1. Group on Scientific Research into ME: Neuroendocrinology of CFS/ME Dr Anthony Cleare Reader, Kings College London, Institute of Psychiatry

2. Background Series of studies from our research group into the neuroendocrinology of CFS/ME, beginning in 1994 Focussing on the role of cortisol, the end product of the hypothalamo-pituitary-adrenal axis Original theory came from the known effects of low cortisol in other illnesses, including fatigue

3. NEGATIVE FEEDBACK METABOLIC EFFECTS

4. Questions addressed Is cortisol low? Is there abnormal control of cortisol? Is cortisol related to symptoms? When does cortisol change in the natural history of CFS? What are the causes of altered cortisol?

5. 1. Is there low cortisol output in CFS?

6. 24 h Urinary Free Cortisol Output Cleare et al, Am J Psych, 2001

7. Salivary Cortisol in CFS Jerjes et al, 2005

8. Summary of literature Basal Studies Urine – 4/6 low cortisol Serial blood samples – 3/6 low cortisol Serial saliva samples – 2/5 low cortisol About 50% studies support low cortisol Cleare, Endo Rev, 2003

9. 2. Is there an abnormal control of cortisol release?

10. HPA axis in CFS Cleare et al, J Clin Endocrinol Metab, 2001 CRH Test - cortisol response Roberts et al, Br J Psychiatry, 2004 Salivary cortisol response to awakening

11. Summary of Literature Challenge Studies (ACTH and/or cortisol response to a variety of challenges) Overall - 11/16 blunted, none enhanced Cleare, Endo Rev, 2003

12. 3. Is low cortisol is related to the symptom of fatigue in CFS? Randomised, double blind, placebo- controlled trial of a low dose cortisol replacement strategy (hydrocortisone 5- 10mg) to raise levels of cortisol

13. Hydrocortisone therapy in CFS Effect on fatigue Cleare et al, Lancet, 1999

14. 4. When do patients develop low cortisol levels in the evolution of the illness?

15. Prospective Cohort Studies Prospective model of a fatigue syndrome using high risk cohorts – post-viral (EBV infection) and postoperative naturalistic salivary cortisol profiles. Cohort followed up after EBV infection No relation of low cortisol to fatigue (acute, 3 and 6 months) Cohort assessed pre and post major surgery No relation of low cortisol to fatigue (acutely, 3 weeks and 6 months) Low cortisol not a risk factor pre-operatively Candy et al, Psychol Med, 2003; Rubin et al, Psychosom Med, 2004

16. Phase of Illness Conclusions Acute/sub acute fatigue – No link to cortisol Early chronic fatigue (6 months) – No link to cortisol Late chronic fatigue – Low cortisol Cortisol does not appear to be a primary cause of fatigue in these cohorts But – studies are of CF, and too small to exclude a different pattern in tightly defined CFS

17. 5. What causes changes in cortisol levels and regulation? Are they a primary feature of the illness or secondary to some of the consequences of being ill with CFS? If some HPA axis disturbance is secondary to effects of the illness – e.g. physical inactivity, sleep disturbance, stress levels etc. – then therapy targeting these (e.g. CBT) should reverse the HPA axis changes

18. CBT in CFS: Endocrine Effects All significant at P<0.05 Daily cortisol output, (saliva) unchallenged Response to CRH challenge: Cortisol (a) (b)

19. Lower cortisol pre-treatment predicted a worse response to CBT Responders 100 (70) nmol/day Non-responders 70 (44) nmol/day (P<0.05) (urinary free cortisol)

20. Cognitive Behavioural Therapy in CFS Conclusions CBT has biological effects - normalisation of the HPA axis Most likely exerts HPA axis effects via normalisation of factors mediating HPA axis disturbance such as sleep, deconditioning, inactivity, stress, etc.

21. Proposed multidimensional model of HPA axis changes in CFS Illness phase Sleep Psychiatric Illness Past Abuse Medication Stress Physical Activity Diet/weight change Other trait – e.g. genetic Unknown factor(s) HPA axis change (heterogeneous) Contributes to fatigue maintenance

22. Future research Aetiological work –Longitudinal, prospective studies –High risk cohorts –Large enough to detect subgroups (if present) –Multidisciplinary – integrative understanding of different factors Treatment studies –Improving therapies and therapy options –Targeting the right patients