Jeroen Decoster

Genetic Variation Underlying Psychosis-inducing Effects of Cannabis: Critical Review and Future Directions

Cannabis use is associated with an increased risk for psychotic disorder, yet most cannabis users do not develop psychosis, suggesting that other factors are also involved. This paper reviews the available evidence suggesting that differential sensitivity to the psychosis-inducing effects of cannabis may be related to underlying genetic liability. There is robust evidence that persons at psychometric risk for psychosis are most vulnerable to display psychotic symptoms subsequent to the use of cannabis. Multiple studies have also found that persons at familial risk for psychosis have an increased sensitivity to the effects of cannabis. Together, these findings support the concept of a biological interaction between cannabis use and ones underlying genetic vulnerability. At the molecular-genetic level, however, few (if any) interactions have been consistently replicated, although a reported interaction with variation in AKT1 is promising and deserves further follow-up. The apparent lack of consistent replication can be ascribed to problems of initial gene selection, statistical power, a bias towards positive results and insufficient attempts at true replication, leading to the conclusion that increased sample sizes, greater density of genetic markers and a stronger focus on true replication are necessary. The major challenge for molecular-genetic gene-environment interaction research will be to combine the agnostic detection of disorder-associated genetic variants from genome-wide studies with the hypothesis-based approach from epidemiological and neurobiological studies. Possible strategies for future cannabis interaction studies are discussed.

Epigenetic Genes and Emotional Reactivity to Daily Life Events: A Multi-Step Gene-Environment Interaction Study

Recent human and animal studies suggest that epigenetic mechanisms mediate the impact of environment on development of mental disorders. Therefore, we hypothesized that polymorphisms in epigenetic-regulatory genes impact stress-induced emotional changes. A multi-step, multi-sample gene-environment interaction analysis was conducted to test whether 31 single nucleotide polymorphisms (SNPs) in epigenetic-regulatory genes, i.e. three DNA methyltransferase genes DNMT1, DNMT3A, DNMT3B, and methylenetetrahydrofolate reductase (MTHFR), moderate emotional responses to stressful and pleasant stimuli in daily life as measured by Experience Sampling Methodology (ESM). In the first step, main and interactive effects were tested in a sample of 112 healthy individuals. Significant associations in this discovery sample were then investigated in a population-based sample of 434 individuals for replication. SNPs showing significant effects in both the discovery and replication samples were subsequently tested in three other samples of: (i) 85 unaffected siblings of patients with psychosis, (ii) 110 patients with psychotic disorders, and iii) 126 patients with a history of major depressive disorder. Multilevel linear regression analyses showed no significant association between SNPs and negative affect or positive affect. No SNPs moderated the effect of pleasant stimuli on positive affect. Three SNPs of DNMT3A (rs11683424, rs1465764, rs1465825) and 1 SNP of MTHFR (rs1801131) moderated the effect of stressful events on negative affect. Only rs11683424 of DNMT3A showed consistent directions of effect in the majority of the 5 samples. These data provide the first evidence that emotional responses to daily life stressors may be moderated by genetic variation in the genes involved in the epigenetic machinery.

Single-subject classification of schizophrenia patients based on a combination of oddball and mismatch evoked potential paradigms

OBJECTIVE The diagnostic process for schizophrenia is mainly clinical and has to be performed by an experienced psychiatrist, relying primarily on clinical signs and symptoms. Current neurophysiological measurements can distinguish groups of healthy controls and groups of schizophrenia patients. Individual classification based on neurophysiological measurements mostly shows moderate accuracy. We wanted to examine whether it is possible to distinguish controls and patients individually with a good accuracy. To this end we used a combination of features extracted from the auditory and visual P300 paradigms and the mismatch negativity paradigm. METHODS We selected 54 patients and 54 controls, matched for age and gender, from the data available at the UPC Kortenberg. The EEG-data were high- and low-pass filtered, epoched and averaged. Features (latencies and amplitudes of component peaks) were extracted from the averaged signals. The resulting dataset was used to train and test classification algorithms. First on separate paradigms and then on all combinations, we applied Naïve Bayes, Support Vector Machine and Decision Tree, with two of its improvements: Adaboost and Random Forest. RESULTS For at least two classifiers the performance increased significantly by combining paradigms compared to single paradigms. The classification accuracy increased from at best 79.8% when trained on features from single paradigms, to 84.7% when trained on features from all three paradigms. CONCLUSION A combination of features originating from three evoked potential paradigms allowed us to accurately classify individual subjects as either control or patient. Classification accuracy was mostly above 80% for the machine learners evaluated in this study and close to 85% at best.

White noise speech illusion and psychosis expression: An experimental investigation of psychosis liability

Background An association between white noise speech illusion and psychotic symptoms has been reported in patients and their relatives. This supports the theory that bottom-up and top-down perceptual processes are involved in the mechanisms underlying perceptual abnormalities. However, findings in nonclinical populations have been conflicting. Objectives The aim of this study was to examine the association between white noise speech illusion and subclinical expression of psychotic symptoms in a nonclinical sample. Findings were compared to previous results to investigate potential methodology dependent differences. Methods In a general population adolescent and young adult twin sample (n = 704), the association between white noise speech illusion and subclinical psychotic experiences, using the Structured Interview for Schizotypy—Revised (SIS-R) and the Community Assessment of Psychic Experiences (CAPE), was analyzed using multilevel logistic regression analyses. Results Perception of any white noise speech illusion was not associated with either positive or negative schizotypy in the general population twin sample, using the method by Galdos et al. (2011) (positive: ORadjusted: 0.82, 95% CI: 0.6–1.12, p = 0.217; negative: ORadjusted: 0.75, 95% CI: 0.56–1.02, p = 0.065) and the method by Catalan et al. (2014) (positive: ORadjusted: 1.11, 95% CI: 0.79–1.57, p = 0.557). No association was found between CAPE scores and speech illusion (ORadjusted: 1.25, 95% CI: 0.88–1.79, p = 0.220). For the Catalan et al. (2014) but not the Galdos et al. (2011) method, a negative association was apparent between positive schizotypy and speech illusion with positive or negative affective valence (ORadjusted: 0.44, 95% CI: 0.24–0.81, p = 0.008). Conclusion Contrary to findings in clinical populations, white noise speech illusion may not be associated with psychosis proneness in nonclinical populations.

Psychological and Biological Validation of a Novel Digital Social Peer Evaluation Experiment (digi-SPEE)

INTRODUCTION Negative social evaluation is associated with psychopathology. Given the frequency of evaluation through increasingly prevalent virtual social networks, increased understanding of the effects of this social evaluation is urgently required. METHODS A new digital social peer evaluation experiment (digi-SPEE) was developed to mimic everyday online social interactions between peers. Participants received mildly negative feedback on their appearance, intelligence, and congeniality. Two hundred and forty-one young people [58.9% female, aged 18.9 years (15 to 34)] from an ongoing novel general population twin study participated in this study. Positive affect (PA), negative affect (NA), implicit self-esteem, and cortisol were assessed before and after exposure to the social evaluation experiment. RESULTS The social evaluation experiment decreased PA (B=-5.25, p<.001) and implicit self-esteem (B=-.19; p<.001), whereas it increased NA (B=5.99; p<.001) and cortisol levels (B=.07; p<.001). Females (PA: B=-7.62; p<.001; NA: B=8.28; p<.001) and participants with higher levels of general psychological distress (PA: B=-.04, p=.035; NA: B=.06; p=.028) showed stronger affective responses. Stressor-induced cortisol increase was stronger in adolescents under the age of 18 than in participants 18 years and older (B=-.06, p=.002). CONCLUSION The digi-SPEE represents a social evaluation stressor that elicits biological and implicit and explicit mental changes that are relevant to mechanisms of psychopathology.

Network Approach to Understanding Emotion Dynamics in Relation to Childhood Trauma and Genetic Liability to Psychopathology: Replication of a Prospective Experience Sampling Analysis

Background: The network analysis of intensive time series data collected using the Experience Sampling Method (ESM) may provide vital information in gaining insight into the link between emotion regulation and vulnerability to psychopathology. The aim of this study was to apply the network approach to investigate whether genetic liability (GL) to psychopathology and childhood trauma (CT) are associated with the network structure of the emotions “cheerful,” “insecure,” “relaxed,” “anxious,” “irritated,” and “down”—collected using the ESM method. Methods: Using data from a population-based sample of twin pairs and siblings (704 individuals), we examined whether momentary emotion network structures differed across strata of CT and GL. GL was determined empirically using the level of psychopathology in monozygotic and dizygotic co-twins. Network models were generated using multilevel time-lagged regression analysis and were compared across three strata (low, medium, and high) of CT and GL, respectively. Permutations were utilized to calculate p values and compare regressions coefficients, density, and centrality indices. Regression coefficients were presented as connections, while variables represented the nodes in the network. Results: In comparison to the low GL stratum, the high GL stratum had significantly denser overall (p = 0.018) and negative affect network density (p < 0.001). The medium GL stratum also showed a directionally similar (in-between high and low GL strata) but statistically inconclusive association with network density. In contrast to GL, the results of the CT analysis were less conclusive, with increased positive affect density (p = 0.021) and overall density (p = 0.042) in the high CT stratum compared to the medium CT stratum but not to the low CT stratum. The individual node comparisons across strata of GL and CT yielded only very few significant results, after adjusting for multiple testing. Conclusions: The present findings demonstrate that the network approach may have some value in understanding the relation between established risk factors for mental disorders (particularly GL) and the dynamic interplay between emotions. The present finding partially replicates an earlier analysis, suggesting it may be instructive to model negative emotional dynamics as a function of genetic influence.

Is sensitivity to daily stress predictive of onset or persistence of psychopathology

PURPOSE The aim of the current study was to replicate findings in adults indicating that higher sensitivity to stressful events is predictive of both onset and persistence of psychopathological symptoms in a sample of adolescents and young adults. In addition, we tested the hypothesis that sensitivity to mild stressors in particular is predictive of the developmental course of psychopathology. METHODS We analyzed experience sampling and questionnaire data collected at baseline and one-year follow-up of 445 adolescent and young adult twins and non-twin siblings (age range: 15-34). Linear multilevel regression was used for the replication analyses. To test if affective sensitivity to mild stressors in particular was associated with follow-up symptoms, we used a categorical approach adding variables on affective sensitivity to mild, moderate and severe daily stressors to the model. RESULTS Linear analyses showed that emotional stress reactivity was not associated with onset (β=.02; P=.56) or persistence (β=-.01; P=.78) of symptoms. There was a significant effect of baseline symptom score (β=.53; P<.001) and average negative affect (NA: β=.19; P<.001) on follow-up symptoms. Using the categorical approach, we found that affective sensitivity to mild (β=.25; P<.001), but not moderate (β=-.03; P=.65) or severe (β=-.06; P=.42), stressors was associated with symptom persistence one year later. DISCUSSION We were unable to replicate previous findings relating stress sensitivity linearly to symptom onset or persistence in a younger sample. Whereas sensitivity to more severe stressors may reflect adaptive coping, high sensitivity to the mildest of daily stressors may indicate an increased risk for psychopathology.

Evidence that the association of childhood trauma with psychosis and related psychopathology is not explained by gene-environment correlation: A monozygotic twin differences approach

BACKGROUND Converging evidence supports childhood trauma as possible causal risk for psychosis and related psychopathology. However, studies have shown that baseline psychotic symptoms may actually increase risk for subsequent victimization, suggesting that exposure to CT is not random but may result from pre-existing vulnerability. Therefore, studies testing whether the association between CT and psychopathology persists when accounting for gene-environment correlation are much needed. METHODS A monozygotic (MZ) twin differences approach was used to examine whether differences in CT exposure among MZ twin pairs would be associated with MZ differences in symptoms. As MZ twins are genetically identical, within-pair correlations between CT exposure and psychopathology rule out the possibility that the association is solely attributable to gene-environment correlation. 266 monozygotic twins (133 pairs) from a larger general population study were available for analysis. RESULTS CT was associated with symptoms of psychosis (B = 0.62; SE = 0.08, p < .001) and overall psychopathology (B = 43.13; SE = 6.27; p < .001). There were measurable differences within pairs in CT exposure and symptoms, allowing for meaningful within-pair differences. Within-pair differences in CT exposure were associated with within-pair differences in symptoms of psychosis (B = 0.35; SE = 0.16; p = .024), as well as with overall psychopathology (B = 29.22; SE = 12.24; p = .018), anxiety (B = 0.65; SE = 0.21; p = .002) and depression (B = 0.37; SE = 0.18; p = .043). CONCLUSION While it is not unlikely that pre-existing vulnerability may increase the risk for traumatic exposures, such gene-environment correlation does not explain away the association between CT and psychopathology. The present findings thus suggest that at least part of the association between CT and psychopathology may be causal.

O4.4. DOES POLYGENIC RISK SCORE FOR SCHIZOPHRENIA MODERATE THE MOMENTARY AFFECTIVE AND PSYCHOTIC REACTIONS TO DAILY-LIFE STRESSORS?

Abstract Background Studies using the event sampling method (ESM), a structured diary technique measuring subjective experiences and emotional fluctuations in daily life, have consistently shown that individuals reporting psychotic experiences display a heightened emotional reactivity to minor stressors—a neuropsychological mechanism that likely contributes to the development and perpetuation of psychotic experiences. Except a few undersized non-replicated candidate-gene studies showing an association between genetic variations and elevated momentary stress reactivity, genetic underpinnings of emotion reactivity to momentary stressors have not been investigated. Therefore, by leveraging a large general population twin dataset of ESM, we aimed to investigate—for the first time—whether the polygenic risk score (PRS) for schizophrenia moderates stress reactivity (psychotic experiences (PE) and negative affect (NA) in response to momentary stress). Methods Data were derived from a general population adolescent and young adult twin sample. The total sample included 638 participants (Monozygotic = 202, Dizygotic = 436). ESM variables were randomly measured at 10 times/day over 6 consecutive days. For the main analyses, we assessed ESM information on PE (suspiciousness, loss of control, racing thoughts, pervasive thoughts, difficulties to express thoughts), NA (feeling lonely, anxious, listless, down, guilty), and event-related stress (pleasantness of the most important event since last entry); and for additional explorative analyses we assessed social stress (participants were asked with whom they are (e.g. nobody or family) and to rate the pleasantness of the social situation). PRS were trained on the results from the Psychiatric Genetics Consortium-2 SZ. Multilevel regression analyses, taking into account of multiple observations nested within twins who were clustered within family, were used to analyze the moderating effects of PRS (at p-value < 0.05) on the relationship between momentary stress and NA or PE. All analyses were adjusted for age, sex and 2 principle components. Results There were significant main effects of momentary stress (event stress: b = 0.065, p < 0.001, 95% CI = 0.048, 0.082; social stress: b = 0.128; p < 0.001; 95% CI = 0.111, 0.145) on PE. However, neither the main effects of PRS on PE nor the interaction between PRS and momentary stress on PE were significant. The analysis with NA as dependent variable indicated main effects of momentary stress (event stress: b = 0.096; p <0.001; 95% CI = 0.081, 0.111; social stress: b = 0.180; p < 0.001; 95% CI = 0.164, 0.197), but no main effect of PRS. There was a significant negative interaction between PRS and both event-related stress (b = -0.016; p = 0.024; 95% CI = -0.031, -0.002) and social stress (b = -0.017; p = 0.024; 95% CI = -0.031, -0.002) on NA. Discussion This is the first study investigating the influence of molecular genetic risk for schizophrenia on momentary stress reactivity, measured using an ecologically valid diary method. These results suggest that PRS for schizophrenia does not have an effect on psychotic stress responses, while increased genetic risk for schizophrenia showed a buffering effect on the association between momentary stress and NA. It is possible that individuals with high PRS for schizophrenia might have emotional response deficits, a characteristic of the clinical phenotype. Alternatively, these individuals might have been less accurate in self-evaluating momentary stress, attributing high values to stressors that genuinely do not have an impact on their emotion regulation. Future studies, investigating both clinical and general populations, are required to elucidate the impact of PRS on stress reactivity.

Sensitivity to peer evaluation and its genetic and environmental determinants : Findings from a population-based twin study

Adolescents and young adults are highly focused on peer evaluation, but little is known about sources of their differential sensitivity. We examined to what extent sensitivity to peer evaluation is influenced by interacting environmental and genetic factors. A sample of 354 healthy adolescent twin pairs (n = 708) took part in a structured, laboratory task in which they were exposed to peer evaluation. The proportion of the variance in sensitivity to peer evaluation due to genetic and environmental factors was estimated, as was the association with specific a priori environmental risk factors. Differences in sensitivity to peer evaluation between adolescents were explained mainly by non-shared environmental influences. The results on shared environmental influences were not conclusive. No impact of latent genetic factors or gene-environment interactions was found. Adolescents with lower self-rated positions on the social ladder or who reported to have been bullied more severely showed significantly stronger responses to peer evaluation. Not genes, but subjective social status and past experience of being bullied seem to impact sensitivity to peer evaluation. This suggests that altered response to peer evaluation is the outcome of cumulative sensitization to social interactions.