Faculty Bibliography

Background: Maternal psychological stress during pregnancy has been associated with the risk for mood disorders in offspring, although there is no consensus about the influence of the timing of the stress on outcomes. We examined the relationship of prenatal stress at specific times in pregnancy to the incidence of mood disorders in offspring using data from a large birth cohort. Methods: We linked data on 90,079 offspring born in Jerusalem in 1964-76 to Israel's psychiatric registry. We used proportional hazards models to evaluate the link between discharge diagnoses and gestational age during the Arab-Israeli war of June, 1967. Results: Those in their first trimester of fetal development during the war were significantly more likely to be admitted to hospitals for any mood disorders (RR=3.01, 1.68-5.39, p=.0002), and the subgroups of bipolar disorder (2.44; 1.0-5.99; p=.054) and "other" mood disorders (3.61; 1.68-7.80; p=.001). Mood disorders were substantially increased in offspring whose mothers had been in the third month of pregnancy in June, 1967 (5.54, 2.73-11.24, p< .0001). Conclusion: These findings suggest that acute maternal stress in early pregnancy may contribute to the etiology of mood disorders in offspring. They point to the third month of fetal development as a moment of special vulnerability

BACKGROUND: Paternal age related schizophrenia (PARS) has been proposed as a subgroup of schizophrenia with distinct etiology, pathophysiology and symptoms. This study uses a k-means clustering analysis approach to generate hypotheses about differences between PARS and other cases of schizophrenia. METHODS: We studied PARS (operationally defined as not having any family history of schizophrenia among first and second-degree relatives and fathers' age at birth >/=35years) in a series of schizophrenia cases recruited from a research unit. Data were available on demographic variables, symptoms (Positive and Negative Syndrome Scale; PANSS), cognitive tests (Wechsler Adult Intelligence Scale-Revised; WAIS-R) and olfaction (University of Pennsylvania Smell Identification Test; UPSIT). We conducted a series of k-means clustering analyses to identify clusters of cases containing high concentrations of PARS. RESULTS: Two analyses generated clusters with high concentrations of PARS cases. The first analysis (N=136; PARS=34) revealed a cluster containing 83% PARS cases, in which the patients showed a significant discrepancy between verbal and performance intelligence. The mean paternal and maternal ages were 41 and 33, respectively. The second analysis (N=123; PARS=30) revealed a cluster containing 71% PARS cases, of which 93% were females; the mean age of onset of psychosis, at 17.2, was significantly early. CONCLUSIONS: These results strengthen the evidence that PARS cases differ from other patients with schizophrenia. Hypothesis-generating findings suggest that features of PARS may include a discrepancy between verbal and performance intelligence, and in females, an early age of onset. These findings provide a rationale for separating these phenotypes from others in future clinical, genetic and pathophysiologic studies of schizophrenia and in considering responses to treatment

OBJECTIVE: Schizophrenia affects men more than women, but this may not be true at all ages. This study examines the incidence of first hospitalization for treatment of schizophrenia in each sex over different ages. METHODS: We compared the incidence of first admission for treatment in a cohort of 46,388 males and 43,680 females followed from birth until ages 29-41, using life tables and proportional hazards methods. RESULTS: Life table estimates of cumulative incidence by age 40 were 1.44% in males and 0.86% in females. For over all ages the relative risk (RR) in males was 1.6 (95% confidence limits=1.4-1.8) compared with females. Before age 17 there was no significant difference between the sexes (RR=0.86, 0.56-1.3). Excess risk in males was observed only from age 17 (RR=1.7, 1.4-1.9). There was no evidence of the incidence in females catching up with that in males, during the 30s. CONCLUSION: In this population, there was a significant change, over age, in the relative incidence of first hospitalization for schizophrenia between the sexes; the excess incidence in males first developed at age 17

The effect of a family history of schizophrenia on the risk for this disorder in the offspring has rarely been examined in a prospective population cohort accounting for the sex of the proband and the first-degree relatives, and certainly not with respect to later paternal age. The influence of affected relatives on offspring risk of schizophrenia was estimated using Cox proportional hazards regression in models that accounted for sex, relation of affected first degree relatives and paternal age in the prospective population-based cohort of the Jerusalem Perinatal Schizophrenia Study. Of all first-degree relatives, an affected mother conferred the highest risk to male and female offspring among the cases with paternal age <35 years, however, female offspring of fathers >/=35 years with an affected sister had the highest risk (RR = 8.8; 95% CI = 3.9-19.8). The risk seen between sisters of older fathers was fourfold greater than the risk to sisters of affected females of younger fathers (RR = 2.2, 95% CI 0.7-6.7). The test for interaction was significant (P = 0.03). By contrast, the risk of schizophrenia to brothers of affected males was only doubled between older (RR = 3.3, 95% 1.6-6.6) and younger fathers (RR = 1.6, 95% CI 0.7-3.5). The most striking finding from this study was the very large increase in risk of schizophrenia to sisters of affected females born to older fathers. The authors speculate that the hypothesized paternally expressed genes on the X chromosome might play some role in these observations

Epigenetics holds promise to explain some puzzles concerning the risk and course of psychiatric disorders. Epigenetic information is essential as a set of operating instructions for the genome, which is heritable with DNA. The epigenetic regulation of gene expression can plausibly be influenced by the environment of one's ancestors, prenatal exposures, and by early life events. Some epigenetic mechanisms may alter neurophysiology throughout life by programming gene expression, perhaps in anticipation of certain life experiences. These epigenetic signals are only meta-stable and may be perturbed by stochastic events, errors, or by environmental toxins. This introduction considers the possibility that epigenetic change that may occur as paternal age advances or during fetal adversity may be causally related to the susceptibility for schizophrenia