ReviewCortisol stress reactivity across psychiatric disorders: A systematic review and meta-analysis
Introduction
In order to successfully deal with stress, an adaptive and efficient response of the organism is essential. The hypothalamus-pituitary-adrenal (HPA) axis and its end product cortisol play a crucial role in the response to stress. A dynamic cortisol response, marked by a rapid rise and decline in cortisol levels following stress, is thought to be adaptive and to facilitate adequate coping with perceived threats in the environment. Conversely, changes in cortisol stress reactivity may increase susceptibility to the negative effects of stress. Prolonged, excessive or insufficient activation of the HPA axis may lead to changes in the brain and may subsequently result in the development of psychiatric disorders (McEwen, 2004). Indeed, exposure to repetitive stress is a major risk factor for many psychiatric disorders, including schizophrenia (Holtzman et al., 2013), bipolar disorder (Agnew-Blais and Danese, 2016), major depressive disorder (Kendler et al., 1999), and anxiety disorders (Moreno-Peral et al., 2014). Generally, HPA axis reactivity is assumed to play a crucial role in this relationship between stress and psychopathology (Holtzman et al., 2013, Heim et al., 2008).
Over the past two decades, an increasing number of studies have employed psychosocial stress tests to examine whether psychiatric disorders are associated with changes in HPA axis and cortisol stress reactivity. These laboratory stress tests probe an individual’s response to acute social stress and may serve as a proxy for the response to stressful situations in real life. Even though these studies have the potential to inform about HPA axis functionality across psychiatric disorders, the interpretation of the current evidence is hampered by two factors. First, standardized cortisol outcomes based on all available cortisol data (e.g. areas under the curve) (Pruessner et al., 2003), are often not reported in original articles. This problem is reflected in a recent meta-analysis which focused on cortisol levels during the anticipatory and peak phase of the stress response (Ciufolini et al., 2014). Second, the current evidence cannot be reliably interpreted without taking parameters into account which influence stress-induced cortisol levels. Among these parameters, sex and age are known to affect cortisol stress reactivity (Kirschbaum et al., 1999, Kudielka et al., 2004). In support, sex hormones change cortisol stress reactivity (Stephens et al., 2016, Juster et al., 2016). Also, it is currently unknown whether changes in cortisol stress reactivity are consistent across psychiatric disorders and whether these effects are irreversible or dependent on symptomatic state. Finally, several studies suggest an association between medication use and HPA axis activity (Houtepen et al., 2015, Cohrs et al., 2006, Manthey et al., 2011). Detailed information on these relevant parameters is often lacking in the original studies and their influence has not been systematically reviewed.
We here present a meta-analysis of the scientific literature on cortisol reactivity in response to acute psychosocial stress across psychiatric disorders. To this end, we obtained standardized cortisol data from the original studies, as well as data on sex, age, current or remitted symptoms, and medication use. We carried out stratified analyses to investigate whether cortisol stress reactivity across psychiatric disorders depends on sex and current symptomatic state.
Section snippets
Literature search and study selection
We searched Pubmed on September 1st 2016 for studies investigating cortisol reactivity in response to a laboratory psychosocial stressor in individuals with any psychiatric disorder (DSM axis I) compared with healthy controls (for search terms see Supplementary Table S1, Appendix A). Reference lists of selected articles were screened for additional articles. A minimum of three independent studies was needed for any psychiatric disorder to be included in the meta-analysis. To be selected for
General
Study characteristics are shown in Table 1. Additional information on method of diagnostic assessment, medication use, contraception use and type of psychosocial stress intervention is included in the Supplementary Information (Supplementary Table S3, Appendix A). In addition, the graphs of cortisol levels over time from the original studies are included in the Supplementary Information (Supplementary Fig. S1, Appendix A).
Major depressive disorder (MDD)
For MDD, a total of 14 studies were included. Eight studies investigated
Discussion
In this meta-analysis we investigated the cortisol response to psychosocial stress across psychiatric disorders. We found sex-specific changes in cortisol stress reactivity for MDD and anxiety disorders. Specifically, we found that women with current MDD or an anxiety disorder exhibited a blunted cortisol stress response compared with healthy controls, whereas men with current MDD or SAD showed an elevated cortisol response. For schizophrenia, the cortisol response to psychosocial stress was
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JVZ and RRS contributed equally to the manuscript.