analysis.

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.

Autism risk following antidepressant medication during pregnancy.

BACKGROUND: Previous studies have examined if maternal antidepressant medication during pregnancy increase the risk of autism spectrum disorder (ASD) in the offspring, but the results have been conflicting. METHODS: In a population-based cohort of 179 007 children born in 2006 and 2007 and followed through 2014 when aged 7 and 8, we estimated relative risks (RRs) of ASD and 95% confidence intervals (CIs) from Cox regression in children exposed to any antidepressant medication during pregnancy, and nine specific antidepressant drugs. Analyses were adjusted for potential confounders and were conducted in the full population sample, and in a clinically relevant sub-sample of mothers with at least one diagnosis of depression or anxiety during life. RESULTS: The adjusted RR of ASD in children of mothers who used antidepressant medication during pregnancy was estimated at 1.23 (95% CI 0.96-1.57), and at 1.07 (95% CI 0.80-1.43) in women with a history of depression or anxiety. Analyses of specific antidepressants initially revealed increased RRs of offspring ASD confined to citalopram and escitalopram (RR: 1.47; 95% CI 0.92-2.35) and clomipramine (RR: 2.86; 95% CI 1.04-7.82). CONCLUSION: Medication with antidepressants during pregnancy does not appear to be causally associated with an increased risk of ASD in the offspring. Instead, the results suggest that the association is explained by factors related to the underlying susceptibility to psychiatric disorders. Based on these findings, the risk of ASD in the offspring should not be a consideration to withhold treatment with commonly used antidepressant drugs from pregnant women.

Initial severity and efficacy of risperidone in autism: Results from the RUPP trial.

BACKGROUND: Risperidone is a common psychopharmacological treatment for irritability in autism spectrum disorder (ASD). It is not well-established how effective risperidone is across the initial symptom severity range. This study aims to examine the influence of baseline severity on the efficacy of risperidone in the treatment of ASD. METHODS: Participants were from the NIMH funded RUPP multisite, randomized, double-blind trial that compared risperidone to placebo to treat autistic disorder with severe tantrums, aggression, or self-injury. Participants were aged 5 to 17, and randomly assigned to risperidone (n=49) or placebo (n=52). Baseline and change scores were computed with the Aberrant Behavior Checklist (ABC) parent assessed scales with irritability as the primary outcome, as well as the clinician assessed ABC Irritability subscale, and Clinical Global Impression Scale. RESULTS: The relationship between baseline severity and change scores for the risperdone and placebo groups was examined with eight competing three-level mixed-effects models for repeated measure models. Significant (P<0.01) interactions between treatment and baseline severity were observed for parent ABC ratings of irritability and lethargy only. Greater magnitudes of the differences between risperidone and placebo were observed from moderate to very severe baseline severity on irritability and lethargy. Initial severity values over approximately 30 had a strong effect on symptom change [irritability: effect size (ES)=1.9, number needed to treat (NNT)=2, lethargy ES=0.9, NNT=5]. CONCLUSIONS: Parents may expect benefits of risperidone on irritability and lethargy with moderate to severe symptoms of ASD. TRIAL REGISTRATION: Registry name: ClinicalTrials.gov, trial identifier: NCT00005014, URL: http://www.clinicaltrials.gov/ct2/show/NCT00005014?term=NCT00005014&rank=1, registered on March 31, 2000.

Exposure to genocide and the risk of schizophrenia: a population-based study.

BACKGROUND: No evidence exists on the association between genocide and the incidence of schizophrenia. This study aims to identify critical periods of exposure to genocide on the risk of schizophrenia. METHOD: This population-based study comprised of all subjects born in European nations where the Holocaust occurred from 1928 to 1945, who immigrated to Israel by 1965 and were indexed in the Population Register (N = 113 932). Subjects were followed for schizophrenia disorder in the National Psychiatric Case Registry from 1950 to 2014. The population was disaggregated to compare groups that immigrated before (indirect exposure: n = 8886, 7.8%) or after (direct exposure: n = 105 046, 92.2%) the Nazi or fascist era of persecutions began. The latter group was further disaggregated to examine likely initial prenatal or postnatal genocide exposures. Cox regression modelling was computed to compare the risk of schizophrenia between the groups, adjusting for confounders. RESULTS: The likely direct group was at a statistically (p < 0.05) greater risk of schizophrenia (hazard ratio = 1.27, 95% confidence interval 1.06-1.51) than the indirect group. Also, the likely combined in utero and postnatal, and late postnatal (over age 2 years) exposure subgroups were statistically at greater risk of schizophrenia than the indirect group (p < 0.05). The likely in utero only and early postnatal (up to age 2 years) exposure subgroups compared with the indirect exposure group did not significantly differ. These results were replicated across three sensitivity analyses. CONCLUSIONS: This study showed that genocide exposure elevated the risk of schizophrenia, and identified in utero and postnatal (combined) and late postnatal (age over 2 years) exposures as critical periods of risk.

Age of onset group characteristics in forensic patients with schizophrenia.

This study aims to empirically identify age of onset groups and their clinical and background characteristics in forensic patients with schizophrenia. Hospital charts were reviewed of all 138 forensic patients with schizophrenia admitted to Geha Psychiatric Hospital that serves a catchment area of approximately 500,000 people, from 2000 to 2009 inclusive. Admixture analysis empirically identified early- (M=19.99, SD=3.31) and late-onset groups (M=36.13, SD=9.25). Early-onset was associated with more suicide attempts, violence before the age of 15, and early conduct problems, whereas late-onset was associated with a greater likelihood of violence after the age of 18 and marriage (P<0.01). The current findings provide clinicians with a unique direction for risk assessment and indicate differences in violence between early- and late-onset schizophrenia, particularly co-occurrence of harmful behavioral phenotypes.

Advancing paternal age and risk of autism: new evidence from a population-based study and a meta-analysis of epidemiological studies.

Advanced paternal age has been suggested as a risk factor for autism, but empirical evidence is mixed. This study examines whether the association between paternal age and autism in the offspring (1) persists controlling for documented autism risk factors, including family psychiatric history, perinatal conditions, infant characteristics and demographic variables; (2) may be explained by familial traits associated with the autism phenotype, or confounding by parity; and (3) is consistent across epidemiological studies. Multiple study methods were adopted. First, a Swedish 10-year birth cohort (N=1 075 588) was established. Linkage to the National Patient Register ascertained all autism cases (N=883). Second, 660 families identified within the birth cohort had siblings discordant for autism. Finally, meta-analysis included population-based epidemiological studies. In the birth cohort, autism risk increased monotonically with increasing paternal age. Offspring of men aged ≥50 years were 2.2 times (95% confidence interval: 1.26-3.88: P=0.006) more likely to have autism than offspring of men aged ≤29 years, after controlling for maternal age and documented risk factors for autism. Within-family analysis of discordant siblings showed that affected siblings had older paternal age, adjusting for maternal age and parity (P<0.0001). Meta-analysis demonstrated advancing paternal age association with increased risk of autism across studies. These findings provide the strongest evidence to date that advanced paternal age is a risk factor for autism in the offspring. Possible biological mechanisms include de novo aberration and mutations or epigenetic alterations associated with aging.

Pathways to functional outcomes in schizophrenia: the role of premorbid functioning, negative symptoms and intelligence.

BACKGROUND: Social and intellectual premorbid functioning are generally estimated retrospectively, and related to clinical or hospitalization outcomes in schizophrenia. Yet the relationship between premorbid functioning assessed prior to psychiatric hospitalization and postmorbid functional outcomes has not been examined. OBJECTIVES: To test competing models of the relationship between (a) functional outcomes with (b) premorbid functioning assessed on nationally administered tests prior to psychiatric hospitalization, postmorbid intellectual functioning and symptomatology using a historical prospective design. METHODS: Ninety one inpatient and outpatient males with schizophrenia or schizoaffective disorder, aged 19 to 35, were examined using the Positive and Negative Syndrome Scale, the WAIS-III and Strauss and Carpenter social and occupational functional outcome scale. Premorbid intelligence and social functioning data were obtained from national standardized tests administered during high school prior to first hospitalization for schizophrenia. RESULTS: Path modeling showed that premorbid intelligence and behavioral functioning directly predicted postmorbid IQ and negative symptoms, and indirectly predicted postmorbid social and occupational functioning via negative symptoms. Item level analysis indicated that better social and occupational outcomes occurred in a group with few negative symptoms. CONCLUSIONS: Premorbid functioning, postmorbid IQ and negative symptoms are related, yet the relationship between premorbid functioning and postmorbid functional outcomes appears to be mediated by postmorbid negative symptoms.