People who have experienced traumatic events, especially those who develop posttraumatic stress disorder (PTSD), have elevated rates of mortality, morbidity, and health care utilization.1–4 PTSD can result in maladaptive physiological response that exact cumulative physical costs in the form of allostatic load which is associated with memory impairment, weakened immune function, cardiovascular disease, and metabolic disorders.5–9 The hypothalamic pituitary axis (HPA) plays a critical role in the allostatic process and the HPA axis is often dysregulated among people with PTSD.5,7–10 An important indication of HPA axis function is cortisol output, and abnormal cortisol levels are pathophysiological indicators of PTSD. Moreover, cortisol plays an important role in central nervous system function (learning, memory, emotion), metabolic systems (glucose use and storage), inflammation response, and lymphocyte maturation.11,12 Cortisol is a critical biological intermediary, and high cortisol output is associated with stress-induced diseases; therefore reductions in cortisol may translate to better health outcomes for veterans affected by traumatic stress.1–7,12
Traumatized people have diverse biological responses to stress which are associated with HPA axis dysregulation and abnormal cortisol output with high levels of cortisol (hypercortisolism) or abnormally low cortisol output (hypocortisolism).13–17 This variability in HPA activity and cortisol output is believed to be greatly influenced by a person’s response to a stressor, and both generally increase with subjective distress.12 Hypercortisolism and hypocortisolism are implicated in the origins and exacerbation of PTSD and are associated with abnormal secretion of cortisol upon awakening (cortisol awakening response, CAR) and across the waking hours (diurnal cortisol rhythm).16–23 The CAR is a distinct measurement for an individual’s diurnal cortisol rhythm, and long-term alteration in the CAR appear to be associated with psychosocial and biological health. Healthy individuals experiencing episodic short-term stressors, exhibit normal or moderately heightened CAR profiles.16–22 CAR magnitude is believed to be linked to activation of memory, representation of the self, anticipation of demands of the coming day, and the previous days experiences.21–23 These are examples of cognitive states which are future oriented, ruminating on past events, but not present-moment focused.
Although the HPA axis and cortisol association is clear in healthy populations; studies with unwell populations, such as those with PTSD, have been inconclusive on the association between PTSD and changes in cortisol in response to treatment.12–15,22–24 Some studies report lower diurnal cortisol output among veterans with PTSD and depression, but not lower CAR when compared with veterans without PTSD.23,24 Whereas other studies have found both higher diurnal cortisol output and higher CAR among individuals with a history of trauma compared with those without, particularly among people with comorbid depression.10,25,26
Research has noted that the variability in biological response to PTSD is associated with a person’s cognitive appraisal and subjective response to stressors.12 As such the psychosomatic impact of PTSD necessitates holistic interventions that address both mind and body. One such promising strategy is the Mindfulness Based Stress Reduction (MBSR) program modeled after the curriculum developed by Kabat-Zinn27 at the Center for Mindfulness in Medicine, Health Care and Society at the University of Massachusetts Medical Center. Mindfulness-based meditation, the core of MBSR practice, has been shown to decrease stress, depression, and anxiety which are often comorbid with PTSD.28–32 MBSR cultivates cognitive skills that enable individuals to objectively reappraise stressors thereby interrupting psychological reactivity and concomitant increases in the physiological stress response. MBSR reduces PTSD-associated physiological arousal, and it is hypothesized that symptom improvement following MBSR treatment may be associated with changes in cortisol levels.33–35 Researchers have found that decreases in psychological distress symptoms are accompanied by reductions in diurnal cortisol levels, these concomitant changes indicate improved regulation of the HPA axis.34–36 Among the few published studies that demonstrate significant improvements in PTSD symptoms among veterans who engage in mindfulness meditation, to date these studies have relied on psychometric measures.37–39 Although there is a propensity toward psychometric measures in PTSD treatment research, the importance of understanding biological mechanisms of traumatic stress symptom clusters are critical to improving PTSD treatments.40,41
Adoption of biomarkers like cortisol to objectively measure outcomes are complicated by inconsistencies in the literature regarding the relationship between PTSD and cortisol, regardless of treatment.13,22,36,42 To address the challenges in understanding cortisol as a biomarker for assessing PTSD symptom improvement, this study examined cortisol as a biological correlate of improvement among veterans engaged in MBSR. The primary purpose of this study was to assess the efficacy of a brief primary care MBSR (PC-MBSR) program for veterans with PTSD by examining changes in cortisol as an objective biomarker. We hypothesized that engagement in PC-MBSR would reduce diurnal cortisol output and CAR among veterans with PTSD.
Participants and Recruitment
Participants were veterans recruited from primary care (PC) clinics at a Veterans Affairs (VA) Medical Center. On the basis of the annual PC-PTSD screen administered to all veterans in VA PC, veterans who scored a 2 or higher on the PC-PTSD screen were referred to the study by their PC providers or Operation Iraqi Freedom (OIF)/Operation Enduring Freedom (OEF)/Operation New Dawn (OND) case managers. All referred veterans were subsequently screened for military trauma exposure and the presence of current traumatic stress symptoms. Veterans were eligible for the study if they met criteria for subthreshold PTSD or diagnostic-level PTSD related to military service, as measured by the Clinician-administered PTSD Scale (CAPS).43 Veterans who met one or more of the following criteria were not eligible for enrollment in the study: (a) gross cognitive impairment as measured by the Blessed Orientation-Memory-Concentration44; (b) moderate to severe traumatic brain injury (TBI) (as measured by the VA TBI Assessments present in patients’ medical charts); (c) recent suicide attempt (past 2 mo) or desire to commit suicide; (d) engagement in psychotherapy or mental health counseling outside of VA PC within the past 2 months; (e) a desire to begin PTSD specialty treatment; or (f) change in psychotropic medication within the past 2 months outside of VA PC. Of note, after enrollment 6 participants started a new psychiatric medication or had a change in dose.
Participants were randomized to the intervention Primary Care brief Mindfulness Program (PCbMP) or active control Primary Care Treatment as Usual (PC-TAU) conditions. Participants assigned to the PC-TAU condition continued to receive the typical PC treatment for veterans presenting with similar PTSD and subthreshold PTSD. This was part of a larger study that encompassed psychometric measures collected at baseline, week 4 and week 12; including the Patient Health Questionnaire 9 (PHQ-9)45 to measure depression and the military PTSD Checklist (PCL).46,47 Following the 12-week assessment period, the PC-TAU participants were given the option of participating in the brief PCbMP program.
Salivary Sample Collection
Measurement of cortisol levels in saliva is a valid representation of the free form of cortisol steroid found in blood.48 Salivary cortisol can be collected by study participants throughout the day thereby providing an in vivo valid assessment of endogenous cortisol secretion across the diurnal rhythm.
Veterans participating in this study were asked to, and instructed on how to, provide 5 saliva samples each day at specified times for 2 consecutive days for a total of 10 samples. Following the protocol recommended by leading researchers in the field of salivary cortisol analysis, multiple saliva samples (n=5/d) were obtained for 2 consecutive days, so an average diurnal cortisol profile could be established with greater reliability of the cortisol values at each of the 5 time points.20,49 This collection protocols were conducted at baseline and at follow-up (4 wk from the start of the mindfulness intervention).
Determination of Salivary Cortisol
Saliva samples were stored in a −70°C freezer, then shipped to the Center for Interdisciplinary Salivary Bioscience Research (CISBR) at the Johns Hopkins University where they were analyzed. Samples were assayed in duplicate for salivary cortisol at the CISBR using a highly sensitive enzyme immunoassay without modification to the manufacturers recommended protocol.50 The test used 25 µL of sample, had a lower limit of sensitivity of 0.007 mg/dL, range of sensitivity from 0.007 to 3.0 mg/dL, and average intra-assay and interassay coefficients of variation of <5% and 10%. Salivary cortisol levels >4.0 ug/dL are physiologically impossible in saliva and such numbers likely indicate sample contamination endogenous source of cortisol-like material in saliva.20 One subject’s cortisol values for day one of the 2 days of follow-up collection were outside the feasible maximum of 4.0 ug/dL (11.2 ug/dL); this subject’s day 1 data were eliminated and only values for day 2 samples were used at follow-up.
The PCbMP Intervention
Participants randomized to PCbMP attended weekly in-person 90-minute mindfulness-based meditation group sessions for 4 consecutive weeks led by an experienced trained MBSR facilitator. The PCbMP was designed to enhance emotional regulation and cognitive reappraisal of stressors. To support home practice, participants were given a copy of the book Full Catastrophe Living: Using the Wisdom of Your Body and Mind to Face Stress, Pain, and Illness and audio CDs containing prerecorded guided practice (5-, 10-, 30-, 45-min body scans and guided meditation; and 30-min standing and lying yoga) made by the facilitator to support home practice.27 Given the brevity of the intervention, home practice using audio-guided body scan, meditation, and yoga was strongly encouraged, in addition to select relevant readings.
Our cortisol analysis encompassed 3 calculations; area under the curve (AUC) with respect to total AUC or ground (AUCg), AUC with respect to increase from baseline (AUCi), and CAR, to derive indexes based on repeated cortisol measurements over time. AUC measures are often used in endocrinological studies to provide a global index of hormonal exposure over time and index changes beyond baseline (first awakening measure) over the course of the day.50,51
Analysis of longitudinal changes in diurnal cortisol present in each individual for AUCg and AUCi were calculated using formulas recommended by Preussner.51 AUCg reflects total cortisol output during the day, which enables calculation of baseline cortisol measures and reactivity between measures taking full advantage of the information provided to predict cortisol profiles while maintaining degrees of freedom and are based on the distance from zero (or ground). We also used AUCi, which ignores the distance from zero and highlights changes over time. The AUCi formula estimates cortisol output from the formula for AUCg, but eliminates the measurement of cortisol output between the ground and first waking salivary measure. AUCi best indicates responsiveness to change in diurnal cortisol output as an index of stress reactivity.51
The CAR formula for this study is based on the first awakening salivary cortisol sample of the day and the cortisol sample collected at 45 minutes after awakening. We used the CAR formula developed by Pruessner et al.51
Complete cortisol data were available at baseline and 4-week follow-up assessments for 40 subjects. Participants with <1 missing cortisol sample per day were included in the final sample and missing values were replaced by multiple imputation using SPSS 20, which avoids problems inherent in mean substitution and exclusion of cases with missing data while retaining error variance lost from regression-based single imputation.52
To assess treatment effect we conducted repeated-measures ANOVA measuring pre-post changes in the CAR, AUCg, and AUCi comparing cortisol changes between the PC-MBSR and PC-TAU groups. We also conducted correlation analysis of pre-post changes in depression (PHQ-9 score), PTSD (PCL score), and cortisol (CAR, AUCi, AUCg).
To assess within group changes over time we conducted matched participant pairwise analysis; with a conservative 2-tailed test criterion for P≤0.05, whereby each subject served as their own baseline control against which changes were measured. As is often the case in this type of biomarker analysis, there was substantial variability in the data and the distribution of the data were non-normal. To correct for the non-normal data distribution the cortisol data were log transformed. Because of the small sample size multiple paired sample t test analyses were conducted using bootstrapping methods recommended for smaller samples.53 The estimates presented are based on 5000 bootstrapped samples using an a priori level of statistical significance set at α=0.05. Log-transformation combined with bootstrapping methods improves type I error control and probability for small samples with non-normal distribution.
There was variability in the number of PC-MBSR sessions completed (possible range of 1 to 4 sessions). Two participants completed 1 session; 1 participant completed 2 sessions; 7 participants completed 3 sessions; and 9 completed all 4 PC-MBSR sessions. Therefore, the treatment group was segmented into completers (those who engaged in all 4 PC-MBSR sessions), and noncompleters (those who participated in 1 to 3 sessions). The control group was comprised of veterans randomized into PC-TAU who attended no MBSR sessions.
The final study cohort included 40 participants, with n=21 subjects in the PC-TAU control group and n=19 in the PC-MBSR treatment group. The demographic data and PTSD baseline scores are presented by group in Table 1. We conducted ANOVA to assess potential between group differences in baseline PTSD severity scores and found no significant differences (F2,39=1.1, P=0.35). As noted in the Methods section, our final analysis included 3 groups: (a) control group (PC- TAU engaged in no PCbMP sessions); (b) PCbMP noncompleters (those who participated in 1 to 3 MBSR sessions); and (c) PCbMP completers (those who engaged in all 4 PCbMP sessions). Participant’s rate of compliance with cortisol collection procedures were not correlated at baseline with severity of PTSD (r=0.04; P=0.8), depression (r=−0.07; P=0.6), or insomnia (r=−0.09; P=0.5).
Between Group Differences for AUCi
The group by time comparison revealed significant treatment effect on AUCi (F2,39 =7.1, P=0.01) with significant increases in AUCi among the PC-TAU group (−88±135 to −154±480), whereas PC-MBSR AUCi declined from −78±72 at baseline to −61±132 at follow-up. No significant group by time differences were found between groups for CAR or AUCg.
Within Group Differences for CAR
Participants who completed all 4 PCbMP sessions significantly reduced their CAR by a mean of 0.2 µg/dL; whereas subjects in the PC-TAU and noncompleters had no significant changes in their CAR profiles. Noncompleters had no significant changes for any cortisol measures. Changes in cortisol for each group are presented in Table 2. Figures 1 to 3 illustrate the baseline and follow-up diurnal cortisol and AUC patterns for each of the 3 groups. The first 2 data points on each graph line show the CAR. Error bars represent SEs for each mean cortisol measurement on the graph.
Correlation Analysis for Cortisol and Psychometric Measures
Correlational analysis of pre-post changes in depression (PHQ-9 score), PTSD (PCL score) and cortisol (CAR, AUCi, AUCg) by group did not reveal significant correlations between cortisol and any psychometric measures for any of the 3 groups. When analyzed as a group there was a significant negative correlation (−0.39, P=0.02) between changes in AUCi and depression (PHQ-9 score).
Our analyses reveal significant positive changes in cortisol (eg, reduction in CAR) associated with treatment condition and number of MBSR sessions completed. The significant reduction in CAR among PCbMP completers is not a flattening of CAR or diurnal rhythm, but rather a shift from a sharp-peaked CAR to a moderate smooth hill. Whereas the PC-TAU and noncompleters CAR profiles remained sharply elevated (see Figs. 1 and 3 for comparison)
The findings reported here indicate that PCbMP may be a viable integrative PTSD treatment for the VA, and other primary health care systems. However, for participants to yield benefits, a minimum dose-response of 4 weeks of MBSR practice appear necessary to yield biological improvements associated with cortisol output. PCbMP noncompleters had no significant changes in cortisol measures. Thus further indicating that there is a dose-response, or threshold effect, required to improve neurobiological functions impacted by PCbMP participation. Our findings are reinforced by recommendations made by Kearney et al30 who also concluded that completion of a minimum of 4 mindfulness sessions were required for improvements in depression and quality of life among veterans with PTSD.
To understand how PCbMP may lead to reductions in cortisol one needs to examine the facets of mindfulness, cognition, and behavior associated with mindfulness-based practice. The significant decrease in CAR for these participants may be attributed in part to cognitive behavioral skills, cultivated through PCbMP practice, that enabled participants to be more present-moment focused upon awakening, as opposed to rumination of past experiences or anxious anticipation of future demands. We arrive at this conclusion based on research that has found the magnitude of CAR to be partially affected by the anticipation of demands of the day and influenced by the events and experiences of the prior day.22,23,54
Research has also shown that intentional regulation of negative affect enables effective responses to stressful experiences through the engagement of regions of the prefrontal cortex and the amygdala which are known to influence HPA and cortisol.54 Mindfulness-based meditation cultivates awareness of emotions, potentially engaging regions of the prefrontal cortex that support healthy emotional self-regulation rather than unconscious reactivity responses from the amygdala. Neuroscientists have found that mindfulness-based meditation can lead to structural changes in the hippocampus which modulates cortical arousal and regulates emotional.55 Such factors may have influenced reductions in the CAR among the PCbMP completers. Empirical work is needed to test such suppositions.
The benefits of PCbMP from the present study further support the potential benefits of mindfulness-based interventions for people with PTSD.7,28–35,56 Although the use of mindfulness has been incorporated into protocols for the treatment of PTSD, and demonstrated efficacy as an enhancement to traditional treatments for trauma-related symptoms, until now there has been limited biological study of its efficacy for veterans with PTSD.37,38 Our study also supports the use of biomarkers such as cortisol as an objective measure of responsiveness to PTSD treatment. The use of diurnal cortisol measures to assess PTSD-related HPA function may provide health care professionals with a useful objective measure.
Screening and diagnosis of PTSD in PC, coupled with referral to PCbMP can be an effective, relatively efficient (4 wk), low cost (group format) means of treating a broad range of physical and psychological symptoms associated with PTSD. Whereas this study focuses on the promise of PCbMP as a complimentary and integrative treatment for veterans with PTSD; other studies have found MBSR to be effective in reducing physical pain and physiological distress that often cooccur with PTSD.27,35,37–39 The benefits of mindfulness-based strategies for multiple health problems also contribute to its cost-effectiveness and viability in health care settings.
There are several limitations in this study. The number of participants in the group that completed the full PCbMP was relatively small, and larger studies are needed to validate our findings. The cortisol analysis also lacked follow-up to measure potential lasting changes beyond the 4-week intervention. Additional RCT studies examining longitudinal changes in diurnal cortisol (AUCg and AUCi) and CAR among veterans with PTSD who participate in PCbMP are needed.
Determining the optimal structure and length of PCbMP for PTSD offered through the VA or other health care systems needs further research; our findings indicate that there is a dose-response indicating a minimal 4-week PCbMP practice threshold effect. On the basis of the results of this study, we cannot determine if the minimal dose-response is related to the time engaged in group meditation led by a trained facilitator (4 weekly session×90 min); the application and integration of mindfulness practices into one’s life over a 4-week period; or a combination of both. The clinical implications of this study with regard to objective biomarker measurements indicate that the measurement of salivary diurnal cortisol may be a useful biological marker for identification of improvements in PTSD-related physiological dysregulation for veterans participating in PCbMP. These promising findings were accomplished with a small, randomized, control trial and should be validated through replication.
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Keywords:© 2014 by Lippincott Williams & Wilkins.
mindfulness; cortisol; veterans; PTSD; primary care