Association between genetic and socioenvironmental risk for schizophrenia during upbringing in a UK longitudinal cohort.

BACKGROUND: Associations of socioenvironmental features like urbanicity and neighborhood deprivation with psychosis are well-established. An enduring question, however, is whether these associations are causal. Genetic confounding could occur due to downward mobility of individuals at high genetic risk for psychiatric problems into disadvantaged environments. METHODS: We examined correlations of five indices of genetic risk [polygenic risk scores (PRS) for schizophrenia and depression, maternal psychotic symptoms, family psychiatric history, and zygosity-based latent genetic risk] with multiple area-, neighborhood-, and family-level risks during upbringing. Data were from the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally-representative cohort of 2232 British twins born in 1994-1995 and followed to age 18 (93% retention). Socioenvironmental risks included urbanicity, air pollution, neighborhood deprivation, neighborhood crime, neighborhood disorder, social cohesion, residential mobility, family poverty, and a cumulative environmental risk scale. At age 18, participants were privately interviewed about psychotic experiences. RESULTS: Higher genetic risk on all indices was associated with riskier environments during upbringing. For example, participants with higher schizophrenia PRS (OR = 1.19, 95% CI = 1.06-1.33), depression PRS (OR = 1.20, 95% CI = 1.08-1.34), family history (OR = 1.25, 95% CI = 1.11-1.40), and latent genetic risk (OR = 1.21, 95% CI = 1.07-1.38) had accumulated more socioenvironmental risks for schizophrenia by age 18. However, associations between socioenvironmental risks and psychotic experiences mostly remained significant after covariate adjustment for genetic risk. CONCLUSION: Genetic risk is correlated with socioenvironmental risk for schizophrenia during upbringing, but the associations between socioenvironmental risk and adolescent psychotic experiences appear, at present, to exist above and beyond this gene-environment correlation.

Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression.

The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38 802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analysed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis) with qualifying unpublished data, were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations.

Interaction between childhood maltreatment on immunogenetic risk in depression: Discovery and replication in clinical case-control samples.

Major depressive disorder (MDD) is a prevalent disorder with moderate heritability. Both MDD and interpersonal adversity, including childhood maltreatment, have been consistently associated with elevated inflammatory markers. We investigated interaction between exposure to childhood maltreatment and extensive genetic variation within the inflammation pathway (CRP, IL1b, IL-6, IL11, TNF, TNFR1, and TNFR2) in relation to depression diagnosis. The discovery RADIANT sample included 262 cases with recurrent DSM-IV/ICD-10 MDD, and 288 unaffected controls. The replication Münster cohort included 277 cases with DSM-IV MDD, and 316 unaffected controls. We identified twenty-five single nucleotide polymorphisms (SNPs) following multiple testing correction that interacted with childhood maltreatment to predict depression in the discovery cohort. Seven SNPs representing independent signals (rs1818879, rs1041981, rs4149576, rs616645, rs17882988, rs1061622, and rs3093077) were taken forward for replication. Meta-analyses of the two samples presented evidence for interaction with rs1818879 (IL6) (RD=0.059, SE=0.016, p<0.001), with the replication Münster sample approaching statistical significance in analyses restricted to recurrent MDD and controls following correction for multiple testing (q=0.066). The CRP locus (rs3093077) showed a similar level of evidence for interaction in the meta-analysis (RD=0.092, SE=0.029, p=0.002), but less compelling evidence in the replication sample alone (recurrent MDD q=0.198; all MDD q=0.126). Here we present evidence suggestive of interaction with childhood maltreatment for novel loci in IL-6 (rs1818879) and CRP (rs3093077), increasing risk of depression. Replication is needed by independent groups, targeting these specific variants and interaction with childhood maltreatment on depression risk.

Hot and cold executive functions in youth with psychotic symptoms.

BACKGROUND: Psychotic symptoms are common in children and adolescents and may be early manifestations of liability to severe mental illness (SMI), including schizophrenia. SMI and psychotic symptoms are associated with impairment in executive functions. However, previous studies have not differentiated between 'cold' and 'hot' executive functions. We hypothesized that the propensity for psychotic symptoms is specifically associated with impairment in 'hot' executive functions, such as decision-making in the context of uncertain rewards and losses. METHODS: In a cohort of 156 youth (mean age 12.5, range 7-24 years) enriched for familial risk of SMI, we measured cold and hot executive functions with the spatial working memory (SWM) task (total errors) and the Cambridge Gambling Task (decision-making), respectively. We assessed psychotic symptoms using the semi-structured Kiddie Schedule for Affective Disorders and Schizophrenia interview, Structured Interview for Prodromal Syndromes, Funny Feelings, and Schizophrenia Proneness Instrument - Child and Youth version. RESULTS: In total 69 (44.23%) youth reported psychotic symptoms on one or more assessments. Cold executive functioning, indexed with SWM errors, was not significantly related to psychotic symptoms [odds ratio (OR) 1.36, 95% confidence interval (CI) 0.85-2.17, p = 0.204). Poor hot executive functioning, indexed as decision-making score, was associated with psychotic symptoms after adjustment for age, sex and familial clustering (OR 2.37, 95% CI 1.25-4.50, p = 0.008). The association between worse hot executive functions and psychotic symptoms remained significant in sensitivity analyses controlling for general cognitive ability and cold executive functions. CONCLUSIONS: Impaired hot executive functions may be an indicator of risk and a target for pre-emptive early interventions in youth.

Impact of childhood adversities on specific symptom dimensions in first-episode psychosis.

BACKGROUND: The relationship between childhood adversity (CA) and psychotic disorder is well documented. As the adequacy of the current categorical diagnosis of psychosis is being increasingly questioned, we explored independent associations between different types of CA and specific psychotic symptom dimensions in a well-characterized sample of first-episode psychosis (FEP) patients. METHOD: This study involved 236 FEP cases aged 18-65 years who presented for the first time to psychiatric services in South London, UK. Psychopathology was assessed with the Positive and Negative Syndrome Scale and confirmatory factor analysis was used to evaluate the statistical fit of the Wallwork/Fortgang five-factor model of psychosis. CA prior to 17 years of age (physical abuse, sexual abuse, parental separation, parental death, and being taken into care) was retrospectively assessed using the Childhood Experience of Care and Abuse Questionnaire. RESULTS: Childhood sexual abuse [ß = 0.96, 95% confidence interval (CI) 0.40-1.52], childhood physical abuse (ß = 0.48, 95% CI 0.03-0.93) and parental separation (ß = 0.60, 95% CI 0.10-1.11) showed significant associations with the positive dimension; while being taken into care was associated with the excited dimension (ß = 0.36, 95% CI 0.08-0.65), independent of the other types of CA. No significant associations were found between parental death and any of the symptom dimensions. CONCLUSIONS: A degree of specificity was found in the relationships between different types of CA and psychosis symptom dimensions in adulthood, suggesting that distinct pathways may be involved in the CA-psychosis association. These potentially different routes to developing psychosis merit further empirical and theoretical exploration.

Psychological processes underlying the association between childhood trauma and psychosis in daily life: an experience sampling study.

BACKGROUND: Evidence has accumulated that implicates childhood trauma in the aetiology of psychosis, but our understanding of the putative psychological processes and mechanisms through which childhood trauma impacts on individuals and contributes to the development of psychosis remains limited. We aimed to investigate whether stress sensitivity and threat anticipation underlie the association between childhood abuse and psychosis. METHOD: We used the Experience Sampling Method to measure stress, threat anticipation, negative affect, and psychotic experiences in 50 first-episode psychosis (FEP) patients, 44 At-Risk Mental State (ARMS) participants, and 52 controls. Childhood abuse was assessed using the Childhood Trauma Questionnaire. RESULTS: Associations of minor socio-environmental stress in daily life with negative affect and psychotic experiences were modified by sexual abuse and group (all p FWE < 0.05). While there was strong evidence that these associations were greater in FEP exposed to high levels of sexual abuse, and some evidence of greater associations in ARMS exposed to high levels of sexual abuse, controls exposed to high levels of sexual abuse were more resilient and reported less intense negative emotional reactions to socio-environmental stress. A similar pattern was evident for threat anticipation. CONCLUSIONS: Elevated sensitivity and lack of resilience to socio-environmental stress and enhanced threat anticipation in daily life may be important psychological processes underlying the association between childhood sexual abuse and psychosis.

Polygenic interactions with environmental adversity in the aetiology of major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is a common and disabling condition with well-established heritability and environmental risk factors. Gene-environment interaction studies in MDD have typically investigated candidate genes, though the disorder is known to be highly polygenic. This study aims to test for interaction between polygenic risk and stressful life events (SLEs) or childhood trauma (CT) in the aetiology of MDD. METHOD: The RADIANT UK sample consists of 1605 MDD cases and 1064 controls with SLE data, and a subset of 240 cases and 272 controls with CT data. Polygenic risk scores (PRS) were constructed using results from a mega-analysis on MDD by the Psychiatric Genomics Consortium. PRS and environmental factors were tested for association with case/control status and for interaction between them. RESULTS: PRS significantly predicted depression, explaining 1.1% of variance in phenotype (p = 1.9 × 10(-6)). SLEs and CT were also associated with MDD status (p = 2.19 × 10(-4) and p = 5.12 × 10(-20), respectively). No interactions were found between PRS and SLEs. Significant PRSxCT interactions were found (p = 0.002), but showed an inverse association with MDD status, as cases who experienced more severe CT tended to have a lower PRS than other cases or controls. This relationship between PRS and CT was not observed in independent replication samples. CONCLUSIONS: CT is a strong risk factor for MDD but may have greater effect in individuals with lower genetic liability for the disorder. Including environmental risk along with genetics is important in studying the aetiology of MDD and PRS provide a useful approach to investigating gene-environment interactions in complex traits.

Biological and psychosocial risk factors for psychotic major depression.

AIMS: Few studies have investigated risk factors for psychotic major depression (PMD). We aimed to investigate the biological and psychosocial risk factors associated with PMD compared with other psychotic disorders. METHODS: Based on the aetiology and ethnicity in schizophrenia and other psychoses (ÆSOP) study, we used a case-control study to identify and recruit, at baseline and 10-year follow-up, all first episode cases of psychosis, presenting for the first time to specialist mental health services in defined catchment areas in the UK. Population-based controls were recruited from the same areas. Data were collected on: sociodemographics; social isolation; childhood adversity; life events; minor physical anomalies; and neurological soft signs. RESULTS: Living alone (aOR = 2.26, CI = 1.21-4.23), basic level qualification (aOR = 2.89, CI = 1.08-7.74), being unemployed (aOR = 2.12, CI = 1.13-3.96), having contact with friends less than monthly (aOR = 4.24, CI = 1.62-11.14), having no close confidants (aOR = 4.71, CI = 2.08-10.68), having experienced childhood adversity (aOR = 2.57, CI = 1.02-6.44), family history of mental illness (aOR = 10.68, CI = 5.06-22.52), family history of psychosis (aOR = 12.85, CI = 5.24-31.51), and having more neurological soft signs (aOR = 1.15, CI = 1.07-1.24) were all associated with a follow-up diagnosis of PMD and schizophrenia. Few variables associated with PMD were also associated with a diagnosis of bipolar disorder. Minor physical anomalies were associated with a follow-up diagnosis of schizophrenia and bipolar disorder, but not PMD. CONCLUSIONS: Risk factors associated with PMD appear to overlap with those for schizophrenia, but less so for bipolar disorder. Future work on the differential aetiology of PMD, from other psychoses is needed to find the 'specifier' between PMD and other psychoses. Future research on aetiology in PMD, and perhaps other psychoses, should account for diagnostic change.

Childhood sleep disturbance and risk of psychotic experiences at 18: UK birth cohort.

BACKGROUND: Sleep disturbances are commonly reported in the psychosis prodrome, but rarely explored in relation to psychotic experiences. AIMS: To investigate the relationship between specific parasomnias (nightmares, night terrors and sleepwalking) in childhood and later adolescent psychotic experiences. METHOD: The sample comprised 4720 individuals from a UK birth cohort. Mothers reported on children's experience of regular nightmares at several time points between 2 and 9 years. Experience of nightmares, night terrors and sleepwalking was assessed using a semi-structured interview at age 12. Psychotic experiences were assessed at ages 12 and 18 using a semi-structured clinical interview. RESULTS: There was a significant association between the presence of nightmares at 12 and psychotic experiences at 18 when adjusted for possible confounders and psychotic experiences at 12 (OR = 1.62, 95% CI 1.19-2.20). The odds ratios were larger for those who reported persistent psychotic experiences. CONCLUSIONS: The presence of nightmares might be an early risk indicator for psychosis.

The impact of childhood adversity on the persistence of psychotic symptoms: a systematic review and meta-analysis.

BACKGROUND: Evidence suggests that childhood adversity is associated with the development of psychotic experiences (PE), psychotic symptoms and disorders. However, less is known regarding the impact of early adversity on the persistence of PE and clinically relevant psychosis. Thus we conducted a systematic review of the association between childhood adversity and the course of PE and symptoms over time. METHOD: A systematic search of Medline, EMBASE and PsychINFO databases was undertaken to identify articles published between January 1956 and November 2014. We included studies conducted on general population samples, individuals at ultra-high risk (UHR) of psychosis, and patients with full-blown psychotic disorders. A meta-analysis was performed on a subgroup. RESULTS: A total of 20 studies were included. Of these, 17 reported positive associations between exposure to overall or specific subtypes of childhood adversity and persistence of PE or clinically relevant psychotic symptoms. A meta-analysis of nine studies yielded a weighted odds ratio of 1.76 [95% confidence interval (CI) 1.19-2.32, p < 0.001] for general population studies and 1.55 (95% CI 0.32-2.77, p = 0.007) for studies conducted using clinical populations. CONCLUSIONS: The available evidence is limited but tentatively suggests that reported exposure to adverse events in childhood is associated with persistence of PE and clinically relevant psychotic symptoms. This partially strengthens the case for addressing the consequences of early adversity in individuals presenting with psychotic phenomena to improve long-term outcomes. However, the heterogeneity of studies was high which urges caution in interpreting the results and highlights the need for more methodologically robust studies.

Childhood trauma and schizotypy: a systematic literature review.

BACKGROUND: Schizotypy is a complex concept, commonly defined as a genetic vulnerability to schizophrenia that falls on a continuum between healthy variation and severe mental illness. There is a growing body of evidence supporting an association between childhood trauma and increased psychotic experiences and disorders. However, the evidence as to whether there is a similar association with schizotypy has yet to be systematically synthesized and assessed. METHOD: We conducted a systematic search of published articles on the association between childhood trauma and schizotypy in four major databases. The search covered articles from 1806 to 1 March 2013 and resulted in 17,003 articles in total. Twenty-five original research studies met the eligibility criteria and were included in this review. RESULTS: All 25 studies supported the association between at least one type of trauma and schizotypy, with odds ratios (ORs) ranging between 2.01 and 4.15. There was evidence supporting the association for all types of trauma, with no differential effects. However, there was some variability in the quality of the studies, with most using cross-sectional designs. Individuals who reported adverse experiences in childhood scored significantly higher on positive and negative/disorganized schizotypy compared to those who did not report such experiences. CONCLUSIONS: All forms of childhood trauma and other stressful events (e.g. bullying) were found to be associated with schizotypy, with especially strong associations with positive schizotypy. However, because of the methodological limitations of several studies and a lack of further exploration of different possible mechanistic pathways underlying this association, more research is required.

Bullying in elementary school and psychotic experiences at 18 years: a longitudinal, population-based cohort study.

BACKGROUND: Victims of bullying are at risk for psychotic experiences in early adolescence. It is unclear if this elevated risk extends into late adolescence. The aim of this study was to test whether bullying perpetration and victimization in elementary school predict psychotic experiences in late adolescence. METHOD: The current study is based on the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective community-based study. A total of 4720 subjects with bullying perpetration and victimization were repeatedly assessed between the ages of 8 and 11 years by child and mother reports. Suspected or definite psychotic experiences were assessed with the Psychosis-Like Symptoms semi-structured interview at age 18 years. RESULTS: Controlling for child's gender, intelligence quotient at age 8 years, childhood behavioural and emotional problems, and also depression symptoms and psychotic experiences in early adolescence, victims [child report at 10 years: odds ratio (OR) 2.4, 95% confidence interval (CI) 1.6-3.4; mother report: OR 1.6, 95% CI 1.1-2.3], bully/victims (child report at 10 years: OR 3.1, 95% CI 1.7-5.8; mother: OR 2.9, 95% CI 1.7-5.0) and bullies (child report at 10 years: OR 4.9, 95% CI 1.3-17.7; mother: OR 1.2, 95% CI 0.46-3.1, n.s.) had a higher prevalence of psychotic experiences at age 18 years. Path analysis revealed that the association between peer victimization in childhood and psychotic experiences at age 18 years was only partially mediated by psychotic or depression symptoms in early adolescence. CONCLUSIONS: Involvement in bullying, whether as victim, bully/victim or bully, may increase the risk of developing psychotic experiences in adolescence. Health professionals should ask routinely during consultations with children about their bullying of and by peers.

Cannabis use and first-episode psychosis: relationship with manic and psychotic symptoms, and with age at presentation.

BACKGROUND: Cannabis use has been reported to be associated with an earlier onset of symptoms in patients with first-episode psychosis, and a worse outcome in those who continue to take cannabis. In general, studies have concentrated on symptoms of psychosis rather than mania. In this study, using a longitudinal design in a large naturalistic cohort of patients with first-episode psychosis, we investigated the relationship between cannabis use, age of presentation to services, daily functioning, and positive, negative and manic symptoms. METHOD: Clinical data on 502 patients with first-episode psychosis were collected using the MiData audit database from seven London-based Early Intervention in psychosis teams. Individuals were assessed at two time points--at entry to the service and after 1 year. On each occasion, the Positive and Negative Syndrome Scale, Young Mania Rating Scale and Global Assessment of Functioning Scale disability subscale were rated. At both time points, the use of cannabis and other drugs of abuse in the 6 months preceding each assessment was recorded. RESULTS: Level of cannabis use was associated with a younger age at presentation, and manic symptoms and conceptual disorganization, but not with delusions, hallucinations, negative symptoms or daily functioning. Cannabis users who reduced or stopped their use following contact with services had the greatest improvement in symptoms at 1 year compared with continued users and non-users. Continued users remained more symptomatic than non-users at follow-up. CONCLUSIONS: Effective interventions for reducing cannabis use may yield significant health benefits for patients with first-episode psychosis.

Antidepressant Exposure and DNA Methylation: Insights from a Methylome-Wide Association Study.

Importance: Understanding antidepressant mechanisms could help design more effective and tolerated treatments. Objective: Identify DNA methylation (DNAm) changes associated with antidepressant exposure. Design: Case-control methylome-wide association studies (MWAS) of antidepressant exposure were performed from blood samples collected between 2006-2011 in Generation Scotland (GS). The summary statistics were tested for enrichment in specific tissues, gene ontologies and an independent MWAS in the Netherlands Study of Depression and Anxiety (NESDA). A methylation profile score (MPS) was derived and tested for its association with antidepressant exposure in eight independent cohorts, alongside prospective data from GS. Setting: Cohorts; GS, NESDA, FTC, SHIP-Trend, FOR2107, LBC1936, MARS-UniDep, ALSPAC, E-Risk, and NTR. Participants: Participants with DNAm data and self-report/prescription derived antidepressant exposure. Main Outcomes and Measures: Whole-blood DNAm levels were assayed by the EPIC/450K Illumina array (9 studies, N exposed = 661, N unexposed = 9,575) alongside MBD-Seq in NESDA (N exposed = 398, N unexposed = 414). Antidepressant exposure was measured by self- report and/or antidepressant prescriptions. Results: The self-report MWAS (N = 16,536, N exposed = 1,508, mean age = 48, 59% female) and the prescription-derived MWAS (N = 7,951, N exposed = 861, mean age = 47, 59% female), found hypermethylation at seven and four DNAm sites (p < 9.42x10 -8 ), respectively. The top locus was cg26277237 ( KANK1, p self-report = 9.3x10 -13 , p prescription = 6.1x10 -3 ). The self-report MWAS found a differentially methylated region, mapping to DGUOK-AS1 ( p adj = 5.0x10 -3 ) alongside significant enrichment for genes expressed in the amygdala, the "synaptic vesicle membrane" gene ontology and the top 1% of CpGs from the NESDA MWAS (OR = 1.39, p < 0.042). The MPS was associated with antidepressant exposure in meta-analysed data from external cohorts (N studies = 9, N = 10,236, N exposed = 661, f3 = 0.196, p < 1x10 -4 ). Conclusions and Relevance: Antidepressant exposure is associated with changes in DNAm across different cohorts. Further investigation into these changes could inform on new targets for antidepressant treatments. 3 Key Points: Question: Is antidepressant exposure associated with differential whole blood DNA methylation?Findings: In this methylome-wide association study of 16,536 adults across Scotland, antidepressant exposure was significantly associated with hypermethylation at CpGs mapping to KANK1 and DGUOK-AS1. A methylation profile score trained on this sample was significantly associated with antidepressant exposure (pooled f3 [95%CI]=0.196 [0.105, 0.288], p < 1x10 -4 ) in a meta-analysis of external datasets. Meaning: Antidepressant exposure is associated with hypermethylation at KANK1 and DGUOK-AS1 , which have roles in mitochondrial metabolism and neurite outgrowth. If replicated in future studies, targeting these genes could inform the design of more effective and better tolerated treatments for depression.

Specificity of childhood psychotic symptoms for predicting schizophrenia by 38 years of age: a birth cohort study.

BACKGROUND: Childhood psychotic symptoms have been used as a subclinical phenotype of schizophrenia in etiological research and as a target for preventative interventions. However, recent studies have cast doubt on the specificity of these symptoms for schizophrenia, suggesting alternative outcomes such as anxiety and depression. Using a prospective longitudinal birth cohort we investigated whether childhood psychotic symptoms predicted a diagnosis of schizophrenia or other psychiatric disorders by 38 years of age. METHOD: Participants were drawn from a birth cohort of 1037 children from Dunedin, New Zealand, who were followed prospectively to 38 years of age (96% retention rate). Structured clinical interviews were administered at age 11 to assess psychotic symptoms and study members underwent psychiatric assessments at ages 18, 21, 26, 32 and 38 to obtain past-year DSM-III-R/IV diagnoses and self-reports of attempted suicides since adolescence. RESULTS: Psychotic symptoms at age 11 predicted elevated rates of research diagnoses of schizophrenia and posttraumatic stress disorder (PTSD) and also suicide attempts by age 38, even when controlling for gender, social class and childhood psychopathology. No significant associations were found for persistent anxiety, persistent depression, mania or persistent substance dependence. Very few of the children presenting with age-11 psychotic symptoms were free from disorder by age 38. CONCLUSIONS: Childhood psychotic symptoms were not specific to a diagnosis of schizophrenia in adulthood and thus future studies of early symptoms should be cautious in extrapolating findings only to this clinical disorder. However, these symptoms may be useful as a marker of adult mental health problems more broadly.

Abnormal cortisol awakening response predicts worse cognitive function in patients with first-episode psychosis.

BACKGROUND: Cognitive impairment, particularly in memory and executive function, is a core feature of psychosis. Moreover, psychosis is characterized by a more prominent history of stress exposure, and by dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. In turn, stress exposure and abnormal levels of the main HPA axis hormone cortisol are associated with cognitive impairments in a variety of clinical and experimental samples; however, this association has never been examined in first-episode psychosis (FEP). METHOD: In this study, 30 FEP patients and 26 controls completed assessment of the HPA axis (cortisol awakening response and cortisol levels during the day), perceived stress, recent life events, history of childhood trauma, and cognitive function. The neuropsychological battery comprised general cognitive function, verbal and non-verbal memory, executive function, perception, visuospatial abilities, processing speed, and general knowledge. RESULTS: Patients performed significantly worse on all cognitive domains compared to controls. In patients only, a more blunted cortisol awakening response (that is, more abnormal) was associated with a more severe deficit in verbal memory and processing speed. In controls only, higher levels of perceived stress and more recent life events were associated with a worse performance in executive function and perception and visuospatial abilities. CONCLUSIONS: These data support a role for the HPA axis, as measured by cortisol awakening response, in modulating cognitive function in patients with psychosis; however, this association does not seem to be related to the increased exposure to psychosocial stressors described in these patients.

The varying impact of type, timing and frequency of exposure to childhood adversity on its association with adult psychotic disorder.

BACKGROUND: Childhood adversity has been associated with onset of psychosis in adulthood but these studies have used only general definitions of this environmental risk indicator. Therefore, we sought to explore the prevalence of more specific adverse childhood experiences amongst those with and without psychotic disorders using detailed assessments in a large epidemiological case-control sample (AESOP). METHOD: Data were collected on 182 first-presentation psychosis cases and 246 geographically matched controls in two UK centres. Information relating to the timing and frequency of exposure to different types of childhood adversity (neglect, antipathy, physical and sexual abuse, local authority care, disrupted living arrangements and lack of supportive figure) was obtained using the Childhood Experience of Care and Abuse Questionnaire. RESULTS: Psychosis cases were three times more likely to report severe physical abuse from the mother that commenced prior to 12 years of age, even after adjustment for other significant forms of adversity and demographic confounders. A non-significant trend was also evident for greater prevalence of reported severe maternal antipathy amongst those with psychosis. Associations with maternal neglect and childhood sexual abuse disappeared after adjusting for maternal physical abuse and antipathy. Paternal maltreatment and other forms of adversity were not associated with psychosis nor was there evidence of a dose-response effect. CONCLUSIONS: These findings suggest that only specific adverse childhood experiences are associated with psychotic disorders and only in a minority of cases. If replicated, this greater precision will ensure that research into the mechanisms underlying the pathway from childhood adversity to psychosis is more fruitful.

Like father like daughter: sex-specific parent-of-origin effects in the transmission of liability for psychotic symptoms to offspring.

Children of parents with major mood and psychotic disorders are at increased risk of psychopathology, including psychotic symptoms. It has been suggested that the risk of psychosis may be more often transmitted from parent to opposite-sex offspring (e.g., from father to daughter) than to same-sex offspring (e.g., from father to son). To test whether sex-specific transmission extends to early manifestations of psychosis, we examined sex-specific contributions to psychotic symptoms among offspring of mothers and fathers with depression, bipolar disorder and schizophrenia. We assessed psychotic symptoms in 309 offspring (160 daughters and 149 sons) aged 8-24 years (mean=13.1, s.d.=4.3), of whom 113 had a mother with schizophrenia, bipolar disorder or major depression and 43 had a father with schizophrenia, bipolar disorder or major depression. In semi-structured interviews, 130 (42%) offspring had definite psychotic symptoms established and confirmed by psychiatrists on one or more assessments. We tested the effects of mental illness in parents on same-sex and opposite-sex offspring psychotic symptoms in mixed-effect logistic regression models. Psychotic symptoms were more prevalent among daughters of affected fathers and sons of affected mothers than among offspring of the same sex as their affected parent. Mental illness in the opposite-sex parent increased the odds of psychotic symptoms (odds ratio (OR)=2.65, 95% confidence interval (CI) 1.43-4.91, P=0.002), but mental illness in the same-sex parent did not have a significant effect on psychotic symptoms in offspring (OR=1.13, 95% CI 0.61-2.07, P=0.697). The opposite-sex-specific parent-of-origin effects may suggest X chromosome-linked genetic transmission or inherited chromosomal modifications in the etiology of psychotic symptoms.

Do cognitive schema mediate the association between childhood trauma and being at ultra-high risk for psychosis?

Exposure to childhood trauma has been associated with psychotic symptoms, being at ultra-high risk for psychosis (UHR), and psychotic disorders such as schizophrenia. Negative self-beliefs have been shown to partially mediate the relationship between childhood trauma and paranoia and have been shown to be characteristic of patients with psychosis. However, whether the association between childhood trauma and being at high risk of developing psychosis (e.g., UHR) and paranoia symptoms is mediated by altered cognitive schema is unknown and warrants investigation to inform preventive interventions. Data was collected on 30 UHR patients from Outreach and Support in South London about exposure to childhood trauma, cognitive schema, paranoia and cannabis use. Relative to healthy controls (n = 38), UHR patients were significantly more likely to report exposure to various types of childhood trauma (emotional and sexual abuse, and emotional and physical neglect), had more negative schema and less positive schema about themselves and others, and were more likely to use cannabis more than once a month. Emotional neglect was found to be significantly associated with UHR status even after controlling for the effects of previous exposure to cannabis use (b = 0.262, 95% CI: 0.115-0.408), and this association was partially mediated by negative self-schema (b = 0.045, 95% CI: 0.004-0.159). Similarly, emotional neglect was significantly associated with paranoia (b = 1.354, 95% CI: 0.246-2.462), and this association was partially mediated by negative self-schema (b = 0.988, 95% CI: 0.323-1.895). These findings provide preliminary evidence about the cognitive mechanisms that may underlie the association between childhood trauma and later risk for psychosis.

Revisiting the association between childhood trauma and psychosis in bipolar disorder: A quasi-dimensional path-analysis.

BACKGROUND: Childhood trauma has been associated with a more severe clinical expression of bipolar disorder (BD). However, the results that specifically associated traumatic events and psychotic features in BD have been inconsistent, possibly due to the low resolution of the phenotypes being used. METHODS: 270 normothymic patients with BD completed the Childhood Trauma Questionnaire (CTQ) and the Peters Delusion Inventory (PDI) that assessed 21 delusional beliefs. Patients were characterized for the lifetime presence of psychotic features during episodes and cannabis misuse in accordance with DSM-IV. We performed a series of path analyses to investigate the links from three types of childhood abuse (physical, sexual and emotional) directly to delusional beliefs and psychotic features, and indirectly through cannabis misuse. RESULTS: A first path analysis showed no link between any of the childhood abuse types and psychotic features when only a categorical definition of psychosis was used. When incorporating the quasi-dimensional measure of delusional beliefs in a second path analysis, we found that emotional and physical abuse and cannabis misuse were each directly associated with PDI score. PDI score and psychotic features were strongly correlated. Childhood abuse did not operate through cannabis misuse to increase delusional beliefs. Including type of BD in the model did not alter the results. CONCLUSION: Emotional and physical abuse, but also cannabis misuse, increased delusional beliefs in patients with BD. Using a quasi-dimensional measure of psychotic symptoms in BD provided higher resolution of the psychosis phenotype and helped reconcile ambiguous findings from previous studies.