Inez Myin-Germeys

Psychosocial Stress and Psychosis. A Review of the Neurobiological Mechanisms and the Evidence for Gene-Stress Interaction

This article presents evidence suggesting that psychosocial stress may increase risk for psychosis, especially in the case of cumulative exposure. A heuristically useful framework to study the underlying mechanisms is the concept of behavioral sensitization that stipulates that exposure to psychosocial stress--such as life events, childhood trauma, or discriminatory experiences--may progressively increase the behavioral and biological response to subsequent exposures. The neurobiological substrate of sensitization may involve dysregulation of the hypothalamus-pituitary-adrenal axis, contributing to a hypothesized final common pathway of dopamine sensitization in mesolimbic areas and increased stress-induced striatal dopamine release. It is argued that, in order to reconcile genetic and environmental influences on the development of psychosis, gene-environment interactions may be an important mechanism in explaining between-subject differences in risk following (cumulative) exposure to psychosocial stress. To date, most studies suggestive of gene-stress interaction have used proxy measures for genetic vulnerability such as a family history of psychosis; studies investigating interactions between molecular genetic measures and psychosocial stressors are still relatively scarce. Preliminary evidence suggests that polymorphisms within the catechol-O-methyltransferase and brain-derived neurotrophic factor genes may interact with psychosocial stress in the development of psychosis; however, extensive further investigations are required to confirm this.

Does the Concept of “Sensitization” Provide a Plausible Mechanism for the Putative Link Between the Environment and Schizophrenia?

Previous evidence reviewed in Schizophrenia Bulletin suggests the importance of a range of different environmental factors in the development of psychotic illness. It is unlikely, however, that the diversity of environmental influences associated with schizophrenia can be linked to as many different underlying mechanisms. There is evidence that environmental exposures may induce, in interaction with (epi)genetic factors, psychological or physiological alterations that can be traced to a final common pathway of cognitive biases and/or altered dopamine neurotransmission, broadly referred to as sensitization, facilitating the onset and persistence of psychotic symptoms. At the population level, the behavioral phenotype for sensitization may be examined by quantifying, in populations exposed to environmental risk factors associated with stress or dopamine-agonist drugs, (1) the increased rate of persistence (indicating lasting sensitization) of normally transient developmental expressions of subclinical psychotic experiences and (2) the subsequent increased rate of transition to clinical psychotic disorder.

Evidence that the COMTVal158Met polymorphism moderates sensitivity to stress in psychosis: An experience‐sampling study

Gene–environment interactions involving the catechol‐O‐methyltransferase Val158Met polymorphism (COMTVal158Met) have been implicated in the causation of psychosis. Evidence from general population studies suggests that Met/Met subjects are sensitive to stress, a trait associated with psychosis. We hypothesized that the Met allele would moderate the effects of stress on negative affect (NA) in controls, and on NA and psychosis in patients with a psychotic disorder. Thirty‐one patients with a psychotic disorder and comorbid cannabis misuse and 25 healthy cannabis users were studied with the experience sampling method (ESM), a structured diary technique assessing current context and emotional and psychotic experiences in daily life. A significant interaction between COMTVal158Met genotype and ESM stress in the model of NA was found for patients (interaction χ2u2009=u20097.4, Pu2009=u20090.02), but not for controls (interaction χ2u2009=u20093.8, Pu2009=u20090.15). In the model of ESM psychosis, a significant interaction between COMTVal158Met genotype and ESM stress was also apparent (interaction χ2u2009=u200911.6, Pu2009<u20090.01), with Met/Met patients showing the largest increase in psychotic experiences as well as NA in reaction to ESM stress. The findings suggest that the COMTVal158Met polymorphism moderates affective and psychotic responses to stress in patients with psychosis, providing evidence for gene–environment interaction mechanisms in the formation of psychotic symptoms.

COMT ValMet moderation of cannabis-induced psychosis: a momentary assessment study of 'switching on' hallucinations in the flow of daily life

Objective:u2002 A functional polymorphism in the catechol‐o‐methyltransferase gene (COMT Val158Met) may moderate the psychosis‐inducing effects of cannabis. In order to extend this finding to dynamic effects in the flow of daily life, a momentary assessment study of psychotic symptoms in response to cannabis use was conducted.

Psychotic reactivity in borderline personality disorder

Glaser J‐P, Van Os J, Thewissen V, Myin‐Germeys I. Psychotic reactivity in borderline personality disorder.

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.

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

Peerbooms O, Rutten BPF, Collip D, Lardinois M, Lataster T, Thewissen V, Mafi Rad S, Drukker M, Kenis G, van Os J, Myin‐Germeys I, van Winkel R. Evidence that interactive effects of COMT and MTHFR moderate psychotic response to environmental stress.

Evidence that self-reported psychotic experiences represent the transitory developmental expression of genetic liability to psychosis in the general population

It has been suggested that self‐reported, common, non‐clinical psychotic experiences may represent the transitory developmental expression of distributed genetic risk for psychosis. In a sample of female MZ (176 pairs) and DZ twins (113 pairs), cross‐twin, cross‐trait analyses were conducted to investigate the association between repeated continuous measures of self‐reported psychotic experiences (PE—three measures over 18 months), assessed with the CAPE, in one twin and clinical interview categorical measures of psychotic symptoms (PS), assessed with SCID‐I, in the other twin. The results showed that in MZ but not DZ pairs (interaction: χ2u2009=u20097.9, dfu2009=u20091, Pu2009=u20090.005), the cross‐twin association between PE and PS was large and significant (standardized effect size: 0.26, 95% CI: 0.10–0.42) and of similar magnitude as the within‐twin PE–PS association (standardized effect size: 0.28, 95% CI: 0.10–0.45), demonstrating both PE validity and genetic effects. In addition, the cross‐twin association between PE and PS was significantly larger (interaction: χ2u2009=u200920.3, dfu2009=u20091, Pu2009<u20090.0001) for younger MZ twins (standardized effect size: 0.67, 95% CI: 0.44–0.90) than older MZ twins (standardized effect size: −0.05, 95% CI: −0.26 to 0.16), demonstrating developmental effects. This study indicates that self‐reported psychotic experiences in the general population may represent the developmental expression of population genetic risk for psychosis.

The association between cognition and functional outcome in first-episode patients with schizophrenia: mystery resolved?

Objective:u2002 The presence of a prospective association between cognition and functional outcome in first episode patients with schizophrenia is much debated.

Childhood negative experiences and subclinical psychosis in adolescence: a longitudinal general population study

Background:u2002 Accumulating evidence suggests that experiences of trauma and victimization during childhood are associated with an increased risk to develop clinical and subclinical psychosis in adulthood. A recent cross‐sectional study showed a significant association between trauma and psychotic experiences in adolescents. The current study aimed to extend these findings by investigating the longitudinal effects of negative life experiences on the risk for subclinical psychotic symptoms 2 years later in an adolescent general community sample.