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Group on Scientific Research into ME: Neuroendocrinology of CFS/ME. Dr Anthony Cleare Reader, Kings College London, Institute of Psychiatry. Background. Series of studies from our research group into the neuroendocrinology of CFS/ME, beginning in 1994
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Group on Scientific Research into ME:Neuroendocrinology of CFS/ME Dr Anthony Cleare Reader, Kings College London, Institute of Psychiatry
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
NEGATIVE FEEDBACK METABOLIC EFFECTS
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?
24 h Urinary Free Cortisol Output Cleare et al, Am J Psych, 2001
Salivary Cortisol in CFS Jerjes et al, 2005
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
HPA axis in CFS CRH Test - cortisol response Salivary cortisol response to awakening Cleare et al, J Clin Endocrinol Metab, 2001 Roberts et al, Br J Psychiatry, 2004
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
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
Hydrocortisone therapy in CFSEffect on fatigue Cleare et al, Lancet, 1999
4. When do patients develop low cortisol levels in the evolution of the illness?
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
Phase of IllnessConclusions • 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
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
CBT in CFS:Endocrine Effects (a) (b) Response to CRH challenge: Cortisol Daily cortisol output, (saliva) unchallenged All significant at P<0.05
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)
Cognitive Behavioural Therapy in CFSConclusions • 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.
Proposed multidimensional model of HPA axis changes in CFS HPA axis change (heterogeneous) Contributes to fatigue maintenance
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