Dina Collip

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.

FKBP5 as a possible moderator of the psychosis-inducing effects of childhood trauma

BACKGROUND 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. AIMS To examine the role of FKBP5-trauma interactions in the partly stress-related psychosis phenotype. METHOD 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). RESULTS 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. CONCLUSIONS 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.

COMT Val158Met-stress interaction in psychosis: role of background psychosis risk.

Background: The interplay between the catechol‐O‐methyltransferase (COMT) Val158Met polymorphism and environmental stress may have etiological relevance for psychosis, but differential effects have been reported in healthy control and patient groups, suggesting that COMT Val158Met interactions with stress may be conditional on background genetic risk for psychotic disorder. Methods: Patients with a nonaffective psychotic disorder (n = 86) and control participants (n = 109) were studied with the experience sampling method (a structured diary technique) in order to assess stress, negative affect and momentary psychotic symptoms in the flow of daily life. Results: Multilevel analyses revealed significant three‐way interactions between group status (patient or control), COMT genotype and stress in the model of negative affect (χ2(2) = 13.26, P < 0.01) as well as in the model of momentary psychotic symptoms (χ2(2) = 6.92, P < 0.05). Exploration of the three‐way interaction revealed that in patients, COMT genotype moderated the association between stress and negative affect (χ2(4) = 11.50, P < 0.005), as well as the association between stress and momentary psychosis (χ2(4) = 12.79, P < 0.005). Met/Met genotype patients showed significantly increased psychotic and affective reactivity to stress in comparison to the Val/Met and Val/Val genotypes. In contrast, healthy controls did not display large or significant COMT Val158Met X stress interactions. Conclusions: Important differences exist in the effect of COMT Val158Met on stress reactivity, which may depend on background risk for psychotic disorder. Differential sensitivity to environmental stress occasioned by COMT Val158Met may be contingent on higher order interactions with genetic variation underlying psychotic disorder.

REVIEW: Genome-Wide Findings in Schizophrenia and the Role of Gene–Environment Interplay

The recent advent of genome‐wide mass‐marker technology has resulted in renewed optimism to unravel the genetic architecture of psychotic disorders. Genome‐wide association studies have identified a number of common polymorphisms robustly associated with schizophrenia, in ZNF804A, transcription factor 4, major histocompatibility complex, and neurogranin. In addition, copy number variants (CNVs) in 1q21.1, 2p16.3, 15q11.2, 15q13.3, 16p11.2, and 22q11.2 were convincingly implicated in schizophrenia risk. Furthermore, these studies have suggested considerable genetic overlap with bipolar disorder (particularly for common polymorphisms) and neurodevelopmental disorders such as autism (particularly for CNVs). The influence of these risk variants on relevant intermediate phenotypes needs further study. In addition, there is a need for etiological models of psychosis integrating genetic risk with environmental factors associated with the disorder, focusing specifically on environmental impact on gene expression (epigenetics) and convergence of genes and environment on common biological pathways bringing about larger effects than those of genes or environment in isolation (gene–environment interaction). Collaborative efforts that bring together expertise in statistics, genetics, epidemiology, experimental psychiatry, brain imaging, and clinical psychiatry will be required to succeed in this challenging task.

Psychosocial stress is associated with in vivo dopamine release in human ventromedial prefrontal cortex: A positron emission tomography study using [18F]fallypride

Rodent studies suggest that prefrontal dopamine neurotransmission plays an important role in the neural processing of psychosocial stress. Human studies investigating stress-induced changes in dopamine levels, however, have focused solely on striatal dopamine transmission. The aim of this study was to investigate in vivo dopamine release in the human prefrontal cortex in response to a psychosocial stress challenge, using the highly selective dopamine D₂/₃ PET radioligand [¹⁸F]fallypride in healthy subjects. Twelve healthy subjects (age (y): 39.8; SD=15.8) underwent a single dynamic Positron Emission Tomography (PET) scanning session after intravenous administration of 185.2 (SD=10.2) MBq [¹⁸F]fallypride. Psychosocial stress was initiated at 100 min postinjection. PET data were analyzed using the linearized simplified reference region model (LSRRM), which accounts for time-dependent changes in [¹⁸F]fallypride displacement. Voxel-based statistical maps, representing specific D₂/₃ binding changes, were computed to localize areas with increased ligand displacement after task initiation, reflecting dopamine release. The psychosocial stress challenge induced detectable amounts of dopamine release throughout the prefrontal cortex, with dopaminergic activity in bilateral ventromedial prefrontal cortex being associated with subjectively rated experiences of psychosocial stress. The novel finding that a mild psychosocial stress in humans induces increased levels of endogenous dopamine in the PFC indicates that the dynamics of the dopamine-related stress response cannot be interpreted by focusing on mesolimbic brain regions alone.

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

Lataster T, Collip D, Lardinois M, van Os J, Myin‐Germeys I. Evidence for a familial correlation between increased reactivity to stress and positive psychotic symptoms.

Time-Lagged Moment-to-Moment Interplay Between Negative Affect and Paranoia: New Insights in the Affective Pathway to Psychosis

Evidence suggests that affect plays a role in the development of psychosis but the underlying mechanism requires further investigation. This study examines the moment-to-moment dynamics between negative affect (NA) and paranoia prospectively in daily life. A female general population sample (n = 515) participated in an experience sampling study. Time-lagged analyses between increases in momentary NA and subsequent momentary paranoia were examined. The impact of childhood adversity, stress sensitivity (impact of momentary stress on momentary NA), and depressive symptoms on these time-lagged associations, as well as associations with follow-up self-reported psychotic symptoms (Community Assessment of Psychic Experiences and the Symptom Checklist-90-Revised) were investigated. Moments of NA increase resulted in a significant increase in paranoia over 180 subsequent minutes. Both stress sensitivity and depressive symptoms impacted on the transfer of NA to paranoia. Stress sensitivity moderated the level of increase in paranoia during the initial NA increase, while depressive symptoms increased persistence of paranoid feelings from moment to moment. Momentary paranoia responses to NA increases were associated with follow-up psychotic symptoms. Examination of microlevel momentary experience may thus yield new insights into the mechanism underlying co-occurrence of altered mood states and psychosis. Knowledge of the underlying mechanism is required in order to determine source and place where remediation should occur.

Psychiatric Diagnosis Revisited: Towards a System of Staging and Profiling Combining Nomothetic and Idiographic Parameters of Momentary Mental States

Background Mental disorders may be reducible to sets of symptoms, connected through systems of causal relations. A clinical staging model predicts that in earlier stages of illness, symptom expression is both non-specific and diffuse. With illness progression, more specific syndromes emerge. This paper addressed the hypothesis that connection strength and connection variability between mental states differ in the hypothesized direction across different stages of psychopathology. Methods In a general population sample of female siblings (mostly twins), the Experience Sampling Method was used to collect repeated measures of three momentary mental states (positive affect, negative affect and paranoia). Staging was operationalized across four levels of increasing severity of psychopathology, based on the total score of the Symptom Check List. Multilevel random regression was used to calculate inter- and intra-mental state connection strength and connection variability over time by modelling each momentary mental state at t as a function of the three momentary states at t-1, and by examining moderation by SCL-severity. Results Mental states impacted dynamically on each other over time, in interaction with SCL-severity groups. Thus, SCL-90 severity groups were characterized by progressively greater inter- and intra-mental state connection strength, and greater inter- and intra-mental state connection variability. Conclusion Diagnosis in psychiatry can be described as stages of growing dynamic causal impact of mental states over time. This system achieves a mode of psychiatric diagnosis that combines nomothetic (group-based classification across stages) and idiographic (individual-specific psychopathological profiles) components of psychopathology at the level of momentary mental states impacting on each other over time.

From Epidemiology to Daily Life: Linking Daily Life Stress Reactivity to Persistence of Psychotic Experiences in a Longitudinal General Population Study

Subclinical psychotic experiences at the level of the general population are common, forming an extended psychosis phenotype with clinical psychosis. Persistence of subclinical experiences is associated with transition to later mental disorder. Increased daily life stress reactivity is considered an endophenotype for psychotic disorders. We examined, in a longitudinal framework, whether baseline momentary assessment markers of stress reactivity would predict persistence of subclinical psychotic experiences over time. In a general population sample of female twins (N = 566), the Experience Sampling Method (ESM; repetitive random sampling of momentary emotions, psychotic experiences and context) was used to assess (emotional and psychotic) daily life stress reactivity. Persistence of subclinical psychotic experiences was based on the Community Assessment of Psychic Experiences (CAPE), assessed three times over 14 months post-baseline. It was investigated whether baseline daily life emotional and psychotic stress reactivity predicted persistence of psychotic experiences over time. Higher levels of emotional stress reactivity (a decrease in positive and an increase in negative affect in response to stress), and increased psychotic reactivity to daily stress was found in individuals with persistent psychotic experiences over time compared to individuals with transient psychotic experiences. The results suggest that markers of daily life stress reactivity may predict “macro-level” persistence of normally transient expression of psychotic liability over time. Linking daily life markers of altered reactivity in terms of emotions and psychotic experiences to longitudinal persistence of psychotic experiences, associated with increased risk of transition to overt mental disorder, may contribute to earlier and more accurate diagnosis of risk.

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 Fenigsteins 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.