Source: Journal of Affective Disorders Preprint Date: October 18, 2008 URL: http://www.sciencedirect.com/science/journal/01650327 [Brief report] Salivary cortisol output before and after cognitive behavioural therapy for chronic fatigue syndrome --------------------------------------------------------------------------- Amanda D.L. Roberts(a,b), Andrew S. Papadopoulos(c), Simon Wessely(a,b,c), Trudie Chalder(a,b), Anthony J. Cleare(a,b,c,*) a King's College London, Institute of Psychiatry, Department of Psychological Medicine, De Crespigny Park, London SE5 8AF, UK b Chronic Fatigue Syndrome Research and Treatment Unit, Maudsley Hospital, Denmark Hill, London, UK c National Affective Disorders Unit, Maudsley and Bethlem Royal Hospitals, Denmark Hill, London, UK * Corresponding author. Department of Psychological Medicine, Section of Neurobiology of Mood Disorders, Institute of Psychiatry, 103 Denmark Hill, London SE5 8AF, UK. Tel.: +44 20 7848 5130; fax: +44 20 7848 0783. E-mail address: a.cleare@iop.kcl.ac.uk (A.J. Cleare). Received 21 June 2008; received in revised form 13 September 2008; accepted 14 September 2008 Abstract Background There is evidence that patients with chronic fatigue syndrome (CFS) have mild hypocortisolism. One theory about the aetiology of this hypocortisolism is that it occurs late in the course of CFS via factors such as inactivity, sleep disturbance, chronic stress and deconditioning. We aimed to determine whether therapy aimed at reversing these factors - cognitive behavioural therapy for CFS - could increase cortisol output in CFS. Methods We measured diurnal salivary cortisol output between 0800 and 2000h before and after 15 sessions (or 6 months) of CBT in 41 patients with CDC-defined CFS attending a specialist, tertiary outpatient clinic. Results There was a significant clinical response to CBT, and a significant rise in salivary cortisol output after CBT. Limitations We were unable to control for the passage of time using a non-treated CFS group. Conclusions Hypocortisolism in CFS is potentially reversible by CBT. Given previous suggestions that lowered cortisol may be a maintaining factor in CFS, CBT offers a potential way to address this. Keywords: Chronic fatigue syndrome; Myalgic encephalomyelitis; Cognitive behavioural therapy; HPA axis; Cortisol; Neuroendocrinology 1. Introduction Chronic fatigue syndrome (CFS) is probably a multifactorial condition in which psychological and social factors act alongside biological changes (Wessely et al., 1998). Much biological research has focussed on the hypothalamo-pituitary-adrenal (HPA) axis, with evidence for reduced cortisol output, detectable by sequential salivary samples (Cleare, 2003). Low cortisol may contribute to symptoms since cortisol replacement can ameliorate fatigue and other features of CFS (Cleare et al., 1999; McKenzie et al., 1998). However, most patients studied have been ill for many years; it is not clear whether HPA-axis disturbances are also present before onset or early in the course of CFS, nor to what extent observed HPA-axis disturbances are secondary to inactivity, sleep disturbance, deconditioning or stress (Cleare, 2004). Indeed, it is possible that there is a vicious cycle present in which low levels of cortisol may exacerbate fatigue and other symptoms, leading to a worsening of some of the factors that had initially contributed to lowered cortisol levels. Cognitive behavioural therapy (CBT) is an effective treatment for CFS (Whiting et al., 2001). The primary aim of therapy is to identify, modify and change factors that may be maintaining symptoms. Therapy is individually tailored; components include changing unhelpful patterns of rest and activity, improving sleep patterns, increasing exercise capacity, identifying unhelpful cognitions about the illness or the coping strategies used, using problem solving techniques to reduce stress, and treating anxiety and depression if present (Wessely et al., 1998). In this study we hypothesised that hypocortisolism in CFS is at least partly secondary to inactivity, sleep disturbance, deconditioning and perceived stress, and, therefore, that CBT, which aims to reverse these factors, would lead to increased salivary cortisol output. 2. Method 2.1. Subjects 2.1.1. Subject selection Patients aged 18­65 were recruited from referrals to the CFS clinic at King's College Hospital, London. Detectable organic illness was excluded by a minimum of physical examination, urinalysis, full blood count, urea and electrolytes, thyroid and liver function tests, 9 a.m. cortisol (to screen for Addison's Disease) and ESR. Patients underwent semi-structured interview for CFS (Sharpe et al., 1997) and were included if they met both international consensus criteria for CFS (Fukuda et al., 1994; Sharpe et al., 1991), did not have fibromyalgia (Wolfe et al., 1990) and were suitable for CBT. Suitability for CBT was judged by the assessing clinician using the framework laid out by Sharpe et al. (1997); essentially the process was to exclude factors that could interfere with CBT (such as untreated severe anxiety or depression, personality disorder or unwillingness to change) and seek patient agreement. DSM-IV psychiatric diagnoses were assessed using the Schedules for Clinical Assessment for Neuropsychiatry (SCAN) (WHO, 1994). Female patients were tested during days 1-7 of their menstrual cycle on both occasions, pregnancy having been excluded. 2.1.2. Medication All subjects were free from psychotropic medication, steroids, or medication known to affect the HPA axis for at least 2 months prior to endocrine testing. 2.1.3. Sample size 41 patients (26 female) entered the study (mean age 38.4 years (SD 11.3). The mean length of illness at assessment was 57 (SD 48) months. 16/41 patients had a comorbid DSM-IV diagnosis of a current major depressive episode. Table 1 shows other clinical descriptors. 2.2. Clinical assessment procedures - Patients: filled out the following instruments before and after CBT. - Fatigue: Chalder Fatigue Scale (Chalder et al., 1993); - Psychiatric symptoms: General Health Questionnaire-12 (Goldberg and Blackwell, 1970); Beck Depression Inventory (Beck et al., 1961). - Functional capacity: Medical Outcomes Survey Short Form-36 (Ware and Sherbourne, 1992); Work and Social Adjustment Scale. (Mundt et al., 2002) - Sleep: Pittsburgh Sleep Quality Index (Buysse et al., 1989). Response to therapy was defined using a therapist-rating of "very much improved" or "much improved" on the clinical global impression improvement (CGI) scale (Guy, 1976) blind to cortisol results. The institutional ethics committee approved all procedures. After complete description of the study to the subjects, written informed consent was obtained. 2.3. Cognitive behavioural therapy CBT for CFS has been described in detail elsewhere (Wessely et al., 1998). We used experienced therapists and adhered to set protocols (Deale et al., 1997). Standard therapy comprises 12­15 sessions; to standardize procedures, we retested after 6 months or 15 sessions, whichever was sooner. 2.4. Salivary cortisol A detailed protocol for saliva collection is described elsewhere, including precautions taken to avoid false high values (Roberts et al., 2004). Testing was undertaken at home on any normal weekday except Mondays. Samples were taken at 0800h, 1200h, 1600h and 2000h, kept refrigerated overnight and returned by post in the morning. On arrival at the laboratory, they were frozen at -20 C until assay. After defrosting and centrifuging, cortisol was measured in duplicate using a time-resolved fluoroimmunoassay as described elsewhere (Pariante et al., 2002) except that the rabbit cortisol antibody (product no 2330-5105, batch 21051565; Biogenesis, Poole, UK) and the Europium labelled cortisol were diluted 1/4500 and 1/65 respectively in assay buffer before use. The minimal detectable concentration was about 0.1 nmol/l. The percentage cross-reactivity of the antiserum with other steroids was: prednisolone (28%), 11-deoxycortisol (10%), cortisone and corticosterone (1%). There was none for progesterone, dexamethasone, aldosterone and pregnenolone. All samples of one subject were analyzed in the same run. 2.5. Statistical analysis All data were normally distributed (SPSS version 16). The main outcome measure was total 0800-2000h salivary cortisol output calculated as the area under the curve (AUC) using the trapezoidal method. In addition, we took two secondary measures: the mean of the four samples and the diurnal change (difference between first and last samples), since this latter variable may be altered in CFS (Cleare, 2003). Endocrine and clinical measures were compared: before and after CBT using a paired t-test; and between responders and non-responders using an independent samples t-test (on 38 patients due to missing CBT response data). We calculated Pearson's product-moment coefficients to look at the relation between the post-CBT cortisol and clinical measures. Means are given with SDs or 95% confidence intervals. 3. Results 3.1. Effect of CBT on clinical measures CBT was moderately effective, with significant reductions in fatigue, disability and psychiatric symptoms (Table 1). Overall, 47% of the patients had responded to therapy at the time of repeat testing. 3.2. Effect of co-morbid depression There was no significant effect of comorbid depression on total salivary cortisol output: values were 67.9 (SD 23.9) nmol/l h in those with comorbid depression and 68.4 (SD 16.8) nmol/l h in those without (95% CI -12.4-13.3, t=0.07). This mirrors previous results suggesting no major effect of depression on endocrine variables in CFS (Cleare et al., 2001; Roberts et al., 2004) and we did not stratify for depression in the subsequent analyses. 3.3. Effect of CBT on cortisol output Patients showed increased cortisol levels after CBT both on the AUC and the mean level across the day (Table 2). The salivary day curves are shown in Fig. 1. The mean time of awakening was not different before (0730h, SD 62 min) and after (0750h, SD 57 min) treatment (t=-1.9, P>0.05). The diurnal pattern of cortisol release was not altered by CBT (Table 2). 3.4. Outcome of CBT and cortisol measures There was no differential effect of whether patients were judged to have responded to CBT or not apparent in salivary cortisol measures (Table 3). We also calculated the change in the endocrine variables after CBT (i.e. pre-treatment values subtracted from post-treatment values) and performed an independent t-test on these values between responders and non-responders. There were no significant differences detectable (data not shown). We also looked to see if there were any correlations between clinical and cortisol measures after CBT. There were no correlations with total or mean cortisol output. However, after CBT, a flatter cortisol day curve (i.e. a reduced diurnal change) was associated with worse functioning on the SF-36 social function subscale (r=-0.40, P=0.015) and higher BDI depression scores (r=0.41, P=0.013). 4. Discussion As outlined, hypocortisolism is one of the most often reported biological changes in CFS (Cleare, 2003). We have shown for the first time that cortisol levels can be increased by CBT, with a 16% increase in total cortisol output from 0800-2000h apparent after 6 months of therapy. Our findings are robust due to the careful selection of medication-free subjects, and because patients acted as their own controls before and after CBT, thus excluding other inter-individual factors that might complicate comparisons of HPA axis assessments. Other advantages of the present study include the careful assessment of psychiatric and other comorbidities, and the use of salivary cortisol, a non-stressful method of assessing biologically active hormone. We are not directly able to deduce the mechanism by which CBT increases cortisol levels from this study. However, there is accumulating evidence that HPA axis changes are not a primary feature of CFS, but instead could be a secondary effect of illness. Thus, chronic fatigue six months after Epstein-Barr virus (Candy et al., 2003) or surgery (Rubin et al., 2005) is not associated with HPA axis changes. However, patients who have had CFS for several years, do show HPA axis changes (Cleare, 2003). Since sleep pattern, habitual physical activity levels, physical deconditioning and perceived stress can all exert marked effects on the HPA axis (Cleare, 2003), we hypothesise that these factors, together with potential effects of comorbid psychiatric illness and medication, are largely responsible for the varying degrees of hypocortisolism in longstanding CFS (Cleare, 2004). Since CBT for CFS concentrates on addressing many of these factors, it is plausible that it is via the reversal of these cognitive­behavioural factors that both clinical and endocrine change is produced. This was not a trial of CBT. We found an overall response rate of 47% in this group, with reductions in fatigue and increased physical function, when assessed immediately after six months of therapy, but further improvement may occur in the subsequent six months (Deale et al., 1997). Furthermore, we recruited a group of patients selected also to be suitable for endocrine assessment so this may not represent the response rate for all those given CBT. This study did not assess the response of the HPA axis to challenge. However, as yet no specific HPA axis abnormality has been identified (Cleare, 2003) and the explanation for lowered cortisol levels is most likely multifactorial (Cleare, 2004). Nevertheless, we cannot say what aspects of the HPA axis were changed by CBT to lead to increased cortisol output. Although we interpret the results as indicating a normalisation of whatever has led to hypocortisolism, it is also possible that CBT induces some form of compensation for an underlying deficit. There was no clear link between the clinical response to CBT and the change in cortisol output. This is consistent with cortisol being just one of many factors influencing symptoms in CFS; alternatively, low cortisol could represent an epiphenomenon having little link with symptoms. However, we did find that some clinical measures (social function and depressive symptoms) were linked to a flattened diurnal cortisol profile that persisted after CBT. A final limitation was that we did not use an untreated group of CFS sufferers: since there is clear evidence of the efficacy of CBT we did not feel it would be ethical to delay this for 6 months to act as a control for this experiment. Thus, we cannot exclude the increase in cortisol output being due to factors independent of CBT such as illness progression or repeated testing. However, given the chronicity of our group and the poor prognosis of untreated CFS in specialist care (Wessely et al., 1998) we feel that spontaneous change in the illness is an unlikely explanations for the changes we found. Furthermore, studies following up the long-term stability of cortisol levels in non-elderly adult age groups have overwhelmingly found either no change (Diaz et al., 1989; Schell et al., 2008; Steptoe et al., 1998; Yehuda et al., 2007) or a decrease (Burleson et al., 2003; Evolahti et al., 2006; Feldman et al., 2002; King et al., 2000; Shalev et al., 2008) over time, rather than an increase. In conclusion, we found that CBT for CFS is associated with increased cortisol output from 0800h to 2000h CBT, perhaps through effects of CBT on sleep, perceived stress and physical activity levels. Although previous research suggests that some CFS patients may benefit from low dose hydrocortisone replacement, we suggest that our results, together with the superior evidence base for CBT in CFS, point to CBT being the treatment of choice for the observed mild hypocortisolism in CFS at this time. Role of funding source The study was funded by the Linbury Trust, who provided a project grant to support this research, and by the Psychiatry Research Trust and the King's College Hospital Joint Research Committee. All authors are independent from the funding bodies. The funding sources had no influence over the study design, data analysis and interpretation, the manuscript or the decision to submit for publication. Conflict of interest All authors declare that they have no conflicts of interest in relation to this paper. Acknowledgements We are grateful to Dorothy Blair, Research Nurse in the Chronic Fatigue Syndrome research Unit, for help in subject recruitment and testing, and Lucia Poon in the National Affective Disorders Unit at The Bethlem Royal Hospital for help in sample processing. Figure Caption Fig. 1. Line graph shows salivary free cortisol across the day in 41 patients with CFS tested both before (open circles) and after (closed diamonds) cognitive behavioural therapy (CBT). Inset bar chart shows mean total cortisol output across the day measured as the integrated area under the curve with standard errors of the mean (open bar pre-treatment, closed bar post-treatment; post-treatment output significantly increased [P<0.05, see Table 2]). Tables Table 1. Clinical measures before and after CBT ------------------------------------------------------------------------------------------------ Variable Before CBT After CBT 95% CI for difference ------------------------------------------------------------------------------------------------ Fatigue Chalder Fatigue Scale (0-33) 24.8 (6.1) 21.2 (6.2) 2.6-6.7 (t=4.6)*** Chalder Fatigue Scale (0-11) 11 (4-11) 8.5 (0-11) N/A (z=3.3)*** Psychiatric symptoms General Health Questionnaire (0-36) 17.7 (7.5) 15.3 (8.0) 0.4-5.5 (t=2.4)* Beck Depression Inventory (0-62) 14.9 (9.1) 12.2 (8.2) 0.8-4.0 (t=3.0)** Disability SF-36 physical functioning scale (0-100) 39.7 (23.3) 50.7 (24.8) -17.3 to -6.6 (t=-4.5)*** SF-36 physical role limitations scale (0-100) 25.8 (33.4) 44.4 (34.3) -33.4 to -8.7 (t=-3.5)*** Work and Social Adjustment Scale (0-40) 29.0 (7.8) 25.5 (9.0) 2.3-5.8 (t=4.6)*** Sleep PSQI-global score 7.7 (4.2) 6.8 (4.3) -0.37-2.0 (t=1.4) Clinical global impression Very much or much improved (responders) - 18 (47%) Minimally improved - 13 (34%) No change - 4 (11%) Minimally, much or very much worse - 3 (8%) Missing data 3 ------------------------------------------------------------------------------------------------ Clinical measures in 41 patients with chronic fatigue syndrome before and after cognitive behavioural therapy. Mean values with SD or percentage in parentheses (except Chalder Fatigue Scale 0-11 scoring, where median and range is given). Asterisks represent values significantly improved after CBT by paired t-test or, for Chalder Fatigue Scale 0-11 scoring, Wilcoxon test (* P<0.05; ** P<0.01; *** P<0.001). Table 2. Salivary cortisol measures before and after CBT ------------------------------------------------------------------------------------------------ Measure Before CBT After CBT 95% CI for difference ------------------------------------------------------------------------------------------------ 0800-2000h total output (AUC) (nmol/l h) 68.2 (19.6) 79.4 (21.8) 2.6-19.8 (t=2.62)* Mean value (nmol/l) 6.0 (1.7) 6.8 (1.7) 0.12-1.5 (t=2.37)* Diurnal change (nmol/l) -8.3 (4.6) -8.6 (4.8) -2.0-1.4 (t=-0.35) ------------------------------------------------------------------------------------------------ Mean values with SD in parentheses in 41 patients with chronic fatigue syndrome before and after cognitive behavioural therapy. Asterisks show those variables showing a significant alteration after CBT by paired t-test (* P<0.05). Table 3. Salivary cortisol output in CBT responders and CBT non-responders ------------------------------------------------------------------------------------------------ Measure Treatment Treatment 95% CI for difference non- responders responders ------------------------------------------------------------------------------------------------ 0800-2000h total output (AUC) (nmol/l h) 65.2 (17.2) 71.2 (22.0) -19.2-7.2 (t=-0.92) before CBT 0800-2000h total output (AUC) (nmol/l h) 78.0 (22.8) 79.2 (22.5) -16.2-13.8 (t=-0.17) after CBT Mean value (nmol/l) before CBT 5.7 (1.4) 6.3 (2.0) -1.7-0.5 (t=-1.2) Mean value (nmol/l) after CBT 6.6 (1.8) 6.9 (1.7) -1.4-0.9 (t=-0.5) Diurnal change (nmol/l) before CBT -7.5 (3.9) -8.9 (5.4) -1.8-4.5 (t=0.86) Diurnal change (nmol/l) after CBT -7.6 (4.8) -8.8 (4.9) -1.9-4.4 (t=0.80) ------------------------------------------------------------------------------------------------ Cortisol total output, mean output and diurnal change before and after cognitive behavioural therapy in those responding the therapy (n=18) and those not responding to therapy (n=20). Mean values with SD in parentheses. No differences significant using independent t-test. References Beck, A.T., Ward, C., Mendelson, M., 1961. Beck Depression Inventory (BDI). Archives of General Psychiatry 4, 561-571. Burleson, M.H., Poehlmann, K.M., Hawkley, L.C., Ernst, J.M., Berntson, G.G., Malarkey, W.B., Kiecolt-Glaser, J.K., Glaser, R., Cacioppo, J.T., 2003. Neuroendocrine and cardiovascular reactivity to stress in mid- aged and older women: long-term temporal consistency of individual differences. Psychophysiology 40, 358-369. Buysse, D.J., Reynolds, C.F.d., Monk, T.H., Berman, S.R., Kupfer, D.J., 1989. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Research 28, 193-213. Candy, B., Chalder, T., Cleare, A.J., Wessely, S., Peakman, M., Zuckerman, M., Skowera, A., Weinman, J., Hotopf, M., 2003. Predictors of fatigue following the onset of infectious mono- nucleosis. Psychological Medicine 33, 847-855. Chalder, T., Berelowitz, G., Hirsch, S., Pawlikowska, T., Wallace, P., Wessely, S., Wright, D., 1993. Development of a fatigue scale. Journal of Psychosomatic Research 37, 147-153. Cleare, A.J., 2003. The neuroendocrinology of chronic fatigue syndrome. Endocrine Reviews 24, 236-252. Cleare, A.J., 2004. The HPA axis and the genesis of chronic fatigue syndrome. Trends in Endocrinology and Metabolism 15, 55-59. Cleare, A.J., Heap, E., Malhi, G.S., Wessely, S., O'Keane, V., Miell, J., 1999. Low-dose hydrocortisone in chronic fatigue syndrome: a randomised crossover trial. Lancet 353, 455-458. Cleare, A.J., Miell, J., Heap, E., Sookdeo, S., Young, L., Malhi, G.S., O'Keane, V., 2001. Hypothalamo-pituitary-adrenal axis function in chronic fatigue syndrome, and the effects of low-dose hydrocortisone therapy. Journal of Clinical Endocrinology and Metabolism 86, 3545-3554. Deale, A., Chalder, T., Marks, I., Wessely, S., 1997. A randomised controlled trial of cognitive behaviour versus relaxation therapy for chronic fatigue syndrome. American Journal of Psychiatry 154, 408-414. Diaz, S., Pavez, M., Brandeis, A., Cardenas, H., Croxatto, H.B., 1989. A longitudinal study on cortisol, prolactin and thyroid hormones in users of Norplant subdermal implants or a copper T device. Contraception 40, 505-517. Evolahti, A., Hultcrantz, M., Collins, A., 2006. Women's work stress and cortisol levels: a longitudinal study of the association between the psychosocial work environment and serum cortisol. Journal of Psychosomatic Research 61, 645-652. Feldman, H.A., Longcope, C., Derby, C.A., Johannes, C.B., Araujo, A.B., Coviello, A.D., Bremner, W.J., McKinlay, J.B., 2002. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. Journal of Clinical Endocrinology & Metabolism 87, 589-598. Fukuda, K., Straus, S., Hickie, I., Sharpe, M., Dobbins, J., Komaroff, A., 1994. The chronic fatigue syndrome: a comprehensive approach to its definition and study. Annals of Internal Medicine 121, 953-959. Goldberg, D.P., Blackwell, B., 1970. Psychiatric illness in general practice. A detailed study using a new method of case identification. British Medical Journal 439-443. Guy, W., 1976. ECDEU Assessment Manual for Psychopharmacology, Revised. US Government Printing Office, Washington D.C. King, J.A., Rosal, M.C., Ma, Y., Reed, G., Kelly, T.A., Stanek 3rd, E. J., Ockene, I.S., 2000. Sequence and seasonal effects of salivary cortisol. Behavioral Medicine 26, 67-73. McKenzie, R., O'Fallon, A., Dale, J., Demitrack, M., Sharma, G., Deloria, M., Garica-Borreguero, D., Blackwlder, W., Straus, S., 1998. Low-dose hydrocortisone treatment of chronic fatigue syndrome: results of a placebo-controlled study of its efficacy and safety. Journal of the American Medical Association 280, 1061-1066. Mundt, J.C., Marks, I.M., Shear, K., Griest, J.H., 2002. The work and social adjustment scale: a simple measure of impairment in functioning. British Journal of Psychiatry 180, 461-464. Organisation, W.H., 1994. Schedules for Clinical Assessment in Neuropsychiatry, Version 2.0. Manual. World Health Organization., Geneva. Pariante, C.M., Papadopoulos, A.S., Poon, L., Checkley, S.A., English, J., Kerwin, R.W., Lightman, S., 2002. A novel prednisolone suppression test for the hypothalamic-pituitary-adrenal axis. Biolo- gical Psychiatry 51, 922-930. Roberts, A.D.L., Wessely, S., Chalder, T., Papadopoulos, A., Cleare, A.J., 2004. Salivary cortisol response to awakening in chronic fatigue syndrome. British Journal of Psychiatry 184, 136­141. Rubin, G.R., Hotopf, M.H., Cleare, A.J., 2005. Salivary cortisol as a predictor of postoperative fatigue. Psychosomatic Medicine 67, 441-447. Schell, E., Theorell, T., Hasson, D., Arnetz, B., Saraste, H., 2008. Stress biomarkers' associations to pain in the neck, shoulder and back in healthy media workers: 12-month prospective follow-up. European Spine Journal 17, 393-405. Shalev, A.Y., Videlock, E.J., Peleg, T., Segman, R., Pitman, R.K., Yehuda, R., 2008. Stress hormones and post-traumatic stress disorder in civilian trauma victims: a longitudinal study. Part I: HPA axis responses. International Journal of Neuropsychophar- macology 11, 365-372. Sharpe, M., Archard, L., Banatvala, J., Borysiewicz, L., Clare, A., David, A., Edwards, R., Hawton, K., Lambert, H., Lane, R., McDonald, E., Mowbray, J., Pearson, D., Peto, T., Preedy, V., Smith, A., Smith, D., Taylor, D., Tyrrell, D., Wessely, S., White, P., 1991. Chronic fatigue syndrome: guidelines for research. Journal of the Royal Society of Medicine 84, 118-121. Sharpe, M., Chalder, T., Palmer, I., Wessely, S., 1997. Chronic fatigue syndrome. A practical guide to assessment and management. General Hospital Psychiatry 19, 185-199. Steptoe, A., Wardle, J., Lipsey, Z., Mills, R., Oliver, G., Jarvis, M., Kirschbaum, C., 1998. A longitudinal study of work load and variations in psychological well-being, cortisol, smoking, and alcohol consumption. Annals of Behavioral Medicine 20, 84-91. Ware, J.E., Sherbourne, C.D., 1992. The MOS 36-item short form health survey (SF-36). Medical Care 30, 473-483. Wessely, S., Hotopf, M., Sharpe, M., 1998. Chronic Fatigue and its Syndromes. Oxford University Press, Oxford. Whiting, P., Bagnall, A.M., Sowden, A.J., Cornell, J.E., Mulrow, C.D., Ramirez, G., 2001. Interventions for the treatment and manage- ment of chronic fatigue syndrome: a systematic review. Jama 286, 1360-1368. Wolfe, F., Smythe, H., Yunus, M., Bennett, R., Bombardier, C., Goldenberg, D., Tugwell, P., Campbell, S., Abeles, M., Clark, P., Fam, A., Farber, S., Feichtner, J., Franklin, C., Gatter, R., Hamaty, D., Lessard, J., Lichtbroun, A., Masi, A., McGain, G., Reynolds, W., Romano, T., Russell, I., Sheon, R., 1990. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia: report of the multicenter criteria committee. Arthritis and Rheumatism 33, 160-173. Yehuda, R., Morris, A., Labinsky, E., Zemelman, S., Schmeidler, J., 2007. Ten-year follow-up study of cortisol levels in aging holocaust survivors with and without PTSD. Journal of Traumatic Stress 20, 757-761. -------- (c) 2008 Elsevier / ScienceDirect B.V.