Youth adversity and trajectories of depression/anxiety symptoms in adolescence in the context of intersectionality in the United Kingdom.

BACKGROUND: Youth adversity is associated with persistence of depression and anxiety symptoms. This association may be greater for disadvantaged societal groups (such as females) compared with advantaged groups (e.g. males). Given that persistent symptoms are observed across a range of disadvantaged, minoritized, and neurodivergent groups (e.g. low compared with high socio-economic status [SES]), the intersection of individual characteristics may be an important moderator of inequality. METHODS: Data from HeadStart Cornwall (N = 4441) was used to assess the effect of youth adversity on combined symptoms of depression and anxiety (Strengths and Difficulties Questionnaire emotional problems subscale) measured at three time-points in 11-14-year-olds. Latent trajectories and regressions were estimated for eight intersectionality profiles (based on gender, SES, and hyperactivity/inattention), and moderating effects of the individual characteristics and their intersections were estimated. RESULTS: Youth adversity was associated with higher average depression/anxiety symptoms at baseline (11-12-years) across all intersectionality profiles. The magnitude of effects differed across profiles, with suggestive evidence for a moderating effect of youth adversity on change over time in depression/anxiety symptoms attributable to the intersection between (i) gender and SES; and (ii) gender, SES, and hyperactivity/inattention. CONCLUSIONS: The detrimental effects of youth adversity pervade across intersectionality profiles. The extent to which these effects are moderated by intersectionality is discussed in terms of operational factors. The current results provide a platform for further research, which is needed to determine the importance of intersectionality as a moderator of youth adversity on the development of depression and anxiety symptoms in adolescence.

The Role of Childhood Trauma in Affective Stress Recovery in Early Psychosis: An Experience Sampling Study.

BACKGROUND AND HYPOTHESES: Affective recovery, operationalized as the time needed for affect to return to baseline levels after daily stressors, may be a putative momentary representation of resilience. This study aimed to investigate affective recovery in positive and negative affect across subclinical and clinical stages of psychosis and whether this is associated with exposure to childhood trauma (sexual, physical, and emotional abuse). STUDY DESIGN: We used survival analysis to predict the time-to-recovery from a daily event-related stressor in a pooled sample of 3 previously conducted experience sampling studies including 113 individuals with first-episode psychosis, 162 at-risk individuals, and 94 controls. STUDY RESULTS: Negative affective recovery (ie, return to baseline following an increase in negative affect) was longer in individuals with first-episode psychosis compared with controls (hazard ratio [HR] = 1.71, 95% confidence interval [CI; 1.03, 2.61], P = .04) and in at-risk individuals exposed to high vs low levels of emotional abuse (HR = 1.31, 95% CI [1.06, 1.62], P = .01). Positive affective recovery (ie, return to baseline following a decrease in positive affect) did not differ between groups and was not associated with childhood trauma. CONCLUSIONS: Our results give first indications that negative affective recovery may be a putative momentary representation of resilience across stages of psychosis and may be amplified in at-risk individuals with prior experiences of emotional abuse. Understanding how affective recovery contributes to the development of psychosis may help identify new targets for prevention and intervention to buffer risk or foster resilience in daily life.

Understanding social and clinical associations with unemployment for people with schizophrenia and bipolar disorders: large-scale health records study.

PURPOSE: People with severe mental illness (SMI) experience high levels of unemployment. We aimed to better understand the associations between clinical, social, and demographic inequality indicators and unemployment. METHODS: Data were extracted from de-identified health records of people with SMI in contact with secondary mental health services in south London, UK. A Natural Language Processing text-mining application was applied to extract information on unemployment in the health records. Multivariable logistic regression was used to assess associations with unemployment, in people with SMI. RESULTS: Records from 19,768 service users were used for analysis, 84.9% (n = 16,778) had experienced unemployment. In fully adjusted models, Black Caribbean and Black African service users were more likely to experience unemployment compared with White British service users (Black Caribbean: aOR 1.62, 95% CI 1.45-1.80; Black African: 1.32, 1.15-1.51). Although men were more likely to have experienced unemployment relative to women in unadjusted models (OR 1.36, 95% CI 1.26-1.47), differences were no longer apparent in the fully adjusted models (aOR 1.05, 95% CI 0.97-1.15). The presence of a non-affective (compared to affective) diagnosis (1.24, 1.13-1.35), comorbid substance use (2.02, 1.76-2.33), previous inpatient admissions (4.18, 3.71-4.70), longer inpatient stays (78 + days: 7.78, 6.34-9.54), and compulsory admissions (3.45, 3.04-3.92) were associated with unemployment, in fully adjusted models. CONCLUSION: People with SMI experience high levels of unemployment, and we found that unemployment was associated with several clinical and social factors. Interventions to address low employment may need to also address these broader inequalities.

Variation of subclinical psychosis across 16 sites in Europe and Brazil: findings from the multi-national EU-GEI study.

BACKGROUND: Incidence of first-episode psychosis (FEP) varies substantially across geographic regions. Phenotypes of subclinical psychosis (SP), such as psychotic-like experiences (PLEs) and schizotypy, present several similarities with psychosis. We aimed to examine whether SP measures varied across different sites and whether this variation was comparable with FEP incidence within the same areas. We further examined contribution of environmental and genetic factors to SP. METHODS: We used data from 1497 controls recruited in 16 different sites across 6 countries. Factor scores for several psychopathological dimensions of schizotypy and PLEs were obtained using multidimensional item response theory models. Variation of these scores was assessed using multi-level regression analysis to estimate individual and between-sites variance adjusting for age, sex, education, migrant, employment and relational status, childhood adversity, and cannabis use. In the final model we added local FEP incidence as a second-level variable. Association with genetic liability was examined separately. RESULTS: Schizotypy showed a large between-sites variation with up to 15% of variance attributable to site-level characteristics. Adding local FEP incidence to the model considerably reduced the between-sites unexplained schizotypy variance. PLEs did not show as much variation. Overall, SP was associated with younger age, migrant, unmarried, unemployed and less educated individuals, cannabis use, and childhood adversity. Both phenotypes were associated with genetic liability to schizophrenia. CONCLUSIONS: Schizotypy showed substantial between-sites variation, being more represented in areas where FEP incidence is higher. This supports the hypothesis that shared contextual factors shape the between-sites variation of psychosis across the spectrum.

The temporal association between social isolation, distress, and psychotic experiences in individuals at clinical high-risk for psychosis.

BACKGROUND: Psychotic experiences (PEs) and social isolation (SI) seem related during early stages of psychosis, but the temporal dynamics between the two are not clear. Literature so far suggests a self-perpetuating cycle wherein momentary increases in PEs lead to social withdrawal, which, subsequently, triggers PEs at a next point in time, especially when SI is associated with increased distress. The current study investigated the daily-life temporal associations between SI and PEs, as well as the role of SI-related and general affective distress in individuals at clinical high risk (CHR) for psychosis. METHODS: We used experience sampling methodology in a sample of 137 CHR participants. We analyzed the association between SI, PEs, and distress using time-lagged linear mixed-effects models. RESULTS: SI did not predict next-moment fluctuations in PEs, or vice versa. Furthermore, although SI-related distress was not predictive of subsequent PEs, general affective distress during SI was a robust predictor of next-moment PEs. CONCLUSIONS: Our results suggest that SI and PEs are not directly related on a moment-to-moment level, but a negative emotional state when alone does contribute to the risk of PEs. These findings highlight the role of affective wellbeing during early-stage psychosis development.

Improving our understanding of the social determinants of mental health: a data linkage study of mental health records and the 2011 UK census.

OBJECTIVES: To address the lack of individual-level socioeconomic information in electronic healthcare records, we linked the 2011 census of England and Wales to patient records from a large mental healthcare provider. This paper describes the linkage process and methods for mitigating bias due to non-matching. SETTING: South London and Maudsley NHS Foundation Trust (SLaM), a mental healthcare provider in Southeast London. DESIGN: Clinical records from SLaM were supplied to the Office of National Statistics for linkage to the census through a deterministic matching algorithm. We examined clinical (International Classification of Disease-10 diagnosis, history of hospitalisation, frequency of service contact) and socio-demographic (age, gender, ethnicity, deprivation) information recorded in Clinical Record Interactive Search (CRIS) as predictors of linkage success with the 2011 census. To assess and adjust for potential biases caused by non-matching, we evaluated inverse probability weighting for mortality associations. PARTICIPANTS: Individuals of all ages in contact with SLaM up until December 2019 (N=459 374). OUTCOME MEASURES: Likelihood of mental health records' linkage to census. RESULTS: 220 864 (50.4%) records from CRIS linked to the 2011 census. Young adults (prevalence ratio (PR) 0.80, 95% CI 0.80 to 0.81), individuals living in more deprived areas (PR 0.78, 95% CI 0.78 to 0.79) and minority ethnic groups (eg, Black African, PR 0.67, 0.66 to 0.68) were less likely to match to census. After implementing inverse probability weighting, we observed little change in the strength of association between clinical/demographic characteristics and mortality (eg, presence of any psychiatric disorder: unweighted PR 2.66, 95% CI 2.52 to 2.80; weighted PR 2.70, 95% CI 2.56 to 2.84). CONCLUSIONS: Lower response rates to the 2011 census among people with psychiatric disorders may have contributed to lower match rates, a potential concern as the census informs service planning and allocation of resources. Due to its size and unique characteristics, the linked data set will enable novel investigations into the relationship between socioeconomic factors and psychiatric disorders.

Sociodemographic and clinical predictors of delay to and length of stay with early intervention for psychosis service: findings from the CRIS-FEP study.

PURPOSE: We investigated the influence of sociodemographic and clinical characteristics on delay to early intervention service (EIS) and the length of stay (LOS) with EIS. METHODS: We used incidence data linked to the Clinical Record Interactive Search-First Episode Psychosis (CRIS-FEP) study. We followed the patients from May 2010 to March 2016. We performed multivariable Cox regression to estimate hazard ratios of delay to EIS. Negative binomial regression was used to determine LOS with EIS by sociodemographic and clinical characteristics, controlling for confounders. RESULTS: 343 patients were eligible for an EIS, 34.1% of whom did not receive the service. Overall, the median delay to EIS was 120 days (IQR; 15-1668); and the median LOS was 130.5 days (IQR 0-663). We found that women (adj.HR 0.58; 95%C I 0.42-0.78), living alone (adj.HR: 0.63; 95% CI 0.43-0.92) and ethnicity ('Other': adj.HR 0.47; 95% CI 0.23-0.98) were associated with prolonged delay to EIS. However, family involvement in help-seeking for psychosis (adj.HR 1.37; 95% CI 1.01-1.85) was strongly associated with a shorter delay to EIS. Patients who have used mental health services previously also experienced long delays to EIS. CONCLUSIONS: Our analyses highlight the link between sociodemographic status, help-seeking behaviours, and delay to EIS. Our findings also show the vulnerability faced by those with a previous mental health problem who later develop psychosis in receiving specialist treatment for psychosis. Initiatives that ameliorate indicators of social disadvantage are urgently needed to reduce health inequalities and improve clinical outcomes.

Cannabis use as a potential mediator between childhood adversity and first-episode psychosis: results from the EU-GEI case-control study.

BACKGROUND: Childhood adversity and cannabis use are considered independent risk factors for psychosis, but whether different patterns of cannabis use may be acting as mediator between adversity and psychotic disorders has not yet been explored. The aim of this study is to examine whether cannabis use mediates the relationship between childhood adversity and psychosis. METHODS: Data were utilised on 881 first-episode psychosis patients and 1231 controls from the European network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study. Detailed history of cannabis use was collected with the Cannabis Experience Questionnaire. The Childhood Experience of Care and Abuse Questionnaire was used to assess exposure to household discord, sexual, physical or emotional abuse and bullying in two periods: early (0-11 years), and late (12-17 years). A path decomposition method was used to analyse whether the association between childhood adversity and psychosis was mediated by (1) lifetime cannabis use, (2) cannabis potency and (3) frequency of use. RESULTS: The association between household discord and psychosis was partially mediated by lifetime use of cannabis (indirect effect coef. 0.078, s.e. 0.022, 17%), its potency (indirect effect coef. 0.059, s.e. 0.018, 14%) and by frequency (indirect effect coef. 0.117, s.e. 0.038, 29%). Similar findings were obtained when analyses were restricted to early exposure to household discord. CONCLUSIONS: Harmful patterns of cannabis use mediated the association between specific childhood adversities, like household discord, with later psychosis. Children exposed to particularly challenging environments in their household could benefit from psychosocial interventions aimed at preventing cannabis misuse.

Prevalence, time trends, and correlates of major depressive episode and other psychiatric conditions among young people amid major social unrest and COVID-19 in Hong Kong: a representative epidemiological study from 2019 to 2022.

Background: Hong Kong is among the many populations that has experienced the combined impacts of social unrest and the COVID-19 pandemic. Despite concerns about further deteriorations in youth mental health globally, few epidemiological studies have been conducted to examine the prevalence and correlates of major depressive episode (MDE) and other major psychiatric disorders across periods of population-level changes using diagnostic interviews. Methods: We conducted a territory-wide household-based epidemiological study from 2019 to 2022 targeting young people aged 15-24 years. MDE, generalised anxiety disorder (GAD), panic disorder (PD), and bipolar disorder (BD) were assessed using the Composite International Diagnostic Interview-Screening Scales in 3340 young people. Psychotic disorders were assessed by experienced psychiatrists according to the DSM. Help-seeking patterns were also explored. Findings: 16.6% had any mental disorder (13.7% 12-month MDE, 2.3% BD, 2.1% GAD, 1.0% PD, 0.6% psychotic disorder). The prevalence of MDE increased from 13.2% during period 1 (May 2019-June 2020) to 18.1% during period 2 (July-December 2020), followed by 14.0% during period 3 (January-June 2021) and 13.2% during period 4 (July 2021-June 2022). Different stressors uniquely contributed to MDE across periods: social unrest-related stressors during period 1, COVID-19 stressors during period 2, and personal stressors during periods 3-4. Lower resilience, loneliness, frequent nightmares, and childhood adversity were consistently associated with MDE. Compared to other conditions, those with MDE showed the lowest service utilisation rate (16.7%). Perceiving services to "cost too much" and "talked to friends or relatives instead" were among the major reasons for not seeking help. MDE was also significantly associated with poorer functioning and health-related quality of life. Interpretation: MDE can be sensitive to population-level changes, although its persistently elevated prevalence across the study period is of concern. Efforts to mitigate their impacts on youth mental health alongside personal risk factors are needed. Further work is required to increase the availability and acceptability of youth-targeted mental health services. Funding: Food and Health Bureau (HKSAR Government).

Protocol for secondary data analysis of 4 UK cohorts examining youth adversity and mental health in the context of intersectionality.

BACKGROUND: Youth adversity (e.g., abuse and bullying victimisation) is robust risk factor for later mental health problems (e.g., depression and anxiety). Research shows the prevalence of youth adversity and rates of mental health problems vary by individual characteristics, identity or social groups (e.g., gender and ethnicity). However, little is known about whether the impact of youth adversity on mental health problems differ across the intersections of these characteristics (e.g., white females). This paper reports on a component of the ATTUNE research programme (work package 2) which aims to investigate the impact and mechanisms of youth adversity on depressive and anxiety symptoms in young people by intersectionality profiles. METHODS: The data are from 4 UK adolescent cohorts: HeadStart Cornwall, Oxwell, REACH, and DASH. These cohorts were assembled for adolescents living in distinct geographical locations representing coastal, suburban and urban places in the UK. Youth adversity was assessed using a series of self-report questionnaires and official records. Validated self-report instruments measured depressive and anxiety symptoms. A range of different variables were classified as possible social and cognitive mechanisms. RESULTS AND ANALYSIS: Structural equation modelling (e.g., multiple group models, latent growth models) and multilevel modelling will be used, with adaptation of methods to suit the specific available data, in accord with statistical and epidemiological conventions. DISCUSSION: The results from this research programme will broaden our understanding of the association between youth adversity and mental health, including new information about intersectionality and related mechanisms in young people in the UK. The findings will inform future research, clinical guidance, and policy to protect and promote the mental health of those most vulnerable to the negative consequences of youth adversity.

Parental bonding style and illness severity in a longitudinal study of individuals with first episode psychosis.

A parenting style with high amounts of control combined with low caring or nurturing behaviour has been reported in association with mental disorders including schizophrenia. However, the association of parenting style with illness severity in individuals with schizophrenia has never been evaluated retrospectively or over a longitudinal time course. In a subset (n = 84) of the participants included in the AESOP (Aetiology and Ethnicity in Schizophrenia and Other Psychoses)-10 study, we evaluated participants' perceptions of their own parents' bonding style at the time of their first episode of psychosis using the parental bonding instrument (PBI). We then examined the association between different bonding styles, illness course and severity, and global functioning over a 10-year follow-up. Participants who perceived that their fathers had a more caring and less controlling parenting style showed better functioning at follow-up. However, in contrast to previous research, participants who reported having been subject to uncaring and controlling parenting styles were not found to have a notably worse course of illness or symptom severity over the follow-up period. These results indicate that more optimal parental bonding styles may be associated with better overall functioning in individuals with psychosis but not with other measures of illness outcome.

Differences in Patterns of Stimulant Use and Their Impact on First-Episode Psychosis Incidence: An Analysis of the EUGEI Study.

BACKGROUND: Use of illegal stimulants is associated with an increased risk of psychotic disorder. However, the impact of stimulant use on odds of first-episode psychosis (FEP) remains unclear. Here, we aimed to describe the patterns of stimulant use and examine their impact on odds of FEP. METHODS: We included patients with FEP aged 18-64 years who attended psychiatric services at 17 sites across 5 European countries and Brazil, and recruited controls representative of each local population (FEP = 1130; controls = 1497). Patterns of stimulant use were described. We computed fully adjusted logistic regression models (controlling for age, sex, ethnicity, cannabis use, and education level) to estimate their association with odds of FEP. Assuming causality, we calculated the population-attributable fractions for stimulant use associated with the odds for FEP. FINDINGS: Prevalence of lifetime and recent stimulant use in the FEP sample were 14.50% and 7.88% and in controls 10.80% and 3.8%, respectively. Recent and lifetime stimulant use was associated with increased odds of FEP compared with abstainers [fully adjusted odds ratio 1.74,95% confidence interval (CI) 1.20-2.54, P = .004 and 1.62, 95% CI 1.25-2.09, P < .001, respectively]. According to PAFs, a substantial number of FEP cases (3.35% [95% CI 1.31-4.78] for recent use and 7.61% [95% CI 3.68-10.54] for lifetime use) could have been prevented if stimulants were no longer available and the odds of FEP and PAFs for lifetime and recent stimulant use varied across countries. INTERPRETATION: Illegal stimulant use has a significant and clinically relevant influence on FEP incidence, with varying impacts across countries.

The relationship between genetic liability, childhood maltreatment, and IQ: findings from the EU-GEI multicentric case-control study.

This study investigated if the association between childhood maltreatment and cognition among psychosis patients and community controls was partially accounted for by genetic liability for psychosis. Patients with first-episode psychosis (N = 755) and unaffected controls (N = 1219) from the EU-GEI study were assessed for childhood maltreatment, intelligence quotient (IQ), family history of psychosis (FH), and polygenic risk score for schizophrenia (SZ-PRS). Controlling for FH and SZ-PRS did not attenuate the association between childhood maltreatment and IQ in cases or controls. Findings suggest that these expressions of genetic liability cannot account for the lower levels of cognition found among adults maltreated in childhood.

Synergistic effects of childhood adversity and polygenic risk in first-episode psychosis: the EU-GEI study.

BACKGROUND: A history of childhood adversity is associated with psychotic disorder, with an increase in risk according to the number of exposures. However, it is not known why only some exposed individuals go on to develop psychosis. One possibility is pre-existing polygenic vulnerability. Here, we investigated, in the largest sample of first-episode psychosis (FEP) cases to date, whether childhood adversity and high polygenic risk scores for schizophrenia (SZ-PRS) combine synergistically to increase the risk of psychosis, over and above the effect of each alone. METHODS: We assigned a schizophrenia-polygenic risk score (SZ-PRS), calculated from the Psychiatric Genomics Consortium (PGC2), to all participants in a sample of 384 FEP patients and 690 controls from the case-control component of the EU-GEI study. Only participants of European ancestry were included in the study. A history of childhood adversity was collected using the Childhood Trauma Questionnaire (CTQ). Synergistic effects were estimated using the interaction contrast ratio (ICR) [odds ratio (OR)exposure and PRS - ORexposure - ORPRS + 1] with adjustment for potential confounders. RESULTS: There was some evidence that the combined effect of childhood adversities and polygenic risk was greater than the sum of each alone, as indicated by an ICR greater than zero [i.e. ICR 1.28, 95% confidence interval (CI) -1.29 to 3.85]. Examining subtypes of childhood adversities, the strongest synergetic effect was observed for physical abuse (ICR 6.25, 95% CI -6.25 to 20.88). CONCLUSIONS: Our findings suggest possible synergistic effects of genetic liability and childhood adversity experiences in the onset of FEP, but larger samples are needed to increase precision of estimates.

The association between reasons for first using cannabis, later pattern of use, and risk of first-episode psychosis: the EU-GEI case-control study.

BACKGROUND: While cannabis use is a well-established risk factor for psychosis, little is known about any association between reasons for first using cannabis (RFUC) and later patterns of use and risk of psychosis. METHODS: We used data from 11 sites of the multicentre European Gene-Environment Interaction (EU-GEI) case-control study. 558 first-episode psychosis patients (FEPp) and 567 population controls who had used cannabis and reported their RFUC.We ran logistic regressions to examine whether RFUC were associated with first-episode psychosis (FEP) case-control status. Path analysis then examined the relationship between RFUC, subsequent patterns of cannabis use, and case-control status. RESULTS: Controls (86.1%) and FEPp (75.63%) were most likely to report 'because of friends' as their most common RFUC. However, 20.1% of FEPp compared to 5.8% of controls reported: 'to feel better' as their RFUC (χ2 = 50.97; p < 0.001). RFUC 'to feel better' was associated with being a FEPp (OR 1.74; 95% CI 1.03-2.95) while RFUC 'with friends' was associated with being a control (OR 0.56; 95% CI 0.37-0.83). The path model indicated an association between RFUC 'to feel better' with heavy cannabis use and with FEPp-control status. CONCLUSIONS: Both FEPp and controls usually started using cannabis with their friends, but more patients than controls had begun to use 'to feel better'. People who reported their reason for first using cannabis to 'feel better' were more likely to progress to heavy use and develop a psychotic disorder than those reporting 'because of friends'.

Long-term psychological distress trajectories and the COVID-19 pandemic in three British birth cohorts: A multi-cohort study.

BACKGROUND: Growing evidence suggests that population mental health outcomes have worsened since the pandemic started. The extent that these changes have altered common age-related trends in psychological distress, where distress typically rises until midlife and then falls after midlife in both sexes, is unknown. We aimed to analyse whether long-term pre-pandemic psychological distress trajectories were disrupted during the pandemic, and whether these changes have been different across cohorts and by sex. METHODS AND FINDINGS: We used data from three nationally representative birth cohorts comprising all people born in Great Britain in a single week of 1946 (National Survey of Health and Development, NSHD), 1958 (National Child Development Study, NCDS), or 1970 (British Cohort Study, BCS70). The follow-up data used spanned 39 years in NSHD (1982 to 2021), 40 years in NCDS (1981 to 2001), and 25 years in BCS70 (1996 to 2021). We used psychological distress factor scores, as measured by validated self-reported questionnaires (NSHD: Present State Examination, Psychiatric Symptoms Frequency, and 28- and 12-item versions of General Health Questionnaire; NCDS and BCS70: Malaise Inventory; all: 2-item versions of Generalized Anxiety Disorder scale and Patient Health Questionnaire). We used a multilevel growth curve modelling approach to model the trajectories of distress across cohorts and sexes and obtained estimates of the differences between the distress levels observed during the pandemic and those observed at the most recent pre-pandemic assessment and at the peak in the cohort-specific pre-pandemic distress trajectory, located at midlife. We further analysed whether pre-existing cohort and sex inequalities had changed with the pandemic onset using a difference-in-differences (DiD) approach. The analytic sample included 16,389 participants. By September/October 2020, distress levels had reached or exceeded the levels of the peak in the pre-pandemic life-course trajectories, with larger increases in younger cohorts (standardised mean differences [SMD] and 95% confidence intervals of SMDNSHD,pre-peak = -0.02 [-0.07, 0.04], SMDNCDS,pre-peak = 0.05 [0.02, 0.07], and SMDBCS70,pre-peak = 0.09 [0.07, 0.12] for the 1946, 1958, and 1970 birth cohorts, respectively). Increases in distress were larger among women than men, widening pre-existing sex inequalities (DiD and 95% confidence intervals of DiDNSHD,sex,pre-peak = 0.17 [0.06, 0.28], DiDNCDS,sex,pre-peak = 0.11 [0.07, 0.16], and DiDBCS70,sex,pre-peak = 0.11 [0.05, 0.16] when comparing sex inequalities in the pre-pandemic peak in midlife to those observed by September/October 2020). As expected in cohort designs, our study suffered from high proportions of attrition with respect to the original samples. Although we used non-response weights to restore sample representativeness to the target populations (those born in the United Kingdom in 1946, 1958, and 1970, alive and residing in the UK), results may not be generalisable to other sections within the UK population (e.g., migrants and ethnic minority groups) and countries different than the UK. CONCLUSIONS: Pre-existing long-term psychological distress trajectories of adults born between 1946 and 1970 were disrupted during the COVID-19 pandemic, particularly among women, who reached the highest levels ever recorded in up to 40 years of follow-up data. This may impact future trends of morbidity, disability, and mortality due to common mental health problems.

Exploring the mediation of DNA methylation across the epigenome between childhood adversity and First Episode of Psychosis-findings from the EU-GEI study.

ABTRACT: Studies conducted in psychotic disorders have shown that DNA-methylation (DNAm) is sensitive to the impact of Childhood Adversity (CA). However, whether it mediates the association between CA and psychosis is yet to be explored. Epigenome wide association studies (EWAS) using the Illumina Infinium-Methylation EPIC array in peripheral blood tissue from 366 First-episode of psychosis and 517 healthy controls was performed. Adversity scores were created for abuse, neglect and composite adversity with the Childhood Trauma Questionnaire (CTQ). Regressions examining (I) CTQ scores with psychosis; (II) with DNAm EWAS level and (III) between DNAm and caseness, adjusted for a variety of confounders were conducted. Divide-Aggregate Composite-null Test for the composite null-hypothesis of no mediation effect was conducted. Enrichment analyses were conducted with missMethyl package and the KEGG database. Our results show that CA was associated with psychosis (Composite: OR = 1.68; p = <0.001; abuse: OR = 2.16; p < 0.001; neglect: OR = 2.27; p = <0.001). None of the CpG sites significantly mediated the adversity-psychosis association after Bonferroni correction (p < 8.1 × 10-8). However, 28, 34 and 29 differentially methylated probes associated with 21, 27, 20 genes passed a less stringent discovery threshold (p < 5 × 10-5) for composite, abuse and neglect respectively, with a lack of overlap between abuse and neglect. These included genes previously associated to psychosis in EWAS studies, such as PANK1, SPEG TBKBP1, TSNARE1 or H2R. Downstream gene ontology analyses did not reveal any biological pathways that survived false discovery rate correction. Although at a non-significant level, DNAm changes in genes previously associated with schizophrenia in EWAS studies may mediate the CA-psychosis association. These results and associated involved processes such as mitochondrial or histaminergic disfunction, immunity or neural signalling requires replication in well powered samples. The lack of overlap between mediating genes associated with abuse and neglect suggests differential biological trajectories linking CA subtypes and psychosis.

Cannabis use and psychotic disorders in diverse settings in the Global South: findings from INTREPID II.

BACKGROUND: Cannabis use has been linked to psychotic disorders but this association has been primarily observed in the Global North. This study investigates patterns of cannabis use and associations with psychoses in three Global South (regions within Latin America, Asia, Africa and Oceania) settings. METHODS: Case-control study within the International Programme of Research on Psychotic Disorders (INTREPID) II conducted between May 2018 and September 2020. In each setting, we recruited over 200 individuals with an untreated psychosis and individually-matched controls (Kancheepuram India; Ibadan, Nigeria; northern Trinidad). Controls, with no past or current psychotic disorder, were individually-matched to cases by 5-year age group, sex and neighbourhood. Presence of psychotic disorder assessed using the Schedules for Clinical Assessment in Neuropsychiatry and cannabis exposure measured by the World Health Organisation Alcohol, Smoking and Substance Involvement Screening Test (ASSIST). RESULTS: Cases reported higher lifetime and frequent cannabis use than controls in each setting. In Trinidad, cannabis use was associated with increased odds of psychotic disorder: lifetime cannabis use (adj. OR 1.58, 95% CI 0.99-2.53); frequent cannabis use (adj. OR 1.99, 95% CI 1.10-3.60); cannabis dependency (as measured by high ASSIST score) (adj. OR 4.70, 95% CI 1.77-12.47), early age of first use (adj. OR 1.83, 95% CI 1.03-3.27). Cannabis use in the other two settings was too rare to examine associations. CONCLUSIONS: In line with previous studies, we found associations between cannabis use and the occurrence and age of onset of psychoses in Trinidad. These findings have implications for strategies for prevention of psychosis.

Urbanicity and rates of untreated psychotic disorders in three diverse settings in the Global South.

BACKGROUND: Extensive evidence indicates that rates of psychotic disorder are elevated in more urban compared with less urban areas, but this evidence largely originates from Northern Europe. It is unclear whether the same association holds globally. This study examined the association between urban residence and rates of psychotic disorder in catchment areas in India (Kancheepuram, Tamil Nadu), Nigeria (Ibadan, Oyo), and Northern Trinidad. METHODS: Comprehensive case detection systems were developed based on extensive pilot work to identify individuals aged 18-64 with previously untreated psychotic disorders residing in each catchment area (May 2018-April/May/July 2020). Area of residence and basic demographic details were collected for eligible cases. We compared rates of psychotic disorder in the more v. less urban administrative areas within each catchment area, based on all cases detected, and repeated these analyses while restricting to recent onset cases (<2 years/<5 years). RESULTS: We found evidence of higher overall rates of psychosis in more urban areas within the Trinidadian catchment area (IRR: 3.24, 95% CI 2.68-3.91), an inverse association in the Nigerian catchment area (IRR: 0.68, 95% CI 0.51-0.91) and no association in the Indian catchment area (IRR: 1.18, 95% CI 0.93-1.52). When restricting to recent onset cases, we found a modest positive association in the Indian catchment area. CONCLUSIONS: This study suggests that urbanicity is associated with higher rates of psychotic disorder in some but not all contexts outside of Northern Europe. Future studies should test candidate mechanisms that may underlie the associations observed, such as exposure to violence.

Use of multiple polygenic risk scores for distinguishing schizophrenia-spectrum disorder and affective psychosis categories in a first-episode sample; the EU-GEI study.

BACKGROUND: Schizophrenia (SZ), bipolar disorder (BD) and depression (D) run in families. This susceptibility is partly due to hundreds or thousands of common genetic variants, each conferring a fractional risk. The cumulative effects of the associated variants can be summarised as a polygenic risk score (PRS). Using data from the EUropean Network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) first episode case-control study, we aimed to test whether PRSs for three major psychiatric disorders (SZ, BD, D) and for intelligent quotient (IQ) as a neurodevelopmental proxy, can discriminate affective psychosis (AP) from schizophrenia-spectrum disorder (SSD). METHODS: Participants (842 cases, 1284 controls) from 16 European EU-GEI sites were successfully genotyped following standard quality control procedures. The sample was stratified based on genomic ancestry and analyses were done only on the subsample representing the European population (573 cases, 1005 controls). Using PRS for SZ, BD, D, and IQ built from the latest available summary statistics, we performed simple or multinomial logistic regression models adjusted for 10 principal components for the different clinical comparisons. RESULTS: In case-control comparisons PRS-SZ, PRS-BD and PRS-D distributed differentially across psychotic subcategories. In case-case comparisons, both PRS-SZ [odds ratio (OR) = 0.7, 95% confidence interval (CI) 0.54-0.92] and PRS-D (OR = 1.31, 95% CI 1.06-1.61) differentiated AP from SSD; and within AP categories, only PRS-SZ differentiated BD from psychotic depression (OR = 2.14, 95% CI 1.23-3.74). CONCLUSIONS: Combining PRS for severe psychiatric disorders in prediction models for psychosis phenotypes can increase discriminative ability and improve our understanding of these phenotypes. Our results point towards the potential usefulness of PRSs in specific populations such as high-risk or early psychosis phases.