Marjan Drukker

Childhood Adversities Increase the Risk of Psychosis: A Meta-analysis of Patient-Control, Prospective- and Cross-sectional Cohort Studies

Evidence suggests that adverse experiences in childhood are associated with psychosis. To examine the association between childhood adversity and trauma (sexual abuse, physical abuse, emotional/psychological abuse, neglect, parental death, and bullying) and psychosis outcome, MEDLINE, EMBASE, PsychINFO, and Web of Science were searched from January 1980 through November 2011. We included prospective cohort studies, large-scale cross-sectional studies investigating the association between childhood adversity and psychotic symptoms or illness, case-control studies comparing the prevalence of adverse events between psychotic patients and controls using dichotomous or continuous measures, and case-control studies comparing the prevalence of psychotic symptoms between exposed and nonexposed subjects using dichotomous or continuous measures of adversity and psychosis. The analysis included 18 case-control studies (n = 2048 psychotic patients and 1856 nonpsychiatric controls), 10 prospective and quasi-prospective studies (n = 41 803) and 8 population-based cross-sectional studies (n = 35 546). There were significant associations between adversity and psychosis across all research designs, with an overall effect of OR = 2.78 (95% CI = 2.34–3.31). The integration of the case-control studies indicated that patients with psychosis were 2.72 times more likely to have been exposed to childhood adversity than controls (95% CI = 1.90–3.88). The association between childhood adversity and psychosis was also significant in population-based cross-sectional studies (OR = 2.99 [95% CI = 2.12–4.20]) as well as in prospective and quasi-prospective studies (OR = 2.75 [95% CI = 2.17–3.47]). The estimated population attributable risk was 33% (16%–47%). These findings indicate that childhood adversity is strongly associated with increased risk for psychosis.

Children's health-related quality of life, neighbourhood socio-economic deprivation and social capital. A contextual analysis

Neighbourhood objective socio-economic indicators and community-reported subjective measures of social capital were examined in relation to childrens health-related quality of life in the Netherlands. Three different data-sources were used: (1) objective neighbourhood socio-economic indicators, (2) subjective neighbourhood data on social capital, and (3) individual data of a family cohort study, including questions on childrens health-related quality of life, and family socio-economic status. Multilevel analyses were conducted using both neighbourhood level and individual level data. Neighbourhood socio-economic status and social capital were associated. Measures of socio-economic deprivation and social capital were both non-specifically associated with childrens general health and satisfaction, independent of possible individual-level confounders. However, childrens mental health and behaviour were specifically associated with one aspect of social capital, the degree of informal social control in the neighbourhood.

An experimental study of catechol-o-methyltransferase Val158Met moderation of delta-9-tetrahydrocannabinol-induced effects on psychosis and cognition.

Observational studies have suggested that psychometric psychosis liability and a functional polymorphism in the catechol-O-methyltransferase (COMT Val158Met) gene moderate the psychosis-inducing effect of cannabis. To replicate and extend this finding, a double-blind, placebo-controlled cross-over design was used in which patients with a psychotic disorder (n=30), relatives of patients with a psychotic disorder (n=12), and healthy controls (n=32) were exposed to Δ-9-tetrahydrocannabinol (Δ-9-THC, the principal component of cannabis) or placebo, followed by cognitive assessment and assessment of current psychotic experiences. Previous expression of psychometric psychosis liability was also assessed. Models of current psychotic experiences and cognition were examined with multilevel random regression analyses to assess (i) main effects of genotype and condition, (ii) interactions between condition and genotype, and (iii) three-way interactions between condition, genotype, and psychometric psychosis liability. Carriers of the Val allele were most sensitive to Δ-9-THC-induced psychotic experiences, but this was conditional on prior evidence of psychometric psychosis liability. Δ-9-THC impacted negatively on cognitive measures. Carriers of the Val allele were also more sensitive to Δ-9-THC-induced memory and attention impairments compared to carriers of the Met allele. Experimental effects of Δ-9-THC on cognition and psychosis are moderated by COMT Val158Met genotype, but the effects may in part be conditional on the additional presence of pre-existing psychosis liability. The association between cannabis and psychosis may represent higher order gene–environment and gene–gene interactions.

Do subthreshold psychotic experiences predict clinical outcomes in unselected non-help-seeking population-based samples? A systematic review and meta-analysis, enriched with new results

BACKGROUND The base rate of transition from subthreshold psychotic experiences (the exposure) to clinical psychotic disorder (the outcome) in unselected, representative and non-help-seeking population-based samples is unknown. METHOD A systematic review and meta-analysis was conducted of representative, longitudinal population-based cohorts with baseline assessment of subthreshold psychotic experiences and follow-up assessment of psychotic and non-psychotic clinical outcomes. RESULTS Six cohorts were identified with a 3-24-year follow-up of baseline subthreshold self-reported psychotic experiences. The yearly risk of conversion to a clinical psychotic outcome in exposed individuals (0.56%) was 3.5 times higher than for individuals without psychotic experiences (0.16%) and there was meta-analytic evidence of dose-response with severity/persistence of psychotic experiences. Individual studies also suggest a role for motivational impairment and social dysfunction. The evidence for conversion to non-psychotic outcome was weaker, although findings were similar in direction. CONCLUSIONS Subthreshold self-reported psychotic experiences in epidemiological non-help-seeking samples index psychometric risk for psychotic disorder, with strong modifier effects of severity/persistence. These data can serve as the population reference for selected and variable samples of help-seeking individuals at ultra-high risk, for whom much higher transition rates have been indicated.

Mindfulness Training Increases Momentary Positive Emotions and Reward Experience in Adults Vulnerable to Depression: A Randomized Controlled Trial

OBJECTIVE To examine whether mindfulness-based cognitive therapy (MBCT) increases momentary positive emotions and the ability to make use of natural rewards in daily life. METHOD Adults with a life-time history of depression and current residual depressive symptoms (mean age = 43.9 years, SD = 9.6; 75% female; all Caucasian) were randomized to MBCT (n = 64) or waitlist control (CONTROL; n = 66) in a parallel, open-label, randomized controlled trial. The Experience Sampling Method was used to measure momentary positive emotions as well as appraisal of pleasant activities in daily life during 6 days before and after the intervention. Residual depressive symptoms were measured using the 17-item Hamilton Depression Rating Scale (Hamilton, 1960). RESULTS MBCT compared to CONTROL was associated with significant increases in appraisals of positive emotion (b* = .39) and activity pleasantness (b* = .22) as well as enhanced ability to boost momentary positive emotions by engaging in pleasant activities (b* = .08; all ps < .005). Associations remained significant when corrected for reductions in depressive symptoms or for reductions in negative emotion, rumination, and worry. In the MBCT condition, increases in positive emotion variables were associated with reduction of residual depressive symptoms (all ps < .05). CONCLUSIONS MBCT is associated with increased experience of momentary positive emotions as well as greater appreciation of, and enhanced responsiveness to, pleasant daily-life activities. These changes were unlikely to be pure epiphenomena of decreased depression and, given the role of positive emotions in resilience against depression, may contribute to the protective effects of MBCT against depressive relapse.

Almost All Antipsychotics Result in Weight Gain: A Meta-Analysis

Introduction Antipsychotics (AP) induce weight gain. However, reviews and meta-analyses generally are restricted to second generation antipsychotics (SGA) and do not stratify for duration of AP use. It is hypothesised that patients gain more weight if duration of AP use is longer. Method A meta-analysis was conducted of clinical trials of AP that reported weight change. Outcome measures were body weight change, change in BMI and clinically relevant weight change (7% weight gain or loss). Duration of AP-use was stratified as follows: ≤6 weeks, 6–16 weeks, 16–38 weeks and >38 weeks. Forest plots stratified by AP as well as by duration of use were generated and results were summarised in figures. Results 307 articles met inclusion criteria. The majority were AP switch studies. Almost all AP showed a degree of weight gain after prolonged use, except for amisulpride, aripiprazole and ziprasidone, for which prolonged exposure resulted in negligible weight change. The level of weight gain per AP varied from discrete to severe. Contrary to expectations, switch of AP did not result in weight loss for amisulpride, aripiprazole or ziprasidone. In AP-naive patients, weight gain was much more pronounced for all AP. Conclusion Given prolonged exposure, virtually all AP are associated with weight gain. The rational of switching AP to achieve weight reduction may be overrated. In AP-naive patients, weight gain is more pronounced.

Self-reported Attenuated Psychotic Symptoms as Forerunners of Severe Mental Disorders Later in Life

CONTEXT It has been suggested that attenuated psychotic symptoms (APSs) reported by people who do not have psychotic disorders signal risk for later severe mental illness. OBJECTIVE To investigate this suggestion using follow-up assessments of hospitalization for clinical diagnoses of nonaffective psychotic and other psychiatric disorders. DESIGN Longitudinal cohort study of self-reported APSs with outcome assessment of severe mental illness obtained through linkage with a national hospitalization case registry. SETTING Israel. PARTICIPANTS A stratified full probability sample of 4914 persons aged 25 to 34 years who were screened for psychopathology in the 1980s. MAIN OUTCOME MEASURE Subsequent psychiatric hospitalization was ascertained using the psychiatric hospitalization registry, with a mean follow-up of 24 years. RESULTS After removing subjects with diagnosable psychotic disorders at baseline, 57.2% of the remaining sample reported at least 1 weak (infrequent) APS and 14.3% reported at least 1 strong (frequent) APS in the year preceding the assessment. Self-reported APSs predicted risk of later hospitalization for nonaffective psychotic disorders, mostly during the 5 years after baseline (adjusted odds ratio = 4.31; 95% CI, 2.21-8.41; positive predictive value = 1.27%; population attributable risk fraction = 33%). Also, APSs increased the risk of later hospitalization for other psychiatric disorders, albeit to a lesser extent (adjusted odds ratio = 2.21; 95% CI, 1.02-4.82). CONCLUSIONS Self-reported APSs signal risk for later nonaffective psychotic disorders but are not clinically useful as predictors. The difference between these population-based data and the high-risk literature in terms of the positive predictive value (1% vs 10%, respectively) and the time window of transition (5 years vs 12 months, respectively) can be attributed to the selective enrichment strategies that produce high-risk samples.

Neighbourhood socioeconomic disadvantage and behavioural problems from late childhood into early adolescence

Study objective: This study investigates whether neighbourhood socioeconomic disadvantage may contribute to child behavioural and emotional problems, beyond the effects of parental socioeconomic status. It also examines the influence of neighbourhood disadvantage on changes in the frequency of behavioural problems from late childhood into early adolescence. Design and setting: The study was conducted in a large community sample in Rotterdam, the Netherlands. An index of neighbourhood socioeconomic disadvantage was calculated for each of the city’s 74 neighbourhoods. Multilevel regression analysis estimated effects of neighbourhood disadvantage and individual variables (parental socioeconomic status, child’s gender, and age) on behavioural problems reported by children (Youth Self-Report) and parents (Child Behavior Checklist) and on changes in these scores over a two year follow up. Participants: A cohort of all children born in 1978 and living in Rotterdam. Of those eligible, 73% (n=2587) participated in the first measurement (T1), at 10–12 years; 71% of the T1 respondents participated again two years later (T2), at 12–14 years. Main results: Neighbourhood disadvantage was associated with higher Total, Internalising, and Externalising Problems, as assessed with both the Child Behavior Checklist and the Youth Self-Report, even after controlling for parental socioeconomic status. Neighbourhood disadvantage also seemed to contribute to increases in Total Problems over the follow up. Conclusions: Living in a disadvantaged neighbourhood is associated with greater behavioural problems and may lead to an exacerbation of problems as children move from childhood into adolescence. Public health interventions to improve child mental health must take the neighbourhood environment into account.

Meta-analysis of MTHFR gene variants in schizophrenia, bipolar disorder and unipolar depressive disorder: evidence for a common genetic vulnerability?

Past analyses examining the relationship between genetic variation in the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene and psychiatric disorders have provided mixed and largely inconclusive findings. MTHFR is involved in the one-carbon metabolic pathway which is essential for DNA biosynthesis and the epigenetic process of DNA methylation. We conducted a meta-analysis of all published case-control studies investigating associations between two common MTHFR single nucleotide polymorphisms (SNPs), MTHFR C677T (sample size 29,502) and A1298C (sample size 7934), and the major psychiatric disorders (i) schizophrenia (SZ), (ii) bipolar disorder (BPD), and (iii) unipolar depressive disorder (UDD). In order to examine possible shared genetic vulnerability, we also tested for associations between MTHFR and all of these major psychiatric disorders (SZ, BPD and UDD) combined. MTHFR C677T was significantly associated with all of the combined psychiatric disorders (SZ, BPD and UDD); random effects odds ratio (OR)=1.26 for TT versus CC genotype carriers; confidence interval (CI) 1.09-1.46); meta-regression did not suggest moderating effects of psychiatric diagnosis, sex, ethnic group or year of publication. Although MTHFR A1298C was not significantly associated with the combination of major psychiatric disorders, nor with SZ, there was evidence for diagnostic moderation indicating a significant association with BPD (random effects OR=2.03 for AA versus CC genotype carriers, CI: 1.07-3.86). Meta-analysis on UDD was not possible due to the small number of studies available. This study provides evidence for shared genetic vulnerability for SZ, BPD and UDD mediated by MTHFR 677TT genotype, which is in line with epigenetic involvement in the pathophysiology of these psychiatric disorders.

Reduced Cortical Thickness as an Outcome of Differential Sensitivity to Environmental Risks in Schizophrenia

BACKGROUND The etiology of schizophrenia is thought to involve differential-likely genetically mediated-sensitivity to environmental exposures. However, examination of differential sensitivity in models of psychopathologic constructs is subject to bias because psychopathology itself may distort exposure assessment. The use of neuroimaging phenotypes, conversely, may provide unbiased evidence for differential sensitivity to environmental exposures. This study examined the impact of two environmental exposures associated with both schizophrenia and magnetic resonance imaging (MRI) cerebral alterations in models of cerebral cortical thickness. METHODS T1-weighted MRI scans were acquired from 88 patients with schizophrenia, 98 healthy siblings at higher than average genetic risk for schizophrenia, and 87 control subjects. Freesurfer software was used to measure cortical thickness for 68 brain regions. Associations between 1) cortical thickness and 2) cannabis use and developmental trauma were examined. RESULTS A significant group × developmental trauma interaction (χ(2) = 9.65, p = .01), as well as a significant group × cannabis interaction (χ(2) = 6.04, p = .05) was apparent, indicating differential sensitivity of the patient group, which displayed stronger reductions of cortical thickness for both exposures. A similar pattern was found in the sibling-control comparison for cannabis. For developmental trauma, siblings did not differ from control subjects, displaying an increase in cortical thickness with higher levels of trauma. CONCLUSIONS The findings suggest that schizophrenia and its genetic liability are associated with differential cerebral cortical sensitivity to developmental environmental exposures such as cannabis. Gene-environment interactions may underlie some of the brain alterations observed in patients with schizophrenia and their relatives.