A longitudinal study of the role of cortisol in posttraumatic stress disorder symptom clusters.

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A longitudinal study of the role of cortisol in posttraumatic stress disorder symptom clusters a

Laura Stoppelbein & Leilani Greening

b

a

Department of Psychology, CH415, University of Alabama, Third Avenue South, Birmingham, AL 35294, USA b

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Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA Accepted author version posted online: 14 May 2014.Published online: 17 Jun 2014.

To cite this article: Laura Stoppelbein & Leilani Greening (2015) A longitudinal study of the role of cortisol in posttraumatic stress disorder symptom clusters, Anxiety, Stress, & Coping: An International Journal, 28:1, 17-30, DOI: 10.1080/10615806.2014.923844 To link to this article: http://dx.doi.org/10.1080/10615806.2014.923844

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Anxiety, Stress, & Coping, 2015 Vol. 28, No. 1, 17–30, http://dx.doi.org/10.1080/10615806.2014.923844

A longitudinal study of the role of cortisol in posttraumatic stress disorder symptom clusters Laura Stoppelbeina* and Leilani Greeningb


a

Department of Psychology, CH415, University of Alabama, Third Avenue South, Birmingham, AL 35294, USA; bDepartment of Psychiatry and Human Behavior, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA (Received 17 January 2013; accepted 9 May 2014) Background and Objectives: Research examining the role of cortisol in posttraumatic stress disorder (PTSD) has largely been cross-sectional studies and few studies have examined cortisol in relation to specific symptom clusters. Examining cortisol in relation to specific PTSD symptom clusters could aid in identifying candidates for symptom-specific treatments. Hence, cortisol was examined in relation to specific PTSD symptom clusters including reexperiencing, avoidance, numbing, and hyperarousal symptoms. Design: A repeated-measures longitudinal design was utilized to predict PTSD symptom clusters. Methods: Mothers of children (N = 27) diagnosed with cancer completed a measure of PTSD, and they provided salivary cortisol samples at the time of their child’s diagnosis as well as monthly for the following 12 months. Results: Multi-level modeling analyses revealed that higher cortisol levels were significantly related to higher levels of numbing symptoms. Although numbing symptoms declined as cortisol levels declined across 12 months postcancer diagnosis, mothers with higher cortisol levels still reported more numbing symptoms. Reexperiencing, avoidance, and hyperarousal symptoms were not found to be related to cortisol level across time. Conclusions: The findings offer support for the role of cortisol in the manifestation of numbing symptoms. Further research is recommended with other trauma groups to maximize generalizations. Keywords: cortisol; etiology; neurobiology; posttraumatic stress disorder; women

Research has revealed that as many as 25% of parents of children diagnosed with cancer exhibit posttraumatic stress disorder (PTSD; Pelcovitz et al., 1996) and even more exhibit posttraumatic stress symptoms (PTSS; Manne, DuHamel, Gallelli, Sorgen, & Redd, 1998; Stoppelbein & Greening, 2007). The psychosocial impact of PTSS is far reaching and can include higher risks for comorbid disorders including major depression, suicidality, and anxiety disorders (Brady, Killeen, Brewerton, & Lucerini, 2000; Manne et al., 1998), as well as increased risks for absenteeism from work, unemployment, and the high utilization of health-care services (Hoge, Terhakopian, Castro, Messer, & Engel, 2007). These repercussions underscore the importance of investigating factors contributing to the onset and development of PTSS and PTSD. While a number of psychological and psychosocial variables are linked to PTSD/ PTSS, neurobiological processes are receiving increasing attention as possible factors *Corresponding author. Email: [email protected] © 2014 Taylor & Francis


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L. Stoppelbein and L. Greening

linked to the onset and exacerbation of these symptoms. One system that is often investigated is the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis mediates the stress response through the release of corticotrophin releasing factor (CRF) from the hypothalamus, which in turn stimulates the release of adrenocorticotropin releasing hormone (ACTH) from the pituitary gland. ACTH then stimulates the release of cortisol from the adrenal glands, which acts as part of a feedback loop to regulate HPA axis activity. Although the role of the HPA axis has been examined through cortisol measurements, reviews of the literature have yielded inconclusive findings. Meewisse, Reitsma, de Vries, Gersons, and Olff (2007), for example, conducted a meta-analysis of 37 studies examining basal cortisol level among adults with PTSD and control groups and found no significant differences in their cortisol levels. However, there was significant heterogeneity in the results between the studies, suggesting that population characteristics and methodological factors may have confounded the results. When these factors were taken into consideration, Meewisse et al. (2007) observed lower cortisol levels among females with PTSD as well as survivors of sexual or physical abuse with PTSD, when they were compared to either a non–trauma-exposed control group or a non–PTSD trauma-exposed control group. Others reviewing the role of neuroendocrine factors in PTSD have reported similar methodological confounds in studies conducted to date (e.g., Rasmusson, Vythilingam, & Morgan, 2003). In addition to methodological confounds, there has been very limited research examining how the four symptom clusters of PTSD identified by the American Psychiatric Association (2013) in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) are related to cortisol and to changes in cortisol over time. The four symptom clusters are supported by factor analytic research (Simms, Watson, & Doebbelling, 2002) and include (i) reexperiencing and intrusive symptoms, (ii) avoidance, (iii) emotional numbing, and (iv) hyperarousal symptoms. We propose that examining symptom cluster-cortisol specific relations could be useful because it could be that specific symptom clusters are more closely associated with cortisol/HPA axis functioning, which could help explain the equivocal findings reported to date. For example, while reexperiencing and intrusive symptoms have largely been linked to high levels of cortisol in the literature (DeQuervain, 2008; Goenjian et al., 1996), PTSD has been found to be related to both high and low levels of cortisol. Although limited, there are studies that have attempted to link specific symptom clusters to cortisol level including Delahanty, Raimonde, and Spoonster (2000) who observed a negative relation between cortisol level at the time of an motor vehicle accident (MVA) and reexperiencing/intrusive and avoidance symptoms 1 month later. In addition to limited research on the specific symptom clusters, the majority of the studies examining cortisol in relation to PTSD have examined the relation at one point in time. Using a single assessment precludes examining the relation over time. However, in the few longitudinal studies conducted to date, the relation between cortisol and PTSD has been examined with assessments conducted at varying intervals including several days to several months even years after trauma exposure rather than soon after trauma exposure followed by systematic cortisol assessments over time. Delahanty and his colleagues, for example, examined urinary cortisol at the time of a MVA and found that lower levels of cortisol predicted PTSS 4–6 weeks later among adults (Delahanty et al., 2000; Delahanty, Raimonde, Spoonster, & Cullado, 2003), but that higher levels of cortisol predicted PTSS among child victims (Delahanty, Nugent, Christopher, & Walsh, 2005).


Anxiety, Stress, & Coping

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Similarly, Resnick and her colleagues (Resnick, Yehuda, Pittman, & Foy, 1995) found that lower cortisol in the days following a rape was predictive of future PTSS among survivors who had a previous history of assault; whereas survivors with no history of previous assaults were at risk for PTSS if they exhibited higher cortisol levels following high-severity rapes. The follow-up assessments were completed, on average, 4 weeks to 3 months posttrauma. In a study of firefighters who were followed for as long as 2 years, Heinrichs et al. (2005) did not find cortisol level prior to firefighting training to be predictive of PTSD 24 months later. Although data on the risk of PTSD were collected systematically at 6, 9, 12, and 24 months following training, the pattern of change in cortisol and PTSD across time was not evaluated. In another longitudinal study, of mothers with children diagnosed with cancer, cortisol was found to be positively related to PTSD from the time of the child’s diagnosis with cancer and up to 12 months later (Stoppelbein, Greening, & Fite, 2012). It is further noted that in addition to unsystematic and varying lengths of time for follow-up assessments, there are a limited number of studies that have examined cortisol in relation to specific symptom clusters longitudinally, thereby further precluding conclusions about how cortisol is related to specific symptoms. Hawk et al. (2000) examined specific symptoms of PTSD and did not find support for a symptom cluster–cortisol specific relation 1 month after a MVA; however, they did find a significant negative relation between cortisol 1 month postaccident and numbing symptoms 6 months later. Since Hawk et al. did not examine the relation between cortisol and specific symptom clusters at monthly intervals systematically at regular intervals after trauma exposure, it is not possible to speculate about the specific symptom cluster–cortisol relations across time. For example, even though low cortisol at 1 month posttrauma was related to numbing symptoms 6 months later, did cortisol increase with numbing symptoms across the 6 months? By examining the relation between cortisol and specific symptom clusters with more frequent posttrauma assessments across time following trauma exposure, we would be able to examine the pattern of changes and obtain a more process-oriented perspective of the relation between cortisol and PTSS/PTSD. Furthermore, given that some symptom clusters have been found to be more predictive of PTSD in the future, examining the role of cortisol in the manifestation of more specific symptom clusters could prove beneficial from both a physiological and clinical perspective (Brewin, Andrews, Rose, & Kirk, 1999; Kangas, Henry, & Bryant, 2005). For example, as emphasized by Davidson and van der Kolk (1996), treatments such as pharmacological agents “need to be targeted at specific subsets of symptoms” of PTSD to be effective. Hence, the purpose of the present study was to assess the relation between cortisol and specific symptom clusters of PTSD longitudinally, from the onset of trauma exposure and at multiple intervals up to 1 year after exposure. Participants included mothers of children diagnosed with new-onset pediatric cancer. In addition to their child being diagnosed with a life-threatening illness, these women witnessed their children endure painful treatments for the next 10–12 months. Time was expected to be inversely related to the severity of PTSS across the four symptom clusters, with the highest levels of symptoms occurring at the time of the cancer diagnosis because of the initial threat associated with the diagnosis. Cortisol was expected to be positively related to PTSS clusters at monthly assessments, and changes in symptoms across time were expected to be a function of cortisol. The dependent variables were the four symptom clusters identified by the American Psychiatric Association (2013) in the DSM-5.

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Methods Participants This study was approved by the Institutional Review Board before initiating recruitment. Thirty-three mothers of children diagnosed with cancer within the past 1–2 weeks were approached at a university medical center’s pediatric oncology service to participate. One mother declined citing lack of interest, and two women were excluded because they were not the biological mother. Other exclusion criteria included history of a psychiatric diagnosis or substance abuse and an endocrine disorder or use of synthetic glucocorticoid, exogenous steroid treatment, or exposure to a traumatic event other than their child’s cancer diagnosis, within the past month. Three mothers were excluded for one of these latter criteria, leaving a total of 27 participants. The participants ranged from 22 to 43 years of age (M age = 30.13, SD = 5.74), and their children were on average 7.5 years old at the time of their cancer diagnosis (SD = 5.90). Approximately half (52%) of the mothers were African-American; the remaining were Caucasian (48%). Most of the women (48%) were married to the child’s father, the others were either separated/ divorced (26%), never married (17%), or remarried (9%). At the conclusion of the study, all of the children had been treated with chemotherapy and 14% had also received radiation.

Materials Demographic and health interview Participants completed a brief interview about their child’s disease, demographic (e.g., age, marital status) and maternal health–related information (e.g., use of medications, psychiatric history, smoking, length of time since last menses). Demographic data were used to compute a Hollingshead Index (1975) as a measure of socioeconomic status (SES). Life events checklist The Life Events Checklist (LEC) is a 16-item list of traumatic events that was patterned after Breslau’s (2001) measure of exposure to traumatic events. Respondents indicated whether they personally experienced or witnessed someone experience the listed event and how long ago the event occurred. The total sum score for exposure was used in the analyses. Posttraumatic stress disorder checklist – civilian version The Posttraumatic Stress Disorder Checklist – Civilian Version (PCL-C) is a 17-item selfreport measure of PTSD symptoms for adults (Weathers, Litz, Herman, Huska, & Keane, 1993). Mothers indicated on a 5-point Likert scale ranging from 1 (not at all) to 5 (extremely) how much they agreed with statements pertaining to PTSD symptomatology in response to their child being diagnosed with cancer. A cut-off score ≥50 merits a PTSD diagnosis (Weathers et al., 1993). Internal consistency is high, Cronbach α = .94 and was high in the present study, α = .95, for the total scale. Cronbach αs were high to acceptable for each of the symptom clusters across the 12-month assessment period (α = .86–.94 for reexperiencing symptoms, .81–.90 for avoidance symptoms, .85–.91 for the numbing


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symptoms, and .80–.91 for hyperarousal symptoms). Construct validity is supported by high correlations, r values > .75, with other established measures of PTSD (Conybeare, Behar, Solomon, Newman, & Borkovec, 2012), including a structured interview (Andrykowski, Cordova, Studts, & Miller, 1998). The PCL-C has also demonstrated good sensitivity, .71, and specificity, .87 (Stoppelbein & Greening, 2007).


Cortisol Salivary cortisol provides a reliable and accurate index of free plasma cortisol and avoids confounds that could arise from the stress of drawing blood intravenously (Bhagwagar, Hafizi, & Cowen, 2002). Approximately 2 ml of saliva were collected from each participant using a preweighed Salivette kit and stored in a subzero freezer at 80°C until all data collection was completed. A displacement radioimmunoassay procedure was used to analyze the samples. The saliva samples were extracted with ethanol, lyophilized, and reconstituted using the buffer provided in the corticosterone radioimmunoassay kit (MP Biomedicals, Orangeburg, NY, formerly ICN Biomedical). Kit instructions were followed with the following modifications: except for standards all reagents are used at half strength; the lowest kit standard (12.5 ng) was serially diluted twice to yield 6-ng and 3-ng standards. Duplicate samples were analyzed as a group in a single assay after completing data collection for the study to prevent possible confounds with interassay variability. Intra-assay variability was 0.01% for these samples. Cortisol levels were evaluated as a continuous variable with a range of 3 nmol/ml to approximately 16 nmol/ml.

Procedure After obtaining approval from the medical center’s Institutional Review Board, mothers were informed about the study, provided written consent, and then completed the demographic and health interview, the LEC, and the PCL-C 1–2 weeks after their child was diagnosed with cancer. The mothers also provided a saliva sample between 3:00 and 5:00 p.m. on the day of the initial assessment; and then second and third samples between 6:00 and 8:00 a.m. and 3:00 and 5:00 p.m., respectively, the following day. The researcher confirmed that at least 45 minutes had passed since the participant had consumed food, liquid, or used tobacco prior to obtaining each saliva sample. Monthly follow-up assessments were conducted in which the mothers completed the LEC and the PCL-C. They also provided three saliva samples at the same time as designated at the initial assessment. These follow-up assessments were conducted for 12 months and occurred in the medical facility while the child received outpatient or inpatient treatment. If the child was being treated on an outpatient basis, the mother completed the measures at the clinic and was given verbal and written instructions on the procedure for collecting the saliva samples for the following day at home. A research assistant telephoned the mothers at the times designated for collecting the saliva samples to remind them and to follow-up on their compliance with the instructions. This cortisol sampling procedure allowed us to collect saliva for a 24-hour period with as much experimental control as possible with in-home collections and to maximize compliance. The participants were instructed to store their collected samples in a freezer until a courier arrived within 24 hours to collect the samples. Salivary cortisol is stable at room temperature or colder

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for 2–3 weeks (Groschl, Wagner, Rauh, & Dorr, 2001). If the child was treated on an inpatient basis, a researcher collected the three saliva samples at the designated times. All saliva samples were stored in a subzero freezer until data collection was completed. Participants were compensated for their participation.


Data analyses Preliminary analyses included examining the participant’s mean PCL-C score at each assessment. The area under the curve (AUC) with respect to ground was also calculated to assess cortisol levels for each assessment point. The AUC with respect to ground was used to estimate changes in diurnal hormone secretions and to assess overall hormonal output over time (Pruessner, Kirschbaum, Meinlschmid, & Hellhammer, 2003). Previous research suggests that PTSS is significantly related to demographic variables such as age and SES (Norris & Slone, 2007) and that cortisol is related to women’s menstrual cycle (Symonds, Gallagher, Thompson, & Young, 2004). Hence, demographic variables, phase of menstrual cycle, PTSS clusters, and cortisol were examined in correlational analyses as possible covariates. The date of the respondent’s last menses was used to determine the phase of menstrual cycle.

Longitudinal analyses The primary goal of the study was to examine the relation between cortisol and PTSS clusters longitudinally using repeated measurements across time. Since the observations of each mother at each month were likely dependent (i.e., repeated measures nested within participants), a statistical approach that accounts for the dependency in the data was necessary. Hence, an approach that is commonly used to analyze longitudinal data – mixed-effects model – was used to test the hypothesis that high AUC would predict higher PTSS across time. Although mixed-effects models focus initially on the regression relationship restricted to observations on a single individual, the model is then extended to multiple individuals by allowing some pieces of the model to vary from individual to individual in a proscribed manner while other components remain the same. In other words, constructing a mixed-effects model focuses on the introduction of random effects – the pieces of the model that vary across individuals – in addition to the fixed effects of factors of interest, that is, factors that are assumed identical for every individual. Mixed models are called “mixed” because they use both fixed and random effects in the same analyses. These models correspond to a hierarchy of levels with the repeated, correlated measurements occurring among all of the lower level units for each particular upper level unit. For example, the repeated measures in this study were nested within mothers; hence, hierarchically the measurements would be lower level units that are subsumed under a higher level unit, which is the participant. The mixed-effects model also indirectly describes and interprets the covariance structure in longitudinal observations. Hence, a series of mixed-effects regression equations for each PTSS cluster was estimated and evaluated while controlling for the other three symptom clusters to test if each symptom cluster was a function of cortisol. It is noted that the mixed-model regression approach has significant advantages over other approaches to modeling repeated-measures data collected longitudinally. Specifically, allowing individual scores to vary from the overall group mean reduces error in the



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model, which ultimately increases power (Raudenbush & Bryk, 2002). In addition, by using maximum likelihood estimation, the random-effects model allows for all available data on each participant to be included and is not affected by randomly missing data points (Gueorguieva & Krystal, 2004). Since further discussion of the mixed-effects model is beyond the scope of this paper, it is recommended that Raudenbush and Bryk (2002) be reviewed for further information. When considering sample size for mixed models that examine individual changes longitudinally, it is recommended that the person-by-time observations be used to determine power (Muthen & Curran, 1997). The present study’s 324 person-by-time observations offer more than adequate power to detect effects in spite of the relatively small sample size (Raudenbush & Bryk, 2002). Models were estimated using SAS Proc Mixed version 9.3 with maximum likelihood estimation (Littell, Milliken, Stroup, & Wolfinger, 1996). Each model included a random intercept, which permits estimation of individual variability. In addition, time-varying predictors were included in the models. Time-varying predictors are variables that vary from one assessment to another. The specific models that tested cortisol AUC (i.e., overall hormonal output over the 24-hour period) as a predictor of PTSS clusters longitudinally were estimated in three steps. First, linear and quadratic effects of time were estimated to determine how the outcome variable (PTSS cluster) changed over time while controlling for the other three symptom clusters. After the best fitting model for time was established, cortisol AUC was added as a time-varying predictor to determine whether the predictor variable predicted the outcome variable. Finally, the Time × Cortisol AUC interaction was tested to examine whether change in the outcome variable depended on the level of the predictor variable longitudinally. When a significant interaction was detected, the regression model was conditioned at high and low levels of the independent variable (1 SD above and below the sample mean) to examine the nature of the interaction as recommended by Aiken and West (1991).

Results Descriptive statistics for the PCL-C revealed that the mean PCL-C score for the women fell below the clinical cut-off score of 50 at each of the 12 assessment points (M = 29.24–39.87, SD = 11.21–15.67), with the highest scores occurring at the time of diagnosis. The percentage of mothers above the clinical cut-off score for the total PCL-C ranged from 26% at the initial assessment to 4% at the 12-month assessment. Descriptive statistics for the PTSS clusters revealed that mean scores for the reexperiencing cluster ranged from 7.58 to 10.83 (SD = 3.34–5.20), from 2.81 to 4.93 (SD = 1.56–2.69) for the avoidance cluster, from 8.07 to 10.65 (SD = 2.15–4.73) for the numbing cluster, and from 10.47 to 13.91 (SD = 4.31–5.56) for the hyperarousal symptom cluster across the 12 assessment points (see Table 1). In cross-sectional analyses, cortisol AUC was observed to be significantly related to reexperiencing (r values = .44–.74, p < .05), avoidance (r values = .33–.73, p > .05), and numbing symptoms (r values = .37–.78, p < .05) at each assessment point with the exception of months 1, 2 and 5; whereas cortisol AUC was significantly related to hyperarousal symptoms (r values = .44–.81, p < .05) across all assessment points except at diagnosis as well as at months 1, 2, and 5. Finally, correlational analyses revealed that age, SES, tobacco use, LEC score, and stage of menstrual cycle were not significantly related to either cortisol AUC or to any of the PTSS clusters.

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Table 1. Means and SDs for reexperiencing, avoidance, numbing, and hyperarousal symptoms and cortisol across time.


Reexperiencing

Baseline Month 1 Month 2 Month 3 Month 4 Month 5 Month 6 Month 7 Month 8 Month 9 Month 10 Month 11 Month 12

Numbing

Avoidance

Hyperarousal

Cortisol AUC

M

SD

M

SD

M

SD

M

SD

M

SD

N

10.83 9.63 9.57 9.42 9.42 8.75 8.50 8.21 8.21 8.22 7.58 8.00 7.66

5.20 4.66 4.18 4.24 4.37 4.86 3.99 3.99 3.34 3.69 3.59 4.05 4.26

10.65 9.57 9.73 9.69 9.53 9.91 9.42 9.06 8.78 8.42 8.38 8.19 8.07

4.43 4.13 3.65 4.11 4.42 4.73 4.27 3.93 3.75 3.17 3.44 2.15 3.53

4.48 3.86 4.55 4.93 4.24 3.93 3.63 3.55 3.61 3.33 3.21 3.28 2.81

2.69 1.79 2.09 2.17 2.19 2.03 1.77 2.04 1.94 1.61 1.75 1.81 1.56

13.91 12.86 13.54 12.47 13.24 12.23 11.42 11.29 11.15 10.47 10.61 10.50 10.70

5.56 5.31 4.90 4.50 5.53 4.64 4.63 4.93 5.10 4.40 4.31 4.99 4.60

2.46 2.44 2.33 2.88 3.03 3.18 3.86 2.54 2.20 2.76 3.49 3.11 1.86

1.97 2.42 1.78 4.04 3.63 3.80 7.84 3.59 1.25 2.29 4.62 4.44 1.18

27 27 26 27 25 26 27 27 26 27 27 25 27

AUC, area under the curve; M, mean; SD, standard deviation; N, sample size.

Tests of relation between cortisol AUC and PTSS clusters longitudinally To test the relation between cortisol AUC and the four PTSS clusters longitudinally, we conducted mixed-model regression analyses with cortisol AUC as the predictor variable and a PTSS cluster (e.g., reexperiencing symptoms) as the criterion variable. There were significant random intercepts observed for each PTSS cluster (zs = 10.33–10.46, p < .0001). There was also a linear effect of time (B = −.08 to −.17, p < .001); however, the addition of the quadratic effect was not significant in either equation (B = −.01 to .01). As a result, subsequent models for predicting each of the PTSS clusters only included the linear effect of time. Cortisol AUC was then added to the model while controlling for the other three PTSS clusters and time but did not emerge as a significant predictor (B = −.01, p > .05). The interaction variable, Time × Cortisol AUC, was then added to each model and a statistically significant effect was observed for the numbing symptom cluster only (B = −.02, p < .01). Exploratory analyses were subsequently performed to examine the nature of the significant interaction effect for numbing symptoms, which entailed dividing the participants into two groups – high versus low cortisol AUC groups – with the high group representing the mothers who obtained cortisol levels that are one or more standard deviations above the mean and the mothers in the low cortisol group obtained scores that are one or more standard deviations below the mean. Variation in the numbing symptoms for these two groups was examined across the 12 months following their child’s cancer diagnosis. The findings revealed that the numbing symptoms decreased over time for the high-level cortisol group (B = −.64, p < .001); whereas there was not a statistically significant change across time for this symptom cluster for the low cortisol group (B = .02, p = .21; see Figure 1). The relation between cortisol AUC and total PTSS was also examined using mixedmodel regression analyses with cortisol AUC as the predictor variable and the PCL-C sum score as the criterion variable. As observed for the PTSS clusters, there was significant


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6

5 High cortisol

Low cortisol

Centered numbing symptom scores


4

3

2

1

0

-1

-2

0

1

2

3

4

5

6 7 Time (months)

8

9

10

11

12

Figure 1. Interaction effect: centered score for numbing symptoms at each monthly assessment for women with high and low levels of cortisol.

linear effect, such that PTSS decreased across time (B = −.59, p < .0001), but there was no significant effect for a quadratic trend (B = .01, p > .05). Hence, only the linear effect of time was retained in subsequent models. Models included a significant random intercept, z = 3.14, p = .001, suggesting individual variability in overall levels of PTSS. Cortisol AUC was then added to the model and emerged as a significant predictor of total PTSS, such that higher levels of cortisol AUC were associated with higher levels of PTSS (B = .12, p = .02). Finally, the interaction variable, Time × Cortisol AUC, was included in the model, revealing a significant interaction (B = −.05, p = .006). The model was conditioned at high and low levels of cortisol AUC (i.e., ≥1 SDs ± the mean, respectively) to examine the nature of the interaction, which revealed that PTSS decreased across time among the mothers with high levels of cortisol (B = −.97, p < .0001), but did not change across time for mothers with low levels of cortisol (B = .003, p > .05).

Discussion PTSD is a syndrome that includes the manifestation of symptoms from four different categories – reexperiencing, avoidance, numbing, and hyperarousal – that have been supported by factor analytic studies (Simms et al., 2002). As predicted, we found that cortisol level – a measure of stress response – was positively related to each of these clusters of symptoms when examined cross-sectionally. But when examined longitudinally and after controlling for the other three symptom clusters, cortisol predicted only one


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cluster of symptoms – numbing symptoms. These findings are consistent with previous studies examining PTSS (e.g., DeQuervain, 2008; Hawk et al., 2000; Stoppelbein et al., 2012), but do not support the report of Glover and Poland (2002) of lower 24-hour urinary cortisol secretion among mothers of children with cancer and who also met criteria for PTSD, when compared to mothers without PTSD. However, more recent longitudinal research with mothers of children diagnosed with cancer supports a positive relation between PTSD and cortisol (Stoppelbein et al., 2012). Explanations for equivocal findings to date on the relation between PTSS and cortisol have included methodological issues, with one being the timing of assessments since trauma exposure. Glover and Poland (2002), for example, assessed mothers more than 1 year posttrauma exposure, whereas others have waited up to 5 years after trauma exposure before conducting assessments (Goenjian et al., 1996). We found when examining the mothers’ PTSS from the initial point of trauma exposure (i.e., child’s cancer diagnosis) and at successive months for 12 months that cortisol was positively related to numbing symptoms at each month and that cortisol-predicted numbing symptoms across the 12 months. Although the mothers with high levels of cortisol were at risk for numbing symptoms and they exhibited more symptoms than the mothers with low levels of cortisol, their numbing symptoms declined as time passed. Perhaps the mothers with high levels of cortisol were more vulnerable because they were more physically reactive to the threat associated with their child’s cancer diagnosis including the painful medical treatments and the uncertainty of their child’s prognosis. Although cortisol AUC was found to be positively related to reexperiencing, avoidance and hyperarousal symptoms within each assessment point, no interaction effects were observed across time. Other research (e.g., Bierer et al., 2006) has also failed to support a relation between cortisol and these symptoms longitudinally. One explanation for these findings includes evidence suggesting that any number of neurotransmitters among the cascade of neurochemical reactions to traumatic events may account for the manifestation of the different PTSS clusters (Neumeister, Henry, & Krystal, 2007). Serotonin depletion, for example, has been linked to exaggerated emotional arousal and might play more of a prominent role in hyperarousal symptoms than other neurotransmitters (van der Kolk, 1996). A second possible explanation for the equivocal findings on the relation between cortisol and PTSS might include the trauma survivors’ past trauma history. Low levels of cortisol, for example, has been linked to more PTSS among trauma survivors with past trauma exposure, whereas high levels of cortisol have been linked to more PTSS among survivors with no previous history of trauma exposure (Resnick et al., 1995). Hence, future research evaluating specific symptom cluster–cortisol relations might include comparisons among survivors with and without previous trauma exposure. Interestingly, correlations between cortisol and PTSS clusters were not found to be significant 1, 2, and 5 months after the children were diagnosed with cancer in the present study. There were no known medical events or other events that were specific to these time points and that would account for the lack of significant relations. Perhaps the relations were not significant at months 1 and 2 because the mothers were still in shock from the diagnosis and mobilizing their efforts toward initiating treatment and providing support for their child and hence were not yet experiencing PTSS. Not finding a relation at month 5 might be an artifact of the upcoming 6-month anniversary of the child’s cancer diagnosis and PTSS symptoms being experienced regardless of cortisol level because of



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the anticipation of this half-year mark. This hypothesis is highly speculative; hence, further longitudinal research is recommended. It is postulated that since not all trauma survivors develop PTSS, some individuals may be more susceptible to developing symptoms. One risk factor for developing PTSS could be a hypersensitive HPA axis. As observed in the present study, women with higher cortisol levels, which suggests a more reactive HPA axis, tended to report more reexperiencing, avoidance, numbing, and hyperarousal symptoms at each assessment point. Interestingly, the women with higher cortisol levels showed a decline in numbing symptoms across time, yet their cortisol level and scores for numbing symptoms were still higher than the women in the low-cortisol/low-PTSS group. Hence, the women with low cortisol levels did not appear as vulnerable to these symptoms as women with high cortisol levels. Perhaps exposure to stressful medical procedures and reminders about the uncertainty of their child’s prognosis contributed to the hyperreactive women’s higher PTSS during the year postdiagnosis, as exposure to trauma reminders has been found to be related to higher cortisol levels among trauma survivors (Elzinga, Schmahl, Vermetten, van Dyck, & Bremner, 2003; Stoppelbein et al., 2012). High levels of cortisol may, in turn, increase the risk of numbing symptoms.

Clinical implications Identifying women with high cortisol levels at the time of traumatic exposure or soon after may assist with triage for treating PTSS. Given that research has shown that PTSS is predictive of future PTSD, intervening at the time of trauma exposure might aid with minimizing the risk of further PTSS as well as PTSD. Trauma-focused cognitive– behavioral treatment and other treatments (e.g., pharmacological agents) found to be effective for treating PTSD, for example, may be provided at this stage as a preventive measure rather than waiting until survivors develop PTSD. Survivors with high levels of cortisol might be targeted for such treatments because of their possible greater risk. It is further recommended that exposure to trauma-related stimuli and further stress should be minimized and/or prevented after trauma exposure because trauma survivors exhibiting higher levels of cortisol might be more vulnerable to heightened levels of PTSS than individuals who do not show elevated levels of cortisol at the time of trauma exposure.

Methodological limitations This is the first study known to date that investigated the relation between cortisol and specific symptom clusters of PTSD longitudinally from the time of trauma exposure and at monthly intervals over the course of a year. Nevertheless, there are some methodological shortcomings to consider. First, although the relatively small sample size might initially be regarded as a limitation, the present sample size is consistent with similar studies (Glover & Poland, 2002; Stoppelbein et al., 2012) and the current study’s 324 person-by-time observations provided adequate power to detect significant effects (Muthen & Curran, 1997; Raudenbush & Bryk, 2002). Secondly, although women are twice as likely as men to be diagnosed with PTSD (Olff, Langeland, Draijer, & Gersons, 2007), further research with men is recommended to maximize generalizations of the findings. Victims of other types of traumatic events, including episodic events, and survivors with and without past trauma exposure should also be included in future


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research to further maximize generalizations and to assess for possible differences in outcomes. Another limitation is that the assessment of PTSS was based on a standardized selfreport measure. While the PCL-C is a well-validated measure that is often used in trauma research, future research might also include a structured interview of PTSD as well. Although retrospective self-reports have been used in similar studies to measure phase of menstrual cycle, it is recommended that future replications use more objective and unbiased measures. It is also noted that the salivary cortisol sample collection procedure used in the present study included three collection points. Although some past studies have included only one sample collection, more recent studies have included more sample collections within a 12-hour or 15-hour timeframe after trauma exposure. The sample collection points for the present study were selected to match the peak in diurnal cortisol (30–60 minutes after waking) and then when cortisol would have been expected to have declined (3:00–5:00 pm). While more samples within 24 hours would have been desired, the three collection samples allowed for maximizing experimental control of the in-home collections and for obtaining compliance. Nevertheless, further research that includes collecting more cortisol samples is recommended. Finally, further research examining other psychiatric symptoms, such as depression, in relation to cortisol is recommended to support possible differential relations.

Conclusions In conclusion, PTSD is a potentially debilitating disorder that afflicts nearly 13 million people nationwide. While there have been significant efforts to understand neuroendocrinological correlates of PTSD and PTSS, much of this research has examined correlations between biological markers and PTSS at one point in time. The present investigation used multiple assessments of cortisol and PTSD symptom clusters from the onset of trauma exposure, followed by monthly assessments for up to 1-year posttrauma exposure. The present findings revealed a positive relation between cortisol and PTSS and that mothers exhibiting high levels of cortisol exhibited a decline in numbing symptoms over time but still exhibited significantly more numbing symptoms than mothers who exhibited low levels of cortisol. In addition to providing evidence for pursuing further psychophysiological research on the role of cortisol in the manifestation of specific symptom clusters of PTSD with a broader cross-section of trauma survivors, the present findings offer potential clinical implications for triage and, hopefully, for preventing specific PTSS clusters. Funding This work was supported by the Center for Psychiatric Neuroscience, University of Mississippi Medical Center, Institutional Development Award Program of the National Center for Research Resources [NIH Grant Number P20 RR17701]. References Aiken, L. S., & West, S. G. (1991). Testing and interpreting interactions in multiple regression. Thousand Oaks, CA: Sage.



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