Longitudinal associations between alcohol use, smoking, genetic risk scoring and symptoms of depression in the general population: a prospective 6-year cohort study.

BACKGROUND: Alcohol consumption, smoking and mood disorders are leading contributors to the global burden of disease and are highly comorbid. Yet, their interrelationships have remained elusive. The aim of this study was to examine the multi-cross-sectional and longitudinal associations between (change in) smoking and alcohol use and (change in) number of depressive symptoms. METHODS: In this prospective, longitudinal study, 6646 adults from the general population were included with follow-up measurements after 3 and 6 years. Linear mixed-effects models were used to test multi-cross-sectional and longitudinal associations, with smoking behaviour, alcohol use and genetic risk scores for smoking and alcohol use as independent variables and depressive symptoms as dependent variables. RESULTS: In the multi-cross-sectional analysis, smoking status and number of cigarettes per day were positively associated with depressive symptoms (p < 0.001). Moderate drinking was associated with less symptoms of depression compared to non-use (p = 0.011). Longitudinally, decreases in the numbers of cigarettes per day and alcoholic drinks per week as well as alcohol cessation were associated with a reduction of depressive symptoms (p = 0.001-0.028). Results of genetic risk score analyses aligned with these findings. CONCLUSIONS: While cross-sectionally smoking and moderate alcohol use show opposing associations with depressive symptoms, decreases in smoking behaviour as well as alcohol consumption are associated with improvements in depressive symptoms over time. Although we cannot infer causality, these results open avenues to further investigate interventions targeting smoking and alcohol behaviours in people suffering from depressive symptoms.

[Interplay between genetic background and environmental factors in psychiatry: current situation and future prospects]. / Samenspel tussen genetische achtergrond en omgevingsfactoren in de psychiatrie: stand van zaken en toekomstperspectief.

BACKGROUND: The hypothesis that etiopathogeneses of psychiatric disorders are determined by interplay between genetic background and environmental factors, as well their interactions can increasingly be put to direct scientific test, based on a wave of methodological, technological and knowledge developments.
AIM: To provide insight into and to provide perspective on some important scientific developments and facilitate challenges in this area.
METHOD: Narrative overview of the scientific literature and formulation of a concept and future perspective.
RESULTS: The overview points to concrete progress in the fields of genetic epidemiology, environmental analyses, gene-environment interactions and epigenetics in psychiatry. For example, recent studies have provided evidence for the existence of interactions and correlations between genetic and environmental factors, interdependence of risk-influencing effects of environmental factors, and translational neurobiological studies have identified biological processes that influence the impact of (or the response to) environmental influences on individuals mediate. These important steps to translate epidemiological research into testable biological hypotheses are facilitated by new techniques and the availability of large and relevant clinical and biological datasets.
CONCLUSION: Scientific progress on the interplay between genetic background and environmental factors enriches the conceptual framework of the etiopathogenesis of mental disorders and provides a future perspective in which we are likely to receive answers to a number of clinically relevant questions in the coming decade.
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Examining the independent and joint effects of genomic and exposomic liabilities for schizophrenia across the psychosis spectrum.

AIMS: Psychosis spectrum disorder has a complex pathoetiology characterised by interacting environmental and genetic vulnerabilities. The present study aims to investigate the role of gene-environment interaction using aggregate scores of genetic (polygenic risk score for schizophrenia (PRS-SCZ)) and environment liability for schizophrenia (exposome score for schizophrenia (ES-SCZ)) across the psychosis continuum. METHODS: The sample consisted of 1699 patients, 1753 unaffected siblings, and 1542 healthy comparison participants. The Structured Interview for Schizotypy-Revised (SIS-R) was administered to analyse scores of total, positive, and negative schizotypy in siblings and healthy comparison participants. The PRS-SCZ was trained using the Psychiatric Genomics Consortiums results and the ES-SCZ was calculated guided by the approach validated in a previous report in the current data set. Regression models were applied to test the independent and joint effects of PRS-SCZ and ES-SCZ (adjusted for age, sex, and ancestry using 10 principal components). RESULTS: Both genetic and environmental vulnerability were associated with case-control status. Furthermore, there was evidence for additive interaction between binary modes of PRS-SCZ and ES-SCZ (above 75% of the control distribution) increasing the odds for schizophrenia spectrum diagnosis (relative excess risk due to interaction = 6.79, [95% confidential interval (CI) 3.32, 10.26], p < 0.001). Sensitivity analyses using continuous PRS-SCZ and ES-SCZ confirmed gene-environment interaction (relative excess risk due to interaction = 1.80 [95% CI 1.01, 3.32], p = 0.004). In siblings and healthy comparison participants, PRS-SCZ and ES-SCZ were associated with all SIS-R dimensions and evidence was found for an interaction between PRS-SCZ and ES-SCZ on the total (B = 0.006 [95% CI 0.003, 0.009], p < 0.001), positive (B = 0.006 [95% CI, 0.002, 0.009], p = 0.002), and negative (B = 0.006, [95% CI 0.004, 0.009], p < 0.001) schizotypy dimensions. CONCLUSIONS: The interplay between exposome load and schizophrenia genetic liability contributing to psychosis across the spectrum of expression provide further empirical support to the notion of aetiological continuity underlying an extended psychosis phenotype.

Polygenic liability for schizophrenia and childhood adversity influences daily-life emotion dysregulation and psychosis proneness.

OBJECTIVE: To test whether polygenic risk score for schizophrenia (PRS-S) interacts with childhood adversity and daily-life stressors to influence momentary mental state domains (negative affect, positive affect, and subtle psychosis expression) and stress-sensitivity measures. METHODS: The data were retrieved from a general population twin cohort including 593 adolescents and young adults. Childhood adversity was assessed using the Childhood Trauma Questionnaire. Daily-life stressors and momentary mental state domains were measured using ecological momentary assessment. PRS-S was trained on the latest Psychiatric Genetics Consortium schizophrenia meta-analysis. The analyses were conducted using multilevel mixed-effects tobit regression models. RESULTS: Both childhood adversity and daily-life stressors were associated with increased negative affect, decreased positive affect, and increased subtle psychosis expression, while PRS-S was only associated with increased positive affect. No gene-environment correlation was detected. There is novel evidence for interaction effects between PRS-S and childhood adversity to influence momentary mental states [negative affect (b = 0.07, P = 0.013), positive affect (b = -0.05, P = 0.043), and subtle psychosis expression (b = 0.11, P = 0.007)] and stress-sensitivity measures. CONCLUSION: Exposure to childhood adversities, particularly in individuals with high PRS-S, is pleiotropically associated with emotion dysregulation and psychosis proneness.

Phenotypic factors associated with amisulpride-induced weight gain in first-episode psychosis patients (from the OPTiMiSE cohort).

OBJECTIVE: Antipsychotic-induced weight gain (AiWG) is a debilitating adverse effect of most antipsychotics. First-episode psychosis patients are particularly vulnerable to the detrimental consequences of AiWG. Amisulpride has good efficacy and tolerability. We here aimed to identify the phenotypic factors associated with amisulpride-induced weight gain in first-episode psychosis patients. METHOD: Data were collected from the Optimization of Treatment and Management of Schizophrenia in Europe trial. Multivariable regression models with various phenotypic variables (N = 305) were performed with absolute AiWG and clinically relevant AiWG (≥7% AiWG) as outcomes. RESULTS: Four weeks of amisulpride treatment increased body weight from 69.7 to 72.4 kg (P < 0.001). In the regression model of absolute AiWG, unemployment (ß = 0.94, P = 0.016), younger age (ß = -0.07, P = 0.031) and absence of current comorbid major depression disorder (ß = -1.61, P = 0.034) were positively associated with absolute AiWG. In the regression model of clinically relevant AiWG, unemployment (OR = 2.83, P = 0.001), schizophreniform disorder (OR = 2.00, P = 0.025) and low baseline weight (OR = 0.97, P = 0.032) increased the likelihood of clinically relevant AiWG. CONCLUSIONS: Clinicians prescribing amisulpride should consider the relatively high susceptibility to AiWG in unemployed first-episode patients with psychosis, in particular young subjects with a diagnosis of schizophreniform disorder. We advise to carefully monitor these patients and, when needed, implement weight-reducing strategies.

The slow death of the concept of schizophrenia and the painful birth of the psychosis spectrum.

The concept of schizophrenia only covers the 30% poor outcome fraction of a much broader multidimensional psychotic syndrome, yet paradoxically has become the dominant prism through which everything 'psychotic' is observed, even affective states with mild psychosis labelled 'ultra-high risk' (for schizophrenia). The inability of psychiatry to frame psychosis as multidimensional syndromal variation of largely unpredictable course and outcome - within and between individuals - hampers research and recovery-oriented practice. 'Psychosis' remains firmly associated with 'schizophrenia', as evidenced by a vigorous stream of high-impact but non-replicable attempts to 'reverse-engineer' the hypothesized biological disease entity, using case-control paradigms that cannot distinguish between risk for illness onset and risk for poor outcome. In this paper, the main issues surrounding the concept of schizophrenia are described. We tentatively conclude that with the advent of broad spectrum phenotypes covering autism and addiction in DSM5, the prospect for introducing a psychosis spectrum disorder - and modernizing psychiatry - appears to be within reach.

Rabies virus vaccine as an immune adjuvant against cancers and glioblastoma: new studies may resurrect a neglected potential

To review the literature about the use of Rabies Virus-Vaccine (RV-V) as an anticancer immunotherapeutic modality in the light of recent findings. The literature search in relevant databases with the following key words: Rabies virus, cancer, remission. Remissions occured following RV-V injections in patients with cervical cancer and melanoma. Pilot clinical studies showed that RV-V injections enhanced survival in glioblastoma patients, which is supported by findings in GL261 mouse glioma model. If public health studies demonstrate protective role of RV-V against certain types of cancers, it can be benefitted as a novel immune adjuvant in clinic (AU)

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Application of network methods for understanding mental disorders: pitfalls and promise.

Galvanized with the availability of sophisticated statistical techniques and large datasets, network medicine has emerged as an active area of investigation. Following this trend, network methods have been utilized to understand the interplay between symptoms of mental disorders. This realistic approach that may provide an improved framework into understanding mental conditions and underlying mechanisms is certainly to be welcomed. However, we have noticed that symptom network studies tend to lose sight of the fundamentals, overlook major limitations embedded in study designs, and make inferences that are difficult to justify with current findings. There is concern that disregarding these flaws may halt the progress of the network approach in psychiatry. Therefore, in this paper, we first attempt to identify the pitfalls: (1) a reductionist understanding of medicine and psychiatry, thereby inadvertently reintroducing the dichotomy of medicine (lung cancer) and psychiatry (depression), (2) a shortsighted view of signs and symptoms, (3) overlooking the limitations of available datasets based on scales with embedded latent class structures, (4) overestimating the importance of the current findings beyond what is supported by the study design. By addressing current issues, the hope is to navigate this rapidly growing field to a more methodologically sound and reproducible path that will contribute to our understanding of mental disorders and its underlying mechanisms.

Evidence that polygenic risk for psychotic disorder is expressed in the domain of neurodevelopment, emotion regulation and attribution of salience.

BACKGROUND: The liability-threshold model of psychosis risk predicts stronger phenotypic manifestation of the polygenic risk score (PRS) in the healthy relatives of patients, as compared with healthy comparison subjects. METHODS: First-degree relatives of patients with psychotic disorder (871 siblings and 812 parents) and healthy comparison subjects (n = 523) were interviewed three times in 6 years. Repeated measures of two psychosis phenotypes, the Community Assessment of Psychic Experiences (CAPE; self-report - subscales of positive, negative and depressive symptoms) and the Structured Interview for Schizotypy - Revised (SIS-R; clinical interview - subscales of positive and negative schizotypy), were examined for association with PRS. Interview-based lifetime rate of depressive and manic episodes were also examined, as was association with repeated measures of intelligence quotient (IQ). RESULTS: In the relatives, PRS was associated with CAPE/SIS-R total score (respectively, B = 0.12, 95% CI 0.02-0.22 and B = 0.11, 95% CI 0.02-0.20), the SIS-R positive subscale (B = 0.16, 95% CI 0.04-0.28), the CAPE depression subscale (B = 0.21, 95% CI 0.07-0.34), any lifetime affective episode (OR 3.1, 95% CI 1.04-9.3), but not with IQ (B = -1.8, 95% CI -8.0 to 4.4). In the controls, similar associations were apparent between PRS on the one hand and SIS-R total score, SIS-R positive, SIS-R negative, any lifetime affective episode and, in contrast, lower IQ (B = -8.5, 95% CI -15.5 to -1.6). CONCLUSIONS: In non-ill people, polygenic risk for psychotic disorder is expressed pleiotropically in the domain of neurodevelopment, emotion regulation and attribution of salience. In subjects at elevated genetic risk, emerging expression of neurodevelopmental alterations may create floor effects, obscuring genetic associations.

Rabies virus vaccine as an immune adjuvant against cancers and glioblastoma: new studies may resurrect a neglected potential.

To review the literature about the use of Rabies Virus-Vaccine (RV-V) as an anticancer immunotherapeutic modality in the light of recent findings. The literature search in relevant databases with the following key words: Rabies virus, cancer, remission. Remissions occured following RV-V injections in patients with cervical cancer and melanoma. Pilot clinical studies showed that RV-V injections enhanced survival in glioblastoma patients, which is supported by findings in GL261 mouse glioma model. If public health studies demonstrate protective role of RV-V against certain types of cancers, it can be benefitted as a novel immune adjuvant in clinic.

Evidence that the presence of psychosis in non-psychotic disorder is environment-dependent and mediated by severity of non-psychotic psychopathology.

BACKGROUND: Evidence suggests that in affective, non-psychotic disorders: (i) environmental exposures increase risk of subthreshold psychotic experiences (PEs) and strengthen connectivity between domains of affective and subthreshold psychotic psychopathology; and (ii) PEs are a marker of illness severity. METHOD: In 3021 adolescents from the Early Developmental Stages of Psychopathology cohort, we tested whether the association between PEs and presence of DSM-IV mood disorder (MD)/obsessive-compulsive disorder (OCD) would be moderated by risk factors for psychosis (cannabis use, childhood trauma and urbanicity), using the interaction contrast ratio (ICR) method. Furthermore, we analysed whether the interaction between environment and PEs was mediated by non-psychotic psychopathology. RESULTS: The association between PEs and MD/OCD was moderated by urbanicity (ICR = 2.46, p = 0.005), cannabis use (ICR = 3.76, p = 0.010) and, suggestively, trauma (ICR = 1.91, p = 0.063). Exposure to more than one environmental risk factor increased the likelihood of co-expression of PEs in a dose-response fashion. Moderating effects of environmental exposures were largely mediated by the severity of general non-psychotic psychopathology (percentage explained 56-68%, all p < 0.001). Within individuals with MD/OCD, the association between PEs and help-seeking behaviour, as an index of severity, was moderated by trauma (ICR = 1.87, p = 0.009) and urbanicity (ICR = 1.48, p = 0.005), but not by cannabis use. CONCLUSIONS: In non-psychotic disorder, environmental factors increase the likelihood of psychosis admixture and help-seeking behaviour through an increase in general psychopathology. The findings are compatible with a relational model of psychopathology in which more severe clinical states are the result of environment-induced disturbances spreading through a psychopathology network.

Pharmaceutical industry interactions of psychiatric trainees from 20 European countries.

BACKGROUND: Interactions between the pharmaceutical industry (PI) and psychiatrists have been under scrutiny recently, though there is little empirical evidence on the nature of the relationship and its intensity at psychiatry trainee level. We therefore studied the level of PI interactions and the underlying beliefs and attitudes in a large sample of European psychiatric trainees. METHODS: One thousand four hundred and forty-four psychiatric trainees in 20 European countries were assessed cross-sectionally, with a 62-item questionnaire. RESULTS: The total number of PI interactions in the preceding two months varied between countries, with least interactions in The Netherlands (M (Mean)=0.92, SD=1.44, range=0-12) and most in Portugal (M=19.06, SD=17.44, range=0-100). Trainees were more likely to believe that PI interactions have no impact on their own prescribing behaviour than that of other physicians (M=3.30, SD=1.26 vs. M=2.39, SD=1.06 on a 5-point Likert scale: 1 "completely disagree" to 5 "completely agree"). Assigning an educational role to the pharmaceutical industry was associated with more interactions and higher gift value (IRR (incidence rate ratio)=1.21, 95%CI=1.12-1.30 and OR=1.18, 95%CI=1.02-1.37). CONCLUSIONS: There are frequent interactions between European psychiatric trainees and the PI, with significant variation between countries. We identified several factors affecting this interaction, including attribution of an educational role to the PI. Creating alternative educational opportunities and specific training dedicated to PI interactions may therefore help to reduce the impact of the PI on psychiatric training.