The Translational Future of Stress Neurobiology and Psychosis Vulnerability: A Review of the Evidence

Abstract

Psychosocial stress is a well-established risk factor for psychosis, yet the neurobiological mechanisms underlying this relationship have yet to be fully elucidated. Much of the research in this field has investigated hypothalamic-pituitary-adrenal (HPA) axis function and immuno-inflammatory processes among individuals with established psychotic disorders. However, as such studies are limited in their ability to provide knowledge that can be used to develop preventative interventions, it is important to shift the focus to individuals with increased vulnerability for psychosis (i.e., high-risk groups). In the present article, we provide an overview of the current methods for identifying individuals at high-risk for psychosis and review the psychosocial stressors that have been most consistently associated with psychosis risk. We then describe a network of interacting physiological systems that are hypothesised to mediate the relationship between psychosocial stress and the manifestation of psychotic illness and critically review evidence that abnormalities within these systems characterise high risk populations. We found that studies of high-risk groups have yielded highly variable findings, likely due to (i) the heterogeneity both within and across high-risk samples, (ii) the diversity of psychosocial stressors implicated in psychosis, and (iii) that most studies examine single markers of isolated neurobiological systems. We propose that to move the field forward, we require well-designed, large- scale translational studies that integrate multi-domain, putative stress-related biomarkers to determine their prognostic value in high-risk samples. We advocate that such investigations are highly warranted, given that psychosocial stress is undoubtedly a relevant risk factor for psychotic disorders.

Psychosocial stress moderates the relationship between cerebrospinal fluid lactate dehydrogenase and the duration of untreated psychosis in first-episode psychosis

“…On the other hand, the interplay between stress and vulnerability has been recognized as a factor in the development of psychotic disorders ( 15 – 17 ). Evidence for this diathesis has been gathered from various approaches ( 18 ), encompassing general epidemiology and prospective cohort studies ( 19 – 21 ), adverse childhood experiences ( 22 , 23 ), clinical assessments documenting sensitivity to stress ( 24 , 25 ), analyses of perceived (subjective) stress in patients ( 26 , 27 ), and research on dopamine or hypothalamic–pituitary–adrenal (HPA) axis dysregulation ( 28 – 30 ).…”

“…In this manner, it is thought that early-life adversity and stress can interact with innate and acquired neurobiological factors to play a role in distress and, ultimately, the development of psychotic syndromes ( 28 , 31 ). The experience of stress – psychosocial, biological, or both – influences neurobiology via a range of pathways, including immune, stress/endocrine, redox, and metabolic systems ( 32 ).…”

“…Stress biomarkers seem to have substantial potential as predictors of psychosis and clinical outcomes and may serve as ideal targets for the development of new therapeutic treatments for psychosis ( 34 ). It is also important to balance the timing of the stress response including the immune and inflammatory mechanisms within diathesis-stress models of psychosis, as acute stress and inflammation is usually useful and adaptive, turning off once resolved, whereas chronic stress and inflammation is typically maladaptive and associated with tissue-specific or systemic pathology ( 28 ).…”

Epigenetic factors in the 22q11.2 deletion syndrome in relation to stress and schizophrenia

“…The predominant environmental risk factor for 22q11.2DS patients who develop SCZ could be psychosocial stress [30]. Psychosocial stress can involve epigenetic modifications [31] and has been shown to be associated with SCZ onset [32, 33]. Therefore, we aimed to explore the epigenome in the context of stress to understand the biological mechanisms underlying the incomplete penetrance of SCZ in 22q11.2DS.…”

Thematic Selection: Stress and Stress-related Disorders Developmental and Neuroendocrine Aspects of Stress and Stress-related Disorders (Part 1)

“…The first two articles by Nicolaides et al [ 21 ] and Filetti et al [ 22 ] provide a multifaceted overview of the developmental neuroendocrinology in children and adolescents with a specific focus on the regulation of stress reactivity and child development and behavior. The next two articles by Xenaki et al [ 23 ] and Cullen et al [ 24 ] offer a developmental take on the role of stress and environment and the importance of stress-related research in the neurobiology of psychosis by two expert research groups in the field.…”