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Biological Psychology journal homepage: www.elsevier.com/locate/biopsycho
Review
Cortisol awakening response and psychosocial factors: A systematic review and meta-analysis Yoichi Chida *, Andrew Steptoe Psychobiology Group, Department of Epidemiology and Public Health, University College London, United Kingdom
A R T I C L E I N F O
A B S T R A C T
Article history: Received 14 May 2008 Accepted 21 October 2008 Available online xxx
The magnitude of the cortisol awakening response, a relatively new indicator of hypothalamic–pituitary– adrenocortical (HPA) axis activation, has been related to a number of psychosocial factors. But findings have been inconsistent across studies. We systematically reviewed previous studies investigating the association between the cortisol awakening response and psychosocial factors. 147 eligible studies from 62 articles were identified. Separate analyses were carried out on the increase in cortisol following waking (CARi), and the integrated volume of cortisol released over the waking period (CARauc). We found that the CARi was positively associated with job stress and general life stress. It was negatively associated with fatigue, burnout, or exhaustion. There were less reliable negative associations between the CARi and positive affects. The CARauc was positively related to general life stress and negatively related to posttraumatic stress syndrome. This review concludes that different psychosocial factors are associated with an enhanced or reduced cortisol awakening response. ß 2008 Elsevier B.V. All rights reserved.
Keywords: Depression and anxiety HPA axis Job stress Positive well-being Posttraumatic stress disorder Burnout and fatigue
Contents 1. 2.
3.
4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Data sources and searches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Study selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Data extraction and quality assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Data synthesis and analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Summary of studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Study characteristics and quality. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Meta-analysis of cortisol changes after waking (CARi). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Meta-analysis of overall cortisol output (CARauc) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Differences in CAR across psychosocial factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Underlying mechanisms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. CARi and CARauc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Issues from sensitivity analyses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Limitations and guidelines for future studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
000 000 000 000 000 000 000 000 000 000 000 000 000 000 000 000 000 000 000 000
* Corresponding author at: Psychobiology Group, Department of Epidemiology and Public Health, University College London, 1-19 Torrington Place, London WC1E 6BT, United Kingdom. Tel.: +44 20 7679 8265; fax: +44 20 7916 8542. E-mail address:
[email protected] (Y. Chida). 0301-0511/$ – see front matter ß 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.biopsycho.2008.10.004
Please cite this article in press as: Chida, Y., Steptoe, A., Cortisol awakening response and psychosocial factors: A systematic review and meta-analysis. Biol. Psychol. (2008), doi:10.1016/j.biopsycho.2008.10.004
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1. Introduction Cortisol levels are low in the night but rise in the early hours before waking. After waking up, most people show a further rise, the concentration peaking 20–45 min later. The cortisol awakening response (CAR), first established by Pruessner et al. (1997) as a useful index, can be defined as the change in cortisol concentration that occurs during the first hour after waking from sleep (Clow et al., 2004; Steptoe, 2007). This endocrine marker has been analyzed using a number of different approaches, including repeated measures analysis of samples taken at several time points, simple change scores between waking and 20–45 min later, and area under the curve (AUC) indices (Clow et al., 2004; Pruessner et al., 2003; Fekedulegn et al., 2007). Broadly speaking, two basic parameters have been assessed: the overall volume of cortisol released over the waking period, often measured by integrating the area under the curve imputed from repeated samples (CARauc), and the change (typically increase) of cortisol from the level recorded on waking (CARi) (Pruessner et al., 2003). The CAR has been attracting growing attention from researchers for a number of reasons. First, the introduction of salivary cortisol assessments has allowed response patterns to be measured from salivas collected by research participants at home, without the need for repeated blood sampling. Second, the CAR is an easy parameter of HPA axis function to measure since it does not require laboratory conditions or administration of exogenous agents; rather awakening itself is a consistent, recurring, and strong stimulus for HPA activity (Wilhelm et al., 2007). Third, the CAR is under somewhat independent control from cortisol output during the remainder of the day, and associations between the CAR and cortisol sampled later in the day are low (Schmidt-Reinwald et al., 1999; Edwards et al., 2001a). Fourth, twin studies have documented a genetic influence on the CAR that is distinct from the heritability of daytime cortisol levels (Wu¨st et al., 2000a; Bartels et al., 2003; Kupper et al., 2005). Finally, the magnitude of the CAR appears to be associated with psychosocial factors and health in potentially significant ways, suggesting that it may be a distinctive indicator of HPA function and dysfunction. Early psychological studies of the CAR indicated that the response was heightened among individuals experiencing job stress, overload, and low self-esteem (Schulz et al., 1998; Pruessner et al., 1999; Wu¨st et al., 2000a). It appeared that the CAR might be an indicator of chronic psychosocial stress, and that larger CARs were a marker of neuroendocrine activation as the individual contemplated the challenges of the day ahead. However, negative associations between the CAR and other stress-related constructs emerged (de Vente et al., 2003; Roberts et al., 2004), suggesting that a more nuanced interpretation was required. Steptoe (2007) argued that enhanced CARs were generally related to work stress (e.g., job strain, work overload, and overcommitment to work), other types of life stress (e.g., financial strain, loneliness, poor marital quality), and depression and depressive symptoms. By contrast, a diminished CAR appeared to be present in people suffering from posttraumatic stress syndrome and fatigue-related symptoms, and was also related to positive psychological affect (e.g., happiness, well-being, optimism). Unfortunately, increasing numbers of studies, particularly of depression and depressed mood, have shown inconsistent findings (Pruessner et al., 2003; Bhagwagar et al., 2005; Stetler and Miller, 2005). Several distinct study protocols and approaches to analysis have been employed, and a wide range of psychosocial variables has been investigated. Given the variability of the findings, we believe this literature would benefit from a quantitative meta-analytic approach. The purpose of this systematic review is therefore to synthesize existing data using meta-analytic techniques to address two main
questions. First, what psychosocial factors are associated with larger and smaller CARs? Second, do associations with psychosocial factors differ with study design factors such as control for possible confounders, the number of days or time-points of measurement, participant characteristics (age, gender, and health status), and types of CAR outcomes (CARi or CARauc)? In order to evaluate the consistency of CAR results in relation to psychosocial factors, we divided the constructs tested into eight categories: (1) job stress, including high demands/low control, effort/reward imbalance, and overcommitment; (2) general (non-work) life stress, measured with indicators such as perceived stress, daily hassles and poor marital quality; (3) depression, primarily depressed mood within the normal range, and hopelessness; (4) anxiety, neuroticism, and negative affect; (5) fatigue, burnout, and exhaustion; (6) posttraumatic stress syndrome; (7) positive psychological states or traits. Some of these categories are closely related; however, because of the interest in this literature in relationships with several distinct sets of constructs, we adopted an exploratory approach in which multiple categories were considered. 2. Methods 2.1. Data sources and searches We developed a protocol using a widely recommended method for systematic reviews (Stroup et al., 2000). Electronic searches were done in Medline (1966September 2008); PsycINFO (1872-September 2008); Web of Science (1900September 2008); and PubMed (1950-September 2008). The main search strategy was (‘‘cortisol awakening response’’) OR (‘‘awakening cortisol response’’). In addition, we manually searched the references lists of retrieved publications and reviews. 2.2. Study selection Criteria for inclusion were as follows: (1) English language full-length publication in a peer-reviewed journal; (2) the article investigated associations between psychosocial factors and the CAR; (3) If more than one kind of psychosocial factor was assessed in one article, the associations with cortisol were included separately as separate studies; (4) we included studies evaluating certain mental health problems such as depressive disorders, anxiety disorders, posttraumatic stress disorder, and chronic fatigue syndrome, since these conditions are thought to be related to HPA axis dysregulation (McEwen, 2007). However, (5) we excluded studies of psychotic illnesses and bipolar disorders, because disturbances of cortisol regulation may be secondary in these conditions; (6) studies using low socioeconomic status (SES) as a psychosocial indicator were excluded, because many studies included SES as a covariate, and low SES alone has many consequences apart from greater stress experience; (7) if a cohort overlapped across studies, the paper with smaller sample size or poorer study quality was excluded. 2.3. Data extraction and quality assessment A manual was prepared for coding the studies. The manual was revised during the coding to incorporate important aspects of the located studies. The final list of variables included the following: first author, publication year; sample size with participant characteristics; psychosocial predictors (measurement method); study quality score (0–8); the number of days assessed and time points (min after wakening); CAR indicator; brief results and effect size (correlation coefficient, r) for CARi and CARauc. We extracted the following indicators of cortisol changes following waking or CARi: the area of cortisol increase under the curve (AUCi), the mean value of cortisol values post-awakening minus wakening value (MINC), the absolute difference score or increase of cortisol (AINC), or absolute cortisol values (ACOR) assessed by repeated measures analysis. The overall volume of cortisol released over the waking period (CARauc) was indexed by the total area under the curve (AUCt). We assessed the quality of all manuscripts using a system for scoring methodological quality, based on whether or not potential confounders were addressed, since these can contribute to biases associated with effect estimation. Based on existing evidence (Wu¨st et al., 2000b; Clow et al., 2004; Hellhammer et al., 2007), we considered a study to be of good quality if it considered or controlled age, gender, smoking, participant adherence to salivary sampling (e.g., electronic monitoring, self-reported time of sampling), medication with steroids, clear instructions to participants about the sampling procedure (e.g., the subjects were instructed not to brush their teeth, eat, or drink for at least 15 min before sampling), waking time, and type of sampling day (weekday or weekend). We classified studies arbitrarily into high or low quality categories by whether or not they fulfilled six or more of these eight criteria.
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Y. Chida, A. Steptoe / Biological Psychology xxx (2008) xxx–xxx Study inclusion and data extractions were conducted by one author (Y.C.) and verified by the other (A.S.). Assessments of quality and validity were made independently, and 18 disputes were settled by consensus. 2.4. Data synthesis and analysis We followed meta-analytic procedures that have been described elsewhere (Chida et al., 2008a,b; Chida and Steptoe, 2008; Chida and Hamer, 2008). Briefly, an effect size was calculated from the difference in CAR levels between the control and exposed groups. This was then transformed into r, which gives more weight to larger studies that tend to obtain more reliable estimates of the population effect size. If the raw data were not presented then an F-ratio for the main effect over time was used for conversion to r instead. If there were insufficient data reported to calculate an r-value, we initially contacted the relevant authors to obtain more information. If no relevant convertible statistics were presented, other than a pvalue, we calculated the t-statistic from the p-value and an r-sub (equivalent) (Rosenthal and Rubin, 2003). When a paper reported p < 0.05, 60 years old); pg, pregnant women; pp, postpartum; yg, young subjects (18 years old); m/f refers sex of samples. Predictors: (1) job stress; (2) general life stress; (3) depression or hopelessness; (4) anxiety, neuroticism, and negative affect; (5) fatigue, burnout, or exhaustion; (6) posttraumatic stress syndrome; (7) positive psychological states or traits. CAR confounder score: 1, accounted for; 0, not accounted for; Ag, age; At, awakening time; Ad, participant adherence; In, clear introduction to participants about the sampling procedure; Md, medication of any steroids; Sm, smoking; Sx, sex; W, weekday/weekend. Assessed days: time points (min): D, the number of days studied; time points after post-awakening. Outcome: D, the number of days studied; CARi: AUCi, area of cortisol increase under the curve, AINC, absolute increase of cortisol (max. value of ‘15, 20, 30, 45, or 60 min post-awakening’ minus wakening value), MINC, mean value of ‘15, 20, 30, 45 or 60 min post-awakening’ minus wakening value), ACOR, absolute values post-awakening evaluated by repeated analysis of variables; CARauc: AUCt, total area under the curve. Effect size: r, correlation coefficient.
Table 2 summarizes the detailed characteristics of 145 studies in the review. 3.2. Study characteristics and quality The sample size of the enrolled studies averaged 91.8 participants (range: 12–542). These studies evaluated the following psychosocial factors, listed in order of frequency: general (nonwork) life stress (41 studies, including major life events, caregiver stress, poor marital quality, poor social functioning, loneliness, witnessed violence, early loss event, childhood sexual abuse, etc.); anxiety, neuroticism, or negative affect (26 studies, including negative affect, anxiety, chronic worry, angry, threat, sad, neuroticism, internalizing symptoms, etc.); job stress (22 studies of the demand-control model, effort-reward imbalance model, overcommitment, overload, discontent with work, and time pressure); depression and hopelessness (21 studies); positive psychological states or traits (16 studies of well-being, happiness, optimism, vitality, lively/energetic feelings, self-esteem, and selfefficacy); fatigue, burnout, and exhaustion (16 studies); and posttraumatic stress syndrome (5 studies). The methodological quality scores (0–8) averaged 5.6, with 55.1% (81 studies) scoring 6 or more. 54.4% of the studies measured the CAR for 2 days or more. More studies assessed the CARi (129 studies, 87.8%) than the CARauc (59 studies, 40.1%) (Table 2). 3.3. Meta-analysis of cortisol changes after waking (CARi) The meta-analysis of CARi studies demonstrated positive associations between the magnitude of the CARi and job stress and general life stress (r = 0.061, 95% CI 0.012–0.110, p = 0.015 and r = 0.069 [0.012–0.126], p = 0.017, respectively). By contrast, there tended to be a negative relationship between the CARi and fatigue,
Table 2 Characteristics of the studies included in the meta-analyses. Characteristics
Total study number
Enrolled studies Number
%
147
100
Sample size (average number S.D.)
91.8 85.5
Predictors (1) Job stress (2) General life stress (3) Depression or hopelessness (4) Anxiety, neuroticism, or negative affect (5) Fatigue, burnout, or exhaustion (6) Posttraumatic stress syndrome (7) Positive psychological states or traits
22 41 21 26 16 5 16
Methodological quality score (SD) (1) Age details provided (2) Sex details provided (3) Smoking assessed or controlled (4) Participant adherence assessed (5) Steroid medication controlled (6) Clear instructions to participants (7) Satisfactory measures of awakening time (8) Weekday/weekend taken into account Quality score 6 or more Number of days assessed 1 day 2 days 3 days 4 days or more Outcomes CAR cortisol changes following waking (CARi) CAR total volume of cortisol released (CARauc)
5.62 1.50 126 136 95 103 95 101 77 89 81
15.0 27.9 14.3 17.7 10.9 3.4 10.9
85.7 92.5 64.6 70.1 64.6 68.7 52.4 60.5 55.1
67 53 23 4
45.6 36.1 15.6 2.7
129 59
87.8 40.1
CAR, cortisol awakening response; S.D., standard deviation.
Please cite this article in press as: Chida, Y., Steptoe, A., Cortisol awakening response and psychosocial factors: A systematic review and meta-analysis. Biol. Psychol. (2008), doi:10.1016/j.biopsycho.2008.10.004
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burnout, or exhaustion (r = 0.065 [ 0.138–0.010], p = 0.089). Depression and hopelessness, anxiety, neuroticism, or negative affect, posttraumatic stress syndrome, and positive psychological states or traits were not associated with the CARi in the overall meta-analyses. These findings were not accompanied by publication bias. The analyses on aggregate effect sizes confirmed the positive association between CARi and job stress (Fig. 2). When we limited the meta-analysis to studies with high methodological quality scores (6), the positive associations between CARi and job stress remained significant. Additionally,
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the CARi was inversely related to posttraumatic stress syndrome in methodologically stronger studies. By contrast, the association with general life stress was no longer significant. We carried out subgroup meta-analyses separating the four different types of CARi indicator. These showed a positive association with general life stress for ACOR, and inverse associations with positive psychological factors for both AUCi and MINC. Depression or hopelessness was negatively associated with CARi in the analyses of AINC and AUCi, and so was fatigue, burnout, or exhaustion in AUCi. In studies that assessed the CAR for
Fig. 2. CARi: results of meta-analyses, subgrouping, and sensitivity analyses r, correlation coefficient; AINC, absolute increase of cortisol; AUCi, area of cortisol increase under the curve; MINC, mean value of ‘15, 20, 30, 45 or 60 min post-awakening’ minus wakening value; ACOR, absolute values post-awakening evaluated by repeated analysis of variables; bold numbers indicate p < 0.05; CI, confidence interval. *Indicates significant publication bias by Egger’s method (p < 0.10).
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2 days or more, there were positive associations between CARi and general life stress and negative associations with depression or hopelessness. The studies that assessed the CAR over 3 or more time-points showed that the CARi was significantly associated with general life stress, fatigue, burnout, or exhaustion, and positive psychological states or traits. Since the general life stress category was heterogenous, we analyzed separately different types of negative life experience, including childhood and recent life events, low social support and loneliness. The effects were not significant in these analyses, but the number of studies contributing to each category was small (data not shown).
assessed the CARauc for 3 time-points or more were significant (Fig. 3). 4. Discussion To our knowledge, this is the first systematic review using meta-analytic methods to confirm that psychosocial factors are differentially associated with an enhanced or reduced CAR. These associations differed somewhat across study design factors, including study methodology quality score and the number of days or time-points assessed, and between the two types of CAR outcome.
3.4. Meta-analysis of overall cortisol output (CARauc) 4.1. Differences in CAR across psychosocial factors There were fewer studies of the overall level of cortisol release over the waking period compared with the CARi. In particular, only two studies of job stress could be identified. Nevertheless, the magnitude of the CARauc was positively related to general life stress (r = 0.132 [0.044–0.218], p = 0.003). These overall findings were not accompanied by publication bias. The analysis on aggregate effect sizes also confirmed a positive association between CARauc and general life stress. The subgroup metaanalyses revealed a significant association between general life stress and the CARauc in studies of men. Other factors such as age and the health status of the sample were not related to the CARauc in studies of general life stress. When analysis was limited to studies with high methodological quality scores, significant associations were found not only with general life stress, but also with posttraumatic stress syndrome and with positive psychological states or traits. None of the analyses restricted to studies that
The most robust findings from these meta-analyses indicate that job stress and general life stress are associated with an increased CAR, whereas fatigue, burnout, or exhaustion are characterized by a reduced CAR. It is interesting that there is some evidence for positive psychological traits being related to a reduced CAR, and this is consistent with positive characteristics having biological correlates that are the opposite of negative affective responses (Steptoe et al., 2007). A relationship between posttraumatic stress syndrome and a reduced CAR was also observed, but only in the methodologically better studies. Several of the factors associated with a reduced CAR differ from the experience of general and work stress in eliciting a conservation/ withdrawal response rather than active engagement with the environment. The lack of overall associations between depression and the CAR was not because of an absence of effects, but rather
Fig. 3. CARauc: results of meta-analyses, subgrouping, and sensitivity analyses r, correlation coefficient; bold numbers indicate p < 0.05; CI, confidence interval. *Indicates significant publication bias by Egger’s method (p < 0.10).
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because depression has been related both to increased (Bhagwagar et al., 2003; Pruessner et al., 2003) and reduced (Stetler and Miller, 2005; Ellenbogen et al., 2006) CARs. These discrepancies may relate to the intensity of depression, with some studies investigating major depressive disorder while others concerned elevated depressed mood in the normal range. Additionally, some studies managed less than complete control for factors associated with depression. It is interesting that studies involving two or more days of CAR assessment showed an inverse association with depression, whereas those involving three or more time points of saliva sampling showed a positive relationship. However, it is striking that when analyses were limited to studies with high methodological quality scores, the positive association between the CARi and job stress and between the CARauc and general life stress remained significant. It should be noted that nearly all the studies reviewed were cross-sectional, so the causal significance of associations is unclear. However, one recent study assessed changes in financial strain over 3-year period, and demonstrated that a reduction in financial strain was accompanied by a decrease in the CAR, indicating a parallel between changes in chronic stress and the magnitude of the CAR (Steptoe et al., 2005). More acutely, Adam et al. (2006) showed that greater loneliness, sadness or threat 1 day predicted an increased CAR on the following morning, while a larger CAR was in turn associated with lower fatigue over the subsequent day. 4.2. Underlying mechanisms The association between psychosocial factors and the CAR could be mediated through behavioral pathways. For example, psychosocial factors are thought to influence behavioral processes related to the CAR including smoking (Steptoe and Ussher, 2006; Badrick et al., 2007), awakening time (Edwards et al., 2001b; Federenko et al., 2004; Kudielka et al., 2006), sleep duration and quality (Wu¨st et al., 2000b), and obesity (Steptoe et al., 2004a; Therrien et al., 2007b). However, significant associations between psychosocial factors and the CAR persisted even after controlling for factors such as smoking and waking time, suggesting that other pathways may also be involved. Although we cannot rule out other unmeasured factors that could potentially have confounded the associations observed, direct physiological pathways probably also contribute to associations between psychosocial factors and the CAR. As Wilhelm et al. (2007) have noted, waking up is associated with a profound and global activation of neocortical networks mediated mainly by the brain stem arousing systems (Steriade and McCarley, 2005). On a psychological level, this arousal is presumably linked to the reactivation of memory representations residing in neocortical circuits. There might be a preferential reactivation of representations that are deeply rooted and serve trait-like functions in the organization of personality, identity and the self, as well as of representations that have remained preactivated from more acute experiences, thereby increasing CAR. Indeed, the CAR is abolished in patients with memory disorders due to damage in the frontal lobes or the hippocampal region (Buchanan et al., 2004; Wolf et al., 2005). These analyses indicate that psychosocial factors such as fatigue, burnout, or exhaustion and probably posttraumatic stress syndrome were found to be negatively associated with CAR. One possible explanation is that the mechanisms underlying the CAR become exhausted, as in other cases of hypocortisolism. It is notable, for example, that the phenomenon of hypocortisolism has not only been reported for patients with PTSD, but was also observed in patients with several bodily disorders including chronic fatigue syndrome, fibromyalgia, hypertension, rheumatoid arthritis, and asthma, and many of these disorders have been
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related to chronic stress (Heim et al., 2000; McEwen, 2007; Wirtz et al., 2007). A second possibility is that in conditions such as burnout and fatigue, sleep patterns are seriously disrupted (Ekstedt et al., 2006). The CAR is thought to be due to 2–4 secretory bursts over the period after waking. If sleep patterns are disturbed, perhaps people become aroused to levels near consciousness before they define themselves as awake. The secretory bursts may then be distributed over a longer time period, so the CAR itself is smaller. Coupling cortisol assessments with objective indicators of sleep and waking (polysomnography, heart rate monitoring and actigraphy) would help resolve this issue (Kupper et al., 2005; Wilhelm et al., 2007; Dockray et al., 2008). We focused on the psychosocial correlates of the CAR. The degree to which these effects are related to health states remains to be determined. However, there have been a number of interesting observations suggesting that the CAR changes may be linked with physical health risk. For example, the CAR has been positively associated with waist/hip ratio in men, suggesting it may be a marker of HPA dysfunction in abdominal adiposity (Wallerius et al., 2003; Steptoe et al., 2004a). Another study assessed relationships with the rate of healing of experimentally administered wounds on healthy volunteers (Ebrecht et al., 2004). Wound healing was slower in people with a larger CAR. Eller et al. (2005) reported that the progression of subclinical atherosclerosis, indexed by carotid intima–media thickness, was accelerated in women with a greater CAR, while a recent comparison of patients with and without documented coronary artery disease showed greater CARauc values in the disease group (Bhattacharyya et al., 2008). Therefore, it is conceivable that variations in the CAR stimulated by psychosocial factors may affect later health states. 4.3. CARi and CARauc The current review confirmed that associations with psychosocial factors varied across the two types of CAR outcome. The change in cortisol relative to waking values has been the primary measure of the CAR, with fewer studies of the overall level of cortisol release (CARauc). The latter of course depends on the cortisol level present on waking; if the waking cortisol level is high, then the CARauc will be large even if the increase following waking is minimal. One recent study carried out under controlled laboratory conditions demonstrated that the cortisol increase after waking is a response to awakening, and is distinct from the circadian rise in HPA activity in the morning hours (Wilhelm et al., 2007). Furthermore, the CARauc but not the CARi is correlated with 12-h diurnal mean cortisol concentration (Edwards et al., 2001a). The CARi may therefore be a more appropriate measure for assessing HPA activation following waking in relation to psychosocial factors. 4.4. Issues from sensitivity analyses The subgroup meta-analyses by four different CARi indicators revealed a positive association with general life stress for ACOR, and inverse associations with positive psychological factors in studies assessing both AUCi and MINC but not AINC. Depression or hopelessness was negatively related to the CARi as measured with AINC or AUCi, while fatigue, burnout, or exhaustion were negatively associated when only the AUCi was recorded. It is, however, difficult to conclude that there are specific associations between particular measures of the AUCi and psychosocial factors, since there were insufficient studies to evaluate relationships between each indicator and psychosocial categories. Additionally, it should be noted that the different measures of change after
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waking are highly intercorrelated. If, for example, only two cortisol samples are taken – one on waking and a second after 30 or 45 min – then the MINC and AINC measures are identical. In the analyses of studies involving measurement for at least 2 days, the positive association between the CARi and general life stress, and the negative associations with depression or hopelessness were significant, while the relationship with job stress shown in the overall analyses was no longer reliable. Unfortunately, it is difficult to decide on the basis of this review whether these discrepancies are due to the greater reliability of having assessments on more days, or the number of studies analysed. For example, the nonsignificant relationship between job stress and the AUCi with 2 or more days monitoring was based on only eight studies, whereas the association with general life stress that remained significant involved 20 studies. Moreover, CAR confounders might mask associations, since more than half of the studies involving at least 2 days measurement which showed no psychosocial associations had rather poor methodological quality scores (5). It has recently been argued that at least 6 days of measurement are needed to assess the CARi reliably, and 2 days for the CARauc (Hellhammer et al., 2007). However, there is also important between-day covariation between the CAR and psychosocial experience (Adam et al., 2006). It is also possible that more strict control of adherence to measurement protocols and timing will increase measurement reliability without the need for multiple days of assessment (Broderick et al., 2004; Thorn et al., 2006). Another method of assessing the robustness of effects was to limit the analyses to studies that measured the CAR over at least 3 time points. The results from two time points (such as waking and 30 min later) may be misleading if peak CARs occur over a wide time window (15–45 min). It is notable that in the analyses of studies with 3 measurement points, the associations between the CARi and general life stress, depression or hopelessness, fatigue, burnout or exhaustion, and positive psychological states or traits, were confirmed. Some of the overall meta-analyses demonstrated significant heterogeneities as indexed by the Q-test. This implies that there was heterogeneity within categories of psychosocial factor, resulting either from differences in population characteristics (e.g., gender and health status) or from differences in study methodology (e.g., study quality and design). In an attempt to evaluate which variables affected these heterogeneities, we carried out sensitivity analyses by population characteristics and study methodologies. Interestingly, the overall heterogeneities were not consistently reduced by sensitivity analyses; for instance, the heterogeneity in the overall association between CARi and general life stress was no longer significant in the sensitivity analysis of studies assessing cortisol at 3 or more time-points, while it remained significant in studies assessing the CAR for 2 or more days. Therefore, these overall heterogeneity effects are probably due to a complex combination of two or more study population characteristics and methodologies. We cannot completely delineate the causes for these heterogeneities, because the number of studies was too small for carrying out more refined sensitivity analyses. 4.5. Limitations and guidelines for future studies Our review has several limitations. It was restricted to the evaluation of results in published papers. We found evidence of publication biases a few of the subgroup meta-analyses (e.g., studies of anxiety, neuroticism, or negative affect involving 2 days), though not in the main meta-analyses. This may imply a positive publication bias, if authors are more likely to submit, or editors accept, positive than null (negative or inconclusive) results.
It should also be noted that the method of scaling psychosocial factors was inconsistent across studies, with some using binary divisions, others tertiles or quartiles, established cut-off scores, or continuous scores. The mood variables assessed in these metaanalyses included both traits and states, but there were too few studies available usefully to compare these categories. None of the existing measures of the CAR is perfect, since they do not all capture elements such as latency, exact peak levels, and rate of decline following the peak. Taken together, given the small number of studies analyzed and the small combined effect sizes in some analyses, the current findings showing associations between psychosocial factors and the CAR should be interpreted with caution and additional research is needed. The publication of negative or null results would be beneficial, and improvement in study quality is needed, with control for confounders, better identification of delays in taking measures, more days of assessment, and reporting of both the CARi and CARauc. Moreover, the use of prospective designs to investigate the effects of psychosocial factors on the CAR in relation to health outcomes, and the measurement of possible behavioral and biological mediators such as sleep duration and quality, physical activity, obesity, and genetic polymorphisms, would advance this field. 4.6. Conclusions The current meta-analysis showed that different psychosocial factors are associated both with an enhanced and reduced CAR. Although the CAR has only begun to be studied intensively over recent years in stress research, it is already providing valuable information about psychosocial factors and health. Conflict of interest None declared. Acknowledgements We are grateful to colleagues in many research centres for providing the additional data required for meta-analysis. Contributors: Both authors commented critically on the manuscript and agreed the final version. Y.C. was responsible for concept and design, retrieved and screened papers against inclusion criteria, abstracted data from papers, appraised the quality of papers, and performed the analyses. A.S. verified study inclusion and data extractions, appraised quality of papers, commented on the analysis and interpretation, and contributed to writing up. Role of the funding source: This research was funded by the Kanae Foundation for the Promotion of Medical Science (Japan, Y.C.), the Sumitomo Life Social Welfare Services Foundation (Japan, Y.C.), the Medical Research Council (U.K., Y.C.), and the British Heart Foundation (U.K., A.S.). The funders of this research had no role in the study design, analysis and interpretation of data, writing the report, or in the decision to submit the paper for publication.
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Please cite this article in press as: Chida, Y., Steptoe, A., Cortisol awakening response and psychosocial factors: A systematic review and meta-analysis. Biol. Psychol. (2008), doi:10.1016/j.biopsycho.2008.10.004
