Psychosocial stress and psychosis. A review of the neurobiological mechanisms and the evidence for gene-stress interaction

Abstract

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.

Figures

Fig. 1.

A Schematic Illustration of Behavioral Sensitization. Each vertical arrow represents a psychosocial stressor, with the length of the arrow representing its “objective” severity. The stressor induces a certain response, which can be defined in terms of neurochemical (eg, striatal dopamine release, serum cortisol, or homovannillic acid elevation), behavioral (eg, locomotor reaction, cocaine self-administration in animal studies), or psychotic symptom alterations. As illustrated, the repeated exposure to severe psychosocial stress increases the behavioral, neurochemical, or psychometric responses to a later exposure of a new psychosocial stressor, even if this later exposure is not as severe as the previous one(s). This phenomenon is referred to as “behavioral sensitization” and is thought to play an important role in the way how psychosocial stress such as migration, discrimination, urbanicity, and childhood trauma may increase the risk for psychosis. The time intervals between these stressors can be weeks to months or even years, but for the sake of simplicity, the stressors directly follow each other in the above schematic illustration.

Fig. 2.

First-Degree Relatives With High Homovanillic Acid (HVA) Response to the Metabolic Stressor 2-Deoxy-D-Glucose Display an Increased Psychotic Reaction to Small Stressors in the Flow of Daily Life, but No Such Response Was Found in First-Degree Relatives With Low HVA Response. This effect was not found in the healthy controls. Figure adapted from Biol Psychiatry 2005;58: 105–110.

Fig. 3.

Illustration of a Typical Example of Gene-Environment Interaction. In situation A, there is no exposure to the environmental pathogen. In this situation, the risk for the disease outcome (eg, psychosis), as expressed on the y-axis, is similar for the low and the high susceptibility genotype. In situation B, there is additional exposure to the environmental pathogen. In the low susceptibility genotype, the risk for the disease outcome remains similar, whereas in the high susceptibility genotype there is an increase in risk.