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The present study examines whether neuroticism is predicted by genetic vulnerability, summarized as polygenic risk score for neuroticism (PRSN), in interaction with bullying, parental bonding, and childhood adversity. Data were derived from a general population adolescent and young adult twin cohort. The final sample consisted of 202 monozygotic and 436 dizygotic twins and 319 twin pairs. The Short Eysenck Personality questionnaire was used to measure neuroticism. PRSN was trained on the results from the Genetics of Personality Consortium (GPC) and United Kingdom Biobank (UKB) cohorts, yielding two different PRSN. Multilevel mixed-effects models were used to analyze the main and interacting associations of PRSN, childhood adversity, bullying, and parental bonding style with neuroticism. We found no evidence of gene–environment correlation. PRSN thresholds of .005 and .2 were chosen, based on GPC and UKB datasets, respectively. After correction for confounders, all the individual variables were associated with the expression of neuroticism: both PRSN from GPC and UKB, childhood adversity, maternal bonding, paternal bonding, and bullying in primary school and secondary school. However, the results indicated no evidence for gene–environment interaction in this cohort. These results suggest that genetic vulnerability on the one hand and negative life events (childhood adversity and bullying) and positive life events (optimal parental bonding) on the other represent noninteracting pathways to neuroticism.
Cognitive models propose that behavioural responses to voices maintain distress by preventing disconfirmation of negative beliefs about voices. We used Experience Sampling Methodology (ESM) to examine the hypothesized maintenance role of behavioural responses during daily life.
Thirty-one outpatients with frequent voices completed a smartphone-based ESM questionnaire 10 times a day over 9 days, assessing voice-related distress; resistance and compliance responses to voices; voice characteristics (intensity and negative content); appraisals of voice dominance, uncontrollability and intrusiveness.
In line with predictions, behavioural responses were associated with voice appraisals (dominance and uncontrollability), but not voice characteristics. Greater resistance and compliance were reported in moments of increased voice distress, but these associations did not persist after controlling for concurrent voice appraisals and characteristics. Voice distress was predicted by appraisals, and, unexpectedly, also by voice characteristics. As predicted, compliance and resistance were related to increases in distress at subsequent timepoints, whilst antecedent voice appraisals and characteristics had no such effect. Compliance, but not resistance, additionally predicted subsequent increases in voice uncontrollability. In both cases, the reverse models showed no association, indicating directional effects of responses on subsequent distress, and of compliance on uncontrollability appraisals.
These results provide support for the cognitive model by suggesting that momentary behavioural and emotional responses to voices are associated with concurrent negative voice appraisals. Findings suggest that behavioural responses may be driven by voice appraisals, rather than directly by distress, and may in turn maintain voice appraisals and associated distress during the course of daily life.
Meta-analyses suggest that clinical psychopathology is preceded by dimensional behavioral and cognitive phenotypes such as psychotic experiences, executive functioning, working memory and affective dysregulation that are determined by the interplay between genetic and nongenetic factors contributing to the severity of psychopathology. The liability to mental ill health can be psychometrically measured using experimental paradigms that assess neurocognitive processes such as salience attribution, sensitivity to social defeat and reward sensitivity. Here, we describe the TwinssCan, a longitudinal general population twin cohort, which comprises 1202 individuals (796 adolescent/young adult twins, 43 siblings and 363 parents) at baseline. The TwinssCan is part of the European Network of National Networks studying Gene-Environment Interactions in Schizophrenia project and recruited from the East Flanders Prospective Twin Survey. The main objective of this project is to understand psychopathology by evaluating the contribution of genetic and nongenetic factors on subclinical expressions of dimensional phenotypes at a young age before the onset of disorder and their association with neurocognitive processes, such as salience attribution, sensitivity to social defeat and reward sensitivity.
Depression has been associated with abnormalities in neural underpinnings of Reward Learning (RL). However, inconsistencies have emerged, possibly owing to medication effects. Additionally, it remains unclear how neural RL signals relate to real-life behaviour. The current study, therefore, examined neural RL signals in young, mildly to moderately depressed – but non-help-seeking and unmedicated – individuals and how these signals are associated with depressive symptoms and real-life motivated behaviour.
Individuals with symptoms along the depression continuum (n = 87) were recruited from the community. They performed an RL task during functional Magnetic Resonance Imaging and were assessed with the Experience Sampling Method (ESM), completing short questionnaires on emotions and behaviours up to 10 times/day for 15 days. Q-learning model-derived Reward Prediction Errors (RPEs) were examined in striatal areas, and subsequently associated with depressive symptoms and an ESM measure capturing (non-linearly) how anticipation of reward experience corresponds to actual reward experience later on.
Significant RPE signals were found in the striatum, insula, amygdala, hippocampus, frontal and occipital cortices. Region-of-interest analyses revealed a significant association between RPE signals and (a) self-reported depressive symptoms in the right nucleus accumbens (b = −0.017, p = 0.006) and putamen (b = −0.013, p = .012); and (b) the quadratic ESM variable in the left (b = 0.010, p = .010) and right (b = 0.026, p = 0.011) nucleus accumbens and right putamen (b = 0.047, p < 0.001).
Striatal RPE signals are disrupted along the depression continuum. Moreover, they are associated with reward-related behaviour in real-life, suggesting that real-life coupling of reward anticipation and engagement in rewarding activities might be a relevant target of psychological therapies for depression.
Recently, there has been renewed interest in the application of assumptions from complex systems theory in the field of psychopathology. One assumption, with high clinical relevance, is that sudden transitions in symptoms may be anticipated by rising instability in the system, which can be detected with early warning signals (EWS). Empirical studies support the idea that this principle also applies to the field of psychopathology. The current manuscript discusses whether assumptions from complex systems theory can additionally be informative with respect to the specific symptom dimension in which such a transition will occur (e.g. whether a transition towards anxious, depressive or manic symptoms is most likely). From a complex systems perspective, both EWS measured in single symptom dynamics and network symptom dynamics at large are hypothesized to provide clues regarding the direction of the transition. Challenging research designs are needed to provide empirical validation of these hypotheses. These designs should be able to follow sudden transitions ‘live’ using frequent observations of symptoms within individuals and apply a transdiagnostic approach to psychopathology. If the assumptions proposed are supported by empirical studies then this will signify a large improvement in the possibility for personalized estimations of the course of psychiatric symptoms. Such information can be extremely useful for early intervention strategies aimed at preventing specific psychiatric problems.
Poor sleep is a risk factor for depression, but little is known about the underlying mechanisms.
Disentangling potential mechanisms by which sleep may be related to depression by zooming downto the ‘micro-level’ of within-person daily life patterns of subjective sleep and affect usingthe experience sampling method (ESM).
A population-based twin sample consisting of 553 women underwent a 5-day baseline ESM protocolassessing subjective sleep and affect together with four follow-up assessments of depression.
Sleep was associated with affect during the next day, especially positive affect. Daytime negative affect was not associated with subsequent night-time sleep. Baseline sleep predicted depressive symptoms across the follow-up period.
The subtle, repetitive impact of sleep on affect on a daily basis, rather than the subtle repetitive impact of affect on sleep, may be one of the factors on the pathway to depression in women.
FK506 binding protein 5 (FKBP5) has repeatedly been shown to be a critical determinant of post-traumatic stress disorder (PTSD) and depression following childhood trauma.
To examine the role of FKBP5-trauma interactions in the partly stress-related psychosis phenotype.
In 401 general population twins, four functional polymorphisms were examined in models of psychosis and Cortisol, and followed up in models of psychosis in three samples at different familial liability (175 controls, 200 unaffected siblings and 195 patients with a psychotic disorder).
The most consistent finding was an interaction between childhood trauma and rs9296158/rs4713916 on psychotic symptoms and Cortisol in the twin sample, combined with a directionally similar interaction in siblings (rs4713916) and patients (rs9296158), A-allele carriers at both polymorphisms being most vulnerable to trauma.
Trauma may increase the risk of psychosis through enduring changes in the Cortisol feedback loop, similar to that for PTSD, suggesting comparable biological mechanisms for psychosis across diagnostic boundaries.
There appears to be consensus that patients with only one or two prior
depressive episodes do not benefit from treatment with mindfulness-based
cognitive therapy (MBCT).
To investigate whether the effect of MBCT on residual depressive symptoms
is contingent on the number of previous depressive episodes (trial number
Currently non-depressed adults with residual depressive symptoms and a
history of depression ($2 prior episodes: n = 71; $3
episodes: n = 59) were randomised to MBCT
(n = 64) or a waiting list (control:
n = 66) in an open-label, randomised controlled
trial. The main outcome measured was the reduction in residual depressive
symptoms (Hamilton Rating Scale for Depression, HRSD-17).
Mindfulness-based cognitive therapy was superior to the control condition
across subgroups (β =–0.56, P<0.001). The interaction
between treatment and subgroup was not significant (β = 0.45,
P = 0.16).
Mindfulness-based cognitive therapy reduces residual depressive symptoms
irrespective of the number of previous episodes of major depression.
The focus of research in depression is on negative affect. However, positive affect is under-investigated and plays an important role in resilience against depression by neutralizing the effects of genetic vulnerability to depression.
Although (hypo)manic symptoms are common in adolescence, transition to
adult bipolar disorder is infrequent.
To examine whether the risk of transition to bipolar disorder is
conditional on the extent of persistence of subthreshold affective
In a 10-year prospective community cohort study of 3021 adolescents and
young adults, the association between persistence of affective symptoms
over 3 years and the 10-year clinical outcomes of incident DSM–IV
(hypo)manic episodes and incident use of mental healthcare was
Transition to clinical outcome was associated with persistence of
symptoms in a dose-dependent manner. Around 30–40% of clinical outcomes
could be traced to prior persistence of affective symptoms.
In a substantial proportion of individuals, onset of clinical bipolar
disorder may be seen as the poor outcome of a developmentally common and
usually transitory non-clinical bipolar phenotype.
Daily-life stress sensitivity is associated with depression, but prospective data are lacking.
To examine associations between baseline ecological daily-life stress sensitivity and later depression, and to identify genetic and non-genetic factors moderating the transition from stress sensitivity to depression.
Daily-life stress sensitivity was assessed at baseline in twins (n = 502). One baseline and four follow-up measurements of depressive symptoms and negative life events were collected, as well as interview-based diagnoses at baseline and last follow-up. Hypothesised genetic markers were determined.
Baseline stress sensitivity was associated with increased depressive symptoms at follow-up and risk of major depressive disorder. Both genetic liability and major life events moderated the probability of transition from stress sensitivity to depression.
Onset of depression is attributable to pre-onset ecological measurements of stress sensitivity, particularly where genetic liability is high and individuals have reached a stage where the influence of competing environmental causes is low.
Psychiatric studies are characterised by large numbers of variables, clinical outcomes that are difficult to measure, small sample sizes and conflicting results. Study designs are classified along the axes of time (longitudinal or cross-sectional design), level of causal inference (descriptive or analytical design) and role of the investigator (observational or experimental). Descriptive designs can be used to examine associations between exposures and outcomes in such a way that the results may lead to the formulation of more specific hypotheses regarding the causal implications of the exposure-disease relationship. The case-control design is suitable to examine aetiological heterogeneity or different exposures resulting in the same outcome, because a range of exposures in patients and control subjects can be assessed. Medical scientific studies generally have two main interests in the examination of the results: examination of the morbidity force of a disease phenotype in populations and examination of associations.
A bias to develop negative affect in response to daily life stressors may be an important depression endophenotype, but remains difficult to assess.
To assess this mood bias endophenotype, uncontaminated by current mood, in the course of daily life.
The experience samping method was used to collect multiple appraisals of daily life event-related stress and negative affect in 279 female twin pairs. Cross-twin, cross-trait associations between daily life mood bias and DSM – IV depression were conducted.
Probands whose co-twins were diagnosed with lifetime depression showed a stronger mood bias to stress than those with co-twins without such a diagnosis, independent of probands' current depressive symptoms and to a greater extent in monozygotic twins than in dizygotic twins.
Genetic liability to depression is in part expressed as the tendency to display negative affect in response to minor stressors in daily life. This trait may represent a true depression endophenotype.
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