Applying Mendelian randomization to appraise causality in relationships between smoking, depression and inflammation.

Smoking, inflammation and depression commonly co-occur and may be mechanistically linked. However, key questions remain around the direction of association and the influence of residual confounding. We aimed to characterize the association between lifetime smoking and depression, as well as to assess the role that genetically-predicted C-reactive protein (CRP) level, (an archetypal generalized inflammatory marker) and/or IL-6 activity, as a potential explanation for this association. We performed inverse variance weighted Mendelian randomization (MR) analyses using recently published summary-level GWAS data for lifetime smoking index, CRP levels, and depression. A subset of inflammatory-related genetic variants from the lifetime smoking GWAS were also used to assess the potential inflammatory causal pathways between smoking and depression. The analysis indicated reciprocal relationships of lifetime smoking with depression (ORSmk-Dep = 2.01, 95% CI 1.71-2.37, p < 0.001; ORDep-Smk = 1.09, 95% CI 1.06-1.13, p < 0.001), CRP levels and IL-6 activity (ORSmk-CRP = 1.40, 95% CI 1.21-1.55, p < 0.001; ORCRP-Smk = 1.03, 95% CI 1.02-1.05, p < 0.001, ORIL-6/CRP-Smk = 1.06 (1.03-1.09), p < 0.001). These associations were also supported by the majority of the robust MR methods performed. We did not find evidence for a reciprocal relationship between CRP levels (using > 500 genetic instruments for CRP) and depression (ORCRP-Dep = 1.01, 95% CI 0.99-1.04; ORDep-CRP = 1.03, 95% CI 0.99-1.07). We observed little variation in the IVW estimates between smoking and depression when we limited the genetic variants assessed to those related to measures of generalized inflammation, but we found evidence for an attenuation of the smoking-depression association in multivariable mendelian randomization when adjusting for IL-6 activity, suggesting that the IL-6 pathway may be at least in part responsible for the association of smoking and depression. Our study supports potential bidirectional causal associations between lifetime smoking and depression which may be at least in part explained by the IL-6 signalling pathway. The IL-6 pathway may represent a putative therapeutic target for smoking and to mitigate the effects of smoking on depression.

Childhood immuno-metabolic markers and risk of depression and psychosis in adulthood: A prospective birth cohort study.

BACKGROUND: Metabolic and inflammatory disorders commonly co-occur with depression and psychosis, with emerging evidence implicating immuno-metabolic dysfunction in their aetiology. Previous studies have reported metabolic dysfunction and inflammation in adults with depression and psychosis. However, longitudinal studies testing the direction of association, and the effects of different dimensions of early-life immuno-metabolic dysfunction on adult psychopathology are limited. METHODS: Using data from 3258 birth cohort participants we examined longitudinal associations of three metabolic hormones (leptin, adiponectin, insulin) at age 9 with risks for depression- and psychosis-spectrum outcomes at age 24. In addition, using nine immuno-metabolic biomarkers (leptin, adiponectin, insulin, interleukin-6, C-Reactive protein, low density lipoprotein, high density lipoprotein, triglycerides, and BMI), we constructed an exploratory bifactor model showing a general immuno-metabolic factor and three specific factors (adiposity, inflammation, and insulin resistance), which were also used as exposures. RESULTS: Childhood leptin was associated with adult depressive episode (adjusted odds ratio (aOR)= 1.31; 95% CI, 1.02-1.71) and negative symptoms (aOR=1.15; 95% CI, 1.07-1.24), but not positive psychotic symptoms. The general immuno-metabolic factor was associated with atypical depressive symptoms (aOR=1.07; 95% CI, 1.01-1.14) and psychotic experiences (aOR=1.21; 95% CI, 1.02-1.44). The adiposity factor was associated with negative symptoms (aOR=1.07; 95% CI 1.02-1.12). Point estimates tended to be larger in women, though 95% credible intervals overlapped with those for men. In women, the inflammatory factor was associated with depressive episodes (aOR=1.27; 95% CI, 1.03-1.57). CONCLUSIONS: While general immuno-metabolic dysfunction in childhood may contribute to risks for both psychotic and depressive symptoms in adulthood, childhood adiposity and inflammation appear to be particularly linked to affective (depressive and negative), but not positive psychotic symptoms.

Cardiometabolic risk prediction algorithms for young people with psychosis: a systematic review and exploratory analysis.

OBJECTIVE: Cardiometabolic risk prediction algorithms are common in clinical practice. Young people with psychosis are at high risk for developing cardiometabolic disorders. We aimed to examine whether existing cardiometabolic risk prediction algorithms are suitable for young people with psychosis. METHODS: We conducted a systematic review and narrative synthesis of studies reporting the development and validation of cardiometabolic risk prediction algorithms for general or psychiatric populations. Furthermore, we used data from 505 participants with or at risk of psychosis at age 18 years in the ALSPAC birth cohort, to explore the performance of three algorithms (QDiabetes, QRISK3 and PRIMROSE) highlighted as potentially suitable. We repeated analyses after artificially increasing participant age to the mean age of the original algorithm studies to examine the impact of age on predictive performance. RESULTS: We screened 7820 results, including 110 studies. All algorithms were developed in relatively older participants, and most were at high risk of bias. Three studies (QDiabetes, QRISK3 and PRIMROSE) featured psychiatric predictors. Age was more strongly weighted than other risk factors in each algorithm. In our exploratory analysis, calibration plots for all three algorithms implied a consistent systematic underprediction of cardiometabolic risk in the younger sample. After increasing participant age, calibration plots were markedly improved. CONCLUSION: Existing cardiometabolic risk prediction algorithms cannot be recommended for young people with or at risk of psychosis. Existing algorithms may underpredict risk in young people, even in the face of other high-risk features. Recalibration of existing algorithms or a new tailored algorithm for the population is required.

Insulin resistance and obesity, and their association with depression in relatively young people: findings from a large UK birth cohort.

BACKGROUND: Depression frequently co-occurs with disorders of glucose and insulin homeostasis (DGIH) and obesity. Low-grade systemic inflammation and lifestyle factors in childhood may predispose to DGIH, obesity and depression. We aim to investigate the cross-sectional and longitudinal associations among DGIH, obesity and depression, and to examine the effect of demographics, lifestyle factors and antecedent low-grade inflammation on such associations in young people. METHODS: Using the Avon Longitudinal Study of Parents and Children birth cohort, we used regression analyses to examine: (1) cross-sectional and (2) longitudinal associations between measures of DGIH [insulin resistance (IR); impaired glucose tolerance] and body mass index (BMI) at ages 9 and 18 years, and depression (depressive symptoms and depressive episode) at age 18 years and (3) whether sociodemographics, lifestyle factors or inflammation [interleukin-6 (IL-6) at age 9 years] confounded any such associations. RESULTS: We included 3208 participants. At age 18 years, IR and BMI were positively associated with depression. These associations may be explained by sociodemographic and lifestyle factors. There were no longitudinal associations between DGIH/BMI and depression, and adjustment for IL-6 and C-reactive protein did not attenuate associations between IR/BMI and depression; however, the longitudinal analyses may have been underpowered. CONCLUSIONS: Young people with depression show evidence of DGIH and raised BMI, which may be related to sociodemographic and lifestyle effects such as deprivation, smoking, ethnicity and gender. In future, studies with larger samples are required to confirm this. Preventative strategies for the poorer physical health outcomes associated with depression should focus on malleable lifestyle factors.

Identifying key targets for interventions to improve psychological wellbeing: replicable results from four UK cohorts.

BACKGROUND: An increasing importance is being placed on mental health and wellbeing at individual and population levels. While there are several interventions that have been proposed to improve wellbeing, more evidence is needed to understand which aspects of wellbeing are most influential. This study aimed to identify key items that signal improvement of mental health and wellbeing. METHODS: Using network analysis, we identified the most central items in the graph network estimated from the well-established Warwick-Edinburgh Mental Well-being Scale (WEMWBS). Results were compared across four major UK cohorts comprising a total of 47,578 individuals: the Neuroscience in Psychiatry Network, the Scottish Schools Adolescent Lifestyle and Substance Use Survey, the Northern Ireland Health Survey, and the National Child Development Study. RESULTS: Regardless of gender, the three items most central in the network were related to positive self-perception and mood: 'I have been feeling good about myself'; 'I have been feeling confident'; and 'I have been feeling cheerful'. Results were consistent across all four cohorts. CONCLUSIONS: Positive self-perception and positive mood are central to psychological wellbeing. Psychotherapeutic and public mental health interventions might best promote psychological wellbeing by prioritising the improvement of self-esteem, self-confidence and cheerfulness. However, empirical testing of interventions using these key targets is needed.

Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions.

Inflammatory cytokines are commonly elevated in acute depression and are associated with resistance to monoaminergic treatment. To examine the potential role of cytokines in the pathogenesis and treatment of depression, we carried out a systematic review and meta-analysis of antidepressant activity of anti-cytokine treatment using clinical trials of chronic inflammatory conditions where depressive symptoms were measured as a secondary outcome. Systematic search of the PubMed, EMBASE, PsycINFO and Cochrane databases, search of reference lists and conference abstracts, followed by study selection process yielded 20 clinical trials. Random effect meta-analysis of seven randomised controlled trials (RCTs) involving 2370 participants showed a significant antidepressant effect of anti-cytokine treatment compared with placebo (standardised mean difference (SMD)=0.40, 95% confidence interval (CI), 0.22-0.59). Anti-tumour necrosis factor drugs were most commonly studied (five RCTs); SMD=0.33 (95% CI; 0.06-0.60). Separate meta-analyses of two RCTs of adjunctive treatment with anti-cytokine therapy and eight non-randomised and/or non-placebo studies yielded similar small-to-medium effect estimates favouring anti-cytokine therapy; SMD=0.19 (95% CI, 0.00-0.37) and 0.51 (95% CI, 0.34-0.67), respectively. Adalimumab, etanercept, infliximab and tocilizumab all showed statistically significant improvements in depressive symptoms. Meta-regression exploring predictors of response found that the antidepressant effect was associated with baseline symptom severity (P=0.018) but not with improvement in primary physical illness, sex, age or study duration. The findings indicate a potentially causal role for cytokines in depression and that cytokine modulators may be novel drugs for depression in chronically inflamed subjects. The field now requires RCTs of cytokine modulators using depression as the primary outcome in subjects with high inflammation who are free of other physical illnesses.

Association between childhood infection, serum inflammatory markers and intelligence: findings from a population-based prospective birth cohort study.

A link between infection, inflammation, neurodevelopment and adult illnesses has been proposed. The objective of this study was to examine the association between infection burden during childhood - a critical period of development for the immune and nervous systems - and subsequent systemic inflammatory markers and general intelligence. In the Avon Longitudinal Study of Parents and Children, a prospective birth cohort in England, we examined the association of exposure to infections during childhood, assessed at seven follow-ups between age 1·5 and 7·5 years, with subsequent: (1) serum interleukin 6 and C-reactive protein (CRP) levels at age 9; (2) intelligence quotient (IQ) at age 8. We also examined the relationship between inflammatory markers and IQ. Very high infection burden (90+ percentile) was associated with higher CRP levels, but this relationship was explained by body mass index (adjusted odds ratio (OR) 1·19; 95% confidence interval (CI) 0·95-1·50), maternal occupation (adjusted OR 1·23; 95% CI 0·98-1·55) and atopic disorders (adjusted OR 1·24; 95% CI 0·98-1·55). Higher CRP levels were associated with lower IQ; adjusted ß = -0·79 (95% CI -1·31 to -0·27); P = 0·003. There was no strong evidence for an association between infection and IQ. The findings indicate that childhood infections do not have an independent, lasting effect on circulating inflammatory marker levels subsequently in childhood; however, elevated inflammatory markers may be harmful for intellectual development/function.

Childhood inflammatory markers and intelligence as predictors of subsequent persistent depressive symptoms: a longitudinal cohort study.

BACKGROUND: To identify developmental sub-groups of depressive symptoms during the second decade of life, a critical period of brain development, using data from a prospective birth cohort. To test whether childhood intelligence and inflammatory markers are associated with subsequent persistent depressive symptoms. METHODS: IQ, a proxy for neurodevelopment, was measured at age 8 years. Interleukin 6 (IL-6) and C-reactive protein, typical inflammatory markers, were measured at age 9 years. Depressive symptoms were measured six times between 10 and 19 years using the short mood and feelings questionnaire (SMFQ), which were coded as binary variable and then used in latent class analysis to identify developmental sub-groups of depressive symptoms. RESULTS: Longitudinal SMFQ data from 9156 participants yielded three distinct population sub-groups of depressive symptoms: no symptoms (81.2%); adolescent-onset symptoms (13.2%); persistent symptoms (5.6%). Lower IQ and higher IL-6 levels in childhood were independently associated with subsequent persistent depressive symptoms in a linear, dose-response fashion, but not with adolescent-onset symptoms. Compared with the group with no symptoms the adjusted odds ratio for persistent depressive symptoms per s.d. increase in IQ was 0.80 (95% CI, 0.68-0.95); that for IL-6 was 1.20 (95% CI, 1.03-1.39). Evidence for an association with IL-6 remained after controlling for initial severity of depressive symptoms at 10 years. There was no evidence that IL-6 moderated or mediated the IQ-persistent depressive symptom relationship. CONCLUSIONS: The results indicate potentially important roles for two distinct biological processes, neurodevelopment and inflammation, in the aetiology of persistent depressive symptoms in young people.

Immunopsychiatry: important facts.

Accumulating evidence indicate a role for the immune system particularly inflammation and autoimmunity in the aetiology of major psychiatric disorders such as depression and schizophrenia. In this paper, we discuss some of the key advances in immunopsychiatry in order to highlight to psychiatrists and other health professionals how an increased understanding of this field might enhance our knowledge of illness mechanism and approaches to treatment. We present a brief overview of clinical research that link inflammation and autoimmunity with depression and psychosis, including potential role of inflammation in treatment response, current evidence for the effectiveness of immune-modulating treatment for depression and psychosis, and possible role of inflammation in common physical comorbidities for these disorders such as coronary heart disease and diabetes mellitus. Gaining a better understanding of the role of immune system could be paradigm changing for psychiatry. We need collaborations between clinicians and scientists to deliver high-quality translational research in order to fully realise the clinical potential of this exciting and rapidly expanding field.

Early motor developmental milestones and schizophrenia: A systematic review and meta-analysis.

The neurodevelopmental hypothesis of schizophrenia proposes that impaired brain development is a cause of the illness. Early motor developmental milestones, such as learning to walk, are predictors of later schizophrenia but studies have not been systematically reviewed. The aim of the present systematic review and meta-analysis was to explore the association between early motor developmental milestones and the risk of adult schizophrenia. In addition, we updated a systematic review on motor function and risk of schizophrenia. The PubMed, PsycINFO and Scopus databases were searched for original research articles published up to July 2015. Motor milestones were measured between ages 0 and 13years. Random effect meta-analysis calculated effect estimates (Hedges' g) for the association between individual motor milestones and schizophrenia risk. An electronic database and selected articles reference list search identified 5990 articles after removing duplicates. Sixty-nine full text articles were assessed for eligibility of which six were included in the review. Five studies provided sufficient data for meta-analyses. The following motor milestones were significantly associated with adult schizophrenia risk: walking unsupported (g=0.46; 95% CI 0.27-0.64; p<0.001), standing unsupported (g=0.28; 0.16-0.40; p<0.001) and sitting unsupported (g=0.18; 0.05-0.31; p=0.007). Results for the milestones 'holding head up' and 'grabbing object' were not statistically significant. Delayed walking, sitting and standing unsupported were associated with adult onset schizophrenia. The findings emphasise the importance of timely achievement of these motor milestones in childhood and can contribute to the identification of individuals at risk of psychosis.

A comparison of the cumulative incidence and early risk factors for psychotic disorder in young adults in the Northern Finland Birth Cohorts 1966 and 1986.

AIMS: Few studies have compared time trends for the incidence of psychosis. To date, the results have been inconsistent, showing a decline, an increase or no significant change. As far as we know, no studies explored changes in prevalence of early risk factors. The aim of this study was to investigate differences in early risk factors and cumulative incidences of psychosis by type of psychosis in two comparable birth cohorts. METHODS: The Northern Finland Birth cohorts (NFBCs) 1966 (N = 12 058) and 1986 (N = 9432) are prospective general population-based cohorts with the children followed since mother's mid-pregnancy. The data for psychoses, i.e. schizophrenia (narrow, spectrum), bipolar disorder with psychotic features, major depressive episode with psychotic features, brief psychosis and other psychoses (ICD 8-10) were collected from nationwide registers including both inpatients and outpatients. The data on early risk factors including sex and place of birth of the offspring, parental age and psychosis, maternal education at birth were prospectively collected from the population registers. The follow-up reached until the age of 27 years. RESULTS: An increase in the cumulative incidence of all psychoses was seen (1.01% in NFBC 1966 v. 1.90% in NFBC 1986; p < 0.001), which was due to an increase in diagnosed affective and other psychoses. Earlier onset of cases and relatively more psychoses in women were observed in the NFBC 1986. Changes in prevalence of potential early risk factors were identified, but only parental psychosis was a significant predictor in both cohorts (hazard ratios ≥3.0; 95% CI 1.86-4.88). The difference in psychosis incidence was not dependent on changes in prevalence of studied early risk factors. CONCLUSIONS: Surprisingly, increase in the cumulative incidence of psychosis and also changes in the types of psychoses were found between two birth cohorts 20 years apart. The observed differences could be due to real changes in incidence or they can be attributable to changes in diagnostic practices, or to early psychosis detection and treatment.

Childhood interleukin-6, C-reactive protein and atopic disorders as risk factors for hypomanic symptoms in young adulthood: a longitudinal birth cohort study.

BACKGROUND: There are no existing longitudinal studies of inflammatory markers and atopic disorders in childhood and risk of hypomanic symptoms in adulthood. This study examined if childhood: (1) serum interleukin-6 (IL-6) and C-reactive protein (CRP); and (2) asthma and/or eczema are associated with features of hypomania in young adulthood. METHOD: Participants in the Avon Longitudinal Study of Parents and Children, a prospective general population UK birth cohort, had non-fasting blood samples for IL-6 and CRP measurement at the age of 9 years (n = 4645), and parents answered a question about doctor-diagnosed atopic illness before the age of 10 years (n = 7809). These participants completed the Hypomania Checklist at age 22 years (n = 3361). RESULTS: After adjusting for age, sex, ethnicity, socio-economic status, past psychological and behavioural problems, body mass index and maternal postnatal depression, participants in the top third of IL-6 values at 9 years, compared with the bottom third, had an increased risk of hypomanic symptoms by age 22 years [adjusted odds ratio 1.77, 95% confidence interval (CI) 1.10-2.85, p < 0.001]. Higher IL-6 levels in childhood were associated with adult hypomania features in a dose-response fashion. After further adjustment for depression at the age of 18 years this association remained (adjusted odds ratio 1.70, 95% CI 1.03-2.81, p = 0.038). There was no evidence of an association of hypomanic symptoms with CRP levels, asthma or eczema in childhood. CONCLUSIONS: Higher levels of systemic inflammatory marker IL-6 in childhood were associated with hypomanic symptoms in young adulthood, suggesting that inflammation may play a role in the pathophysiology of mania. Inflammatory pathways may be suitable targets for the prevention and intervention for bipolar disorder.

Mood, anxiety and psychotic phenomena measure a common psychopathological factor.

BACKGROUND: Psychotic phenomena are common in the general population but are excluded from diagnostic criteria for mild to moderate depression and anxiety despite their co-occurrence and shared risk factors. We used item response theory modelling to examine whether the co-occurrence of depressive, anxiety and psychotic phenomena is best explained by: (1) a single underlying factor; (2) two separate, uncorrelated factors; (3) two separate yet linked factors; or (4) two separate domains along with an underlying 'common mental distress' (CMD) factor. We defined where, along any latent continuum, the psychopathological items contributed most information. METHOD: We performed a secondary analysis of cross-sectional, item-level information from measures of depression, anxiety and psychotic experiences in 6617 participants aged 13 years from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort and 977 participants aged 18 years from the ROOTS schools-based sample. We replicated results from one sample in the other and validated the latent factors against an earlier parental measure of mental state. RESULTS: In both cohorts depression, anxiety and psychotic items were best represented as a bi-factor model with a single, unitary CMD factor on which psychotic items conveyed information about the more severe end (model 4); residual variation remained for psychotic items. The CMD factor was significantly associated with the prior parental measure. CONCLUSIONS: Psychotic phenomena co-occur with depression and anxiety in teenagers and may be a marker of severity in a single, unitary dimension of CMD. Psychotic phenomena should be routinely included in epidemiological assessments of psychiatric morbidity, otherwise the most severe symptomatology remains unmeasured.

A population-based longitudinal study of childhood neurodevelopmental disorders, IQ and subsequent risk of psychotic experiences in adolescence.

BACKGROUND: Schizophrenia has a neurodevelopmental component to its origin, and may share overlapping pathogenic mechanisms with childhood neurodevelopmental disorders (NDs). Nevertheless, longitudinal studies of psychotic outcomes among individuals with NDs are limited. We report a population-based prospective study of six common childhood NDs, subsequent neurocognitive performance and the risk of psychotic experiences (PEs) in early adolescence. METHOD: PEs were assessed by semi-structured interviews at age 13 years. IQ and working memory were measured between ages 9 and 11 years. The presence of six NDs (autism spectrum, dyslexia, dyspraxia, dysgraphia, dysorthographia, dyscalculia) was determined from parent-completed questionnaires at age 9 years. Linear regression calculated the mean difference in cognitive scores between children with and without NDs. Associations between NDs and PEs were expressed as odds ratios (ORs) with 95% confidence intervals (CIs); effects of cognitive deficits were examined. Potential confounders included age, gender, father's social class, ethnicity and maternal education. RESULTS: Out of 8220 children, 487 (5.9%) were reported to have NDs at age 9 years. Children with, compared with those without, NDs performed worse on all cognitive measures; the adjusted mean difference in total IQ was 6.84 (95% CI 5.00-8.69). The association between total IQ and NDs was linear (p < 0.0001). The risk of PEs was higher in those with, compared with those without, NDs; the adjusted OR for definite PEs was 1.76 (95% CI 1.11-2.79). IQ (but not working memory) deficit partly explained this association. CONCLUSIONS: Higher risk of PEs in early adolescence among individuals with childhood ND is consistent with the neurodevelopmental hypothesis of schizophrenia.

Clinical and sociodemographic comparison of people at high-risk for psychosis and with first-episode psychosis.

OBJECTIVE: To compare clinical and sociodemographic characteristics previously associated with psychosis, between individuals at high-risk for psychosis (HR) and patients experiencing a first episode psychosis (FEP), to achieve a better understanding of factors associated with psychosis. METHOD: Cross-sectional comparison of 30 individuals at HR with 30 age-gender matched FEP, presenting to an early intervention service for psychosis. Participants were followed-up for 2 years to establish the proportion of HR who made the transition into FEP. RESULTS: Both groups showed similar socio-clinical characteristics, including immigration status, employment history, marital status, family history of psychotic illness, self-harm and alcohol and drug use. The HR group had a lower level of education, higher burden of trauma, earlier onset of psychiatric symptoms and a longer delay in accessing specialised services. A younger onset of symptoms was associated with a longer delay in accessing services in both groups. After a 2 year follow-up, only three (10%) of the HR group made a transition into FEP. CONCLUSION: The similarities observed between individuals at HR and those with FEP suggest that known variables associated with psychosis may be equally prevalent in people at HR who do not develop a psychotic disorder.

Prenatal maternal infection, neurodevelopment and adult schizophrenia: a systematic review of population-based studies.

BACKGROUND: Disruption of foetal development by prenatal maternal infection is consistent with a neurodevelopmental model of schizophrenia. Whether specific prenatal infections are involved, their timing and the mechanisms of any effect are all unknown. We addressed these questions through a systematic review of population-based studies. METHOD: Electronic and manual searches and rigorous quality assessment yielded 21 studies that included an objective assessment of individual-level prenatal maternal infection and standardized psychotic diagnoses in adult offspring. Methodological differences between studies necessitated a descriptive review. RESULTS: Results for prenatal maternal non-specific bacterial, respiratory or genital and reproductive infection differed between studies, which reported up to a two- to fivefold increased risk of schizophrenia. Evidence for herpes simplex virus type 2 (HSV-2) and Toxoplasma gondii was mixed; some studies reported up to a doubling of schizophrenia risk. Prenatal HSV-1 or cytomegalovirus (CMV) infections were not associated with increased risk. Exposure to influenza or other infections during early pregnancy may be more harmful than later exposure. Increased proinflammatory cytokines during pregnancy were also associated with risk. Prenatal infection was associated with structural and functional brain abnormalities relevant to schizophrenia. CONCLUSIONS: Prenatal exposure to a range of infections and inflammatory responses may be associated with risk of adult schizophrenia. Larger samples, mediation and animal models should be used to investigate whether there is a 'sensitive period' during development, and the effects of prenatal infections on neurodevelopment. Inclusion of genetic and immunological information should help to elucidate to what extent genetic vulnerability to schizophrenia may be explained by vulnerability to infection.

Does maternal body mass index during pregnancy influence risk of schizophrenia in the adult offspring?

Maternal obesity in pregnancy has been linked with several adverse outcomes in offspring including schizophrenia. The rising prevalence of obesity may contribute to an increase in the number of schizophrenia cases in the near future; therefore, it warrants further exploration. We reviewed current evidence regarding maternal body mass index (BMI) in pregnancy and risk of schizophrenia in adult offspring. We searched PubMed and Embase databases and included studies that were based on large and representative population-based datasets. A qualitative review was undertaken due to heterogeneity between studies. Four studies with 305 cases of schizophrenia and 24,442 controls were included. Maternal obesity (pre-pregnant BMI over 29 or 30 compared with mothers with low or average BMI) was associated with two- to threefold increased risk of schizophrenia in the adult offspring in two birth cohorts. High maternal BMI at both early and late pregnancy also increased risk of schizophrenia in the offspring. Discrepant findings from one study could be attributable to sample characteristics and other factors. The area needs more research. Future studies should take into account obstetric complications, diabetes, maternal infections and immune responses that might potentially mediate this association.