Markers of inflammation and cannabis exposure are associated with an increased risk of mental disorders. In the current study, we investigated associations between cannabis use and biomarkers of inflammation.

Utilizing a sample of 914 participants from the Avon Longitudinal Study of Parents and Children, we investigated whether interleukin-6 (IL-6), tumor necrosis factor α (TNFα), C-reactive protein (CRP), and soluble urokinase plasminogen activator receptor (suPAR) measured at age 24 were associated with past year daily cannabis use, less frequent cannabis use, and no past year cannabis use. We adjusted for a number of covariates including sociodemographic measures, body mass index, childhood trauma, and tobacco smoking. We found evidence of a strong association between daily or near daily cannabis use and suPAR.

We did not find any associations between less frequent cannabis use and suPAR. We did not find evidence of an association between IL-6, TNFα or CRP, and cannabis use.

Our finding that frequent cannabis use is strongly associated with suPAR, a biomarker of systemic chronic inflammation implicated in neurodevelopmental and neurodegenerative processes is novel. These findings may provide valuable insights into biological mechanisms by which cannabis affects the brain and impacts the risk of serious mental disorders.

Cannabis has been associated with poorer mental health, but little is known of the effect of synthetic cannabinoids or cannabidiol (often referred to as CBD).

To investigate associations of cannabis, synthetic cannabinoids and cannabidiol with mental health in adolescence.

We conducted a cross-sectional analysis with 13- to 14-year-old adolescents across England and Wales in 2019–2020. Multilevel logistic regression was used to examine the association of lifetime use of cannabis, synthetic cannabinoids and cannabidiol with self-reported symptoms of probable depression, anxiety, conduct disorder and auditory hallucinations.

Of the 6672 adolescents who participated, 5.2% reported using of cannabis, 1.9% reported using cannabidiol and 0.6% reported using synthetic cannabinoids. After correction for multiple testing, adolescents who had used these substances were significantly more likely to report a probable depressive, anxiety or conduct disorder, as well as auditory hallucinations, than those who had not. Adjustment for socioeconomic disadvantage had little effect on associations, but weekly tobacco use resulted in marked attenuation of associations. The association of cannabis use with probable anxiety and depressive disorders was weaker in those who reported using cannabidiol than those who did not. There was little evidence of an interaction between synthetic cannabinoids and cannabidiol.

To our knowledge, this study provides the first general population evidence that synthetic cannabinoids and cannabidiol are associated with probable mental health disorders in adolescence. These associations require replication, ideally with prospective cohorts and stronger study designs.

Experiencing exceptionally threatening or horrifying traumas can lead to posttraumatic stress disorder (PTSD). Increasing political unrest/war/natural disasters worldwide could cause more traumatic events and change the population burden of PTSD. Most PTSD research is based on surveys, prone to selection/recall biases with inconsistent results. The aim was therefore, to use register-based data to identify the occurrence of PTSD and contributing factors in the Swedish general population.

This register-based cohort study used survival analysis. Individuals born between 1960–1995, aged ≥15 years, registered and living in Sweden, not emigrating, anytime between 1990–2015, not receiving specialized care for PTSD before 2006 were included (N = 4,673,764), and followed from their 15th/16th birth date until first PTSD diagnosis between 2006–2016 or study endpoint (31-December-2016). PTSD cases (ICD-10: F43.1) were identified from the national patient register. Mean follow-up time was 18.8 years.

Between 2006–2016, the incidence of specialized healthcare utilization for PTSD nearly doubled, and 0.7% of the study population received such care. The highest risk was observed for refugees [aHR 8.18; 95% CI:7.85–8.51] and for those with depressive disorder [aHR 4.51; 95% CI:3.95–5.14]. Higher PTSD risk was associated with female sex, older age, low education, single parenthood, low household income, urbanicity, and being born to a foreign-born parent.

PTSD is more common among refugee migrants, individuals with psychiatric disorders, and the socioeconomically disadvantaged. It is important that provision of services for PTSD are made available, particularly to these higher risk, and often hard-to-reach groups.

Psychotic experiences are reported by 5–10% of young people, although only a minority persist and develop into psychotic disorders. It is unclear what characteristics differentiate those with transient psychotic experiences from those with persistent psychotic experiences that are more likely to be of clinical relevance.

To investigate how longitudinal profiles of psychotic experiences, created from assessments at three different time points, are influenced by early life and co-occurring factors.

Using data from 8045 individuals from a birth cohort study, longitudinal profiles of psychotic experiences based on semi-structured interviews conducted at 12, 18 and 24 years were defined. Environmental, cognitive, psychopathological and genetic determinants of these profiles were investigated, along with concurrent changes in psychopathology and cognition.

Following multiple imputations, the distribution of longitudinal profiles of psychotic experiences was none (65.7%), transient (24.1%), low-frequency persistent (8.4%) and high-frequency persistent (1.7%). Individuals with high-frequency persistent psychotic experiences were more likely to report traumatic experiences, other psychopathology, a more externalised locus of control, reduced emotional stability and conscientious personality traits in childhood, compared with those with transient psychotic experiences. These characteristics also differed between those who had any psychotic experiences and those who did not.

These findings indicate that the same risk factors are associated with incidence as with persistence of psychotic experiences. Thus, it might be that the severity of exposure, rather than the presence of specific disease-modifying factors, is most likely to determine whether psychotic experiences are transient or persist, and potentially develop into a clinical disorder over time.

Traumatic experiences are associated with a higher risk of psychotic illnesses, but little is known about potentially modifiable mechanisms underlying this relationship. This study aims to examine whether post-traumatic stress disorder (PTSD) symptoms mediate the relationship between trauma and psychotic experiences (PEs).

We used data from the Avon Longitudinal Study of Parents and Children to examine whether: PTSD symptoms mediate the relationships between (a) childhood trauma and adolescent PEs (study of adolescent PEs; n = 2952), and (b) childhood/adolescent trauma and PEs in early adulthood (study of adult PEs; n = 2492). We examined associations between variables using logistic regression, and mediation using the parametric g-computation formula.

Exposure to trauma was associated with increased odds of PEs (adolescent PEs: ORadjusted 1.48, 95% CI 1.23–1.78; adult PEs: ORadjusted 1.57, 95% CI 1.25–1.98) and PTSD symptoms (adolescent PTSD: ORadjusted 1.59, 95% CI 1.31–1.93; adult PTSD: ORadjusted 1.50, 95% CI 1.36–1.65). The association between PTSD symptoms and PE was stronger in adolescence (ORadjusted 4.63, 95% CI 2.34–9.17) than in adulthood (ORadjusted 1.62, 95% CI 0.80–3.25). There was some evidence that PTSD symptoms mediated the relationship between childhood trauma and adolescent PEs (proportion mediated 14%), though evidence of mediation was weaker for adult PEs (proportion mediated 8%).

These findings are consistent with the hypothesis that PTSD symptoms partly mediate the association between trauma exposure and PEs. Targeting PTSD symptoms might help prevent the onset of psychotic outcomes.

The COVID-19 pandemic and mitigation measures are likely to have a marked effect on mental health. It is important to use longitudinal data to improve inferences.

To quantify the prevalence of depression, anxiety and mental well-being before and during the COVID-19 pandemic. Also, to identify groups at risk of depression and/or anxiety during the pandemic.

Data were from the Avon Longitudinal Study of Parents and Children (ALSPAC) index generation (n = 2850, mean age 28 years) and parent generation (n = 3720, mean age 59 years), and Generation Scotland (n = 4233, mean age 59 years). Depression was measured with the Short Mood and Feelings Questionnaire in ALSPAC and the Patient Health Questionnaire-9 in Generation Scotland. Anxiety and mental well-being were measured with the Generalised Anxiety Disorder Assessment-7 and the Short Warwick Edinburgh Mental Wellbeing Scale.

Depression during the pandemic was similar to pre-pandemic levels in the ALSPAC index generation, but those experiencing anxiety had almost doubled, at 24% (95% CI 23–26%) compared with a pre-pandemic level of 13% (95% CI 12–14%). In both studies, anxiety and depression during the pandemic was greater in younger members, women, those with pre-existing mental/physical health conditions and individuals in socioeconomic adversity, even when controlling for pre-pandemic anxiety and depression.

These results provide evidence for increased anxiety in young people that is coincident with the pandemic. Specific groups are at elevated risk of depression and anxiety during the COVID-19 pandemic. This is important for planning current mental health provisions and for long-term impact beyond this pandemic.

Maternal smoking has known adverse effects on fetal development. However, research on the association between maternal smoking during pregnancy and offspring intellectual disability (ID) is limited, and whether any associations are due to a causal effect or residual confounding is unknown.

Cohort study of all Danish births between 1995 and 2012 (1 066 989 persons from 658 335 families after exclusions), with prospectively recorded data for cohort members, parents and siblings. We assessed the association between maternal smoking during pregnancy (18.6% exposed, collected during prenatal visits) and offspring ID (8051 cases, measured using ICD-10 diagnosis codes F70–F79) using logistic generalised estimating equation regression models. Models were adjusted for confounders including measures of socio-economic status and parental psychiatric diagnoses and were adjusted for family averaged exposure between full siblings. Adjustment for a family averaged exposure allows calculation of the within-family effect of smoking on child outcomes which is robust against confounders that are shared between siblings.

We found increased odds of ID among those exposed to maternal smoking in pregnancy after confounder adjustment (OR 1.35, 95% CI 1.28–1.42) which attenuated to a null effect following adjustment for family averaged exposure (OR 0.91, 95% CI 0.78–1.06).

Our findings are inconsistent with a causal effect of maternal smoking during pregnancy on offspring ID risk. By estimating a within-family effect, our results suggest that prior associations were the result of unmeasured genetic or environmental characteristics of families in which the mother smokes during pregnancy.

It is not clear to what extent associations between schizophrenia, cannabis use and cigarette use are due to a shared genetic etiology. We, therefore, examined whether schizophrenia genetic risk associates with longitudinal patterns of cigarette and cannabis use in adolescence and mediating pathways for any association to inform potential reduction strategies.

Associations between schizophrenia polygenic scores and longitudinal latent classes of cigarette and cannabis use from ages 14 to 19 years were investigated in up to 3925 individuals in the Avon Longitudinal Study of Parents and Children. Mediation models were estimated to assess the potential mediating effects of a range of cognitive, emotional, and behavioral phenotypes.

The schizophrenia polygenic score, based on single nucleotide polymorphisms meeting a training-set p threshold of 0.05, was associated with late-onset cannabis use (OR = 1.23; 95% CI = 1.08,1.41), but not with cigarette or early-onset cannabis use classes. This association was not mediated through lower IQ, victimization, emotional difficulties, antisocial behavior, impulsivity, or poorer social relationships during childhood. Sensitivity analyses adjusting for genetic liability to cannabis or cigarette use, using polygenic scores excluding the CHRNA5-A3-B4 gene cluster, or basing scores on a 0.5 training-set p threshold, provided results consistent with our main analyses.

Our study provides evidence that genetic risk for schizophrenia is associated with patterns of cannabis use during adolescence. Investigation of pathways other than the cognitive, emotional, and behavioral phenotypes examined here is required to identify modifiable targets to reduce the public health burden of cannabis use in the population.

There is a wealth of literature on the observed association between childhood trauma and psychotic illness. However, the relationship between childhood trauma and psychosis is complex and could be explained, in part, by gene–environment correlation.

The association between schizophrenia polygenic scores (PGS) and experiencing childhood trauma was investigated using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Norwegian Mother, Father and Child Cohort Study (MoBa). Schizophrenia PGS were derived in each cohort for children, mothers, and fathers where genetic data were available. Measures of trauma exposure were derived based on data collected throughout childhood and adolescence (0–17 years; ALSPAC) and at age 8 years (MoBa).

Within ALSPAC, we found a positive association between schizophrenia PGS and exposure to trauma across childhood and adolescence; effect sizes were consistent for both child or maternal PGS. We found evidence of an association between the schizophrenia PGS and the majority of trauma subtypes investigated, with the exception of bullying. These results were comparable with those of MoBa. Within ALSPAC, genetic liability to a range of additional psychiatric traits was also associated with a greater trauma exposure.

Results from two international birth cohorts indicate that genetic liability for a range of psychiatric traits is associated with experiencing childhood trauma. Genome-wide association study of psychiatric phenotypes may also reflect risk factors for these phenotypes. Our findings also suggest that youth at higher genetic risk might require greater resources/support to ensure they grow-up in a healthy environment.

Smoking prevalence is higher amongst individuals with schizophrenia and depression compared with the general population. Mendelian randomisation (MR) can examine whether this association is causal using genetic variants identified in genome-wide association studies (GWAS).

We conducted two-sample MR to explore the bi-directional effects of smoking on schizophrenia and depression. For smoking behaviour, we used (1) smoking initiation GWAS from the GSCAN consortium and (2) we conducted our own GWAS of lifetime smoking behaviour (which captures smoking duration, heaviness and cessation) in a sample of 462690 individuals from the UK Biobank. We validated this instrument using positive control outcomes (e.g. lung cancer). For schizophrenia and depression we used GWAS from the PGC consortium.

There was strong evidence to suggest smoking is a risk factor for both schizophrenia (odds ratio (OR) 2.27, 95% confidence interval (CI) 1.67–3.08, p < 0.001) and depression (OR 1.99, 95% CI 1.71–2.32, p < 0.001). Results were consistent across both lifetime smoking and smoking initiation. We found some evidence that genetic liability to depression increases smoking (β = 0.091, 95% CI 0.027–0.155, p = 0.005) but evidence was mixed for schizophrenia (β = 0.022, 95% CI 0.005–0.038, p = 0.009) with very weak evidence for an effect on smoking initiation.

These findings suggest that the association between smoking, schizophrenia and depression is due, at least in part, to a causal effect of smoking, providing further evidence for the detrimental consequences of smoking on mental health.

There is increasing evidence that smoking is a risk factor for severe mental illness, including bipolar disorder. Conversely, patients with bipolar disorder might smoke more (often) as a result of the psychiatric disorder.

We conducted a bidirectional Mendelian randomisation (MR) study to investigate the direction and evidence for a causal nature of the relationship between smoking and bipolar disorder.

We used publicly available summary statistics from genome-wide association studies on bipolar disorder, smoking initiation, smoking heaviness, smoking cessation and lifetime smoking (i.e. a compound measure of heaviness, duration and cessation). We applied analytical methods with different, orthogonal assumptions to triangulate results, including inverse-variance weighted (IVW), MR-Egger, MR-Egger SIMEX, weighted-median, weighted-mode and Steiger-filtered analyses.

Across different methods of MR, consistent evidence was found for a positive effect of smoking on the odds of bipolar disorder (smoking initiation ORIVW = 1.46, 95% CI 1.28–1.66, P = 1.44 × 10−8, lifetime smoking ORIVW = 1.72, 95% CI 1.29–2.28, P = 1.8 × 10−4). The MR analyses of the effect of liability to bipolar disorder on smoking provided no clear evidence of a strong causal effect (smoking heaviness betaIVW = 0.028, 95% CI 0.003–0.053, P = 2.9 × 10−2).

These findings suggest that smoking initiation and lifetime smoking are likely to be a causal risk factor for developing bipolar disorder. We found some evidence that liability to bipolar disorder increased smoking heaviness. Given that smoking is a modifiable risk factor, these findings further support investment into smoking prevention and treatment in order to reduce mental health problems in future generations.

Recent studies suggest psychotic and eating disorders can be comorbid and could have shared genetic liability. However, this comorbidity has been overlooked in the epidemiological literature.

To test whether polygenic risk scores (PRS) for schizophrenia are associated with disordered eating behaviours and body mass index (BMI) in the general population.

Using data from the Avon Longitudinal Study of Parents and Children and random-effects logistic and linear regression models, we investigated the association between PRS for schizophrenia and self-reported disordered eating behaviours (binge eating, purging, fasting and excessive exercise) and BMI at 14, 16 and 18 years.

Of the 6920 children with available genetic data, 4473 (64.6%) and 5069 (73.3%) had at least one disordered eating and one BMI outcome measurement, respectively. An s.d. increase in PRS was associated with greater odds of having binge eating behaviours (odds ratio, 1.36; 95% CI 1.16–1.60) and lower BMI (coefficient, −0.03; 95% CI, −0.06 to −0.01).

Our findings suggest the presence of shared genetic risk between schizophrenia and binge eating behaviours. Intermediate phenotypes such as impaired social cognition and irritability, previously shown to be positively correlated in this sample with schizophrenia PRS, could represent risk factors for both phenotypes. Shared genetic liability between binge eating and schizophrenia could also explain higher rates of metabolic syndrome in individuals with schizophrenia, as binge eating could be a mediator of this association in drug-naïve individuals. The finding of an association between greater PRS and lower BMI, although consistent with existing epidemiological and genetic literature, requires further investigation.

None.

Studies involving clinically recruited samples show that genetic liability to schizophrenia overlaps with that for several psychiatric disorders including bipolar disorder, major depression and, in a population study, anxiety disorder and negative symptoms in adolescence.

We examined whether, at a population level, association between schizophrenia liability and anxiety disorders continues into adulthood, for specific anxiety disorders and as a group. We explored in an epidemiologically based cohort the nature of adult psychopathology sharing liability to schizophrenia.

Schizophrenia polygenic risk scores (PRSs) were calculated for 590 European-descent individuals from the Christchurch Health and Development Study. Logistic regression was used to examine associations between schizophrenia PRS and four anxiety disorders (social phobia, specific phobia, panic disorder and generalised anxiety disorder), schizophrenia/schizophreniform disorder, manic/hypomanic episode, alcohol dependence, major depression, and – using linear regression – total number of anxiety disorders. A novel population-level association with hypomania was tested in a UK birth cohort (Avon Longitudinal Study of Parents and Children).

Schizophrenia PRS was associated with total number of anxiety disorders and with generalised anxiety disorder and panic disorder. We show a novel population-level association between schizophrenia PRS and manic/hypomanic episode.

The relationship between schizophrenia liability and anxiety disorders is not restricted to psychopathology in adolescence but is present in adulthood and specifically linked to generalised anxiety disorder and panic disorder. We suggest that the association between schizophrenia liability and hypomanic/manic episodes found in clinical samples may not be due to bias.

None.

Being bullied by a sibling has been recently identified as a potential risk factor for developing depression and self-harm. It is unknown whether this risk extends to other serious mental health problems such as psychosis. We investigated whether sibling bullying victimization or perpetration in middle childhood was prospectively associated with psychotic disorder in early adulthood.

The current study investigated 6988 participants of the Avon Longitudinal Study of Parents and Children, a UK community-based birth cohort. Sibling bullying was reported at 12 years and psychotic disorder was assessed via a semi-structured interview at 18 years.

Involvement in sibling bullying was associated with psychotic disorder in a dose-response fashion, even after controlling for a range of confounders. Those involved several times a week were 2–3 times more likely to meet criteria for a psychotic disorder [odds ratio (OR); 95% confidence interval (CI)]: victimization (OR 2.74; CI 1.28–5.87); perpetration (OR 3.16; CI 1.35–7.41). Categorical analysis indicated that particularly victims (OR 3.10; CI 1.48–6.50) and bully-victims (OR 2.66; CI 1.24–5.69) were at increased risk of psychotic disorder. Involvement in both sibling and peer bullying had a dose-effect relationship with a psychotic disorder, with those victimized in both contexts having more than four times the odds for a psychotic disorder (OR 4.57; CI 1.73–12.07).

Parents and health professionals should be aware of the adverse long-term effects of sibling bullying.

Intellectual ability may be an endophenotypic marker for bipolar disorder.

Within a large birth cohort, we aimed to assess whether childhood IQ (including both verbal IQ (VIQ) and performance IQ (PIQ) subscales) was predictive of lifetime features of bipolar disorder assessed in young adulthood.

We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a large UK birth cohort, to test for an association between measures of childhood IQ at age 8 years and lifetime manic features assessed at age 22–23 years using the Hypomania Checklist-32 (HCL-32; n=1881 individuals). An ordinary least squares linear regression model was used, with normal childhood IQ (range 90–109) as the referent group. We adjusted analyses for confounding factors, including gender, ethnicity, handedness, maternal social class at recruitment, maternal age, maternal history of depression and maternal education.

There was a positive association between IQ at age 8 years and lifetime manic features at age 22–23 years (Pearson's correlation coefficient 0.159 (95% CI 0.120–0.198), P>0.001). Individuals in the lowest decile of manic features had a mean full-scale IQ (FSIQ) which was almost 10 points lower than those in the highest decile of manic features: mean FSIQ 100.71 (95% CI 98.74–102.6) v. 110.14 (95% CI 107.79–112.50), P>0.001. The association between IQ and manic features was present for FSIQ, VIQ and for PIQ but was strongest for VIQ.

A higher childhood IQ score, and high VIQ in particular, may represent a marker of risk for the later development of bipolar disorder. This finding has implications for understanding of how liability to bipolar disorder may have been selected through generations. It will also inform future genetic studies at the interface of intelligence, creativity and bipolar disorder and is relevant to the developmental trajectory of bipolar disorder. It may also improve approaches to earlier detection and treatment of bipolar disorder in adolescents and young adults.

Children with 22q11.2 deletion syndrome (22q11.2DS) have been reported to have high rates of cognitive and psychiatric problems.

To establish the nature and prevalence of psychiatric disorder and neurocognitive impairment in children with 22q11.2DS and test whether risk of psychopathology is mediated by the children's intellectual impairment.

Neurocognition and psychopathology were assessed in 80 children with 22q11.2DS (mean age 10.2 years, s.d. = 2.1) and 39 sibling controls (mean age 10.9 years, s.d. = 2.0).

More than half (54%) of children with 22q11.2DS met diagnostic criteria for one or more DSM-IV-TR psychiatric disorder. These children had lower IQ (mean 76.8, s.d. = 13.0) than controls (mean 108.6, s.d. = 15.2) (P<0.001) and showed a range of neurocognitive impairments. Increased risk of psychopathology was not mediated by intellectual impairment.

22q11.2DS is not related to a specific psychiatric phenotype in children. Moreover, the deletion has largely independent effects on IQ and risk of psychopathology, indicating that psychopathology in 22q11.2DS is not a non-specific consequence of generalised cognitive impairment.

A putative interaction between cannabis and variation at rs4680 within the catechol-methyl-transferase (COMT) gene on psychosis has been reported, but not adequately replicated.

To examine whether the relative risk of developing psychosis following use of cannabis is dependent upon variation within COMT.

A longitudinal study of 2630 individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort who completed questionnaire-based assessments for cannabis use at age 14 and incident psychotic experiences at age 16. Six SNPs within COMT were genotyped.

There was no evidence of an interaction under multiplicative models between cannabis use and COMT on the risk of developing psychotic experiences in our primary analyses. In sensitivity analyses we observed highly variable evidence of interaction, whereby psychotomimetic effects of cannabis were greater in methionine homozygotes under some scenarios, but in valine homozygotes under others.

Cannabis increases risk of psychosis irrespective of underlying COMT genotypes. These findings argue against the widely held belief that the relative risk of developing psychosis following use of cannabis is dependent upon variation within COMT. The public health message about the potential increase in risk of psychotic disorders following cannabis use should not be tempered by reports that this harm is subgroup specific in the absence of robust evidence of replication.