Relations among posttraumatic stress disorder, comorbid major depression, and HPA function: A systematic review and meta-analysis

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Abstract

Exposure to traumatic stress is associated with increased risk for posttraumatic stress disorder (PTSD) and alterations of hypothalamic–pituitary–adrenocortical (HPA) function. Research linking traumatic stress with HPA function in PTSD has been inconsistent, however, in part due to (a) the inclusion of trauma-exposed individuals without PTSD (TE) in control groups and (b) a failure to consider comorbid major depressive disorder (MDD) and moderating variables. This meta-analysis of 47 studies (123 effect sizes, N = 6008 individuals) revealed that daily cortisol output was lower for PTSD (d = −.36, SE = .15, p = .008) and PTSD + MDD (d = −.65, SE = .25, p = .008) groups relative to no trauma controls (NTC); TE and NTC groups did not differ significantly from each other. Afternoon/evening cortisol was lower in TE (d = −.25, SE = .09, p = .007) and PTSD (d = −.27, SE = .12, p = .021) groups and higher in PTSD + MDD groups (d = .49, SE = .24, p = .041) relative to NTC. Post-DST cortisol levels were lower in PTSD (d = −.40, SE = .12, p < .001), PTSD + MDD (d = −.65, SE = .14, p < .001), and TE groups (d = −.53, SE = .14, p < .001) relative to NTC. HPA effect sizes were moderated by age, sex, time since index event, and developmental timing of trauma exposure. These findings suggest that enhanced HPA feedback function may be a marker of trauma-exposure rather than a specific mechanism of vulnerability for PTSD, whereas lower daily cortisol output may be associated with PTSD in particular.

Highlights

► Daily cortisol output was lower for PTSD and PTSD + MDD groups relative to NTC. ► No significant differences between TE and NTC groups in daily cortisol output. ► Afternoon cortisol was lower in PTSD groups relative to NTC. ► Afternoon cortisol was higher in PTSD + MDD groups relative to NTC. ► Post-DST cortisol levels were lower in PTSD, PTSD + MDD, TE groups relative to NTC.

Introduction

Traumatic stress is characterized by the direct experience or witnessing of actual or threatened death or serious injury, or a threat to physical integrity, and responses that include intense fear, helplessness, or horror (American Psychiatric Association, 2000). Epidemiological studies indicate that 82% of individuals in the U.S. have experienced at least one traumatic event in their lifetime (Sledjeski, Speisman, & Dierker, 2008). Exposure to trauma dramatically increases vulnerability to a variety of psychiatric disorders, most commonly Posttraumatic Stress Disorder (PTSD) and Major Depressive Disorder (MDD). Estimates of the conditional risk for developing these disorders in the context of trauma vary widely and underscore their complex etiologies.

Approximately 8 to 18% of trauma-exposed individuals develop PTSD (e.g., Breslau et al., 1998, Kessler et al., 1995, Sledjeski et al., 2008) and 7 to 19% develop MDD (e.g., MacMillan et al., 2001, Shalev et al., 1998). Moreover, rates of comorbid MDD among individuals meeting diagnostic criteria for PTSD have been reported to be as high as 37% (e.g., Breslau, Davis, Andreski, & Peterson, 1991). Examining differences in the way individuals with PTSD with or without MDD respond to stress and comparing them to individuals exposed to trauma (TE1) who do not develop PTSD (with or without MDD) may help identify possible mechanisms underlying vulnerability to these disorders. In addition, contrasting individuals with PTSD to those with PTSD + MDD may further our understanding of such comorbidity in relation to the stress response. Therefore, the goal of the current meta-analysis was to examine alterations of the stress response system in individuals diagnosed with PTSD or PTSD + MDD as compared to trauma-exposed (TE) individuals without PTSD or MDD, and never-traumatized controls (NTC).

The hypothalamic–pituitary–adrenocortical (HPA; Stratakis & Chrousos, 1995) axis is one of three major systems activated as part of the stress response (Teicher, Andersen, Polcari, Anderson, & Navalta, 2002) and is a potential source of vulnerability to trauma-related psychopathology (e.g., Yehuda, 2002). The stress response system promotes adaptation, or allostasis, by allowing organisms to accommodate to changing conditions in their environment (McEwen & Seeman, 1999). Stress exposure triggers emotional responses, including activation in the limbic system that initiates HPA activity via connections with the hypothalamus. Neurons in the paraventricular nucleus of the hypothalamus then secrete corticotropin releasing hormone (CRH), which travels through the hypophyseal portal circulation and stimulates the anterior pituitary to release adrenocorticotropin hormone (ACTH). The ACTH signal, in turn, is carried through the peripheral circulation to the adrenal cortex where it triggers the production and release of cortisol, a glucocorticoid hormone responsible for a variety of regulatory functions in the central nervous system, metabolic system, and immune system (Sapolsky, Romero, & Munck, 2000). This entire process is referred to here as HPA feed-forward function. Elevated cortisol levels typically inhibit the HPA via negative feedback mechanisms in the pituitary, hypothalamus, and hippocampus (Jacobson and Sapolsky, 1991, Munck et al., 1984, Sapolsky et al., 1986). This latter process reflects HPA feedback function. Thus, the HPA axis plays an important role in both the stress response and the maintenance of homeostasis (Sapolsky, 1992).

Basal cortisol activity throughout the day represents an aggregation of circadian oscillations and superimposed activation related to stressful challenges. Basal cortisol levels can be measured from samples of saliva, blood, urine, or cerebrospinal fluid. Each of these measures of cortisol output offers unique temporal foci on diurnal HPA functioning, with saliva and blood samples reflecting activity within a 10–60 min window, and urine samples reflecting activity over a 15–24 h period (Baum & Grunberg, 1995). Diurnal rhythm of cortisol levels vary, typically increasing in the early morning, peaking approximately 15–30 min after awakening (Schmidt-Reinwald et al., 1999), diminishing over the course of the day, and reaching a nadir at the end of the activity phase (Bailey & Heitkemper, 1991). Thus, the measurement of cortisol may vary depending on the method used and time period assessed. Blood and saliva samples are appropriate for measuring cortisol activity when timing is important (e.g., morning/afternoon cortisol). In contrast, both urinary cortisol and an average of multiple saliva/blood samples over the day are appropriate for assessing daily output.

Although elevated cortisol levels are adaptive in the short-run, prolonged activation of the HPA-axis can have adverse effects (McEwen, 2003). This cumulative physiological wear and tear, termed allostatic load, can be caused by frequent stress, and the failure to (a) habituate to recurring stress, (b) inhibit allostatic processes following termination of stress, or (c) mount an adaptive response in some systems that can lead to the hyperactivation of others (McEwen, 1998). Cortisol is an important mediator of allostasis that contributes to allostatic load when it is not efficiently regulated.

One method of assessing cortisol regulation is to examine HPA basal activity and feedback function. These features indicate how effectively cortisol secretion is inhibited as well as patterns of output over the course of the day. Previous meta-analyses have examined basal cortisol levels (Klaassens, Giltay, Cuijpers, van Veen, & Zitman, 2012, Meewisse et al., 2007) and HPA feedback function (Klaassens, Giltay, Cuijpers, van Veen, & Zitman, 2012, Miller et al., 2007) in adults with and without PTSD. The present meta-analysis expands upon these reviews by addressing three important gaps in the literature. First we assessed features of HPA feedback function separately for PTSD and PTSD + MDD groups. Whereas prior reviews suggest that PTSD and MDD are each associated with very different patterns of cortisol activity (e.g., Kendall-Tackett, 2000), cortisol levels among individuals with PTSD and comorbid MDD have not been systematically evaluated with regard to HPA feedback function. Given high rates of comorbid MDD among individuals with PTSD (Breslau et al., 1991), this represents a critical gap in the literature. Second, we examined the impact of time of measurement on HPA basal activity effect sizes in addition to overall daily cortisol output. This is the first meta-analysis to address this question among TE and PTSD + MDD groups. Third, we examined the role of potential moderators of HPA basal activity and feedback function effect sizes, including age, sex, time since onset of focal trauma, and developmental timing of trauma exposure. This is the first meta-analytic review to evaluate the role of time since onset and developmental timing in TE and PTSD + MDD groups.

Whereas PTSD has been associated with lower basal cortisol activity, enhanced HPA feedback function, and a progressive sensitization of the HPA-axis, MDD has been associated with elevated basal cortisol activity, impaired HPA feedback function, and a progressive desensitization of the HPA-axis (Kendall-Tackett, 2000). Although considerable attention has focused on differences in HPA function between individuals with PTSD and MDD, less is known about the stress response in those with comorbid PTSD and MDD. The current meta-analytic review addressed three fundamental questions regarding HPA function in trauma-exposed individuals: (a) Do individuals with TE, PTSD, or PTSD + MDD differ from never-traumatized controls (NTC) with regard to basal cortisol activity and feedback functioning? (b) Do individuals with TE, PTSD, or PTSD + MDD differ from each other on these features of HPA function? (c) Are the relations between trauma-exposure and HPA function moderated by person (i.e., age, sex) and trauma (i.e., time since onset, developmental timing) features? Another relevant comparison group would be trauma-exposed individuals with MDD only (TE + MDD), but a paucity of studies examining HPA activity in this group precluded including them in the current analyses. Because of the conceptual importance of this group, however, we discuss available findings from studies of individuals with TE + MDD regarding HPA basal activity and feedback functioning.

Patterns of HPA activity over the course of the day are influenced by internal factors, such as the suprachiasmatic nucleus in the hypothalamus that regulates circadian rhythms and the timing of the sleep–wake cycle (Weitzman, Czeisler, Zimmerman, & Moore-Ede, 1981), as well as cues from the environment. For example, the magnitude of the cortisol awakening response may be influenced by the experiences of the prior day (Adam, Hawkley, Kudielka, & Cacioppo, 2006). In addition, psychopathology may moderate the relations between external factors and basal HPA activity. For instance, social interactions are associated with steeper rates of decline in cortisol levels over the day in healthy controls but not in individuals with MDD (Stetler, Dickerson, & Miller, 2004). Indeed, a meta-analysis of depression and cortisol responses to stress revealed that depressed individuals (not necessarily in the context of trauma) had lower basal cortisol levels in the morning as compared to healthy controls (Burke, Davis, Otte, & Mohr, 2005). Studies examining basal cortisol activity in trauma-exposed individuals suggest that morning cortisol levels may be lower in TE individuals relative to NTC (Gunnar & Vazquez, 2001), whereas morning cortisol levels in TE + MDD (Juruena et al., 2006), PTSD, and PTSD + MDD groups (Meewisse et al., 2007, Miller et al., 2007) may not differ significantly from NTC.

Afternoon cortisol levels may be affected by exposure to stressful interpersonal interactions characterized by social-evaluative threat during the day. In particular, individuals whose social status is threatened may exhibit elevated afternoon cortisol levels, with shame possibly mediating this relation (Dickerson & Kemeny, 2004). Social withdrawal in response to feelings of loss elicits a flat diurnal profile that may reflect dysregulated circadian rhythms (Stetler et al., 2004, Stetler and Miller, 2005). Elevated afternoon cortisol levels have been found in individuals with MDD both with (Juruena et al., 2006) or without trauma (Burke et al., 205) relative to healthy controls. Previous studies have found similar afternoon cortisol levels in TE compared to NTC individuals (Gunnar & Vazquez, 2001), lower afternoon cortisol levels in PTSD individuals relative to NTC (e.g., Meewisse et al., 2007), and higher afternoon cortisol levels in PTSD + MDD individuals relative to NTC (Young & Breslau, 2004).

Studies of daily cortisol output indicate chronic hypersecretion in individuals with MDD (trauma-exposure not indicated) (Plotsky, Owens, & Nemeroff, 1995) and increased daily output of cortisol in individuals with TE + MDD (Juruena et al., 2006, Kosten et al., 1990). A recent meta-analysis focusing on trauma exposure in adults found no differences in basal cortisol levels between TE and NTC groups or between TE and PTSD groups; however, this review did not examine the possible influence of the timing of measurement (Klaassens et al., 2012). We predicted lower daily cortisol output in individuals with TE or PTSD relative to NTC (Gunnar and Vazquez, 2001, Miller et al., 2007). Due to inconsistencies in the literature, however, we were not able to make predictions regarding daily cortisol output for PTSD + MDD compared to NTC groups.

HPA feedback activity is measured by the rate at which cortisol levels decline following offset of a stressor and is influenced by a variety of factors, including functioning of the feedback arm of the HPA-axis and cognitive and affective processes (McEwen, 1998). The dexamethasone suppression test (DST) measures the extent to which administration of dexamethasone (DEX), a synthetic glucocorticoid, suppresses production of cortisol in the HPA axis. Post-DST cortisol levels are presumed to reflect the strength of negative feedback inhibition, with lower levels indicating stronger suppression.

Studies examining cortisol suppression in patients with MDD typically have administered either 0.5 or 1.0 mg DEX, and have found abnormal feedback inhibition in the form of nonsuppression (also termed “early escape”) from the DST in approximately 40–60% of depressed patients (Carroll and Curtis, 1976, Carroll et al., 1980; see Ribeiro, Tandon, Grunhaus, & Greden, 1993 for a review). In these studies, nonsuppression was defined as a failure to suppress cortisol levels below 5.0 μg/100 dL in response to 1.0 mg DEX. Evidence concerning the efficiency of negative feedback mechanisms in TE + MDD groups is scant, but conforms to prior research on depression. Higher post-DST cortisol levels in individuals with TE + MDD have been reported in two studies (Juruena et al., 2006, Kosten et al., 1990).

Overall, evidence indicates that TE + MDD is associated with impaired negative feedback. Based on a recent meta-analysis (Klaassens et al., 2012), we hypothesized that the TE group would show enhanced HPA negative feedback as reflected in lower post-DST cortisol levels relative to NTC. Results of DST studies administering 0.25 or 0.5 mg DEX in individuals with PTSD have shown lower post-DST cortisol levels than NTC (e.g., Griffin et al., 2005, Stein et al., 1997, Yehuda et al., 1993, Yehuda et al., 2002), suggesting enhanced negative feedback or “super suppression.” A similar pattern appears to hold for individuals with PTSD + MDD (e.g., de Kloet et al., 2007, Yehuda et al., 1993). Therefore, we expected to find enhanced HPA negative feedback in both PTSD and PTSD + MDD groups.

Patterns of basal HPA activity and feedback function change across development. A positive correlation has been found between age and diurnal cortisol secretion, with levels rising gradually during middle childhood and then more rapidly in adolescence (Walker, Walder, & Reynolds, 2001). Studies of HPA function in older adults reveal elevated basal levels (e.g., Deuschle et al., 1997). Studies of both psychological and biological challenge tests have found impaired HPA feedback function in older versus younger participants (Otte et al., 2005). Seeman and Robbins (1994, p. 233) observed that “age-related changes appear primarily in the re-setting of the HPA axis following a challenge,” and speculated that such a pattern could result from cumulative exposure to glucocorticoids. The current meta-analysis extends findings from previous reviews (Klaassens et al., 2012) by examining age as a predictor of HPA basal activity and feedback functioning effect sizes in PTSD + MDD groups versus NTC.

Lifetime prevalence rates of both MDD and PTSD are twice as high in females as males (e.g., Breslau et al., 1998, Kessler et al., 1995). Although men are at greater risk for exposure to potentially traumatic events (Olff, Langeland, Draijer, & Gersons, 2007), the conditional risk of developing PTSD after trauma exposure is twice as high in women (e.g., Giaconia et al., 1995). Among healthy controls, diurnal cortisol levels appear to be lower in women than in men (Van Cauter, Leproult, & Kupfer, 1996). Studies using biological challenge tests have found either no significant sex differences or decreased feedback sensitivity in females (e.g., Heuser et al., 1994, Otte, Neylan, et al., 2005). Regarding diurnal plasma cortisol levels, women with PTSD had significantly lower levels than healthy controls, whereas no significant differences have been found between men with and without PTSD (Meewisse et al., 2007). The current meta-analysis is the first quantitative review of sex differences in HPA basal activity and feedback function effect sizes in PTSD + MDD groups relative to NTC.

An inverse relation has been found between HPA activity and months since onset of chronic stress, such that morning cortisol levels, daily cortisol volume, and post-DEX cortisol levels decrease over time (Miller et al., 2007). A similar pattern appears to hold for traumatic stress, with studies showing decreases in cortisol levels following a focal event (Rasmusson et al., 2001, Yehuda et al., 2001; although see Meewisse et al., 2007). Yehuda, Halligan, Golier, Grossman, and Bierer (2004) found a positive association between amount of cortisol suppression following low dose DST and the number of years since the most recent traumatic event.

Stressful life experiences may trigger initial increases in cortisol levels that precipitate a counter-regulatory response. Over time, however, these levels may diminish and eventually rebound to below normal (e.g., Hellhammer and Wade, 1993, Miller et al., 2007). This potentially adaptive regulatory response may involve a progressive strengthening of negative feedback inhibition (Yehuda, 2002). Traumatic life events—although initially associated with elevations in cortisol and catecholamines—may trigger a divergence in these measures over time culminating in the pattern of low cortisol and high noradrenaline levels typical of adults with chronic PTSD (Pervanidou, 2008). The current meta-analytic review builds on prior work examining PTSD groups (Meewisse et al., 2007, Miller et al., 2007) by examining time elapsed since focal trauma as a potential predictor of effect sizes representing differences in HPA basal activity and feedback functioning between TE and PTSD + MDD groups relative to NTC.

The impact of a traumatic event on HPA-axis functioning may depend on the developmental epoch in which it occurs, with childhood being an important window of vulnerability to the effects of stress. Early exposure to trauma is associated with elevated risk for MDD (Kaufman and Charney, 2001, Pervanidou, 2008) and appears to impact diurnal cortisol rhythm (e.g., Carpenter et al., 2007, Heim, Ehlert, & Hellhammer, 2000). For example, young children who have experienced neglect have been found to have blunted early morning peak cortisol levels and an absence of typical decline over the course of the day (e.g., Carlson and Earls, 1997, Fisher et al., 2000). The current meta-analysis complements the recent meta-analytic review of trauma exposure during adulthood (Klaassens et al., 2012) by examining developmental timing as a predictor of HPA basal activity and feedback function effect sizes.

The primary goals of the present review were to examine cortisol activity among trauma-exposed individuals without either PTSD or MDD (TE), and among individuals with PTSD and PTSD with comorbid MDD, in order to identify features of HPA function that are uniquely associated with PTSD. Using meta-analytic techniques, we estimated the magnitude of cortisol levels under basal and biological challenge conditions in individuals with TE, PTSD, and PTSD + MDD as compared to never-traumatized controls (NTC). Because too few studies were available for persons with TE + MDD, this group could not be included in the meta-analysis.

Prior qualitative reviews exist regarding HPA function in PTSD (e.g., de Kloet et al., 2006, Yehuda, 2002, Yehuda, 2006) and MDD (e.g., Heim, Newport, et al., 2000) across multiple outcomes, diverse methodologies, and with sensitivity to comorbidity. Meta-analyses also have been conducted examining basal HPA activity and feedback functioning in depressed children and adolescents (Lopez-Duran, Kovacs, & George, 2009) and in individuals with PTSD and MDD (Klaassens, Giltay, Cuijpers, van Veen, & Zitman, 2012, Miller et al., 2007), and diurnal cortisol parameters in persons with PTSD and PTSD + MDD (Klaassens, Giltay, Cuijpers, van Veen, & Zitman, 2012, Meewisse et al., 2007). Building on this prior research, the current meta-analysis reviewed studies examining HPA basal activity and feedback functioning in trauma exposed individuals, distinguishing those with PTSD versus PTSD + MDD, and identifying factors that may have contributed to various inconsistencies in this literature.

We examined cortisol outcome variables (i.e., morning levels, afternoon/evening levels, daily output, post-DST levels) in separate analyses and identified the relations of TE, PTSD, and PTSD + MDD to these outcomes, which allowed us to balance the need for studies differing enough for comparisons to be fruitful yet similar enough to render comparisons meaningful. These meta-analytic models addressed three critical questions: (1) What alterations of cortisol secretion are associated with trauma exposure in general (i.e., common to both TE and PTSD groups) and which are specific to PTSD? (2) How does HPA feedback function in individuals with PTSD and those with PTSD and comorbid MDD? and (3) To what extent do HPA feedback function effect sizes in TE, PTSD, and PTSD + MDD individuals relative to NTC vary by age, sex, time since trauma, and developmental timing of trauma exposure?

Section snippets

Selection of studies

Articles for this meta-analysis were identified through searches of PsycINFO, Web of Knowledge, and PubMed databases and included all studies published through December 2011. Initial searches crossed keywords reflecting traumatic stress (abuse, accidents, assault, combat, loss, maltreatment, neglect, rape, refugees, terrorism, torture, trauma, veteran, and war) and trauma-related psychopathology (major depressive disorder, MDD, posttraumatic stress disorder, PTSD) with those reflecting tests

Study-level effect sizes

We computed effect sizes (Cohen's d) for individual studies by subtracting the mean cortisol level of the NTC group from the psychopathology groups (i.e., PTSD or PTSD + MDD) or non-psychopathology group (i.e., TE) mean and dividing by the pooled standard deviation (Rosenthal, 1994), when these statistics were reported. Because studies with larger sample sizes provide more accurate estimates of true population parameters (Shadish & Haddock, 1994), each effect size was weighted by the inverse of

Discussion

The primary aim of the current meta-analytic review of 47 independent studies was to determine whether trauma-exposed individuals with PTSD, PTSD + MDD, or neither (TE) differed from never traumatized controls (NTC) and from each other regarding HPA basal activity and feedback functioning. We were particularly interested in identifying features of HPA function that distinguished trauma-exposed individuals who developed PTSD from those who did not, and whether individuals with PTSD versus those

Limitations and future directions

Limitations of the current meta-analysis should be noted. First, our analyses were based on cross-sectional studies and therefore could not address whether observed HPA characteristics that distinguished TE, PTSD, and PTSD + MDD groups from never traumatized controls were pre-existing vulnerability factors (i.e., trait markers), emerging vulnerability factors (i.e., scar markers), or state-like concomitants of trauma (i.e., state markers). Prospective studies that examine individuals before,

Summary and conclusions

Results of this meta-analytic review revealed reliable differences in HPA outcomes among TE, PTSD, and PTSD + MDD groups relative to NTC. Lower daily cortisol output and enhanced HPA feedback function were found in PTSD and PTSD + MDD groups. Comorbid PTSD + MDD was associated with unique HPA function features (e.g., elevated p.m. cortisol levels relative to NTC) compared to PTSD alone. Reduced HPA basal activity distinguished PTSD and PTSD + MDD groups from TE groups, although TE individuals showed

Acknowledgments

Matthew Morris was supported in part by an Individual NRSA Fellowship (1 F31 MH084425-01A1), Elizabeth Munsterberg Koppitz Graduate Student Fellowship, Vanderbilt Institute for Clinical and Translational Research grant support (1 UL1RR024975 from NCRR/NIH), and a grant (R01MH068391) and training grant (T32MH18921) from the National Institute of Mental Health. Bruce E. Compas was supported by a National Institute of Mental Health grant (R01HM069940). Judy Garber was supported in part by National

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