Childhood maltreatment mediates the effect of the genetic background on psychosis risk in young adults.

Childhood maltreatment (CM) and genetic vulnerability are both risk factors for psychosis, but the relations between them are not fully understood. Guided by the recent identification of genetic risk to CM, this study investigates the hypothesis that genetic risk to schizophrenia also increases the risk of CM and thus impacts psychosis risk. The relationship between schizophrenia polygenetic risk, CM, and psychotic-like experiences (PLE) was investigated in participants from the Utrecht Cannabis Cohort (N = 1262) and replicated in the independent IMAGEN cohort (N = 1740). Schizophrenia polygenic risk score (SZ-PRS) were calculated from the most recent GWAS. The relationship between CM, PRS, and PLE was first investigated using multivariate linear regression. Next, mediation of CM in the pathway linking SZ-PRS and PLE was examined by structural equation modeling, while adjusting for a set of potential mediators including cannabis use, smoking, and neuroticism. In agreement with previous studies, PLE were strongly associated with SZ-PRS (B = 0.190, p = 0.009) and CM (B = 0.575, p < 0.001). Novel was that CM was also significantly associated with SZ-PRS (B = 0.171, p = 0.001), and substantially mediated the effects of SZ-PRS on PLE (proportion mediated = 29.9%, p = 0.001). In the replication cohort, the analyses yielded similar results, confirming equally strong mediation by CM (proportion mediated = 34.7%, p = 0.009). Our results suggest that CM acts as a mediator in the causal pathway linking SZ-PRS and psychosis risk. These findings open new perspectives on the relations between genetic and environmental risks and warrant further studies into potential interventions to reduce psychosis risk in vulnerable people.

Liprin alfa 2 gene expression is increased by cannabis use and associated with neuropsychological function.

The relation of heavy cannabis use with decreased neuropsychological function has frequently been described but the underlying biological mechanisms are still largely unknown. This study investigates the relation of cannabis use with genome wide gene expression and subsequently examines the relations with neuropsychological function. Genome-wide gene expression in whole blood was compared between heavy cannabis users (N = 90) and cannabis naïve participants (N = 100) that were matched for psychotic like experiences. The results were validated using quantitative real-time PCR. Psychotic like experiences were assessed using the Comprehensive Assessment of Psychotic Experiences (CAPE). Neuropsychological function was estimated using four subtasks of the Wechsler Adult Intelligence Scale (WAIS). Subsequent in vitro studies in monocytes and a neuroblastoma cell line investigated expression changes in response to two major psychotropic components of cannabis; tetrahydrocannabinol (THC) and cannabidiol (CBD). mRNA expression of Protein Tyrosine Phosphatase Receptor Type F Polypeptide-Interacting-Protein Alpha-2 (PPFIA2) was significantly higher in cannabis users (LogFold Change 0.17) and confirmed by qPCR analysis. PPFIA2 expression level was negatively correlated with estimated intelligence (B=-22.9, p = 0.002) also in the 100 non-users (B=-28.5, p = 0.037). In vitro exposure of monocytes to CBD led to significant increase in PPFIA2 expression. However, exposure of monocytes to THC and neuroblastoma cells to THC or CBD did not change PPFIA2 expression. Change in PPFIA2 gene expression in response to cannabinoids is a putative mechanism by which cannabis could influence neuropsychological functions. The findings warrant further exploration of the role of PPFIA2 in cannabis induced changes of neuropsychological function, particularly in relation to CBD.

Educational Level, Underachievement, and General Mental Health Problems in 10,866 Adolescents.

OBJECTIVE: Previous research suggests that cognitive functioning is associated with the risk of several adult psychiatric disorders. In this study we investigated whether adolescents who perform worse than expected at secondary school are at a higher risk for general mental health problems. METHODS: In a cross-sectional survey comprising 10,866 Dutch adolescents aged 13 to 16 years, underachievement at secondary school was defined as the discrepancy between predicted school grade and actual grade 1 or 3 years later. Mental health problems were assessed using the Strengths and Difficulties Questionnaire. We investigated the association of underachievement with mental health problems using logistic regression, adjusting for potential confounders. RESULTS: Underachievement was associated with general psychopathology in pupils aged 13 to 14 years (odds ratio [OR], 1.86; 95% confidence interval [CI], 1.47-2.37) and in pupils aged 15 to 16 years (OR, 2.05; 95% CI, 1.67-2.52) in a multivariate analysis including sociodemographic factors. The association between underachievement and mental health problems was attenuated when school factors such as teacher advice and interaction between underachievement and teacher advice were added, but underachievement remained significantly associated with mental health problems in adolescents in the higher educational tracks (pupils aged 13-14 years: OR, 2.22; 95% CI, 1.07-4.60 and OR, 2.41; 95% CI, 1.10-5.30, age 15-16 years: OR, 2.63; 95% CI, 1.38-5.03). In the multivariate analysis including the interaction between underachievement and teacher advice, a significant interaction effect occurs between underachievement and teacher advice in the higher tracks. Values of OR and CI are given for each significant interaction term. In the younger age group (pupils aged 13-14 years) this results in 2 sets of OR and CI. This association was most pronounced for the hyperactivity subscale of the Strengths and Difficulties Questionnaire. CONCLUSIONS: Underachievement at secondary school is associated with general mental health problems, especially with hyperactivity symptoms, in pupils who started at high educational tracks.

Delayed school progression and mental health problems in adolescence: a population-based study in 10,803 adolescents.

BACKGROUND: Accumulating evidence suggests that several adult mental disorders, particularly psychoses, are preceded by impairments in cognitive function, reflected in scholastic underachievement. This study investigates the association between scholastic underachievement and general mental health problems in adolescence, using delay in school progression as a marker of poor scholastic performance. METHOD: Cross-sectional secondary school survey comprising 10,803 adolescents. Participants completed the Strengths and Difficulties Questionnaire (SDQ) to assess mental health problems. The association of delayed school progression with the SDQ was investigated using logistic regression with SDQ as outcome and delayed school progression as primary exposure of interest while adjusting for socio-demographic characteristics, adverse life events, school-related factors, risk taking behaviour, healthy lifestyle and physical health. RESULTS: Unadjusted analysis showed an association between delayed school progression and total mental health problems (OR 1.83, 95% CI 1.27-2.63) in adolescents. After adjusting for other risk factors (socio-demographic factors and life events) in a logistic regression model the association between delayed school progression en mental health problems was attenuated (OR 1.33, 95% CI 0.86-2.05). CONCLUSION: Delayed school progression is associated with general mental health problems in adolescence, but this relationship is heavily confounded by other factors. A causal relationship between impaired cognitive function such as poor scholastic performance and general mental health at adolescence is less likely and delayed school progression may merely be considered an indicator of risk for mental health problems.

Does assessment type matter? A measurement invariance analysis of online and paper and pencil assessment of the Community Assessment of Psychic Experiences (CAPE).

BACKGROUND: The psychometric properties of an online test are not necessarily identical to its paper and pencil original. The aim of this study is to test whether the factor structure of the Community Assessment of Psychic Experiences (CAPE) is measurement invariant with respect to online vs. paper and pencil assessment. METHOD: The factor structure of CAPE items assessed by paper and pencil (N = 796) was compared with the factor structure of CAPE items assessed by the Internet (N = 21,590) using formal tests for Measurement Invariance (MI). The effect size was calculated by estimating the Signed Item Difference in the Sample (SIDS) index and the Signed Test Difference in the Sample (STDS) for a hypothetical subject who scores 2 standard deviations above average on the latent dimensions. RESULTS: The more restricted Metric Invariance model showed a significantly worse fit compared to the less restricted Configural Invariance model (χ(2)(23) = 152.75, p<0.001). However, the SIDS indices appear to be small, with an average of -0.11. A STDS of -4.80 indicates that Internet sample members who score 2 standard deviations above average would be expected to score 4.80 points lower on the CAPE total scale (ranging from 42 to 114 points) than would members of the Paper sample with the same latent trait score. CONCLUSIONS: Our findings did not support measurement invariance with respect to assessment method. Because of the small effect sizes, the measurement differences between the online assessed CAPE and its paper and pencil original can be neglected without major consequences for research purposes. However, a person with a high vulnerability for psychotic symptoms would score 4.80 points lower on the total scale if the CAPE is assessed online compared to paper and pencil assessment. Therefore, for clinical purposes, one should be cautious with online assessment of the CAPE.

The effect of childhood maltreatment and cannabis use on adult psychotic symptoms is modified by the COMT Val¹58Met polymorphism.

BACKGROUND: Cannabis use and childhood maltreatment are independent risk factors for the development of psychotic symptoms. These factors have been found to interact in some but not all studies. One of the reasons may be that childhood maltreatment and cannabis primarily induce psychotic symptoms in genetically susceptible individuals. In this context, an extensively studied psychosis vulnerability gene is catechol-methyl-transferase (COMT). Therefore, we aimed to examine whether the COMT Val(158)Met polymorphism (rs4680) moderates the interaction between childhood maltreatment and cannabis use on psychotic symptoms in the general population. METHOD: The discovery sample consisted of 918 individuals from a cross-sectional study. For replication we used an independent sample of 339 individuals from the general population. RESULTS: A significant three-way interaction was found between childhood maltreatment, cannabis use, and the COMT genotype (rs4680) in the discovery sample (P=0.006). Val-homozygous individuals displayed increased psychotic experiences after exposure to both cannabis use and childhood maltreatment compared to Met-heterozygous and Met-homozygous individuals. Supportive evidence was found in the replication sample with similar effect and direction even though the results did not reach statistical significance (P=0.25). CONCLUSIONS: These findings suggest that a functional polymorphism in the COMT gene may moderate the interaction between childhood maltreatment and cannabis use on psychotic experiences in the general population. In conclusion, the COMT Val(158)Met polymorphism may constitute a genetic risk factor for psychotic symptoms in the context of combined exposure to childhood maltreatment and cannabis use.

Advanced paternal age and vulnerability to psychotic-like experiences in the offspring.

OBJECTIVE: To investigate whether advanced paternal age is associated with increased psychotic-like experiences (PLEs) and increased sensitivity to Cannabis in the offspring. METHODS: A cross-sectional population-based study in 1684 participants aged 18 to 25. RESULTS: We found no association of paternal age with PLEs. Only the positive dimension subscale was associated to paternal age, but that could be largely contributed to outliers. Also no increased sensitivity to Cannabis smoking was apparent. CONCLUSION: In the general population, we did not find robust support for an association between paternal age and vulnerability to PLEs in 18-25year old offspring.

Auditory hallucinations elicit similar brain activation in psychotic and nonpsychotic individuals.

While auditory verbal hallucinations (AVH) are most characteristic for schizophrenia, they also occur in nonpsychotic individuals in the absence of a psychiatric or neurological disorder and in the absence of substance abuse. At present, it is unclear if AVH in these nonpsychotic individuals constitute the same phenomenon as AVH in psychotic patients. Comparing brain activation during AVH between nonpsychotic and psychotic individuals could provide important clues regarding this question. 21 nonpsychotic subjects with AVH and 21 matched psychotic patients indicated the presence of AVH during 3T functional magnetic resonance imaging (fMRI) scanning. To identify common areas of activation during the experience of AVH in both groups, a conjunction analysis was performed. In addition, a 2-sample t-test was employed to discover possible differences in AVH-related activation between the groups. Several common areas of activation were observed for the psychotic and nonpsychotic subjects during the experience of AVH, consisting of the bilateral inferior frontal gyri, insula, superior temporal gyri, supramarginal gyri and postcentral gyri, left precentral gyrus, inferior parietal lobule, superior temporal pole, and right cerebellum. No significant differences in AVH-related brain activation were present between the groups. The presence of multiple common areas of AVH-related activation in psychotic and nonpsychotic individuals, in the absence of significant differences, implicates the involvement of the same cortical network in the experience of AVH in both groups.

Cannabis use and subclinical positive psychotic experiences in early adolescence: findings from a Dutch survey.

AIMS: To investigate the association between early cannabis use and subclinical psychotic experiences, distinguishing between five levels of use: never used, discontinued use (life-time users who did not use in the preceding year), experimental use, regular use and heavy use. DESIGN: Cross-sectional observational study. SETTING: Dutch Health Behaviour in School-aged Children (HBSC) study, 2005 wave. PARTICIPANTS: A total of 4552 secondary school children aged 12-16 years. MEASUREMENTS: Cannabis use, Community Assessment of Psychic Experiences (CAPE) positive scale, confounding factors: age, gender, family affluence, household composition, social support, alcohol use, cigarette smoking, ethnicity and urbanicity. FINDINGS: The association between cannabis use and subclinical positive symptoms was confirmed, and remained significant after extensive adjustment for potential confounders. Associations were found for all user groups, with strongest associations for the discontinued use group (ß = 0.061, P = 0.000) and for the heavy use group (ß = 0.065, P = 0.000). CONCLUSIONS: There is an enduring association between cannabis use at an early age and subclinical positive psychotic experiences, even after abstaining from cannabis for at least 1 year.

Cannabis with high cannabidiol content is associated with fewer psychotic experiences.

OBJECTIVE: Cannabis is associated with psychotic outcomes in numerous studies, an effect that is commonly attributed to Δ (9)-tetrahydrocannabinol (Δ 9-THC). An increasing number of authors identify cannabidiol, another component of the cannabis plant, as an antipsychotic agent. The objective of the current study is to investigate the role of cannabidiol content in the association between cannabis use and psychiatric symptoms in a large non-clinical population of cannabis users. METHODS: In a web-based cross-sectional study we obtained detailed information about cannabis use and subclinical psychiatric experiences using the Community Assessment of Psychic Experiences (CAPE). Different types of cannabis (i.e. marijuana, hashish etc.) have distinctive proportions of Δ 9-THC and cannabidiol. Since average concentrations of Δ 9-THC and cannabidiol in the most popular types of cannabis sold on the Dutch market are annually measured, we were able to estimate exposure to Δ 9-THC and cannabidiol. RESULTS: We included 1877 subjects (mean age 23, SD 6.0) who used the same type of cannabis in the majority of the occasions (in >60% of occasions). We found a significant inverse relationship (F(1,1877): 14.577, p<0.001) between cannabidiol content and self-reported positive symptoms, but not with negative symptoms or depression. The estimated effect size of cannabidiol content was small. CONCLUSION: Although the observed effects are subtle, using high cannabidiol content cannabis was associated with significantly lower degrees of psychotic symptoms providing further support for the antipsychotic potential of cannabidiol.

Screening capacity of the Multidimensional Anxiety Scale for Children (MASC) for DSM-IV anxiety disorders.

BACKGROUND: The Multidimensional Anxiety Scale for Children (MASC) is a widely used self-report questionnaire for the assessment of anxiety symptoms in children and adolescents. METHODS: This study used receiver operating characteristic analyses to investigate the predictive value of the MASC total and scale scores for DSM-IV anxiety diagnoses in a referred sample. Eight- to 18-year-olds (n=212) were assessed with the MASC and Anxiety Disorders Interview Schedule for Children (ADIS-C). RESULTS: The MASC total score did not exceed the threshold for being judged as fair in predicting any ADIS-C/DSM-IV anxiety diagnosis. The Separation Anxiety scale and the Physical Symptoms scale predicted Panic Disorder (PAD) and Agoraphobia fairly accurately. The Social Anxiety scale predicted Social Phobia, and the Separation Anxiety scale predicted PAD to a moderate degree. The MASC scale Harm Avoidance did not predict any ADIS-C/DSM-IV diagnosis. CONCLUSIONS: These results suggest that the MASC may not be a valid screening instrument for DSM-IV diagnoses.

No differences between group versus individual treatment of childhood anxiety disorders in a randomised clinical trial.

BACKGROUND: The present study compares an individual versus a group format in the delivery of manualised cognitive-behavioural therapy (FRIENDS) for children with anxiety disorders. Clinically referred children (aged 8 to 12) diagnosed with Separation Anxiety Disorder (n = 52), Generalised Anxiety Disorder (n = 37), Social Phobia (n = 22) or Specific Phobia (n = 16) were randomly assigned to individual (n = 65) or group (n = 62) treatment. METHOD: Analyses were conducted separately for the intent-to-treat sample and the sample of children who completed treatment. Analyses included chi-square comparisons and regression analyses with treatment format as a predictor. RESULTS: Forty-eight percent of the children in the individual versus 41% in the group treatment were free of any anxiety disorder at post-treatment; 62% versus 54% were free of their primary anxiety disorder. Regression analyses showed no significant difference in outcome between individual and group treatment. CONCLUSIONS: Children improved in both conditions. Choice between treatments could be based on pragmatic considerations such as therapeutic resources, referral rates, and the preference of the parents and the child.

Distinctions between separation anxiety and social anxiety in children and adolescents.

Separation anxiety and social phobia are intertwined to a considerable degree, and high comorbidity rates have been reported. The present study used latent class analysis (LCA) to investigate if classes of children and adolescents with-simultaneously-high rates of separation anxiety and low rates of social anxiety symptoms, or vice versa, could be identified. Eight- to 18-year-olds from a large general population (n=1000) and referred sample (n=735) were assessed with the Multidimensional Anxiety Scale for Children (MASC). With LCA, a separate class of referred 8-11-year-old children with high separation anxiety scores, and simultaneously lower social anxiety scores was identified, next to a class of children with high scores on separation anxiety and social anxiety. In the other groups (referred 12-18-year-olds and children and adolescents from the general population), a class with individuals who specifically scored high on separation anxiety could not be revealed. The results indicated that separation anxiety represents a different construct than social anxiety in referred children (but not in referred adolescents or in the general population). It can be concluded that, in referred children, research regarding etiology and treatment outcome of anxiety symptoms should be aimed specifically at separation anxiety and social anxiety, instead of just investigating a broader anxiety dimension.