Psychoneuroendocrinology (2006) 31, 209215

[Link]/locate/psyneuen

Altered cortisol awakening response in posttraumatic stress disorder

` Michele Wessaa,*, Nicolas Rohlederb, Clemens Kirschbaumb, Herta Flora
a

Department of Clinical and Cognitive Neuroscience, Central Institute of Mental Health, University of Heidelberg, J 5, 68159 Mannheim, Germany b Department of Psychology, Technical University Dresden, Zellescher Weg 17, 01069 Dresden, Germany
Received 14 October 2004; received in revised form 2 May 2005; accepted 14 June 2005

KEYWORDS
Posttraumatic stress disorder; Salivary cortisol; Awakening response

Summary An altered function of the hypothalamicpituitaryadrenal axis is assumed to be characteristic for Posttraumatic Stress Disorder (PTSD), although there is inconsistent empirical evidence. Only few studies examined the awakening cortisol response and a daytime prole in PTSD. Salivary cortisol levels were measured at seven intervals from awakening until 8 PM in trauma-exposed subjects with (NZ29) and without PTSD (NZ19) and in 15 non-exposed controls. While the three groups did not differ with respect to their rst cortisol level immediately after awakening, the expected cortisol increase to awakening 1560 min later was signicantly lower in PTSD patients compared to non-PTSD subjects and healthy controls. This effect remained stable when trauma-exposed subjects with comorbid major depression were excluded from the analysis. A signicant negative correlation between the overall cortisol secretion (AUCG) and overall PTSD symptomatology and hyperarousal symptoms was found. The ndings are discussed in light of the hypothesis of a counterregulation of hyperarousal symptoms and chronic stress in PTSD. Q 2005 Elsevier Ltd. All rights reserved.

1. Introduction
Alterations in the activity of the Hypothalamic PituitaryAdrenal (HPA) axis are thought to be an important factor in the development of stressrelated disorders. In posttraumatic stress disorder a more sensitive negative feedback inhibition, for example, reected by an increased number and

* Corresponding author. Tel.: C49 621 1703 6306; fax: C49 621 1703 6305. E-mail address: wessa@[Link] (M. Wessa).

sensitivity of glucocorticoid receptors (Yehuda et al., 1993), is assumed to result in diminished baseline cortisol levels (Yehuda et al., 1996). However, neuroendocrinological studies in PTSD patients yielded contradictory results showing either decreased baseline levels of cortisol (Yehuda et al., 1993), no differences between PTSD patients and controls (Young and Breslau, 2004) or even higher cortisol levels in PTSD patients (Lemieux and Coe, 1995). This conicting evidence might be related to the fact that the studies were not comparable with respect to sample characteristics that affect HPA axis activity, such as trauma

0306-4530/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/[Link].2005.06.010

210 characteristics, gender, daily activities, nicotine and alcohol abuse or medication status (Rasmusson et al., 2003). So far, only few studies measured the circadian rhythm of cortisol secretion in PTSD, although the increase in salivary cortisol to awakening provides a simple and reliable means of assessing the dynamic activity of the HPA axis (Prussner et al., 1997). Examining the circadian rhythm of cortisol secretion in PTSD patients, Yehuda et al. (1996) reported normal cortisol levels in the morning and lower than normal levels in the later evening. In a recent study, the time since trauma exposure but not PTSD diagnosis itself was found to be positively associated with an increase in saliva cortisol after awakening (Young et al., 2004). Rohleder et al. (2004) examined the awakening cortisol response and a short daytime prole in a small sample of Bosnian refugees and healthy controls. They reported lower daytime cortisol levels and no typical cortisol increase after awakening in PTSD patients compared to the controls. Based on these ndings, the present study investigated the awakening response and daytime prole of a larger and with regard to the experienced traumatic event more heterogeneous sample of trauma-exposed subjects with and without PTSD and the relationship of the cortisol response and PTSD symptoms.

M. Wessa et al. the German Version of the Structured Clinical Interview of DSM-IV (SCID-I; First et al. 1997; German Version: Wittchen et al. 1997) to assess psychiatric disorders other than PTSD. Ten PTSD and 2 non-PTSD subjects had a comorbid major depression. None of the participants met diagnostic criteria for current alcohol or drug abuse/dependence or psychotic disorders. The healthy controls did not meet any diagnostic criteria for mental disorder. The 12 subjects diagnosed with major depression used antidepressant medication, another ve subjects took hypertension-reducing medication. So far, no inuences of these medications on cortisol secretion have been found. As the exclusion of the ve subjects with hypertension from the statistical analyses did not reveal a different pattern of results, these patients remained in the nal sample. Patients diagnosed with major depression and treated with antidepressant medication were excluded in a reanalysis of the cortisol prole. Seven female subjects were on contraceptive medications, however, these subjects were equally distributed among the three groups (c2(2)Z1.00; pZ0.61). All subjects gave written informed consent and the study was approved by the local ethics committee.

2.2. Measures
All trauma-exposed subjects completed the German Version of the Impact of Event Scale-Revised (IES-R; Maercker and Schutzwohl, 1998), the Ger man version of the Center for Epidemiological Studies Depression Scale (CES-D; Hautzinger and Bailer, 1991) and the Assessment of General Stress Susceptibility (FSR; Schulz, Jansen and Schlotz, 2005). The latter has been validated in a sample of 975 subjects and has been shown to be a valid and reliable instrument for the assessment of stress reactivity. The questionnaire consists of 29 items, forming an overall stress reactivity score as well as six subscales (stress reactivity related to work overload, work failure, social conicts, social evaluation, the anticipatory (pre stress) and recovery phase (post-stress) of stress). 2.2.1. HPA axis activity Saliva samples were collected into Salivette tubes (Sarstedt, Numbrecht, Germany), immediately after as well as 30, 45 and 60 min after awakening (awakening response) and at 1100, 1500 and 2000 h (short daytime prole). Participants were instructed not to smoke, drink caffeine, eat or brush their teeth in the sampling period. This instruction was given verbally as well as through

2. Methods and materials

2.1. Subjects
Participants of the study were 31 trauma-exposed persons with PTSD, 23 trauma-exposed subjects without PTSD and 19 healthy controls, who were matched for age, sex and level of education. All participants were Caucasian. From this original sample two subjects with terminal illness as traumatic event and eight subjects showing incongruent data from the self-report diaries and the electronic monitoring device for the sampling of cortisol were excluded from the analyses. Thus, a total sample of 63 subjects (29 PTSD, 19 non-PTSD and 15 healthy controls) remained for the statistical analyses. The PTSD diagnosis was based on the diagnostic criteria of DSM-IV TR (APA, 2000). The experienced traumatic events included severe accidents (NZ30), violent crime (NZ12) and sexual assault or rape (NZ3). The two trauma-exposed groups were not signicantly different with respect to the types of trauma they experienced and the time span since trauma onset. All participants completed

Cortisol Awakening Response in PTSD detailed written information accompanying the sampling tubes. In addition, subjects were asked to complete a diary during the sampling period, which among other information assessed their sleep duration the night before the sampling procedure. Free cortisol levels in saliva were measured using a commercially available chemiluminescence assay (IBL, Hamburg, Germany). Self-reports of wake-up times as well as an electronic monitoring device (MEMS Track Cap, Aardex, Switzerland) were employed to control for any inuence of sampling time. Eight subjects (2 PTSD, 2 non-PTSD, 4 HC) were excluded from the analysis because their selfreported and electronically monitored sampling times were not congruent.

211 2000 h). Group differences in the AUC were calculated by a one-way ANOVA with Bonferronicorrected post-hoc tests. As the individual difference between the sample point 1 h after awakening and 1100 h enters the calculation of the AUC, different wake-up times might inuence the AUC signicantly. Therefore, wake-up times were included as a covariate in the statistical analysis of the AUC. In addition, the AUC was correlated with PTSD symptomatology using Pearson correlations. To control for possible effects of age, sex, intake of contraceptive medication, number of cigarettes smoked on a usual day or differing wake-up times, these variables were included as covariates in the ANOVAs. For differences in sleep duration the night before saliva sampling, a one-way ANOVA with Bonferroni-corrected post-hoc tests was carried out.

3. Statistical analyses
Differences in PTSD symptomatology, depressive symptoms as well as stress reactivity were calculated by one-way analyses of variance (ANOVAs) with Bonferroni-corrected post-hoc tests. Group differences in the awakening cortisol response between PTSD patients, trauma-exposed subjects without PTSD and healthy controls were calculated by a one-way repeated measures ANOVA with four within-group levels (baseline immediately after awakening as well as 30, 45 and 60 min after awakening, i.e. awakening prole). A repeated measures ANOVA with three within-group levels (1100, 1500 and 2000 h) was performed to compute differences in the subsequent circadian prole of free cortisol levels (short daytime prole). When repeated-measures ANOVAs revealed signicant interactions, one-way ANOVAs at the different sample points and Bonferroni-corrected post-hoc tests were performed. As comorbid depression was shown to have a signicant inuence on cortisol secretion, the ANOVAs were again computed for trauma-exposed subjects without. In addition to the awakening and day time prole, the area under curve with respect to baseline cortisol levels (AUCG) was calculated by multiplying the single cortisol samples by the time interval between the sampling points in minutes. For every subject the individual duration between 1 h after awakening and the sampling point at 1100 h was included in the calculation. As it is statistically problematic to combine values from dense sampling and infrequent sampling, the three cortisol levels between awakening and 1 h after awakening were excluded from the AUC calculation. Thus, AUC values were based on four samples (awakening, 1 h later, 1100, 1500 and

4. Results
4.1. Clinical data
PTSD patients and trauma-exposed subjects without PTSD were signicantly different in the overall sum of PTSD symptoms and the symptom clusters reexperiencing, avoidance and hyperarousal (Table 1). In addition, PTSD subjects showed signicantly more depressive symptoms (F(2,60)Z 12.36; p!.001) and higher stress reactivity related to work overload (F(2,58)Z6.24; p!.05), social conicts (F(2,58)Z9.71; p!.001), social evaluation (F(2,58)Z8.39; p!.001), the pre-stress phase (F(2,58)Z8.11; p!.001) as well as overall stress reactivity (F(2,58)Z9.18; p!.001) compared to healthy controls (all p!.01) and nonPTSD subjects (all p!.05). Subjects did not differ signicantly in their stress reactivity with regard to work failure (F(2,58)Z1.24; ns) and post-stress situations (post-stress phase: (F(2,58)Z2.70; ns).

5. Cortisol response
PTSD patients showed a signicantly lower cortisol awakening response than non-PTSD subjects and healthy controls (group effect: F(2,60)Z8.23; p! .001). A signicant group by sampling time interaction (F(6,180)Z3.28, p!.05; 3Z0.72) revealed that the three groups did not differ with regard to baseline cortisol levels immediately after awakening (F(2,60)Z0.82; ns), but that the PTSD patients exhibited a reduced increase of cortisol secretion

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Table 1 Demographic characteristic, PTSD symptoms (IES-R), depression (ADS), stress reactivity (FSR), wake-up times and sleeping hours before the sampling day of the nal sample of PTSD patients (NZ29), trauma-exposed subjects without PTSD (NZ19) and healthy controls (NZ15). PTSD (NZ29) Age (in years) M (SD); range Sex (female/male) PTSD symptoms Overall score Re-experiencing Avoidance Hyperarousal Depression (ADS) Stress reactivity (FSR) Wake-up time M (SD) Sleeping hours before sampling 47.0 (10.8) 2765 13/16 66.00 (23.47) 3.23 (1.26) 2.51 (1.24) 3.45 (1.25) 1.22 (0.38) 65.07 (8.95) 0705 h (0123 h) 7.23 (1.33) NPTSD (NZ19) 48.3 (12.4) 1971 10/9 17.47 (13.40) 1.09 (0.83) 0.73 (0.75) 0.73 (0.62) 0.89 (0.27) 56.47 (9.37) 0704 h (0120 h) 7.34 (1.96) HC (NZ15) 40.5 (13.7) 2067 8/7 0.76 (0.23) 54.00 (7.94) 0800 h (0132 h) 7.78 (0.86) F-Value/p-value F(2,60)Z1.95; ns c2Z.41; ns F(1,46)Z66.62; p!.001 F(1,46)Z42.79; p!.001 F(1,46)Z36.36; p!.001 F(1,46)Z84.71; p!.001 F(2,60)Z12.36; p!.001 F(2,58)Z9.18; p!.001 F(2,60)Z2.39; ns F(2,60)Z.72; ns

30 min (F(2,60)Z8.73; p!.001; PTSD vs. HC: p!.05; PTSD vs. non-PTSD: p!.01), 45 min (F(2, 60)Z6.96; p!.01; PTSD vs. HC: p!.05; PTSD vs. non-PTSD: p!.01) and 60 min (F(2,60)Z4.90; p! .05; PTSD vs. HC: ns) after awakening (Fig. 1). However, the typical cortisol increase after awakening was not completely absent in PTSD patients. Paired comparisons showed a trend towards signicance for the cortisol increase 30 min after awakening in PTSD patients (tZ2.00; pZ.06) but a signicant increase in nonPTSD subjects (tZK 4.49; p!.001) and healthy controls (tZK6.17; p! .001). The cortisol increase was signicantly smaller in PTSD patients than in trauma-exposed subjects without PTSD and healthy controls (F(2,60)Z7.17 p!.01; PTSD vs. HC: p!.01; PTSD vs. nonPTSD: p!.01). The reduced awakening response in PTSD patients compared to both other groups remained when trauma-exposed subjects with comorbid depression were excluded (Fig. 1(b); group effect: F(2,48)Z 5.04, p!.01; PTSD vs. HC: pZ.06; PTSD vs. nonPTSD: p!.05; group!time interaction: F(6,144)Z3.32; p!.05). Single comparisons showed that non-depressed PTSD patients exhibited a signicantly reduced increase of cortisol secretion 30 min after awakening (F(2,48)Z7.83; p!.01; PTSD vs. HC: p!.05; PTSD vs. nonPTSD: p!.001) and 45 min after awakening (F(2,48)Z4.01, p!.05; PTSD vs. HC: pZ.09; PTSD vs. nonPTSD: p!.05). Analysis of the short daytime prole revealed no signicant difference in the cortisol secretion between PTSD patients and trauma-exposed subjects without PTSD and healthy controls (F(2,60)Z 2.45; pZ.10).

(a) 40 Salivary Cortisol (nmol/l)

35 30 25 20 15 10 5 0 1 2 34 5 6

Healthy controls NPTSD PTSD

Time point of saliva collection (b) 40 Salivary Cortisol (nmol/l)

35 30 25 20 15 10 5 0 1 234 5 6 7

Time point of saliva collection

Figure 1 Salivary cortisol response to awakening (1Z awakening, 2Z30 min after awakening, 3Z45 min after awakening, 4Z60 min after awakening) and daytime prole (5Z1100 h, 6Z1500 h and 7Z2000 h) in (a) patients with posttraumatic stress disorder (PTSD; NZ 29), trauma-exposed persons without PTSD (NPTSD; NZ 19) and healthy controls (HC; NZ15) and (b) traumaexposed subjects with and without PTSD, comorbid depression excluded (PTSD: NZ19; NPTSD: NZ19) and healthy controls (NZ15).

Cortisol Awakening Response in PTSD The AUC was signicantly different in the three groups (F(2,60)Z5.50; p!.01), with PTSD patients showing lower values than the nonPTSD subjects (p!.01) and the healthy controls (pZ.08). Among trauma-exposed subjects, the overall PTSD symptom score and the number of hyperarousal symptoms were signicantly negatively correlated with the AUCG (overall symptom score: rZK.30; p!.05; hyperarousal: rZK.40; p!.01). The correlation between avoidance and re-experiencing symptoms and the AUCG were not signicant (re-experiencing: rZK.23; avoidance: rZK.21).

213 without PTSD in cortisol levels after awakening. However, the two ndings are not fully comparable as Young et al. collected only one morning sample and they instructed the subjects to collect that sample within 30 min of awakening. Taking into account our nding of a blunted awakening cortisol response, the one-point cortisol assessment at a certain time interval after awakening might have led to blurred values. In contrast to our results, Neylan and colleagues (2005) found no differences between PTSD patients and trauma-exposed subjects without PTSD in the time course of cortisol, i.e. no reduced cortisol increase after awakening in PTSD patients. However, in line with our ndings and other previous studies (e.g. Yehuda et al., 1996), they observed reduced morning cortisol levels in PTSD patients, as indicated by the AUC of the morning cortisol prole. In our study, cortisol secretion during the day and evening was not affected in PTSD patients compared to both other group, whereas Young et al. (2004) reported elevated cortisol evening levels in PTSD patients compared to nonPTSD subjects and healthy controls. Yet, separating PTSD patients with comorbid depression from those with pure PTSD resulted in different results in Young et al.s study: pure PTSD patients no longer differed from nonPTSD subjects and healthy controls as it was the case in the present study when we excluded PTSD patients with comorbid major depression. The nding of a reduced cortisol awakening response in PTSD patients as shown in the present study suggests some important and interesting implications for the development of PTSD and accompanying changes in neurobiology. Some authors (e.g. Prussner et al., 1997) have suggested that the typical cortisol increase 3060 min after awakening usually reects an enhanced release of ACTH and a lower cortisol awakening response is assumed to be associated with higher glucocorticoid receptor sensitivity, a relatively robust nding in PTSD research (e.g. Yehuda et al., 1993). In addition, the blunted cortisol awakening response does not seem to be specic for PTSD patients, but has recently also been reported for patients with chronic fatigue syndrome (Roberts et al., 2004) and patients with unilateral or bilateral lesions of the hippocampus (Buchanan et al., 2004; Wolf et al., 2005). There is strong evidence that the hippocampus is affected in PTSD patients (Bremner et al., 1997), however, it is not clear whether the observed hippocampal reduction in traumaexposed subjects with PSTD is a predisposing factor or a result of the illness (Gilbertson et al., 2000). Longitudinal studies are needed to clarify the relationship between hippocampal damage and

6. Confounding variables
To control for possible confounding effects, the analyses where repeated with the covariates age, sex, intake of contraceptive medication, cigarette smoking and wake-up times. These covariates showed no signicant impact on the reported group effects or interactions, neither with regard to the morning prole nor overall cortisol secretion (AUC). In addition, one-way ANOVAs of the wakeup-times and the sleeping hours during the night before cortisol sampling showed no signicant differences between the three groups (wake-up times: F(2,60)Z2.39; ns; sleeping hours: F(2,60)Z 0.72; ns).

7. Discussion
In the line with the study by Rohleder et al. (2004), PTSD patients showed a signicantly reduced cortisol increase 3060 min after awakening (awakening response). This effect remained stable after excluding PTSD patients with comorbid major depression and on antidepressant medication and after controlling for possible confounding variables such as age, sex, intake of contraceptive medication, cigarette smoking and wake-up time. Bhagwagar, Hazi and Cowen (2003) found signicantly greater levels of waking salivary cortisol in recovered depressed patients compared to healthy controls. These contrasting results suggest different neurobiological mechanisms in both disorders despite their overlapping symptomatology. In contrast to the blunted cortisol morning response in PTSD patients, baseline cortisol levels immediately after awakening were not signicantly different between the three groups. Similarly, Young et al. (2004) found no differences between PTSD patients and trauma-exposed subjects

214 dysregulation of the HPA axis in the development and maintenance of PTSD. In the present study, the AUC was signicantly negatively correlated with the overall PTSD symptomatology and hyperarousal in trauma-exposed subjects with and without PTSD. Interestingly, Aerni and colleagues (2004) found a signicant treatment effect of low-dose cortisol administration on the intensity of re-experiencing and hyperarousal symptoms in two of three treated patients. Despite the low sample size and possible confounding effects of several variables (other medical treatment of the patients, differing symptom status and elapsed time since the traumatic event) the results point into the same direction. However, our study did not nd a signicant relationship between cortisol secretion and re-experiencing symptoms. The negative relationship between cortisol secretion and the presence of hyperarousal symptoms on the one side and the positive relationship between cortisol administration and reduction of hyperarousal symptoms on the other side might be interpreted in the light of etiological models that assume that hyperarousal symptoms and thus an over-stimulation of the stress response system are counterregulated by symptoms of emotional numbing and reduced cortisol levels (Foa et al., 1995). The heightened stress reactivity in PTSD patients might also be in favour of this interpretation and is even more interesting in the light of previous research that increased levels of perceived stress are associated with elevated waking cortisol concentrations in healthy volunteers (Wust, Federenko, Hellhammer and Kirschbaum, 1999). However, to further understand this relationship and its etiological signicance, studies are needed that measure the cortisol response to awakening and throughout the day in PTSD patients with various symptom patterns, in persons with high risk of developing PTSD (e.g. reghters) and in healthy controls at different stress levels.

M. Wessa et al.
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Acknowledgements
Supported by the Deutsche meinschaft (SFB 636 C1). Forschungsge-

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