3. HPA hormones- cognition and affect
Hippocampus
Central
Central behavioural
Inhibition
effects of CRH
GR Cognitive Effects
of Corticosteroids
Changes in Mood
GR
PVN
CRH AVP
Negative
Pituitary Feedback
ACTH Actions on serotonergic
systems / 5-HT1A function
GLUCOCORTICOID
6. Circadian secretion of cortisol in bipolar disorder
Cervantes, et al. J Psychiatry Neurosci 2001;26(5):411-6.
• Significant difference in
AUC in all phases of
bipolar disorder compared
to healthy controls
• No difference between
depressed, hypomanic
and euthymic bipolar
patients
• i.e. hypercortisolaemia is
not a state marker
7. Cortisol levels in bipolar disorder
350 Controls (F=4.975, df=2,57, p=0.010)
Bipolar patients
300
250
Cortisol (nmol/L)
200
150
100
50
0
1:00pm 1:30pm 2:00pm 2:30pm 3:00pm 3:30pm 4:00pm
Tim e
Data from Gallagher et al. Schizophr Res. 2007 Feb;90(1-3):258-65
10. GR receptors in Schizophrenia, Bipolar
and Unipolar Disorder
GR and MR receptors reduced in post-mortem brains samples in
frontal and temporal cortex (Webster et al, 2002; Xing et al, 2004).
11. Psychiatric adverse effects of
corticosteroids
• Endogenously raised cortisol - Cushing’s
syndrome
High rates of depressive symptoms
• Psychiatric symptoms common following
systemic administration of corticosteroids
(Warrington et al. 2006)
28% experience mild or moderate symptoms
6% experience severe symptoms
Most common symptoms of short term treatment –
euphoria and mania
Most common symptoms of long term treatment –
depression
12. Hypercortisolaemia and cognitive function
• Cushing’ s disease - marked cognitive
impairment (Starkman et al Arch Int Med 1981)
• Acute and chronic administration of
glucocorticoids impairs learning and memory in
animals
• Chronic administration of glucocorticoids -
atrophy of hippocampal neurones
• Administration of corticosteroids to healthy
volunteers impairs cognitive function
(Young et al Psychopharm 1999: for review see Lupien et al PNE,
2004)
17. Spatial Working Memory: Improvement in
between search error rate from baseline
35
30 Advantage of mifepristone over
Improvement in error rate (% )
placebo:
25
mean difference=19.8%,
20 95%CI=4.3 to 35.2
15
10
5
0
-5 mifepristone placebo
-10
-15
Error bars=SEM
18. Correlation between baseline cortisol and spatial working
memory improvement following mifepristone
100
80
(r =0.665, p=0.002)
Spatial Working Memory (% improvement)
60
40
20
0
0 10000 20000 30000 40000 50000 60000 70000
-20
-40
-60
-80
Cortisol (nmol/L/min)
(n.b. No significant correlation between baseline cortisol and baseline SWM performance or HAM-D)
20. Baseline
Active Placebo Control
n 30 30 55
%male 50 57 55
Age 48(9.3) 48(9.5) 45(13.1)
BMI 30(5.0) 29(7.4) 26.0(3.7)
% BP-I 55 55
Age of Onset 27(13.9) 26(11.2)
Duration of current episode
68(80.0) 48(75.4)
(weeks)
Weeks on this medication regime 24(27.6) 36(67.0)
%who are rapid cycling 10 15
% who have a history of attempted
69 47
suicide
% with current suicidal ideation 31 17
% who have previously had ECT 27 21
% with alcohol abuse (DSM-IV) in
10 11
the last 12 months
% with a life time history of alcohol
7 20
dependence
HDRS17 at baseline 20(5.1) 19(4.5)
Watson S et al Biol Psychiatry 2012
21. Spatial Working Memory between
search errors, change from baseline
Watson S et al Biol Psychiatry 2012
22. Relationship between the cortisol response to
treatment and SWM performance at study end
Watson S et al Biol Psychiatry 2012
23. Clinical impact of HPA axis dysfunction
in depression
• Evidence that HPA axis dysregulation in depression is
associated with :-
• a poor response to antidepressants
Abnormal response to metyrapone challenge predicts
poor response to fluoxetine1
Abnormal prednisolone suppression test associated
with poor response to antidepressants2
• a poorer long term outcome
HPA axis dysregulation associated with poor outcome
in naturalistic studies3,4
1- Young EA et al. 2004 3 - Appelhof BC, et al 2006
2- Juruena MF, et al in press 4- Zobel AW et al. 2001
25. Metyrapone augmentation of
antidepressants
n = 63
Antidepressants
= nefazadone or
fluvoxamine
25
(Jahn et al. 2004)
26. Antiglucocorticoid augmentation
of antiDepressants in Depression
Psychobiology
Research Group
(ADD study)
Newcastle, Manchester and Leeds Universities
MHRN
27. Questions for ADD
1. Are the effects of metyrapone found by Jahn also
found in larger, somewhat different but more
representative population?
2. Are metyrapone’s tolerability and safety profile
acceptable in such a group?
3. Are the effects only found in those with more severe
depression?
4. Are the effects only found in those with evidence of
raised cortisol?
5. What is/are the mechanisms(s) of the effect?
6. Are there effects on cognition?
28. ADD Recruitment: Issues
Drug
Drug Recovery plan put
procurement
procurement in operation
delay – FPI late
delay 2011 late
Feb – FPI
Feb 2011
Concerns raised Current rate
Concerns patients
re lack of raised
re lack of patients
in secondary care
in secondary care
Delays with TEWV – First
patient recruited Sept– First
Delays with TEWV 2011
patient recruited Sept 2011
29. Recovery plan
• Alterations to study protocol - Substantial
amendments to REC and MHRA
• Adoption by PCRN – identification of practices and
refinement of searches
• Additional Trust recruited in Manchester and
primary care strategy developed
• New PI and MHRN staff and RA appointed in
TEWV Trust.
• Increased publicity in all centres.
29
30.
31. Consort: Total Patients
Total patients:
877
Source:
Self: 310 Prim. care: 237
Sec. care: 320 N/K: 10
Total not included: 593
Declined: 123 Screened:
Not eligible: 139
No response/ DO: 294
284
N/K: 37
Total excluded: 111
SCID: 10 HAM-D: 52 Eligible:
AXIS-I: 17 AD: 9 MGH: 3 173
Physical: 18 Other: 3
Randomised: DO:
165 8
Week +5 complete: DO:
144 21
Week +24 complete: DO:
XXX XX
32. Conclusions
Good evidence for HPA abnormalities in Bipolar
Disorder and MDD
Cortisol may contribute to the cognitive impairments
found in mood disorders
GR receptors may be a locus for the dysfunction in
the HPA
Cortisol synthesis inhibitors and GR receptor
antagonists may augment SSRIs
WATCH THIS SPACE!
GR receptor antagonists may be antidepressant and
reverse some of the neurocognitive impairments
found in mood disorders
33. Acknowledgements
Stuart Watson, Peter Gallagher, Mel Leitch, Sasha
Gartside, Allan Young, Ian Anderson, Tom Hughes,
Margaret Smith, Lucy Stevens, Sophie Landa, Jane
Barnes, Hamish Mc Allister-Williams MHRN and PCRN
staff etc etc
Our studies are made possible by the generous support
of the Stanley Medical Research Institute, the Medical
Research Council and NIHR/MRC EME Board.
We are grateful to the patients who participated
