Attenuated cortisol response to acute psychosocial stress in individuals at ultra-high risk for psychosis
Introduction
Chronic or cumulative exposure to psychosocial stress is considered an important factor implicated in the pathophysiology of schizophrenia (Phillips et al., 2007, van Winkel et al., 2008). In a recent study, we reported elevated levels of perceived chronic stress in individuals at ultra-high risk for the development of psychosis (UHR) (Pruessner et al., 2011). In accordance with this finding, two other recent studies reported greater distress and negative emotions in response to life events and daily hassles in people at UHR compared to healthy controls (Palmier-Claus et al., 2011, Phillips et al., 2011). These findings supplement previous reports of high emotional reactivity to daily events in first-degree relatives of patients with psychosis (Myin-Germeys et al., 2001) and of more undesirable life events and more distress in response to daily hassles in adolescents with schizotypal personality disorder (SPD) (Tessner et al., 2011). In general, rather than being exposed to a higher number of stressful events, high-risk individuals might perceive events as more stressful than healthy controls (Phillips et al., 2007), a conclusion that has also been drawn for patients with established psychosis (Norman and Malla, 1993a, Norman and Malla, 1993b). Such vulnerability to stress is probably determined largely by the interaction of a person's genetic make-up and the consequences of previous life stressors (Zubin and Spring, 1977). In addition, the subjective experience of stress and its long-term health impact are likely to be influenced by the availability of certain protective factors. For example, patients at high risk for psychosis exhibit deficits in coping skills, social support and self-esteem (Phillips et al., 2011, Pruessner et al., 2011), and both high stress levels and deficits in protective factors can predict symptom severity in the high risk phase (Tessner et al., 2011, Palmier-Claus et al., 2011, Pruessner et al., 2011).
The two major physiological systems responding to stress are the sympathetic nervous system (SNS) and the hypothalamus–pituitary–adrenal (HPA) axis, which set into motion various processes to ensure adaptation to metabolic and behavioral needs in stressful situations (de Kloet et al., 2005, Chrousos, 2009). Neural diathesis stress models propose the endocrine stress system as a likely mediator between the experience of stress and the onset or exacerbation of psychotic symptoms (Walker and Diforio, 1997, Corcoran et al., 2003). Acute stress normally leads to cortisol increase, but animal and human studies have shown that cumulative or chronic exposure to stress can cause pathological alterations in the regulation of the hypothalamus–pituitary–adrenal (HPA) axis with various consequences for subsequent function of the axis and related health outcomes (Heim et al., 2000, McEwen, 2008). In psychosis, elevated cortisol levels are believed to cause alterations in dopamine regulation resulting in psychotic symptoms (Walker and Diforio, 1997). Evidence for a dysregulation of the HPA axis in patients with established psychosis comes from studies reporting elevated baseline cortisol levels (Ryan et al., 2004, Gallagher et al., 2007) and non-suppression to dexamethasone challenge (Muck-Seler et al., 1999). In contrast to these reports of hypercortisolism at baseline, evidence points to lower than normal cortisol levels in patients when the reactivity of the HPA axis is tested, with an attenuated cortisol response to awakening (Pruessner et al., 2008, Mondelli et al., 2009, Pruessner et al., 2013) and in response to acute psychosocial stress (Jansen et al., 1998, Jansen et al., 2000, Brenner et al., 2009, Steen et al., 2011).
Several studies also provide evidence for abnormal HPA regulation in people at elevated risk for psychosis. Compared to healthy controls, patients with schizotypal personality disorder showed higher salivary cortisol levels at baseline (average of three samples taken between 9 and 11 am) (Walker et al., 2001, Mittal et al., 2007), and individuals who subsequently converted to psychosis displayed increased cortisol secretion at initial assessment (Walker et al., 2010). Furthermore, in individuals at high risk for psychosis, the experience of more hassles was associated with a higher cortisol response at 8 am. Similarly, siblings of patients with psychosis presented with higher diurnal cortisol levels and higher cortisol reactivity to negative daily events (Collip et al., 2011). Whereas increased cortisol levels were related to the severity of psychotic like experiences in some studies (Walker et al., 2001, Collip et al., 2011), another study did not find such an association (Thompson et al., 2007b).
No study to date has assessed the cortisol response to acute psychosocial stress in individuals at UHR for psychosis. Our aims for the present study were (1) to compare the cortisol response to an established psychosocial stress task in individuals at clinically high risk for psychosis and healthy controls and (2) to assess the relationship of this endocrine measure with subjective measures of acute and chronic stress and with protective factors. Based on our previous findings in UHR patients and literature regarding patients with clinically confirmed psychosis, we hypothesized higher stress levels, lower ratings on protective factors, and an attenuated cortisol response to a psychosocial stress task in the UHR group compared to healthy controls.
Section snippets
Subjects
Twenty-one patients who met criteria for ‘ultra-high risk’ for psychosis (12 male, 9 female, mean age 20.8, range 16.4–27.2) and 21 healthy, age and gender matched controls (mean age 20.8, range 15.9–27.4) participated in the study. Patients were recruited from the Clinic for Assessment for Youth at Risk (CAYR) and had been identified as presenting with an ‘at risk mental state’ with the Comprehensive Assessment for At Risk Mental States (CAARMS; Yung et al., 2005). Eighteen patients met
Group differences in demographic and psychological variables
Compared to healthy age and gender matched controls, UHR subjects had significantly lower levels of education (Table 1) and exhibited significantly higher levels of depression, a trend for higher perceived stress in the past month and year, and significantly lower ratings on protective factors (self-esteem, social support, and active coping) (see Table 2). In response to the acute psychosocial stress task, UHR patients evaluated the stress task as more stressful than controls (7.5 vs. 6.8/10),
Discussion
In line with our previous findings, individuals at high risk for psychosis reported high levels of depression and chronic stress as well as deficits in self-esteem, social support and coping. Supporting our hypothesis, the UHR group exhibited significantly lower cortisol levels and blood pressure in response to the acute psychosocial stress task than the age and gender matched control group, although people at risk had evaluated the task as slightly more stressful and showed similar increases
Role of funding source
Funding for this research was provided by a NARSAD Young Investigator Award to M. Pruessner. NARSAD had no further role in study design; in the collection, analysis and interpretation of the data; in writing of the manuscript; and in the decision to submit the paper for publication.
Contributors
M. Pruessner and A. Malla designed the study. M. Pruessner, L. Boekestyn and L. Béchard-Evans managed recruitment and testing of participants. M. Pruessner undertook literature search and statistical analysis and wrote the manuscript. S. N. Iyer was a consultant on statistical analyses. A. Malla, S.N. Iyer and J. Pruessner were consultants on the discussion of findings. All authors have contributed to and approved the final manuscript.
Conflict of interest
All authors declare that they have no conflicts of interest.
Acknowledgments
We thank Mrs. Nicole Pawliuk for help with data management. We furthermore acknowledge the assistance of PEPP/CAYR research staff with symptom evaluations in patients and with TSST testing.
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2021, Psychiatry ResearchCitation Excerpt :Underlying increased stress sensitivity appears to be a hypothalamic-pituitary-axis (HPA) dysfunction, as elevated resting cortisol levels are often found in those at psychosis-risk (Aiello et al., 2012; Carol and Mittal, 2015). Others have reported a blunted cortisol awakening response (Day et al., 2014) or a decreased response to stress (Pruessner et al., 2013). Increased sensitivity to stress is known to play an important role in the transitioning to first episode psychosis (Aiello et al., 2012), thus markers of stress sensitivity such as cortisol levels, and potentially behavioral measures like those used in our current study, may be promising in illness prediction.