Group on Scientific Research into ME: Neuroendocrinology of CFS/ME

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Group on Scientific Research into
MENeuroendocrinology of CFS/ME

• Dr Anthony Cleare
• Reader, Kings College London, Institute of
  Psychiatry

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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

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NEGATIVE FEEDBACK
METABOLIC EFFECTS
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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?

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1. Is there low cortisol output in CFS?

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24 h Urinary Free Cortisol Output
Cleare et al, Am J Psych, 2001
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Salivary Cortisol in CFS
Jerjes et al, 2005
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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
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2. Is there an abnormal control of cortisol
release?

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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
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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
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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

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Hydrocortisone therapy in CFSEffect on fatigue
Cleare et al, Lancet, 1999
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4. When do patients develop low cortisol levels
in the evolution of the illness?

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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
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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

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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

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CBT in CFSEndocrine Effects
(a)
(b)
Response to CRH challenge Cortisol
Daily cortisol output, (saliva) unchallenged
All significant at Plt0.05
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Lower cortisol pre-treatment predicted a worse
response to CBT

• Responders 100 (70) nmol/day
• Non-responders 70 (44) nmol/day (Plt0.05)
• (urinary free cortisol)

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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.

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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
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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