C International Psychogeriatric Association 2014 International Psychogeriatrics (2014), 26:9, 1531–1539 doi:10.1017/S1041610214000489
Psychosocial predictors of salivary cortisol among older adults with depression ...........................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................
Jason M. Holland,1 Johanna Rengifo,2 Joseph M. Currier,3 Ruth O’Hara,4 Keith Sudheimer4 and Dolores Gallagher-Thompson4 1
Department of Psychology, University of Nevada, Las Vegas, Nevada, USA Palo Alto University, Palo Alto, California, USA 3 University of South Alabama, Mobile, Alabama, USA 4 Stanford University School of Medicine, Stanford, California, USA 2
ABSTRACT
Background: Previous studies have identified a number of psychosocial risk factors of dysregulated cortisol (frequently referred to as the “stress hormone”) among older adults with depression. However, these studies have typically only examined a handful of risk factors at a time and have sometimes yielded inconsistent results. Method: This study aims to address this gap in the literature by simultaneously examining a range of relevant psychosocial predictors of diurnal cortisol among 54 older adults with a depressive disorder. Salivary cortisol was assessed upon awakening, at 5 PM, and at 9 PM across two consecutive days. Participants also completed measures of global psychosocial stress, current psychiatric symptomatology, pervasive distress (e.g. history of past depression), and protective factors (e.g. social support, resiliency, extent to which one has “made sense” of a significant stressor). Results: High levels of current depressive symptoms, psychiatric comorbidities, past depressive episodes, trait anxiety, and poorer ability to make sense of one’s stress were found to be associated with flatter (more abnormal) cortisol slopes. However, when all of these variables were entered simultaneously in a multiple regression analysis, only history of past depression and the degree of sense made of stress emerged as unique predictors of cortisol in the model. Conclusions: These findings have important implications for identifying depressed elderly individuals with dysregulated cortisol patterns who may be most at risk for health complications. Treatments that aim to limit the chronicity of depression and help to increase the sense made of stress could potentially have a positive impact on health. Key words: geropsychology, biomarkers, physiological changes, mood disorders, aging
Introduction Elevated levels of depressive symptoms are a serious concern for older adults and have been shown to hasten the progression of a number of health conditions and also, increase the likelihood of hospital admission and nursing home placement (Chapman and Perry, 2008). One biological intermediary that may help explain the association between depression and these health outcomes is cortisol (Brown et al., 2004). Cortisol, often Correspondence should be addressed to: Jason M. Holland, Department of Psychology, University of Nevada, Las Vegas, 4505 S. Maryland Parkway, Box 455030, Las Vegas, Nevada 89154-5030, USA. Phone: +702-895-3703; Fax: +702-895-0195. Email: [email protected]. Received 22 Aug 2013; revision requested 10 Nov 2013; revised version received 24 Feb 2014; accepted 3 Mar 2014. First published online 15 April 2014.
referred to as the “stress hormone,” is one of the most widely used biomarkers of hypothalamic– pituitary–adrenocortical (HPA) axis activation, and when abnormally elevated (referred to as hypercortisolism), it can be an indicator of stress and potential psychiatric disturbance (Miller et al., 2007; Stetler and Miller, 2011). Although a number of methods have been used to gauge cortisol dysregulation in behavioral health research, numerous studies have found support for the link between flattened diurnal cortisol slopes (that do not sharply decline across the day) and psychosocial/physiological stress (for a review, see Miller et al., 2007). Notably, flattened cortisol slopes have even been shown to be associated with all-cause mortality and hastened progression of chronic diseases (Kumari et al., 2011).
1532
J. M. Holland et al.
The association between depressive symptoms and dysregulated cortisol is well established, and dysregulated cortisol patterns are particularly common amongst depressed older adults. A recent meta-analysis of 361 studies showed that older adults with depressive disorders were characterized by greater HPA activation compared to nondepressed controls, more so than for younger adults (Stetler and Miller, 2011). These findings highlight the relevance of cortisol dysregulation as a crucial biomarker of depression for geriatric populations. Though not all patients with depression have dysregulated cortisol, this finding is robust and highly consistent across 45+ years of active research. Cortisol dysregulation has been shown to normalize with successful treatment (Greden et al., 1980; Greden et al., 1983; Liotti et al., 2002) and predict future relapses (Zobel et al., 2001). Exogenous corticosteroids given over extended periods of time can also directly induce depression (Ling et al., 1981; Brown and Chandler, 2001). This evidence strongly suggests that cortisol signaling or regulation could be driving depressive symptoms. Both the glucocorticoid cascade theory (Sapolsky et al., 1986) and the corticosteroid receptor theory (Holsboer, 2000) of depression link cortisol production and/or signaling to the etiology of depression through exposure to chronic stress. Given that older adults with depression show particularly high rates of dysregulated cortisol, the present study aims to examine several key psychosocial stress predictors that could prompt dysregulated cortisol among a sample of individuals with geriatric depression. Although studies generally have observed an association between measures of psychosocial stress and cortisol, correlations have varied drastically, with many studies actually finding null results as well (Hjortskov et al., 2004; Ice, 2005; Holland et al., 2011). This lack of consistent findings in the literature may result from differences in assessment tools and conceptualizations of stress (Hjortskov et al., 2004; Holland et al., 2011). In this study, we hope to explore the contributions of several types of psychosocial stress in the context of geriatric depression by incorporating a broad range of assessment tools that tap into multiple domains of stress and distress. To our knowledge, this is the most comprehensive examination of psychosocial predictors of diurnal cortisol among older adults with depression conducted to date. Specifically, in this study we examined several potential psychosocial predictors of cortisol secretion including global measures of psychosocial stress (e.g. current/past stressors, subjective stress), current psychiatric symptomatology (e.g. severity of depressive symptoms, current comorbidities),
indicators of pervasive distress (e.g. history of past depression, trait anxiety), and protective factors (e.g. social support, resilience, meaning made of stress). Global laboratory measures of psychosocial stress, such as the Trier Social Stress Test, have been shown to affect cortisol secretion in many previous studies (for a review, see Dickerson and Kemeny, 2004). However, survey studies of more naturalistic life stress have yielded more mixed results, with some studies finding no associations between measures of perceived stress and cortisol (van Eck et al., 1996; Simpson et al., 2008). Current psychiatric symptoms, particularly depressive symptoms, have also been closely linked with dysregulated cortisol secretion (for a review, see Stetler and Miller, 2011). Still, others suggest that trait markers of distress (e.g. history of depression, trait anxiety) may be more closely linked to abnormal cortisol patterns than current levels of psychiatric symptomatology (Polk et al., 2005; Beluche et al., 2009). Previous studies have also shown that certain aspects of resilience, such as subjective reports of personal strength, appreciation of life, and spiritual growth, as well as strong social support, are predictive of better general health and lower cortisol secretion (Rosal, 2004; Moskowitz and Epel, 2006). In the present study, we simultaneously examined these different indicators of stress and distress as predictors of diurnal cortisol in a sample of older adults with a depressive disorder of some sort (e.g. major depression, dysthymia). We hypothesized that more severe psychosocial stress, current psychiatric symptoms, and indications of pervasive distress will be associated with flatter (more abnormal) diurnal cortisol slopes, and the presence of protective factors (e.g. social support, resilience) will be associated with sharper negative (healthier) diurnal slopes. However, given that this is the first study to simultaneously examine these predictors of cortisol in this population, the extent to which any one predictor (or set of predictors) will emerge as being uniquely associated with diurnal cortisol in the statistical model (i.e. in the presence of other variables) is treated as an exploratory question.
Methods Participants and procedures Following Internal Review Board approval, participants were recruited throughout the San Francisco Bay Area via radio, newspaper, and Internet advertisements, flyers, free talks in senior centers, and referrals from other professionals. In order to be eligible for the study, individuals
Psychosocial predictors of cortisol
had to score 16 or higher on the Center for Epidemiologic Studies Depression Scale (Radloff, 1977) and meet diagnostic criteria for some type of current depressive disorder (e.g. major depression, dysthymic disorder, adjustment disorder with depressed mood), as assessed by the MiniInternational Neuropsychiatric Interview (M.I.N.I.; Sheehan et al., 1998). Those who reported active suicidal ideation or plan to harm themselves, a history of psychosis or mania, or active substance abuse at baseline were excluded from the study, as well as any individual who showed overt evidence of dementia. Data were collected from 60 older adults who met these inclusion/exclusion criteria. In the present analysis, 54 participants were included, given that six participants did not provide two or more reliable saliva samples. These six participants who were excluded from this analysis did not significantly differ from the rest of the sample in terms of demographic factors or depressive symptoms. Participants’ demographic and background information are presented in Table 1. Measures CORTISOL
Salivary cortisol was measured by instructing participants to collect saliva using an oral swab kit upon awakening in the morning, at 5:00 PM, and again at 9:00 PM across two consecutive days. Participants were instructed to freeze each sample immediately after collection and return it to research staff at their next appointment, where it was then stored in a laboratory freezer before being assayed. They were also told not to eat, drink, smoke, brush their teeth, or use mouthwash in the 30 minutes before collection and not to drink alcohol during the 8–10 h before collecting samples or during the two days of collection. Participants were asked to record the exact time of saliva collection as well as any events that might have influenced the saliva sample (e.g. recent smoking or alcohol use) in a sample collection log. On average, saliva samples were collected at 7:14 AM (SD = 1.3 h), 5:07 PM (SD = 1.3 h), and 8:12 PM (SD = 3.9 h). Out of the 327 saliva samples that were collected as part of this study, participants reported violating protocol (e.g. drinking, smoking, and/or eating less than 30 minutes prior to using the swab) for 25 of the samples. Samples that were collected improperly were not used in this analysis. All samples were assayed for salivary cortisol using a highly sensitive enzyme immunoassay (Salimetrics, State College, Pennsylvania, USA). Of note, the test used 25 μL of saliva per determination
1533
Table 1. Demographic and background information (N = 54) N
%
......................................................................................................................................................
Gender Men Women Ethnicity/race Caucasian African American Asian American Latino/Hispanic Native American Marital status Married Divorced Widowed Separated Single Anti-depressant usage Yes No Hormone replacement therapy usage Yes No History of previous depression Yes No Number of comorbid psychiatric disorders 0 1 2 Age Years of education Diurnal cortisol slope Hamilton rating scale for depression
21 33
38.9 61.1
39 2 6 5 2
72.2 3.7 11.1 9.3 3.7
20 17 8 3 5
37.7 32.1 15.1 5.7 9.4
13 41
24.1 75.9
2 52
3.7 96.3
48 5
90.6 9.4
36 12 6 Mean 70.2 15.0 − 0.01 14.4
66.7 22.2 11.1 SD 7.5 2.6 0.01 5.6
and had a lower limit of sensitivity of 0.003 μg/dL, standard curve range from 0.012 μg/dL to 3.0 μg/dL, average intra-assay coefficient of variation of 3.5%, and an average inter-assay coefficient of variation of 5.1%. Method accuracy determined by spike and recovery averaged 100.8%, and linearity determined by serial dilution averaged 91.7%. Values from matched serum and saliva samples show the expected strong linear relationship, r(47) = 0.91, p < 0.0001. To correct for positive skewedness, cortisol values were log transformed prior to conducting statistical analyses. Data collected from the saliva samples across the two consecutive days were combined in order to allow for a more reliable estimate of each participant’s typical diurnal pattern. Diurnal cortisol slope was captured by the slope of the best fitting line for the cortisol
1534
J. M. Holland et al.
measurements. Specifically, slope was represented by unstandardized beta coefficients when logcortisol was regressed onto hours since wake for each participant. PREDICTOR VARIABLES
In addition to examining demographic factors (age, gender, ethnicity/race, years of education, and marital status) and medication usage (antidepressant and estrogen hormone replacement therapy) as predictors of diurnal cortisol slope in the main study analysis, we incorporated several assessments of stress and distress as predictor variables, including global measures of psychosocial stress, current psychiatric symptomatology, indicators of pervasive distress, and resilience/protective factors. Global measures of psychosocial stress: Stressful life events in the past year were assessed with the Elders Life Stress Inventory (ELSI; Aldwin, 1990), which includes a checklist of 31 common stressors in laterlife (e.g. death of a spouse, institutionalization of a spouse/partner, major decrease in activities). The ELSI has demonstrated concurrent validity with self-reported physical health symptoms (Aldwin, 1990). A total score was calculated as a count of stressful life events, with higher scores indicating a higher number of current stressors. The Trauma History Questionnaire (THQ; Hooper et al., 2011) was used to gauge previous traumatic experiences. This widely used scale includes 24 yes/no items that assess (a) crimerelated events, (b) general disaster and trauma, and (c) physical and sexual experiences. A count of the number of events experienced for each of these three categories of stressors was examined in this study. A recent review of research on the THQ found that this instrument is a reliable (e.g. test-retest) and valid (e.g. positively correlated with distress measures) approach to assessing lifetime trauma history in both clinical and non-clinical samples (Hooper et al., 2011). Subjective perceived stress in the past month was assessed with the four-item Perceived Stress Scale (PSS), which has been shown to perform similarly to the full 14-item version (Cohen et al., 1983). Higher scores represent higher levels of perceived stress. This instrument has also demonstrated adequate internal consistency, test-retest reliability, and has been linked with depressive symptomatology in previous work (Cohen et al., 1983). Current psychiatric symptomatology: Severity of depressive symptoms was assessed with the Hamilton Rating Scale for Depression (HRSD; Hamilton, 1960). The HRSD is a well-established interviewerrated tool composed of 17 questions, with higher
scores representing greater severity of depressive symptoms. The HRSD has also demonstrated strong internal reliability and factorial validity (e.g. Hamilton, 1960). Post-traumatic symptomatology was also assessed using the Impact of Events Scale – 6 (IES-6; Thoresen et al., 2010). This brief version has been shown to correlate highly with the full version of the IES-Revised (r = 0.95; Thoresen et al., 2010). Participants responded to these items with regard to the event that was currently “most distressful” for them. Higher scores indicate greater post-traumatic symptomatology. We also assessed for the number of current comorbid DSM-IV axis I disorders, beyond a participant’s primary depressive disorder as assessed by the M.I.N.I. (Sheehan et al., 1998). This approach has been shown to increase the precision of the clinical picture beyond distress measures (Sheehan et al., 1998). of pervasive distress: Neuroticism (a personality trait characterized by worry, moodiness, and negative affect) was assessed using the eightitem neuroticism subscale of the Big Five Inventory (BFI), which has been shown to strongly correlate with self- and peer-ratings of related constructs as well as other established measures of personality (John et al., 2008). Trait anxiety was measured with the Geriatric Anxiety Inventory (GAI), which includes 20 declarative statements (e.g. “I often feel nervous”) to which the participant is asked to agree or disagree that the statement accurately describes them (Pachana et al., 2007). A total score was calculated by summing all of the affirmative responses, with higher scores indicating greater trait anxiety. The GAI has shown excellent internal consistency and concurrent validity with depression and anxiety in normal and psychiatric samples of older adults (Pachana et al., 2007). As part of the clinical interview, participants were also asked (aside from their present symptoms), “When you think back over your life, are there any periods in your life where you felt depressed?” Responses to this question were used to assess the presence/absence of previous episodes of elevated depressive symptoms.
Indicators
Resilience and protective factors: A two-item version of the Connor-Davidson Resilience Scale was used in this study to tap into one’s perception of their ability to “bounce back” from illness or hardship, with higher scores representing greater resilience. This two-item version has been shown to perform similarly to the full version of the measure and has demonstrated strong psychometric properties as
Psychosocial predictors of cortisol
well (e.g. test-retest reliability, convergent/divergent validity; Vaishnavi et al., 2007). Meaning made of stress was assessed with the 16-item Integration of Stressful Life Experiences Scale (ISLES), which includes a Comprehensibility (gauging one’s ability to make sense of a stressful life event) and Footing in the World (measuring the extent to which one’s perception of purpose and meaning in life remain intact following a stressor) subscale (Holland et al., 2010). These subscales were examined separately, and for each, higher scores indicate more adaptive attribution of meaning to a stressful life event. Participants completed this measure with regard to the event that was currently “most distressful” for them. Holland et al.’s (2010) psychometric evaluation supported this two-factor model for the ISLES as well as internal consistency and concurrent associations with severity of mental and physical problems in two samples. The abbreviated Duke Social Support Index (DSSI) is an 11-item measure that was used to assess perceived social support (Koenig et al., 1993). The scale consists of two subscales, social satisfaction and social interaction, which were examined separately in this study. Prior research has demonstrated that this brief version of the DSSI is comparably effective as the original scale in predicting mental and physical health concerns in geriatric samples (Koenig et al., 1993). Plan of analysis We first examined bivariate correlations between each predictor variable and diurnal cortisol slope. Predictor variables that were found to be significantly associated with diurnal cortisol slope in the bivariate analyses (with a two-tailed p < 0.05) were then entered simultaneously into a multiple regression analysis to identify unique predictors of cortisol slope. Four cases had missing data for at least one of the independent variables, and these missing data were handled using multiple imputation. All analyses were performed in MPlus, version 6.11 (Muthén and Muthén, 1998–2010).
Results As shown in Table 2, in the bivariate analyses, severity of current depressive symptoms, number of comorbid DSM-IV axis 1 diagnoses, trait anxiety, and history of past depression were significantly associated with flattened (more abnormal) diurnal cortisol slopes. In addition, those who were more able to make sense of their identified stressor (as assessed by the ISLES – Comprehensibility subscale) had significantly
1535
steeper negative (healthier) diurnal cortisol slopes. Demographic factors, medication usage (antidepressants and estrogen hormone replacement therapy), current life stressors, past trauma, perceived stress, post-traumatic stress disorder (PTSD) symptoms, neuroticism, social support, resilience, and Footing in the World were not found to be significantly associated with diurnal cortisol slope. As shown in Table 3, when the five predictor variables that were found to be significantly associated with diurnal cortisol slope were entered simultaneously into a multiple regression analysis, only history of past depression (β = 0.27, p = 0.02) and the ability to make sense of a target stressor (β = −0.26, p = 0.05) remained statistically significant. As a whole, this multiple regression model accounted for 29.2% of the variability in diurnal cortisol slope, which was statistically significant at the p < 0.001 level.
Discussion In this study we found that (1) none of the global psychosocial stress measures were significantly correlated with dysregulated cortisol patterns; (2) specific assessments of current psychiatric symptomatology (i.e. depressive symptoms and number of comorbid DSM-IV axis I diagnoses), persistent distress (i.e. presence of past depressive episodes and trait anxiety), and resilience (i.e. sense made of a stressful life event) were associated with cortisol in the expected directions; and (3) previous episodes of depression and the ability to make sense of stressful events emerged as the two most robust predictors of cortisol in the statistical model. Several conclusions can be drawn from these results. First, these findings suggest that global assessments of stress, as assessed by checklists of stressful life events, may not be the most robust predictors of diurnal cortisol among depressed older adults. This pattern of results could be due to all of the older adults in this study meeting criteria for a depressive disorder. Most participants may have exceeded a threshold of life stress that is necessary for causing health problems, making the variation in levels of global stress in this sample less meaningful. Of course, it is also notable that many past studies have shown that older adults are often resilient in the aftermath of life stressors (Ong et al., 2009), which could indicate that simple summations of stressful life events may be a relatively poor indicator of one’s internal experience of distress. As hypothesized, high levels of current depressive symptoms, psychiatric comorbidities, past depressive episodes, greater trait anxiety, and
1536
J. M. Holland et al.
Table 2. Bivariate correlations with diurnal cortisol slope (N = 54) CORRELATION WITH DIURNAL CORTISOL SLOPE .........................................................................................................................................................................................................................................................................................................................
Demographic factors: Age Gender (0 = women, 1 = men) Ethnicity/race (0 = ethnic/racial minority, 1 = Caucasian) Years of education Marital status (0 = married, 1 = not married) Medication usage: Anti-depressant usage (0 = no anti-depressant, 1 = anti-depressant) Hormone replacement therapy (HRT) usage (0 = no HRT, 1 = HRT) Global measures of psychosocial stress: Stressful life events in the past year Past trauma – crime-related events Past trauma – general disaster and trauma Past trauma – physical and sexual abuse experiences Current perceived stress Current psychiatric symptomatology: Depressive symptoms Posttraumatic stress symptoms Number of comorbid DSM-IV axis I diagnoses Indicators of pervasive distress: Neuroticism Trait anxiety Presence of previous depressive episode Resilience and protective factors: Resilience Meaning made of stress – Comprehensibility Meaning made of stress – Footing in the World Social satisfaction Social interaction ∗p
0.070 − 0.244 − 0.224 0.027 − 0.110 − 0.105 − 0.143 0.154 − 0.191 − 0.119 0.157 0.232 0.280∗ 0.089 0.357∗∗ 0.211 0.328∗ 0.332∗ − 0.161 − 0.341∗ − 0.236 − 0.197 0.190
< 0.05, ∗∗ p < 0.01.
Table 3. Multiple regression analysis with diurnal cortisol slope as the dependent variable VARIABLE
B
SEB
β
.....................................................................................................................................................................................................................................................................
Severity of current depression (HRSD) Number of comorbid psychiatric diagnoses Trait anxiety (GAI) History of past depression Sense made of stress (ISLES – Comprehensibility)
0.000 0.003 0.000 0.010 −0.001
0.000 0.002 0.000 0.005 0.000
0.137 0.189 0.019 0.269∗ −0.260∗
∗p
< 0.05. B = Unstandardized Beta; SEB = Standard Error of Beta; β = Standardized Beta; HRSD = Hamilton rating scale for depression; GAI = geriatric anxiety inventory; ISLES = integration of stressful life experiences scale.
poorer ability to make sense of stress were found to be associated with flattened (more abnormal) cortisol slopes. However, when all of these predictor variables were entered simultaneously in a multiple regression model, it appeared that past depression and the ability to make sense of stressful events accounted for the majority of the explained variance in diurnal cortisol. The finding related to previous episodes of depression fits well with a theoretical model of cortisol dysregulation contributing to
depression through the accumulation of unmanaged stressors (Sapolsky et al., 1986; Holsboer, 2000). However, it is also possible that past depression contributes independently to current dysregulated cortisol. In particular, individuals with a latelife onset of depression and fewer episodes may be qualitatively distinct from those with a much earlier onset and a greater number of episodes. Specifically, it would seem reasonable to expect that sustained cortisol dysregulation may primarily stem
Psychosocial predictors of cortisol
from prolonged and chronic emotional distress. In contrast, depressive episodes that occur with a lower frequency and duration may not last long enough to bring about enduring physiological changes. Past research would seem to generally support this claim (Polk et al., 2005; Beluche et al., 2009). With regard to the ability to make sense of stressful events, multivariate results also indicated that persons who had adaptively assimilated their life stressors into current meaning structures were less at risk for cortisol dysregulation. In general, this finding aligns with an extensive literature that has shown that the ability to make sense of loss and other stressful life events can have a variety of physical and mental health benefits (Park, 2010). Given the link between psychiatric problems and cortisol dysregulation (Miller et al., 2007; Stetler and Miller, 2011), it was particularly notable that this finding emerged in a sample of already depressed older adults. Namely, in considering clinical samples of this sort, it might be equally important to gauge individuals’ ability to make sense of stressful events as it is to assess their current and past history of depressive symptomatology. Further, it may be that individuals who have dysregulated cortisol are less able to make meaning out of stressful events, but a longitudinal investigation would be required to examine the temporal precedence between these variables. This study is, of course, not without its limitations. In particular, this study is limited by its relatively small sample size, cross-sectional design, and lack of generalizability (e.g. the sample was mostly made up of Caucasian older adults with a fair amount of education). Future studies should attempt to replicate these findings with larger and more diverse samples and use a longitudinal design to better capture the temporal relations among these variables. We could only use the term “predictor” in a statistical sense in this paper and hope that future research will test whether a history of previous depressive episodes and an inability to make sense of stressful life events actually precede dysregulation of cortisol in other samples of geriatric patients. Studies that examine other biomarkers, such as indicators of immune functioning, inflammation, or cell aging, could also significantly advance this line of research in important ways. Notwithstanding these limitations and possibilities for further study, the present investigation is the first to simultaneously examine a comprehensive range of measures of stress and distress as predictors of diurnal cortisol among older adults with depression. The finding that previous episodes of depression and the ability to make sense of stressful events were the two most robust predictors of cortisol in this sample has important implications
1537
for identifying depressed elderly individuals who are most at-risk for health complications. From an intervention standpoint, these findings would suggest that treatments that aim to limit the chronicity of depression and help to increase the ability of clients to make sense of stressful events could potentially have a positive impact on health. For example, meaning-oriented components may be incorporated into traditional cognitive behavioral therapy (CBT) interventions (e.g. “re-authoring” the self-narrative; Neimeyer, 2009, p. 97) to help clients make sense of significant stressors and regain a sense of purpose and direction in life.
Conflict of interest None.
Description of author’s roles J.M. Holland participated in data collection, conducted all statistical analyses, and wrote the majority of the manuscript. J. Rengifo participated in data collection and assisted with the writing of the manuscript. J.M. Currier assisted with the writing of the manuscript. R. O’Hara was the coprincipal investigator for the study and assisted with the writing of the manuscript. K. Sudheimer assisted with the writing of the manuscript. D. Gallagher-Thompson was the principal investigator for the study and assisted with the writing of the manuscript.
Acknowledgments This study was funded by a National Institute of Mental Health (NIMH) exploratory/developmental research grant program (R21 MH091625-01, entitled: Predictors of Positive Outcome in Cognitive Behavior Therapy for Late Life Depression).
References Aldwin, C. M. (1990). The Elders Life Stress Inventory: egocentric and nonegocentric stress. In A. M. P. Stephens, J. H. Crowther, S. E. Hobfoll and D. L. Tennenbaum (eds.), Stress and Coping in Late Life Families (pp. 49–69). New York, NY: Hemisphere. Beluche, I. et al. (2009). Persistence of abnormal cortisol levels in elderly persons after recovery from major depression. Journal of Psychiatric Research, 43, 777–783. doi: 10.1016/j.jpsychires.2008.10.011. Brown, E. S. and Chandler, P. A. (2001). Mood and cognitive changes during systemic corticosteroid therapy.
1538
J. M. Holland et al.
The Primary Care Companion to the Journal of Clinical Psychiatry, 3, 17–21. doi: 10.4088/PCC.v03n0104. Brown, E. S., Varghese, F. P. and McEwen, B. S. (2004). Association of depression with medical illness: does cortisol play a role? Biological Psychiatry, 55, 1–9. doi: 10.1016/S0006-3223(03)00473-6. Chapman, D. P. and Perry, G. S. (2008). Depression and a major component of public health for older adults. Preventing Chronic Disease, 5, A22. http://www.cdc.gov/pcd/issues/2008/jan/07_0150.htm. Cohen, S., Kamarck, T. and Mermelstein, R. (1983). A global measure of perceived stress. Journal of Health and Social Behavior, 24, 385–396. doi: 10.2307/2136404. Dickerson, S. and Kemeny, M. E. (2004). Acute stressors and cortisol responses: a theoretical integration and synthesis of laboratory research. Psychological Bulletin, 130, 355–391. doi: 10.1037/0033-2909.130.3.355. Greden, J. F. et al. (1980). Normalization of dexamethasone suppression test: a laboratory index of recovery from endogenous depression. Biological Psychiatry, 15, 449–458. Greden, J. F., Gardner, R., King, D., Grunhaus, L., Carroll, B. J. and Kronfol, Z. (1983). Dexamethasone suppression tests in antidepressant treatment of melancholia. The process of normalization and test-retest reproducibility. Archives of General Psychiatry, 40, 493–500. doi: 10.1097/00004714-198310000-00025. Hamilton, M. (1960). A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry, 23, 56–61. doi: 10.1136/jnnp.23.1.56. Hjortskov, N., Garde, A. H., Ørbæk, P. and Hansen, A. M. (2004). Evaluation of salivary cortisol as a biomarker of self-reported mental stress in field studies. Stress and Health, 20, 91–98. Holland, J. M., Currier, J. M., Coleman, R. A. and Neimeyer, R. A. (2010). The Integration of Stressful Life Experiences Scale (ISLES): development and initial validation of a new measure. International Journal of Stress Management, 17, 325–352 . doi:10.1037/a0020892. Holland, J. M. et al. (2011). Cortisol outcomes among Caucasian and Latina/Hispanic women caring for a family member with dementia: a preliminary examination of psychosocial predictors and the effect of a psychoeducational intervention. Stress and Health, 27, 334–346. doi: 10.1002/smi.1375. Holsboer, F. (2000). The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology, 23, 477–501. doi: 10.1016/S0893-133X(00)00159-7. Hooper, L. M., Stockton, P., Krupnick, J. L. and Green, B. L. (2011). Development, use, and psychometric properties of the trauma history questionnaire. Journal of Loss and Trauma, 16, 258–283. doi: 10.1080/15325024.2011.572035. Ice, G. H. (2005). Factors influencing cortisol level and slope among community dwelling older adults in Minnesota. Journal of Cross-Cultural Gerontology, 20, 91–108. doi: 10.1007/s10823-005-9085-5. John, O. P., Naumann, L. P. and Soto, C. J. (2008). Paradigm shift to the integrative big five trait taxonomy: history, measurement, and conceptual issues. In O. P. John, R. W. Robins and L. A. Pervin (eds.), Handbook of Personality: Theory and Research (pp. 114–158). New York, NY: Guilford Press.
Koenig, H. G., Westlund, R. E., George, L. K., Hughes, D. C., Blazer, D. G. and Hybels, C. (1993). Abbreviating the Duke Social Support Index for use in chronically ill elderly individuals. Psychosomatics, 34, 61–69. doi: 10.1016/S0033-3182(93)71928-3. Kumari, M., Shipley, M., Stafford, M. and Kivimaki, M. (2011). Association of diurnal patterns in salivary cortisol with all-cause and cardiovascular mortality: findings from the Whitehall II study. Journal of Clinical Endocrinology and Metabolism, 96, 1478–1485. doi: 10.1210/jc.20102137. Ling, M. H., Perry, P. J. and Tsuang, M. T. (1981). Side effects of corticosteroid therapy. Psychiatric aspects. Archives of General Psychiatry, 38, 471–477. doi: 10.1001/ archpsyc.1981.01780290105011. Liotti, M., Mayberg, H. S., McGinnis, S., Brannan, S. L. and Jerabek, P. (2002): Unmasking disease-specific cerebral blood flow abnormalities: mood challenge in patients with remitted unipolar depression. American Journal of Psychiatry, 159, 1830–1840. doi: 10.1176/appi.ajp.159.11.1830. Miller, G., Chen, E. and Zhou, E. (2007). If it goes up, must it come down? Chronic stress and the hypothalamic-pituitary-adrenocortical axis in humans. Psychological Bulletin, 133, 25–45. doi: 10.1037/0033-2909.133.1.25. Moskowitz, J. T. and Epel, E. S. (2006). Benefit finding and diurnal cortisol slope in maternal caregivers: a moderating role for positive emotion. The Journal of Positive Psychology, 1, 83–91. doi: 10.1080/17439760500510510. Muthén, L. K. and Muthén, B. O. (1998–2010). Mplus User’s Guide, 6th edn. Los Angeles, CA: Muthén & Muthén. Neimeyer, R. A. (2009). Constructivist Psychotherapy: Distinctive Features. New York, NY: Routledge. Ong, A. D., Bergeman, C. S. and Boker, S. M. (2009). Resilience comes of age: defining features in later adulthood. Personality, 77, 1777–1804. doi: 10.1111/j.1467-6494.2009.00600.x. Pachana, N. A., Byrne, G. J., Siddle, H., Koloski, N., Harley, E. and Arnold, E. (2007). Development and validation of the Geriatric Anxiety Inventory. International Psychogeriatrics, 19, 103–114. doi: 10.1017/ S1041610206003504. Park, C. L. (2010). Making sense of the meaning literature: an integrative review of meaning making and its effects on adjustment to stressful life events. Psychological Bulletin, 136, 257–301. doi:10.1037/a0018301. Polk, D. E., Cohen, S., Doyle, W. J., Skoner, D. P. and Kirschbaum, C. (2005). State and trait affect as predictors of salivary cortisol in healthy adults. Psychoneuroendocrinology, 30, 261–272. doi: 10.1016/ j.psyneuen.2004.08.004. Radloff, L. S. (1977). The CES-D scale: a self-report depression scale for research in the general population. Applied Psychological Measurement, 1, 385–401. doi: 10.1177/014662167700100306. Rosal, M. C., King, J., Ma, Y. and Reed, G. (2004). Stress, social support, and cortisol: inverse associations? Behavioral Medicine, 30, 11–21. doi: 10.3200/BMED.30.1.11-22. Sapolsky, R. M., Krey, L. C. and McEwen, B. S. (1986). The neuroendocrinology of stress and aging: the
Psychosocial predictors of cortisol glucocorticoid cascade hypothesis. Endocrine Reviews, 7, 284–301. doi: 10.1210/edrv-7-3-284. Sheehan, D. V. et al. (1998). The mini-international neuropsychiatric interview (M.I.N.I): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. Journal of Clinical Psychiatry, 59, 22–33. Simpson, E. A., McConville, G. R., O’Conner, J. M., Stewart-Knox, B. J., Coudray, C. and Strain, J. J. (2008). Salivary cortisol, stress and mood in healthy older adults: the Zenith study. Biological Psychology, 78, 1–9. doi: 10.1016/j.biopsycho.2007.12.001. Stetler, C. and Miller, G. E. (2011). Depression and hypothalamic-pituitary-adrenal activation: a quantitative summary of four decades of research. Psychosomatic Medicine, 73, 114–126. doi: 10.1097/ PSY.0b013e31820ad12b. Thoresen, S., Tambs, K., Hussain, A., Heir, T., Johansen, V. A. and Bisson, J. I. (2010). Brief measure of posttraumatic stress reactions: impact of Event Scale-6.
1539
Social Psychiatry and Psychiatric Epidemiology, 45(3), 405–412. doi: 10.1007/s00127-0090073-x. Vaishnavi, S., Connor, K. and Davidson, J. R. T. (2007). An abbreviated version of the Connor-Davidson Resilience Scale (CD-RISC), the CD-RISC2: psychometric properties and applications in psychopharmacological trials. Psychiatry Research, 152, 293–297. doi: 10.1016/j.psychres.2007.01.006. van Eck, M. M., Nicolson, N. A., Berkof, H. and Sulon, J. (1996). Individual differences in cortisol responses to a laboratory speech task and their relationship to responses to stressful daily events. Biological Psychology, 43, 69–84. doi: 10.1016/0301-0511(95)05159-7. Zobel, A. W., Nickel, T., Sonntag, A., Uhr, M., Holsboer, F. and Ising, M. (2001). Cortisol response in the combined dexamethasone/CRH test as predictor of relapse in patients with remitted depression: A prospective study. Journal of Psychiatric Research, 35, 83–94. doi: 10.1016/S0022-3956(01)00013-9.
Psychosocial predictors of salivary cortisol among older adults with depression ...........................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................
Jason M. Holland,1 Johanna Rengifo,2 Joseph M. Currier,3 Ruth O’Hara,4 Keith Sudheimer4 and Dolores Gallagher-Thompson4 1
Department of Psychology, University of Nevada, Las Vegas, Nevada, USA Palo Alto University, Palo Alto, California, USA 3 University of South Alabama, Mobile, Alabama, USA 4 Stanford University School of Medicine, Stanford, California, USA 2
ABSTRACT
Background: Previous studies have identified a number of psychosocial risk factors of dysregulated cortisol (frequently referred to as the “stress hormone”) among older adults with depression. However, these studies have typically only examined a handful of risk factors at a time and have sometimes yielded inconsistent results. Method: This study aims to address this gap in the literature by simultaneously examining a range of relevant psychosocial predictors of diurnal cortisol among 54 older adults with a depressive disorder. Salivary cortisol was assessed upon awakening, at 5 PM, and at 9 PM across two consecutive days. Participants also completed measures of global psychosocial stress, current psychiatric symptomatology, pervasive distress (e.g. history of past depression), and protective factors (e.g. social support, resiliency, extent to which one has “made sense” of a significant stressor). Results: High levels of current depressive symptoms, psychiatric comorbidities, past depressive episodes, trait anxiety, and poorer ability to make sense of one’s stress were found to be associated with flatter (more abnormal) cortisol slopes. However, when all of these variables were entered simultaneously in a multiple regression analysis, only history of past depression and the degree of sense made of stress emerged as unique predictors of cortisol in the model. Conclusions: These findings have important implications for identifying depressed elderly individuals with dysregulated cortisol patterns who may be most at risk for health complications. Treatments that aim to limit the chronicity of depression and help to increase the sense made of stress could potentially have a positive impact on health. Key words: geropsychology, biomarkers, physiological changes, mood disorders, aging
Introduction Elevated levels of depressive symptoms are a serious concern for older adults and have been shown to hasten the progression of a number of health conditions and also, increase the likelihood of hospital admission and nursing home placement (Chapman and Perry, 2008). One biological intermediary that may help explain the association between depression and these health outcomes is cortisol (Brown et al., 2004). Cortisol, often Correspondence should be addressed to: Jason M. Holland, Department of Psychology, University of Nevada, Las Vegas, 4505 S. Maryland Parkway, Box 455030, Las Vegas, Nevada 89154-5030, USA. Phone: +702-895-3703; Fax: +702-895-0195. Email: [email protected]. Received 22 Aug 2013; revision requested 10 Nov 2013; revised version received 24 Feb 2014; accepted 3 Mar 2014. First published online 15 April 2014.
referred to as the “stress hormone,” is one of the most widely used biomarkers of hypothalamic– pituitary–adrenocortical (HPA) axis activation, and when abnormally elevated (referred to as hypercortisolism), it can be an indicator of stress and potential psychiatric disturbance (Miller et al., 2007; Stetler and Miller, 2011). Although a number of methods have been used to gauge cortisol dysregulation in behavioral health research, numerous studies have found support for the link between flattened diurnal cortisol slopes (that do not sharply decline across the day) and psychosocial/physiological stress (for a review, see Miller et al., 2007). Notably, flattened cortisol slopes have even been shown to be associated with all-cause mortality and hastened progression of chronic diseases (Kumari et al., 2011).
1532
J. M. Holland et al.
The association between depressive symptoms and dysregulated cortisol is well established, and dysregulated cortisol patterns are particularly common amongst depressed older adults. A recent meta-analysis of 361 studies showed that older adults with depressive disorders were characterized by greater HPA activation compared to nondepressed controls, more so than for younger adults (Stetler and Miller, 2011). These findings highlight the relevance of cortisol dysregulation as a crucial biomarker of depression for geriatric populations. Though not all patients with depression have dysregulated cortisol, this finding is robust and highly consistent across 45+ years of active research. Cortisol dysregulation has been shown to normalize with successful treatment (Greden et al., 1980; Greden et al., 1983; Liotti et al., 2002) and predict future relapses (Zobel et al., 2001). Exogenous corticosteroids given over extended periods of time can also directly induce depression (Ling et al., 1981; Brown and Chandler, 2001). This evidence strongly suggests that cortisol signaling or regulation could be driving depressive symptoms. Both the glucocorticoid cascade theory (Sapolsky et al., 1986) and the corticosteroid receptor theory (Holsboer, 2000) of depression link cortisol production and/or signaling to the etiology of depression through exposure to chronic stress. Given that older adults with depression show particularly high rates of dysregulated cortisol, the present study aims to examine several key psychosocial stress predictors that could prompt dysregulated cortisol among a sample of individuals with geriatric depression. Although studies generally have observed an association between measures of psychosocial stress and cortisol, correlations have varied drastically, with many studies actually finding null results as well (Hjortskov et al., 2004; Ice, 2005; Holland et al., 2011). This lack of consistent findings in the literature may result from differences in assessment tools and conceptualizations of stress (Hjortskov et al., 2004; Holland et al., 2011). In this study, we hope to explore the contributions of several types of psychosocial stress in the context of geriatric depression by incorporating a broad range of assessment tools that tap into multiple domains of stress and distress. To our knowledge, this is the most comprehensive examination of psychosocial predictors of diurnal cortisol among older adults with depression conducted to date. Specifically, in this study we examined several potential psychosocial predictors of cortisol secretion including global measures of psychosocial stress (e.g. current/past stressors, subjective stress), current psychiatric symptomatology (e.g. severity of depressive symptoms, current comorbidities),
indicators of pervasive distress (e.g. history of past depression, trait anxiety), and protective factors (e.g. social support, resilience, meaning made of stress). Global laboratory measures of psychosocial stress, such as the Trier Social Stress Test, have been shown to affect cortisol secretion in many previous studies (for a review, see Dickerson and Kemeny, 2004). However, survey studies of more naturalistic life stress have yielded more mixed results, with some studies finding no associations between measures of perceived stress and cortisol (van Eck et al., 1996; Simpson et al., 2008). Current psychiatric symptoms, particularly depressive symptoms, have also been closely linked with dysregulated cortisol secretion (for a review, see Stetler and Miller, 2011). Still, others suggest that trait markers of distress (e.g. history of depression, trait anxiety) may be more closely linked to abnormal cortisol patterns than current levels of psychiatric symptomatology (Polk et al., 2005; Beluche et al., 2009). Previous studies have also shown that certain aspects of resilience, such as subjective reports of personal strength, appreciation of life, and spiritual growth, as well as strong social support, are predictive of better general health and lower cortisol secretion (Rosal, 2004; Moskowitz and Epel, 2006). In the present study, we simultaneously examined these different indicators of stress and distress as predictors of diurnal cortisol in a sample of older adults with a depressive disorder of some sort (e.g. major depression, dysthymia). We hypothesized that more severe psychosocial stress, current psychiatric symptoms, and indications of pervasive distress will be associated with flatter (more abnormal) diurnal cortisol slopes, and the presence of protective factors (e.g. social support, resilience) will be associated with sharper negative (healthier) diurnal slopes. However, given that this is the first study to simultaneously examine these predictors of cortisol in this population, the extent to which any one predictor (or set of predictors) will emerge as being uniquely associated with diurnal cortisol in the statistical model (i.e. in the presence of other variables) is treated as an exploratory question.
Methods Participants and procedures Following Internal Review Board approval, participants were recruited throughout the San Francisco Bay Area via radio, newspaper, and Internet advertisements, flyers, free talks in senior centers, and referrals from other professionals. In order to be eligible for the study, individuals
Psychosocial predictors of cortisol
had to score 16 or higher on the Center for Epidemiologic Studies Depression Scale (Radloff, 1977) and meet diagnostic criteria for some type of current depressive disorder (e.g. major depression, dysthymic disorder, adjustment disorder with depressed mood), as assessed by the MiniInternational Neuropsychiatric Interview (M.I.N.I.; Sheehan et al., 1998). Those who reported active suicidal ideation or plan to harm themselves, a history of psychosis or mania, or active substance abuse at baseline were excluded from the study, as well as any individual who showed overt evidence of dementia. Data were collected from 60 older adults who met these inclusion/exclusion criteria. In the present analysis, 54 participants were included, given that six participants did not provide two or more reliable saliva samples. These six participants who were excluded from this analysis did not significantly differ from the rest of the sample in terms of demographic factors or depressive symptoms. Participants’ demographic and background information are presented in Table 1. Measures CORTISOL
Salivary cortisol was measured by instructing participants to collect saliva using an oral swab kit upon awakening in the morning, at 5:00 PM, and again at 9:00 PM across two consecutive days. Participants were instructed to freeze each sample immediately after collection and return it to research staff at their next appointment, where it was then stored in a laboratory freezer before being assayed. They were also told not to eat, drink, smoke, brush their teeth, or use mouthwash in the 30 minutes before collection and not to drink alcohol during the 8–10 h before collecting samples or during the two days of collection. Participants were asked to record the exact time of saliva collection as well as any events that might have influenced the saliva sample (e.g. recent smoking or alcohol use) in a sample collection log. On average, saliva samples were collected at 7:14 AM (SD = 1.3 h), 5:07 PM (SD = 1.3 h), and 8:12 PM (SD = 3.9 h). Out of the 327 saliva samples that were collected as part of this study, participants reported violating protocol (e.g. drinking, smoking, and/or eating less than 30 minutes prior to using the swab) for 25 of the samples. Samples that were collected improperly were not used in this analysis. All samples were assayed for salivary cortisol using a highly sensitive enzyme immunoassay (Salimetrics, State College, Pennsylvania, USA). Of note, the test used 25 μL of saliva per determination
1533
Table 1. Demographic and background information (N = 54) N
%
......................................................................................................................................................
Gender Men Women Ethnicity/race Caucasian African American Asian American Latino/Hispanic Native American Marital status Married Divorced Widowed Separated Single Anti-depressant usage Yes No Hormone replacement therapy usage Yes No History of previous depression Yes No Number of comorbid psychiatric disorders 0 1 2 Age Years of education Diurnal cortisol slope Hamilton rating scale for depression
21 33
38.9 61.1
39 2 6 5 2
72.2 3.7 11.1 9.3 3.7
20 17 8 3 5
37.7 32.1 15.1 5.7 9.4
13 41
24.1 75.9
2 52
3.7 96.3
48 5
90.6 9.4
36 12 6 Mean 70.2 15.0 − 0.01 14.4
66.7 22.2 11.1 SD 7.5 2.6 0.01 5.6
and had a lower limit of sensitivity of 0.003 μg/dL, standard curve range from 0.012 μg/dL to 3.0 μg/dL, average intra-assay coefficient of variation of 3.5%, and an average inter-assay coefficient of variation of 5.1%. Method accuracy determined by spike and recovery averaged 100.8%, and linearity determined by serial dilution averaged 91.7%. Values from matched serum and saliva samples show the expected strong linear relationship, r(47) = 0.91, p < 0.0001. To correct for positive skewedness, cortisol values were log transformed prior to conducting statistical analyses. Data collected from the saliva samples across the two consecutive days were combined in order to allow for a more reliable estimate of each participant’s typical diurnal pattern. Diurnal cortisol slope was captured by the slope of the best fitting line for the cortisol
1534
J. M. Holland et al.
measurements. Specifically, slope was represented by unstandardized beta coefficients when logcortisol was regressed onto hours since wake for each participant. PREDICTOR VARIABLES
In addition to examining demographic factors (age, gender, ethnicity/race, years of education, and marital status) and medication usage (antidepressant and estrogen hormone replacement therapy) as predictors of diurnal cortisol slope in the main study analysis, we incorporated several assessments of stress and distress as predictor variables, including global measures of psychosocial stress, current psychiatric symptomatology, indicators of pervasive distress, and resilience/protective factors. Global measures of psychosocial stress: Stressful life events in the past year were assessed with the Elders Life Stress Inventory (ELSI; Aldwin, 1990), which includes a checklist of 31 common stressors in laterlife (e.g. death of a spouse, institutionalization of a spouse/partner, major decrease in activities). The ELSI has demonstrated concurrent validity with self-reported physical health symptoms (Aldwin, 1990). A total score was calculated as a count of stressful life events, with higher scores indicating a higher number of current stressors. The Trauma History Questionnaire (THQ; Hooper et al., 2011) was used to gauge previous traumatic experiences. This widely used scale includes 24 yes/no items that assess (a) crimerelated events, (b) general disaster and trauma, and (c) physical and sexual experiences. A count of the number of events experienced for each of these three categories of stressors was examined in this study. A recent review of research on the THQ found that this instrument is a reliable (e.g. test-retest) and valid (e.g. positively correlated with distress measures) approach to assessing lifetime trauma history in both clinical and non-clinical samples (Hooper et al., 2011). Subjective perceived stress in the past month was assessed with the four-item Perceived Stress Scale (PSS), which has been shown to perform similarly to the full 14-item version (Cohen et al., 1983). Higher scores represent higher levels of perceived stress. This instrument has also demonstrated adequate internal consistency, test-retest reliability, and has been linked with depressive symptomatology in previous work (Cohen et al., 1983). Current psychiatric symptomatology: Severity of depressive symptoms was assessed with the Hamilton Rating Scale for Depression (HRSD; Hamilton, 1960). The HRSD is a well-established interviewerrated tool composed of 17 questions, with higher
scores representing greater severity of depressive symptoms. The HRSD has also demonstrated strong internal reliability and factorial validity (e.g. Hamilton, 1960). Post-traumatic symptomatology was also assessed using the Impact of Events Scale – 6 (IES-6; Thoresen et al., 2010). This brief version has been shown to correlate highly with the full version of the IES-Revised (r = 0.95; Thoresen et al., 2010). Participants responded to these items with regard to the event that was currently “most distressful” for them. Higher scores indicate greater post-traumatic symptomatology. We also assessed for the number of current comorbid DSM-IV axis I disorders, beyond a participant’s primary depressive disorder as assessed by the M.I.N.I. (Sheehan et al., 1998). This approach has been shown to increase the precision of the clinical picture beyond distress measures (Sheehan et al., 1998). of pervasive distress: Neuroticism (a personality trait characterized by worry, moodiness, and negative affect) was assessed using the eightitem neuroticism subscale of the Big Five Inventory (BFI), which has been shown to strongly correlate with self- and peer-ratings of related constructs as well as other established measures of personality (John et al., 2008). Trait anxiety was measured with the Geriatric Anxiety Inventory (GAI), which includes 20 declarative statements (e.g. “I often feel nervous”) to which the participant is asked to agree or disagree that the statement accurately describes them (Pachana et al., 2007). A total score was calculated by summing all of the affirmative responses, with higher scores indicating greater trait anxiety. The GAI has shown excellent internal consistency and concurrent validity with depression and anxiety in normal and psychiatric samples of older adults (Pachana et al., 2007). As part of the clinical interview, participants were also asked (aside from their present symptoms), “When you think back over your life, are there any periods in your life where you felt depressed?” Responses to this question were used to assess the presence/absence of previous episodes of elevated depressive symptoms.
Indicators
Resilience and protective factors: A two-item version of the Connor-Davidson Resilience Scale was used in this study to tap into one’s perception of their ability to “bounce back” from illness or hardship, with higher scores representing greater resilience. This two-item version has been shown to perform similarly to the full version of the measure and has demonstrated strong psychometric properties as
Psychosocial predictors of cortisol
well (e.g. test-retest reliability, convergent/divergent validity; Vaishnavi et al., 2007). Meaning made of stress was assessed with the 16-item Integration of Stressful Life Experiences Scale (ISLES), which includes a Comprehensibility (gauging one’s ability to make sense of a stressful life event) and Footing in the World (measuring the extent to which one’s perception of purpose and meaning in life remain intact following a stressor) subscale (Holland et al., 2010). These subscales were examined separately, and for each, higher scores indicate more adaptive attribution of meaning to a stressful life event. Participants completed this measure with regard to the event that was currently “most distressful” for them. Holland et al.’s (2010) psychometric evaluation supported this two-factor model for the ISLES as well as internal consistency and concurrent associations with severity of mental and physical problems in two samples. The abbreviated Duke Social Support Index (DSSI) is an 11-item measure that was used to assess perceived social support (Koenig et al., 1993). The scale consists of two subscales, social satisfaction and social interaction, which were examined separately in this study. Prior research has demonstrated that this brief version of the DSSI is comparably effective as the original scale in predicting mental and physical health concerns in geriatric samples (Koenig et al., 1993). Plan of analysis We first examined bivariate correlations between each predictor variable and diurnal cortisol slope. Predictor variables that were found to be significantly associated with diurnal cortisol slope in the bivariate analyses (with a two-tailed p < 0.05) were then entered simultaneously into a multiple regression analysis to identify unique predictors of cortisol slope. Four cases had missing data for at least one of the independent variables, and these missing data were handled using multiple imputation. All analyses were performed in MPlus, version 6.11 (Muthén and Muthén, 1998–2010).
Results As shown in Table 2, in the bivariate analyses, severity of current depressive symptoms, number of comorbid DSM-IV axis 1 diagnoses, trait anxiety, and history of past depression were significantly associated with flattened (more abnormal) diurnal cortisol slopes. In addition, those who were more able to make sense of their identified stressor (as assessed by the ISLES – Comprehensibility subscale) had significantly
1535
steeper negative (healthier) diurnal cortisol slopes. Demographic factors, medication usage (antidepressants and estrogen hormone replacement therapy), current life stressors, past trauma, perceived stress, post-traumatic stress disorder (PTSD) symptoms, neuroticism, social support, resilience, and Footing in the World were not found to be significantly associated with diurnal cortisol slope. As shown in Table 3, when the five predictor variables that were found to be significantly associated with diurnal cortisol slope were entered simultaneously into a multiple regression analysis, only history of past depression (β = 0.27, p = 0.02) and the ability to make sense of a target stressor (β = −0.26, p = 0.05) remained statistically significant. As a whole, this multiple regression model accounted for 29.2% of the variability in diurnal cortisol slope, which was statistically significant at the p < 0.001 level.
Discussion In this study we found that (1) none of the global psychosocial stress measures were significantly correlated with dysregulated cortisol patterns; (2) specific assessments of current psychiatric symptomatology (i.e. depressive symptoms and number of comorbid DSM-IV axis I diagnoses), persistent distress (i.e. presence of past depressive episodes and trait anxiety), and resilience (i.e. sense made of a stressful life event) were associated with cortisol in the expected directions; and (3) previous episodes of depression and the ability to make sense of stressful events emerged as the two most robust predictors of cortisol in the statistical model. Several conclusions can be drawn from these results. First, these findings suggest that global assessments of stress, as assessed by checklists of stressful life events, may not be the most robust predictors of diurnal cortisol among depressed older adults. This pattern of results could be due to all of the older adults in this study meeting criteria for a depressive disorder. Most participants may have exceeded a threshold of life stress that is necessary for causing health problems, making the variation in levels of global stress in this sample less meaningful. Of course, it is also notable that many past studies have shown that older adults are often resilient in the aftermath of life stressors (Ong et al., 2009), which could indicate that simple summations of stressful life events may be a relatively poor indicator of one’s internal experience of distress. As hypothesized, high levels of current depressive symptoms, psychiatric comorbidities, past depressive episodes, greater trait anxiety, and
1536
J. M. Holland et al.
Table 2. Bivariate correlations with diurnal cortisol slope (N = 54) CORRELATION WITH DIURNAL CORTISOL SLOPE .........................................................................................................................................................................................................................................................................................................................
Demographic factors: Age Gender (0 = women, 1 = men) Ethnicity/race (0 = ethnic/racial minority, 1 = Caucasian) Years of education Marital status (0 = married, 1 = not married) Medication usage: Anti-depressant usage (0 = no anti-depressant, 1 = anti-depressant) Hormone replacement therapy (HRT) usage (0 = no HRT, 1 = HRT) Global measures of psychosocial stress: Stressful life events in the past year Past trauma – crime-related events Past trauma – general disaster and trauma Past trauma – physical and sexual abuse experiences Current perceived stress Current psychiatric symptomatology: Depressive symptoms Posttraumatic stress symptoms Number of comorbid DSM-IV axis I diagnoses Indicators of pervasive distress: Neuroticism Trait anxiety Presence of previous depressive episode Resilience and protective factors: Resilience Meaning made of stress – Comprehensibility Meaning made of stress – Footing in the World Social satisfaction Social interaction ∗p
0.070 − 0.244 − 0.224 0.027 − 0.110 − 0.105 − 0.143 0.154 − 0.191 − 0.119 0.157 0.232 0.280∗ 0.089 0.357∗∗ 0.211 0.328∗ 0.332∗ − 0.161 − 0.341∗ − 0.236 − 0.197 0.190
< 0.05, ∗∗ p < 0.01.
Table 3. Multiple regression analysis with diurnal cortisol slope as the dependent variable VARIABLE
B
SEB
β
.....................................................................................................................................................................................................................................................................
Severity of current depression (HRSD) Number of comorbid psychiatric diagnoses Trait anxiety (GAI) History of past depression Sense made of stress (ISLES – Comprehensibility)
0.000 0.003 0.000 0.010 −0.001
0.000 0.002 0.000 0.005 0.000
0.137 0.189 0.019 0.269∗ −0.260∗
∗p
< 0.05. B = Unstandardized Beta; SEB = Standard Error of Beta; β = Standardized Beta; HRSD = Hamilton rating scale for depression; GAI = geriatric anxiety inventory; ISLES = integration of stressful life experiences scale.
poorer ability to make sense of stress were found to be associated with flattened (more abnormal) cortisol slopes. However, when all of these predictor variables were entered simultaneously in a multiple regression model, it appeared that past depression and the ability to make sense of stressful events accounted for the majority of the explained variance in diurnal cortisol. The finding related to previous episodes of depression fits well with a theoretical model of cortisol dysregulation contributing to
depression through the accumulation of unmanaged stressors (Sapolsky et al., 1986; Holsboer, 2000). However, it is also possible that past depression contributes independently to current dysregulated cortisol. In particular, individuals with a latelife onset of depression and fewer episodes may be qualitatively distinct from those with a much earlier onset and a greater number of episodes. Specifically, it would seem reasonable to expect that sustained cortisol dysregulation may primarily stem
Psychosocial predictors of cortisol
from prolonged and chronic emotional distress. In contrast, depressive episodes that occur with a lower frequency and duration may not last long enough to bring about enduring physiological changes. Past research would seem to generally support this claim (Polk et al., 2005; Beluche et al., 2009). With regard to the ability to make sense of stressful events, multivariate results also indicated that persons who had adaptively assimilated their life stressors into current meaning structures were less at risk for cortisol dysregulation. In general, this finding aligns with an extensive literature that has shown that the ability to make sense of loss and other stressful life events can have a variety of physical and mental health benefits (Park, 2010). Given the link between psychiatric problems and cortisol dysregulation (Miller et al., 2007; Stetler and Miller, 2011), it was particularly notable that this finding emerged in a sample of already depressed older adults. Namely, in considering clinical samples of this sort, it might be equally important to gauge individuals’ ability to make sense of stressful events as it is to assess their current and past history of depressive symptomatology. Further, it may be that individuals who have dysregulated cortisol are less able to make meaning out of stressful events, but a longitudinal investigation would be required to examine the temporal precedence between these variables. This study is, of course, not without its limitations. In particular, this study is limited by its relatively small sample size, cross-sectional design, and lack of generalizability (e.g. the sample was mostly made up of Caucasian older adults with a fair amount of education). Future studies should attempt to replicate these findings with larger and more diverse samples and use a longitudinal design to better capture the temporal relations among these variables. We could only use the term “predictor” in a statistical sense in this paper and hope that future research will test whether a history of previous depressive episodes and an inability to make sense of stressful life events actually precede dysregulation of cortisol in other samples of geriatric patients. Studies that examine other biomarkers, such as indicators of immune functioning, inflammation, or cell aging, could also significantly advance this line of research in important ways. Notwithstanding these limitations and possibilities for further study, the present investigation is the first to simultaneously examine a comprehensive range of measures of stress and distress as predictors of diurnal cortisol among older adults with depression. The finding that previous episodes of depression and the ability to make sense of stressful events were the two most robust predictors of cortisol in this sample has important implications
1537
for identifying depressed elderly individuals who are most at-risk for health complications. From an intervention standpoint, these findings would suggest that treatments that aim to limit the chronicity of depression and help to increase the ability of clients to make sense of stressful events could potentially have a positive impact on health. For example, meaning-oriented components may be incorporated into traditional cognitive behavioral therapy (CBT) interventions (e.g. “re-authoring” the self-narrative; Neimeyer, 2009, p. 97) to help clients make sense of significant stressors and regain a sense of purpose and direction in life.
Conflict of interest None.
Description of author’s roles J.M. Holland participated in data collection, conducted all statistical analyses, and wrote the majority of the manuscript. J. Rengifo participated in data collection and assisted with the writing of the manuscript. J.M. Currier assisted with the writing of the manuscript. R. O’Hara was the coprincipal investigator for the study and assisted with the writing of the manuscript. K. Sudheimer assisted with the writing of the manuscript. D. Gallagher-Thompson was the principal investigator for the study and assisted with the writing of the manuscript.
Acknowledgments This study was funded by a National Institute of Mental Health (NIMH) exploratory/developmental research grant program (R21 MH091625-01, entitled: Predictors of Positive Outcome in Cognitive Behavior Therapy for Late Life Depression).
References Aldwin, C. M. (1990). The Elders Life Stress Inventory: egocentric and nonegocentric stress. In A. M. P. Stephens, J. H. Crowther, S. E. Hobfoll and D. L. Tennenbaum (eds.), Stress and Coping in Late Life Families (pp. 49–69). New York, NY: Hemisphere. Beluche, I. et al. (2009). Persistence of abnormal cortisol levels in elderly persons after recovery from major depression. Journal of Psychiatric Research, 43, 777–783. doi: 10.1016/j.jpsychires.2008.10.011. Brown, E. S. and Chandler, P. A. (2001). Mood and cognitive changes during systemic corticosteroid therapy.
1538
J. M. Holland et al.
The Primary Care Companion to the Journal of Clinical Psychiatry, 3, 17–21. doi: 10.4088/PCC.v03n0104. Brown, E. S., Varghese, F. P. and McEwen, B. S. (2004). Association of depression with medical illness: does cortisol play a role? Biological Psychiatry, 55, 1–9. doi: 10.1016/S0006-3223(03)00473-6. Chapman, D. P. and Perry, G. S. (2008). Depression and a major component of public health for older adults. Preventing Chronic Disease, 5, A22. http://www.cdc.gov/pcd/issues/2008/jan/07_0150.htm. Cohen, S., Kamarck, T. and Mermelstein, R. (1983). A global measure of perceived stress. Journal of Health and Social Behavior, 24, 385–396. doi: 10.2307/2136404. Dickerson, S. and Kemeny, M. E. (2004). Acute stressors and cortisol responses: a theoretical integration and synthesis of laboratory research. Psychological Bulletin, 130, 355–391. doi: 10.1037/0033-2909.130.3.355. Greden, J. F. et al. (1980). Normalization of dexamethasone suppression test: a laboratory index of recovery from endogenous depression. Biological Psychiatry, 15, 449–458. Greden, J. F., Gardner, R., King, D., Grunhaus, L., Carroll, B. J. and Kronfol, Z. (1983). Dexamethasone suppression tests in antidepressant treatment of melancholia. The process of normalization and test-retest reproducibility. Archives of General Psychiatry, 40, 493–500. doi: 10.1097/00004714-198310000-00025. Hamilton, M. (1960). A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry, 23, 56–61. doi: 10.1136/jnnp.23.1.56. Hjortskov, N., Garde, A. H., Ørbæk, P. and Hansen, A. M. (2004). Evaluation of salivary cortisol as a biomarker of self-reported mental stress in field studies. Stress and Health, 20, 91–98. Holland, J. M., Currier, J. M., Coleman, R. A. and Neimeyer, R. A. (2010). The Integration of Stressful Life Experiences Scale (ISLES): development and initial validation of a new measure. International Journal of Stress Management, 17, 325–352 . doi:10.1037/a0020892. Holland, J. M. et al. (2011). Cortisol outcomes among Caucasian and Latina/Hispanic women caring for a family member with dementia: a preliminary examination of psychosocial predictors and the effect of a psychoeducational intervention. Stress and Health, 27, 334–346. doi: 10.1002/smi.1375. Holsboer, F. (2000). The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology, 23, 477–501. doi: 10.1016/S0893-133X(00)00159-7. Hooper, L. M., Stockton, P., Krupnick, J. L. and Green, B. L. (2011). Development, use, and psychometric properties of the trauma history questionnaire. Journal of Loss and Trauma, 16, 258–283. doi: 10.1080/15325024.2011.572035. Ice, G. H. (2005). Factors influencing cortisol level and slope among community dwelling older adults in Minnesota. Journal of Cross-Cultural Gerontology, 20, 91–108. doi: 10.1007/s10823-005-9085-5. John, O. P., Naumann, L. P. and Soto, C. J. (2008). Paradigm shift to the integrative big five trait taxonomy: history, measurement, and conceptual issues. In O. P. John, R. W. Robins and L. A. Pervin (eds.), Handbook of Personality: Theory and Research (pp. 114–158). New York, NY: Guilford Press.
Koenig, H. G., Westlund, R. E., George, L. K., Hughes, D. C., Blazer, D. G. and Hybels, C. (1993). Abbreviating the Duke Social Support Index for use in chronically ill elderly individuals. Psychosomatics, 34, 61–69. doi: 10.1016/S0033-3182(93)71928-3. Kumari, M., Shipley, M., Stafford, M. and Kivimaki, M. (2011). Association of diurnal patterns in salivary cortisol with all-cause and cardiovascular mortality: findings from the Whitehall II study. Journal of Clinical Endocrinology and Metabolism, 96, 1478–1485. doi: 10.1210/jc.20102137. Ling, M. H., Perry, P. J. and Tsuang, M. T. (1981). Side effects of corticosteroid therapy. Psychiatric aspects. Archives of General Psychiatry, 38, 471–477. doi: 10.1001/ archpsyc.1981.01780290105011. Liotti, M., Mayberg, H. S., McGinnis, S., Brannan, S. L. and Jerabek, P. (2002): Unmasking disease-specific cerebral blood flow abnormalities: mood challenge in patients with remitted unipolar depression. American Journal of Psychiatry, 159, 1830–1840. doi: 10.1176/appi.ajp.159.11.1830. Miller, G., Chen, E. and Zhou, E. (2007). If it goes up, must it come down? Chronic stress and the hypothalamic-pituitary-adrenocortical axis in humans. Psychological Bulletin, 133, 25–45. doi: 10.1037/0033-2909.133.1.25. Moskowitz, J. T. and Epel, E. S. (2006). Benefit finding and diurnal cortisol slope in maternal caregivers: a moderating role for positive emotion. The Journal of Positive Psychology, 1, 83–91. doi: 10.1080/17439760500510510. Muthén, L. K. and Muthén, B. O. (1998–2010). Mplus User’s Guide, 6th edn. Los Angeles, CA: Muthén & Muthén. Neimeyer, R. A. (2009). Constructivist Psychotherapy: Distinctive Features. New York, NY: Routledge. Ong, A. D., Bergeman, C. S. and Boker, S. M. (2009). Resilience comes of age: defining features in later adulthood. Personality, 77, 1777–1804. doi: 10.1111/j.1467-6494.2009.00600.x. Pachana, N. A., Byrne, G. J., Siddle, H., Koloski, N., Harley, E. and Arnold, E. (2007). Development and validation of the Geriatric Anxiety Inventory. International Psychogeriatrics, 19, 103–114. doi: 10.1017/ S1041610206003504. Park, C. L. (2010). Making sense of the meaning literature: an integrative review of meaning making and its effects on adjustment to stressful life events. Psychological Bulletin, 136, 257–301. doi:10.1037/a0018301. Polk, D. E., Cohen, S., Doyle, W. J., Skoner, D. P. and Kirschbaum, C. (2005). State and trait affect as predictors of salivary cortisol in healthy adults. Psychoneuroendocrinology, 30, 261–272. doi: 10.1016/ j.psyneuen.2004.08.004. Radloff, L. S. (1977). The CES-D scale: a self-report depression scale for research in the general population. Applied Psychological Measurement, 1, 385–401. doi: 10.1177/014662167700100306. Rosal, M. C., King, J., Ma, Y. and Reed, G. (2004). Stress, social support, and cortisol: inverse associations? Behavioral Medicine, 30, 11–21. doi: 10.3200/BMED.30.1.11-22. Sapolsky, R. M., Krey, L. C. and McEwen, B. S. (1986). The neuroendocrinology of stress and aging: the
Psychosocial predictors of cortisol glucocorticoid cascade hypothesis. Endocrine Reviews, 7, 284–301. doi: 10.1210/edrv-7-3-284. Sheehan, D. V. et al. (1998). The mini-international neuropsychiatric interview (M.I.N.I): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. Journal of Clinical Psychiatry, 59, 22–33. Simpson, E. A., McConville, G. R., O’Conner, J. M., Stewart-Knox, B. J., Coudray, C. and Strain, J. J. (2008). Salivary cortisol, stress and mood in healthy older adults: the Zenith study. Biological Psychology, 78, 1–9. doi: 10.1016/j.biopsycho.2007.12.001. Stetler, C. and Miller, G. E. (2011). Depression and hypothalamic-pituitary-adrenal activation: a quantitative summary of four decades of research. Psychosomatic Medicine, 73, 114–126. doi: 10.1097/ PSY.0b013e31820ad12b. Thoresen, S., Tambs, K., Hussain, A., Heir, T., Johansen, V. A. and Bisson, J. I. (2010). Brief measure of posttraumatic stress reactions: impact of Event Scale-6.
1539
Social Psychiatry and Psychiatric Epidemiology, 45(3), 405–412. doi: 10.1007/s00127-0090073-x. Vaishnavi, S., Connor, K. and Davidson, J. R. T. (2007). An abbreviated version of the Connor-Davidson Resilience Scale (CD-RISC), the CD-RISC2: psychometric properties and applications in psychopharmacological trials. Psychiatry Research, 152, 293–297. doi: 10.1016/j.psychres.2007.01.006. van Eck, M. M., Nicolson, N. A., Berkof, H. and Sulon, J. (1996). Individual differences in cortisol responses to a laboratory speech task and their relationship to responses to stressful daily events. Biological Psychology, 43, 69–84. doi: 10.1016/0301-0511(95)05159-7. Zobel, A. W., Nickel, T., Sonntag, A., Uhr, M., Holsboer, F. and Ising, M. (2001). Cortisol response in the combined dexamethasone/CRH test as predictor of relapse in patients with remitted depression: A prospective study. Journal of Psychiatric Research, 35, 83–94. doi: 10.1016/S0022-3956(01)00013-9.
