Abstract

Schizophrenia and psychosis-spectrum disorders are devastating for the affected individual and pose
a considerable burden on society. High levels of schizotypy, a collection of traits such as unusual
perceptual experiences, cognitive disorganisation, and social anhedonia, have long been recognised
as risk factor for the development of schizophrenia, with a substantial prevalence of high schizotypy
observed in non-clinical population. Psychological and physiological stress reactivity have been
identified as potential mechanisms for moderating vulnerability for the development of
psychopathology, leading to the proposal of the diathesis or vulnerability-stress model of
schizophrenia. However, only little research exists assessing the stress response in schizotypy,
exposing a gap in our understanding of the interactions between factors of vulnerability and
resilience in schizotypy.
Therefore, this thesis aimed to comprehensively explore the relationship between schizotypy levels
in non-clinical populations and the core vulnerability-stress model factors such as genetic risk
represented by minor haplotype of FKBP5 (a gene associated with endocrine stress response),
epigenetic markers such as methylation levels of FKBP5, early life adversity, chronic stress, as well as
resilience factors, such as perceived levels of resilience and coping strategies. In a set of five studies
perception of early life stressors, recent life stressors, acute laboratory stressor (Trier Social Stress
Test), chronic stressors, and a real-life stressor (COVID-19 pandemic) as well as perceived resilience
and coping preferences were investigated in the context of schizotypy. For the first time, not only
acute salivary cortisol levels but also chronic levels of cortisol, DHEA and of other related steroids
were measured in hair of individuals preselected for high and low schizotypy, using the state-of-the-art techniques such as ELISA and LC-MS/MS.
Overall, and in line with the initial hypotheses, high schizotypy levels, in partial interaction with
genetic predisposition and environmental adversity, were associated with higher stress sensitivity
and poorer stress management than low schizotypy levels. This was characterised by attenuated
physiological and increased psychological response to acute and chronic stressors, as well as
perception of higher vulnerability and lower resilience. Increased stress perception was associated
with all schizotypy subscales. All but negative schizotypy subscales were associated with acute and
chronic cortisol response. A prospective-design study over six months identified the increased use of
maladaptive coping strategies to mediate the relationship between schizotypy and levels of
depression and anxiety. Contrary to the hypothesis, no direct genetic effect of stress-associated
genotype of FKBP5 or FKBP5 methylation on schizotypy were found. However, an interaction effect
between minor FKBP5 haplotype and childhood trauma showing lower schizotypy levels was
observed, suggesting a potential protective effect of minor FKBP5 haplotype in the context of low to
moderate early adversity.
Based on these findings, an extended vulnerability-stress model of stress response in schizotypy was
proposed to incorporate possible molecular and behavioural mechanisms. Thus, the present thesis
contributes to a more comprehensive understanding of the relationships between schizotypy, stress
response, and resilience. This knowledge might facilitate future development of more individualised
and targeted interventions to improve stress management in high schizotypy and lower vulnerability
to developing psychosis in some individuals.