Early Environmental Upheaval and the Risk for Schizophrenia.

Why does prenatal exposure to wars, natural disasters, urbanicity, or winter increase the risk for schizophrenia? Research from the last two decades has provided rich insight about the underlying chains of causation at play during environmental upheaval, from conception to early infancy. In this review, we appraise the evidence linking schizophrenia spectrum disorder to prenatal maternal stress, obstetric complications, early infections, and maternal nutrition and other lifestyle factors. We discuss putative mechanisms, including the maternal stress system, perinatal hypoxia, and maternal-offspring immune activation. We propose that gene-environment interactions, timing during development, and sex differentiate the neuropsychiatric outcomes. Future research should pursue the translation of animal studies to humans and the longitudinal associations between early exposures, intermediate phenotypes, and psychiatric disorders. Finally, to paint a comprehensive model of risk and to harness targets for prevention, we argue that risk factors should be situated within the individual's personal ecosystem.

Sex Differences in Clinical and Functional Outcomes among Patients Treated in an Early Intervention Service for Psychotic Disorders: An Observational Study.

OBJECTIVE: It has been shown that men with a longstanding psychotic disorder have worse clinical and functional outcomes than women. Our objectives were to examine whether these sex differences are also present among patients treated in an early intervention service (EIS) for psychosis and to determine if these differences are related to risk factors other than sex. METHOD: Patients (N = 569) were assessed for demographic/clinical characteristics at entry and for symptoms/functioning over 2 years of treatment. Clinical outcomes included remission of positive, negative, and total symptoms. Functional outcomes included good functioning and functional remission. Logistic regression models examined the relationship between sex and outcomes after 1 and 2 years of treatment while controlling for the influence of other risk factors. RESULTS: Men reported to be less educated and have a longer duration of untreated psychosis, poorer childhood and early adolescent premorbid functioning, higher rates of substance abuse/dependence disorders, greater severity of baseline negative symptoms, and poorer baseline social/occupational functioning than women. Women were more likely to achieve symptom remission than men after 2 years of treatment (negative odds ratio [OR], 1.69; 95% confidence interval [CI], 1.02 to 2.78; total OR, 1.79; 95% CI, 1.08 to 2.98). Women were also more likely than men to exhibit good functioning (OR, 1.61; 95% CI, 1.04 to 2.49) after 1 but not after 2 years of treatment. These results did not persist after controlling for other risk factors that could confound these associations (i.e., childhood premorbid functioning and age at onset of psychosis). CONCLUSIONS: Sex differences seen in outcomes among patients treated in an EIS for psychosis may be largely influenced by the disparity of other risk factors that exist between the 2 sexes.

Pathways to functional outcomes following a first episode of psychosis: The roles of premorbid adjustment, verbal memory and symptom remission.

OBJECTIVE: Most studies have investigated either the singular or relative contributions of premorbid adjustment, verbal memory and symptom remission to functional outcomes in first-episode psychosis. Fewer studies have examined the pathways of these factors in impacting functioning. Our study addresses this gap. The objective was to determine whether the relationship between premorbid adjustment and functional outcomes was mediated by verbal memory and symptom remission. METHOD: A total of 334 first-episode psychosis participants (aged 14-35 years) were assessed on premorbid adjustment, verbal memory upon entry, and positive and negative symptom remission and functioning at multiple time points over a 2-year follow-up. RESULTS: Mediation analyses showed that over the first year, the relationship between premorbid adjustment and functioning was mediated by verbal memory and positive symptom remission (ß = -0.18; 95% confidence interval = [-0.51, -0.04]), as well as by verbal memory and negative symptom remission (ß = -0.41; 95% confidence interval = [-1.11, -1.03]). Over 2 years, the relationship between premorbid adjustment and functioning was mediated by verbal memory and only negative symptom remission (ß = -0.38; 95% confidence interval = [-1.46, -0.02]). CONCLUSION: Comparatively less malleable factors (premorbid adjustment and verbal memory) may contribute to functional outcomes through more malleable factors (symptoms). Promoting remission may be an important parsimonious means to achieving better functional outcomes.

Prenatal maternal stress exposure and immune function in the offspring.

The intra-uterine environment provides the first regulatory connection for the developing fetus and shapes its physiological responses in preparation for postnatal life. Psychological stress acts as a programming determinant by setting functional parameters to abnormal levels, thus inducing postnatal maladaptation. The effects of prenatal maternal stress (PNMS) on the developing immune system have been documented mostly through animal studies, but inconsistent results and methodological differences have hampered the complete understanding of these findings. As the immune system follows a similar ontogenic pattern in all mammals, a translational framework based on the developmental windows of vulnerability proposed by immunotoxicology studies was created to integrate these findings. The objective of this review is to examine the available literature on PNMS and immune function in the offspring through the above framework and gain a better understanding of these results by elucidating the moderating influence of the stressor type, timing and duration, and the offspring species, sex and age at assessment. The evaluation of the literature through this framework showed that the effects of PNMS are parameter specific: the moderating effects of timing in gestation were relevant for lymphocyte population numbers, Natural Killer cell function and mitogen-induced proliferation. The presence of an important and directional sexual dimorphism was evident and the influence of the type or duration of PNMS paralleled that of stress in non-pregnant animals. In conclusion, PNMS is a relevant factor in the programming of immune function. Its consequences may be related to disorders with an important immune component such as allergies.

Using natural disasters to study the effects of prenatal maternal stress on child health and development.

Research on the developmental origins of health and disease highlights the plasticity of the human fetus to a host of potential teratogens. Experimental research on laboratory animals has demonstrated a variety of physical and behavioral effects among offspring exposed to prenatal maternal stress (PNMS). However, these studies cannot elucidate the relative effects of the objective stress exposure and the subjective distress in a way that would parallel the stress experience in humans. PNMS research with humans is also limited because there are ethical challenges to designing studies that involve the random assignment of pregnant women to varying levels of independent stressors. Natural disasters present opportunities for natural experiments of the effects of pregnant women's exposure to stress on child development. In this review, we present an overview of the human and animal research on PNMS, and highlight the results of Project Ice Storm which has been following the cognitive, behavioral, motor and physical development of children exposed in utero to the January 1998 Quebec Ice Storm. We have found that both objective degree of exposure to the storm and the mothers' subjective distress have strong and persistent effects on child development, and that these effects are often moderated by the timing of the ice storm in pregnancy and by the child's sex.

Brief communication: prenatal and early postnatal stress exposure influences long bone length in adult rat offspring.

Stress during the prenatal and early postnatal periods (perinatal stress, PS) is known to impact offspring cognitive, behavioral, and physical development, but effects on skeletal growth are not clear. Our objective was to analyze effects of variable, mild, daily PS exposure on adult offspring long bone length. Twelve pregnant rat dams were randomly assigned to receive variable stress from gestational days 14-21 (Prenatal group), postpartum days 2-9 (Postnatal), both periods (Pre-Post), or no stress (Control). Differences in adult offspring tibia and femur length were analyzed among treatment groups. Mean tibia length differed among groups for males (P = 0.016) and females (P = 0.009), and differences for femur length approached significance for males (P = 0.051). Long bone length was shorter among PS-exposed offspring, especially those exposed to postnatal stress (Postnatal and Pre-Post groups). Results persisted when controlling for nose-tail length. These differences might reflect early stunting that is maintained in adulthood, or delayed growth among PS-exposed offspring. This study suggests that PS results in shorter long bones in adulthood, independently of effects on overall body size. Stunting and growth retardation are major global health burdens. Our study adds to a growing body of evidence suggesting that PS is a risk factor for poor linear growth.

The effects of childhood adversity on treatment delays and its components in first-episode psychosis.

Apart from increasing risk for psychotic disorders, childhood adversity has been associated with worse outcomes. One way in which childhood adversity may worsen outcomes is by lengthening treatment delays, which are associated with negative impacts. We tested the influence of childhood trauma on treatment delays, measured as the duration of untreated psychosis (DUP), and its help-seeking and referral components, in a first-episode psychosis cohort (N = 203). We accounted for pertinent social (e.g., migrant status) and other determinants (i.e., age at onset, diagnosis, symptoms) of treatment delays. Multiple linear regression analyses revealed that for a one-unit increase in Childhood Trauma Questionnaire (CTQ) scores, average overall DUP increased by 25%. Higher CTQ scores also significantly predicted help-seeking and referral DUPs. Patients with schizophrenia-spectrum psychosis had longer help-seeking and total DUPs than those with affective psychosis. More severe positive symptoms predicted longer help-seeking DUPs, while more severe negative symptoms predicted longer referral DUPs. Indicators of social disadvantage did not affect DUP. Our results show that childhood trauma increases DUP by prolonging the help-seeking process and delaying access to mental healthcare even after help is sought. Early identification of psychosis among populations with trauma histories seems warranted and can likely positively impact outcomes.

Impact of childhood trauma on positive and negative symptom remission in first episode psychosis.

OBJECTIVE: Early life adversity is suspected to play an important role for onset and course of psychosis, but its relationship with longer-term clinical outcome is not entirely clear. In this longitudinal study, we investigated the impact of childhood trauma (CT) on positive and negative symptom remission in first episode psychosis (FEP) patients over two years. METHODS: A total of 210 FEP patients were assessed with the Childhood Trauma Questionnaire. Patients reporting moderate to severe trauma (CT; N = 114; 54.3%) were compared to those without trauma (N-CT; N = 96; 45.7%). Positive (PSR) and negative symptom remission (NSR) were determined monthly over 24 months following established criteria using the Scale for Assessment of Positive Symptoms and the Scale for Assessment of Negative Symptoms. Global Functioning was evaluated at baseline and 24 months of follow-up. RESULTS: Compared to N-CT patients, CT patients had achieved significantly lower rates of PSR at 12 months and significantly lower rates of NSR at 24 months. A dose-response relationship was observed between the number of trauma categories fulfilled and the number of patients not achieving PSR and NSR at these time points. Higher trauma scores were significantly associated with poor functioning and higher positive and negative symptom severity at 24 months, but not at baseline and 12 months of follow-up. CONCLUSION: Differential effects of CT on clinical outcome may not be apparent at psychosis onset, but only become evident through poor symptomatic remission and general functioning over time. Targeted diagnostic and therapeutic efforts after illness onset might limit these detrimental consequences.

Disengagement in immigrant groups receiving services for a first episode of psychosis.

OBJECTIVE: Although early intervention (EI) programs for psychosis invest in clients remaining engaged in treatment, disengagement remains a concern. It is not entirely clear whether immigrants are likelier to disengage. The rates and predictors of disengagement for immigrant vis-à-vis non-immigrant clients in a Canadian EI setting were analyzed. METHOD: 297 clients were included in a time-to-event analysis with Cox Proportional Hazards regression models. Immigrant status (first- or second-generation immigrant or non-immigrant), age, gender, education, substance abuse, family contact, social and material deprivation and medication non-adherence were tested as predictors of service disengagement. RESULTS: 24.2% (n=72) of the clients disengaged from services before completing two years. Disengagement rates did not differ between first-generation immigrants (23.3%), second-generation immigrants (22.7%) and non-immigrants (25.3%). For all clients, only medication non-adherence predicted disengagement (HR=3.81, 95% CI 2.37-6.14). For first-generation immigrants, age (HR=1.17, 95% CI 1.02-1.34) and medication non-adherence (HR=2.92, 95% CI 1.09-7.85) were significant predictors. For second-generation immigrants, material deprivation (HR=1.03, 95% CI 1.00-1.05) and medication non-adherence (HR=11.07, 95% CI 3.20-38.22) were significant. CONCLUSION: Disengagement rates may be similar between immigrants and non-immigrants, but their reasons for disengagement may differ. Medication adherence was an important predictor for all, but the role of various sociodemographic factors differed by group. Sustaining all clients' engagement in EI programs may therefore require multi-pronged approaches.

Adolescent vs. adult onset of a first episode psychosis: Impact on remission of positive and negative symptoms.

OBJECTIVE: Adolescent-onset psychosis has traditionally been characterized as a more severe form of psychosis with a poorer prognosis. However, it is still unclear if patients with an adolescent-onset have worse symptom remission outcomes. Symptom remission is the principal clinical outcome known to predict quality of life and social functioning in the long term. The goal of this study is to clarify the influence of age of onset of psychosis on symptom remission in a sample of first-episode psychosis patients. METHOD: A total of 246 first-episode psychosis patients were recruited from a specialized early intervention program serving a defined epidemiological catchment area. Age of onset of psychosis (adolescence vs. adulthood) was used as the main predictor, and duration of untreated psychosis (DUP), baseline symptoms, baseline functioning, substance abuse diagnosis, medication adherence and gender were used as covariates in hierarchical regression models predicting the following positive and negative symptom remission outcomes: maximum continuous months in remission and early remission (i.e., occurring in the first three months of follow-up). RESULTS: After controlling for other variables, onset of psychosis in adulthood and shorter DUP predicted early remission of positive symptoms. This effect was stronger in patients with a diagnosis of a schizophrenia-spectrum disorder. Remission of negative symptoms did not depend on age of onset, and was only predicted by baseline negative symptoms. CONCLUSION: Patients with onset of psychosis during adulthood are more likely to achieve early positive symptom remission than those with adolescent onset. This effect might be stronger in patients with a diagnosis of a schizophrenia-spectrum disorder.

DNA methylation mediates the effect of exposure to prenatal maternal stress on cytokine production in children at age 13½ years: Project Ice Storm.

BACKGROUND: Prenatal maternal stress (PNMS) is an important programming factor of postnatal immunity. We tested here the hypothesis that DNA methylation of genes in the NF-κB signaling pathway in T cells mediates the effect of objective PNMS on Th1 and Th2 cytokine production in blood from 13½ year olds who were exposed in utero to the 1998 Quebec ice storm. RESULTS: Bootstrapping analyses were performed with 47 CpGs across a selection of 20 genes for Th1-type cytokines (IFN-γ and IL-2) and Th2-type cytokines (IL-4 and IL-13). Six CpGs in six different NF-κB signaling genes (PIK3CD, PIK3R2, NFKBIA, TRAF5, TNFRSF1B, and LTBR) remained as significant negative mediators of objective PNMS on IFN-γ secretion after correcting for multiple comparisons. However, no mediation effects on IL-2, IL-4 and IL-13 survived Bonferroni correction. CONCLUSIONS: The present study provides preliminary evidence supporting the mediating role of DNA methylation in the association between objective aspects of PNMS and child immune states, favoring a Th2 shift.

Prenatal maternal stress predicts reductions in CD4+ lymphocytes, increases in innate-derived cytokines, and a Th2 shift in adolescents: Project Ice Storm.

The relationship between psychological stress and immunity is well established, but it is not clear if prenatal maternal stress (PNMS) affects the development of the immune system in humans. Our objective was to determine the extent of this influence in a sample of teenagers whose mothers were pregnant during the 1998 Quebec ice storm. As part of a longitudinal study of PNMS, we measured the objective stress exposure and subjective distress of the women soon after the disaster. We obtained blood samples from 37 of their children when they were 13years old to measure cell population percentages and mitogen-induced cytokine production. We found that the mothers' objective degree of PNMS exposure significantly predicted reductions in total and CD4+ lymphocyte proportions, increases in TNF-α, IL-1ß, and IL-6 levels, and an enhancement of the Th2 cytokines IL-4 and IL-13. Sex and timing of PNMS exposure during gestation were also associated with some outcomes. These results show that PNMS is a programming factor that can produce long-lasting consequences on immunity, potentially explaining non-genetic variability in immune-related disorders. This information contributes to the understanding of the mechanisms underlying the influence of PNMS on immune-mediated disorders in humans.

Prenatal maternal stress predicts autism traits in 6½ year-old children: Project Ice Storm.

Research implicates prenatal maternal stress (PNMS) as a risk factor for neurodevelopmental disorders; however few studies report PNMS effects on autism risk in offspring. We examined, prospectively, the degree to which objective and subjective elements of PNMS explained variance in autism-like traits among offspring, and tested moderating effects of sex and PNMS timing in utero. Subjects were 89 (46F/43M) children who were in utero during the 1998 Quebec Ice Storm. Soon after the storm, mothers completed questionnaires on objective exposure and subjective distress, and completed the Autism Spectrum Screening Questionnaire (ASSQ) for their children at age 6½. ASSQ scores were higher among boys than girls. Greater objective and subjective PNMS predicted higher ASSQ independent of potential confounds. An objective-by-subjective interaction suggested that when subjective PNMS was high, objective PNMS had little effect; whereas when subjective PNMS was low, objective PNMS strongly affected ASSQ scores. A timing-by-objective stress interaction suggested objective stress significantly affected ASSQ in first-trimester exposed children, though less so with later exposure. The final regression explained 43% of variance in ASSQ scores; the main effect of sex and the sex-by-PNMS interactions were not significant. Findings may help elucidate neurodevelopmental origins of non-clinical autism-like traits from a dimensional perspective.

Prenatal stress due to a natural disaster predicts insulin secretion in adolescence.

Prenatal stress might increase cardiometabolic disease risk. We measured prenatal stress due to an ice storm in 1998, and measured glucose tolerance among a subsample of 32 exposed adolescents in 2011. Severity of stress was positively associated with insulin secretion, suggesting that prenatal stress independently predicts metabolic outcomes in adolescence.