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.

Social functioning and subclinical psychosis in adolescence: a longitudinal general adolescent population study.

OBJECTIVES: To investigate the longitudinal relationship between subclinical psychotic symptoms and social functioning in a representative general population sample of adolescents. METHOD: Data were derived from a routine general health screening of 1909 adolescents in a circumscribed region. Baseline measurement was in the second grade of secondary school (T0), and follow-up occurred approximately 2 years later (T1). Social functioning and subclinical psychotic symptoms of hallucinations and delusions were assessed at both time points. RESULTS: Baseline (T0) social problems preceded follow-up (T1) subclinical delusions, but not T1 subclinical hallucinations. Similarly, T0 delusions preceded social problems at T1, but T0 hallucinations did not. CONCLUSION: This longitudinal general population study demonstrated a bidirectional association between social problems and delusions, but found no link between social problems and hallucinations. This may reflect a downward negative spiral where delusional thoughts and social problems reinforce each other.

No evidence for attenuated stress-induced extrastriatal dopamine signaling in psychotic disorder.

Stress is an important risk factor in the etiology of psychotic disorder. Preclinical work has shown that stress primarily increases dopamine (DA) transmission in the frontal cortex. Given that DA-mediated hypofrontality is hypothesized to be a cardinal feature of psychotic disorder, stress-related extrastriatal DA release may be altered in psychotic disorder. Here we quantified for the first time stress-induced extrastriatal DA release and the spatial extent of extrastriatal DA release in individuals with non-affective psychotic disorder (NAPD). Twelve healthy volunteers (HV) and 12 matched drug-free NAPD patients underwent a single infusion [(18)F]fallypride positron emission tomography scan during which they completed the control and stress condition of the Montreal Imaging Stress Task. HV and NAPD did not differ in stress-induced [(18)F]fallypride displacement and the spatial extent of stress-induced [(18)F]fallypride displacement in medial prefrontal cortex (mPFC) and temporal cortex (TC). In the whole sample, the spatial extent of stress-induced radioligand displacement in right ventro-mPFC, but not dorso-mPFC or TC, was positively associated with task-induced subjective stress. Psychotic symptoms during the scan or negative, positive and general subscales of the Positive and Negative Syndrome Scale were not associated with stress-induced [(18)F]fallypride displacement nor the spatial extent of stress-induced [(18)F]fallypride displacement in NAPD. Our results do not offer evidence for altered stress-induced extrastriatal DA signaling in NAPD, nor altered functional relevance. The implications of these findings for the role of the DA system in NAPD and stress processing are discussed.

Positive emotions from social company in women with persisting subclinical psychosis: lessons from daily life.

OBJECTIVE: Altered social reward functioning is associated with psychosis irrespective of stage and severity. Examining the role of social reward functioning prospectively in relation to psychotic experiences before these become persistent and potentially disabling can aid in elucidating social mechanisms that induce shifts toward more severe psychotic states, without the confounding effects of clinical disorder. METHOD: In a longitudinal general population sample (N = 566), the experience sampling method (repetitive random sampling of momentary emotions and social context) was used to assess daily life social functioning at baseline. Persistence of subclinical psychotic experiences was based on the Community Assessment of Psychic Experiences assessed three times over 14 months. Analyses examined to what degree i) social context and ii) appreciation thereof differentiated between those who did and did not develop persistent psychotic experiences. RESULTS: Although individuals with persistent psychotic experiences did not differ in overall level of positive effect, the amount of time spent alone or the level of social satisfaction compared to individuals without persistent psychotic experiences, they were more sensitive to the rewarding effects of social company. CONCLUSION: Alterations in social reward experience may form one of the mechanisms that precede the development of the extended psychosis phenotype over time.

Hippocampal volume as marker of daily life stress sensitivity in psychosis.

BACKGROUND: Reduced hippocampal size and increased stress sensitivity are associated with psychotic disorder and familial risk for psychosis. However, to what degree the hippocampus is implicated in daily life stress reactivity has not yet been examined. The current study investigated (i) whether familial risk (the contrast between controls, patients and siblings of patients) moderated the relationship between hippocampal volume (HV) and emotional daily stress reactivity and (ii) whether familial risk (the contrast between controls and siblings of patients) moderated the relationship between HV and cortisol daily stress reactivity. Method T1-weighted magnetic resonance imaging (MRI) scans were acquired from 20 patients with schizophrenia, 37 healthy siblings with familial risk for schizophrenia and 32 controls. Freesurfer 5.0.0 was used to measure HV. The experience sampling method (ESM), a structured momentary assessment technique, was used to assess emotional stress reactivity, that is the effect of momentary stress on momentary negative affect (NA). In addition, in the control and sibling groups, cortisol stress reactivity was assessed using momentary cortisol levels extracted from saliva. RESULTS: Multilevel linear regression analyses revealed a significant three-way interaction between group, HV and momentary stress in both the model of NA and the model of cortisol. Increased emotional stress reactivity was associated with smaller left HV in patients and larger total HV in controls. In line with the results in patients, siblings with small HV demonstrated increased emotional and cortisol stress reactivity compared to those with large HV. CONCLUSIONS: HV may index risk and possibly disease-related mechanisms underlying daily life stress reactivity in psychotic disorder.

Evidence that interactive effects of COMT and MTHFR moderate psychotic response to environmental stress.

OBJECTIVE: A functional interaction between Catechol-O-Methyltransferase (COMT) Val158Met and methylenetetrahydrofolate reductase (MTHFR) C677T has been shown to differentially affect cognition in patients with schizophrenia and healthy controls; the effect of COMT Val158Met × MTHFR interaction on resilience to stress in patients and controls remains to be examined. METHOD: A total of 98 patients with non-affective psychotic disorder and 118 controls were genotyped for MTHFR C677T, MTHFR A1298C, and COMTVal158Met. Daily life reactivity to stress, modelled as the effect of daily life stress on psychotic experiences, was measured using the experience sampling method (ESM). RESULTS: The MTHFR C677T genotype moderated the interaction between COMT Val158Met genotype and stress in patients (P < 0.0001), but not in controls (P = 0.68). Further examination of this interaction revealed that in patients with the MTHFR 677 T-allele, COMT Met/Met individuals displayed the largest increases in psychotic symptoms in reaction to ESM stress [χ(2)(2) = 29.51; P < 0.0001], whereas in patients with the MTHFR 677 C/C genotype no significant COMT Val158Met × ESM stress interaction was apparent [χ(2)(2) = 3.65; P = 0.16]. No moderating effect of MTHFR A1298C was found. CONCLUSION: Stress reactivity associated with COMT Val158Met in patients with psychosis may crucially depend on MTHFR C677T genotype.

Pituitary volume, stress reactivity and genetic risk for psychotic disorder.

BACKGROUND: Hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, associated with increased pituitary volume, may mediate observed alterations in stress reactivity in patients with psychotic disorder. We examined the association between pituitary volume, real-life stress reactivity and genetic liability for psychotic disorder. METHOD: Pituitary volumes were derived from magnetic resonance imaging (MRI) scans of 20 patients with psychotic disorder, 37 non-psychotic siblings of these patients, and 32 controls. The Experience Sampling Method (ESM) was used to measure emotional stress reactivity [changes in negative affect (NA) associated with daily life stress] in the three groups, and biological stress reactivity (changes in cortisol associated with daily life stress) in siblings and controls. Interactions between group, stress and pituitary volume in models of NA and cortisol were examined. RESULTS: Groups did not differ in pituitary volume. Patients showed significantly higher emotional stress reactivity than siblings and controls. In addition, emotional stress reactivity increased with increasing pituitary volume to a greater degree in patients than in controls and siblings. Siblings had higher cortisol levels than controls but did not show increased cortisol reactivity to stress. There was no interaction between pituitary volume, stress and group in the model of cortisol. CONCLUSIONS: Higher pituitary volume was associated with increased emotional stress reactivity in patients with psychotic disorder, siblings and controls. The association was significantly stronger in the patient group, suggesting a process of progressive sensitization mediating clinical outcome.

Daily cortisol, stress reactivity and psychotic experiences in individuals at above average genetic risk for psychosis.

BACKGROUND: Hypothalamic-pituitary-adrenocortical (HPA) axis abnormalities have been found in patients with a psychotic disorder and first-degree relatives of patients with a psychotic disorder react with subtle increases in non-clinical psychotic experiences and negative emotions in the face of everyday stress. The current study investigated whether HPA axis functioning is altered in individuals at above average genetic risk for psychotic disorder, examining diurnal cortisol profiles, cortisol reactivity to daily stressors and the association between HPA axis activity and subclinical psychotic experiences. METHOD: Participants included siblings of patients with a psychotic disorder (n=60) and a healthy comparison group (n=63). The Experience Sampling Method (a structured diary technique) was employed to assess stress, psychotic experiences, negative affect and salivary cortisol repeatedly in the flow of daily life. RESULTS: Multi-level analyses revealed higher diurnal cortisol levels and heightened cortisol reactivity to negative daily events in siblings compared with controls. Diurnal cortisol slope did not differ between the two groups, but momentary increases in psychotic experiences and negative affect were associated with increased cortisol in the sibling group. CONCLUSIONS: Findings support altered HPA axis activity in individuals at above average genetic risk for psychotic disorder, as evidenced by higher diurnal cortisol levels and increased cortisol reactivity to daily stress. Results also suggest a dynamic association between cortisol secretion and the intensity of psychotic-like experiences and negative emotions in daily life, although the direction of this association remains to be elucidated.

Social world interactions: how company connects to paranoia.

BACKGROUND: Experimental studies have indicated that social contact, even when it is neutral, triggers paranoid thinking in people who score high on clinical or subclinical paranoia. We investigated whether contextual variables are predictive of momentary increases in the intensity of paranoid thinking in a sample of participants ranging across a psychometric paranoia continuum. METHOD: The sample (n=154) consisted of 30 currently paranoid patients, 34 currently non-paranoid patients, 15 remitted psychotic patients, 38 high-schizotypy participants, and 37 control subjects. Based on their total score on Fenigstein's Paranoia Scale (PS), three groups with different degrees of paranoia were defined. The Experience Sampling Method (ESM), a structured diary technique, was used to assess momentary social context, perceived social threat and paranoia in daily life. RESULTS: There were differences in the effect of social company on momentary levels of paranoia and perceived social threat across the range of trait paranoia. The low and medium paranoia groups reported higher levels of perceived social threat when they were with less-familiar compared to familiar individuals. The medium paranoia group reported more paranoia in less-familiar company. The high paranoia group reported no difference in the perception of social threat or momentary paranoia between familiar and unfamiliar contacts. CONCLUSIONS: Paranoid thinking is context dependent in individuals with medium or at-risk levels of trait paranoia. Perceived social threat seems to be context dependent in the low paranoia group. However, at high levels of trait paranoia, momentary paranoia and momentary perceived social threat become autonomous and independent of social reality.

Evidence for a familial correlation between increased reactivity to stress and positive psychotic symptoms.

OBJECTIVE: This study tested the hypothesis that stress-reactivity may represent an intermediary phenotype underlying positive psychotic symptoms. It was examined whether: (i) stress-reactivity clusters within families of psychotic patients and (ii) stress-reactivity in relatives cosegregates with positive symptoms in patients. METHOD: The sample consisted of 40 patients and 47 siblings of these patients. The Experience Sampling Method (ESM - a structured diary technique) was used to measure stress-reactivity. Positive symptoms in patients were measured with the Comprehensive Assessment of Symptoms and History. RESULTS: Within-trait, cross-sib associations showed a significant association between stress-reactivity in the patient and stress-reactivity in their siblings. Significant cross-trait, cross-sib associations were established showing a significant association between positive psychotic symptoms in the patient and stress-reactivity in the sibling. CONCLUSION: The findings show familial clustering of increased stress-reactivity, suggesting common aetiological influences, probably both genetic and environmental, underlying stress-reactivity in the siblings and patients. In addition, the results underscore the hypothesis that increased stress-reactivity is an unconfounded mechanism of risk underlying the positive symptoms of psychotic disorders.

[Stress and psychosis: is sensitisation the underlying mechanism?]. / Stress en psychose: vormt sensitisatie het onderliggend mechanisme?

Epidemiological research has shown that stressful environmental factors can play an aetiological role in the development of psychosis. However, the mechanism underlying the link between stress and psychosis is still not fully understood. In this article it is argued that the interaction between stressful environmental factors and epigenetic factors can bring about psychological and biological changes. Both types of change can be referred to as 'sensitisation'. The underlying mechanism of sensitisation can be interpreted on the one hand as cognitive misinterpretations (psychological sensitisation) and on the other hand as altered dopaminergic neurotransmission (biological sensitisation). Both of these deviations can facilitate the onset and persistence of psychotic symptoms. With the help of epidemiological research at psychometric level sensitisation can be quantified as (i) stress-induced persistence (indicating continuous sensitisation) of the normally transient expression of subclinical psychotic experiences during adolescence and early adulthood and as (ii) the increased risk of transition from gradually more persistent subclinical psychotic experiences to a clinical psychotic disorder.

Experience sampling research in psychopathology: opening the black box of daily life.

A growing body of research suggests that momentary assessment technologies that sample experiences in the context of daily life constitute a useful and productive approach in the study of behavioural phenotypes and a powerful addition to mainstream cross-sectional research paradigms. Momentary assessment strategies for psychopathology are described, together with a comprehensive review of research findings illustrating the added value of daily life research for the study of (1) phenomenology, (2) aetiology, (3) psychological models, (4) biological mechanisms, (5) treatment and (6) gene-environment interactions in psychopathology. Overall, this review shows that variability over time and dynamic patterns of reactivity to the environment are essential features of psychopathological experiences that need to be captured for a better understanding of their phenomenology and underlying mechanisms. The Experience Sampling Method (ESM) allows us to capture the film rather than a snapshot of daily life reality of patients, fuelling new research into the gene-environment-experience interplay underlying psychopathology and its treatment.