Salivary cortisol lower in posttraumatic stress disorder.

Cortisol is a hormone secreted by the adrenal gland and regulated by the hypothalamic-pituitary-adrenal (HPA) axis. In the normal acute stress response, cortisol increases as an adaptation to the stressor and then decreases to pre-stressor levels. Cortisol has two distinct secretion patterns: 1) a diurnal rhythm that peaks around 8 a.m. and declines thereafter until midnight, and 2) a cortisol awakening response (CAR) that includes a superimposed peak within one hour after waking (Clow, Thorn, Evans, & Hucklebridge, 2004; Fries, Dettenborn, & Kirschbaum, 2009). Morning cortisol levels or CAR peak within one hour after waking and may be determined by a specific awakening process (Clow, Hucklebridge, & Thorn, 2010); in particular, CAR magnitude may be regulated by the anticipation of the upcoming demands of the day (Fries, et al., 2009) or influenced by the person’s experiences of the previous day (Adam, Hawkley, Kudielka, & Cacioppo, 2006). HPA axis dysregulation as measured by lower cortisol values is associated with posttraumatic stress disorder (PTSD) in most but not all studies (Klaassens, Giltay, Cuijpers, van Veen, & Zitman, 2012; Morris, Compas, & Garber, 2012; Yehuda, 2002, 2006). Discrepancies in findings may result from methodological issues such as sample type (e.g. saliva, serum, or urine), or sample timing variability, or failure to account for important confounding variable such as age, sex, and medication use. This latter problem is evidenced by a meta-analysis that showed no cortisol differences in people with PTSD compared to controls when important factors such as cortisol collection times, medical history, and childhood trauma were not taken into account (Klaassens, et al., 2012), while another larger meta-analysis clearly observed lower cortisol in people with PTSD compared to controls when accounting for collection timing and evaluating the role of potential moderators (e.g. age, gender, cortisol collection timing, time since trauma, developmental timing of trauma exposure) (Morris, et al., 2012). Chida et al. conducted a systematic review and meta-analysis examining CAR in PTSD studies and found that PTSD status was not associated with CAR. However, when including only the three high quality studies a reduced CAR was associated with PTSD (Chida & Steptoe, 2008). Another study since found no association with CAR and PTSD (Laudenslager et al., 2009). Small study size, methodological variability (e.g. not reporting cortisol-affecting medications), and uncontrolled, correlation study designs, while useful as preliminary findings, limit making definitive conclusions about cortisol, CAR and PTSD status. This highlights the importance of conducting larger studies that incorporate cortisol moderating factors into the analysis and their associations with PTSD status. The relationship between cortisol levels and PTSD diagnosis status has been and will continue to be evaluated. However, the assessment of PTSD symptoms rather than just PTSD diagnosis status has been less studied. According to the currently used Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV), PTSD diagnosis requires the presence of three symptom clusters: re-experiencing, numbing/avoiding, and hyper-arousal (American Psychiatric Association, 1994). These clusters consist of diverse symptoms, and each person with PTSD will have a different combination of them. The mechanisms underlying the three symptom clusters are considered different and thus, may require different treatment approaches (Asmundson et al., 2000; O'Donnell, Hegadoren, & Coupland, 2004). Thus, understanding the symptom clusters biological mechanisms may improve future treatments. Others have begun to examine the relationship between PTSD symptoms and cortisol. Yehuda found the relationship between PTSD status in Holocaust survivors mean 24-hour urinary cortisol excretion was due to a substantial association with avoidance subscale scores (r=−0.49 p<.001). Another study evaluated salivary cortisol’s relationship to PTSD symptoms in eight Persian Gulf veterans with PTSD (r=−0.67 p<.05). The other three symptoms clusters were not significant; however, it is unlikely that the study was adequately powered to detect these relationships with only eight participants (Kellner, Baker, & Yehuda, 1997). De Kloet assessed salivary cortisol’s relationship to PTSD in 28 veterans with PTSD finding that morning levels (area under the curve with respect to ground) was negatively correlated with re-experiencing and hyper-arousal and the area under the response curve was negative correlated with re-experiencing, numbing/avoiding and hyper-arousal (de Kloet et al., 2007). Additionally, in another study of 28 trauma-exposed subjects the overall PTSD and hyper-arousal symptom scores were significantly negatively correlated with the morning area under the curve with respect to ground whereas the avoidance and re-experiencing correlations were not (Wessa, Rohleder, Kirschbaum, & Flor, 2006). These studies used correlational analyses to assess the relationship between cortisol, had small subject numbers, and implemented varying methodology to assess cortisol (e.g. urinary total output, single salivary sample, cortisol awakening response with multiple time-point sampling). While attempts have been made to assess the relationship of cortisol to PTSD symptoms clusters, the relationships are still unclear and additional studies evaluating these relationships are warranted. More recently, strong evidence supports the use of a four-factor symptom cluster model of PTSD proposed for DSM-V rather than the currently used three-factor model (Friedman, Resick, Bryant, & Brewin, 2011). The four-factor model proposed for DSM-V includes four symptom clusters: The presence of one or more intrusion symptoms such as: spontaneous or cued recurrent, involuntary, and intrusive distressing memories, dreams or dissociative reactions related to the traumatic event(s); intense or prolonged psychological distress or marked physiological reactions at exposure to cues that symbolize or resemble the traumatic event(s). Persistent avoidance or efforts to avoid one or more stimuli associated with the traumatic event(s): internal processes or external reminders that arouse distressing memories, thoughts, or feelings about or closely associated with the traumatic event(s). Two or more negative alterations in cognitions and mood associated with the traumatic event(s): inability to remember an important aspect of the traumatic event(s); persistent and exaggerated negative beliefs or expectations about oneself, others, or the world; persistent, distorted blame of self or others about the cause or consequences of the traumatic event(s); persistent negative emotional state (e.g., fear, horror, anger, guilt, or shame); markedly diminished interest or participation in significant activities; feelings of detachment or estrangement from others; persistent inability to experience positive emotions; Marked alterations in arousal and reactivity associated with the traumatic event(s) as evidenced by two or more of the following: irritable or aggressive behavior; reckless or self-destructive behavior; hyper-vigilance; exaggerated startle response; problems with concentration; sleep disturbance (e.g., difficulty falling or staying asleep or restless sleep). Cortisol’s relationship to the current PTSD symptom clusters has been examined in a limited way but not its relationship to new model clusters. Thus, cortisol’s relationships to both PTSD symptom classifications are assessed in this study. This study’s goal was to build upon previous research with a larger participant pool accounting for important covariates and a more complete assessment of salivary cortisol’s relationship to PTSD symptom clusters. The rationale for these study goals is based on: 1) most but not all studies report lower cortisol in people with PTSD and there are only a few, small-sample CAR studies with contradictory findings, and 2) cortisol’s relationship to the new PTSD cluster model has yet to be examined. The primary objectives of this cross-sectional study were to: 1) evaluate salivary cortisol in people with PTSD compared to controls, and 2) examine the relationship of salivary cortisol to the DSM-IV and four-factor model PTSD symptom clusters. We hypothesized that the PTSD group would have decreased CAR and total cortisol based on the most recent meta-analysis with a larger number of studies assessed (Morris, et al., 2012). Because of the small number of studies assessing the cortisol’s relationship to PTSD symptom clusters and their heterogeneity, we hypothesized that cortisol would be negatively correlated with PTSD clusters but not which clusters would be correlated.