Experimental medicine – new                 treatments for mood disordersPsychobiologyResearch Group                     P...
HPA Axis and Stress  STRESS                                                  Metabolism /                                 ...
HPA hormones- cognition and affect                                               Hippocampus                            Ce...
HPA axis abnormalities inaffective disorders• Alterations in HPA axis hormones• HPA Activation/feedback tests     Stress ...
Cortisol in Melancholia
Circadian secretion of cortisol in bipolar disorderCervantes, et al.   J Psychiatry Neurosci 2001;26(5):411-6.            ...
Cortisol levels in bipolar disorder                    350                                                      Controls  ...
Dex/CRH in Depressionvon Bardeleben U, Holsboer F. Biol Psychiatry. 1991;29(10):1042-1050.
HPA axis abnormalities in bipolardisorder patients (Watson et al. 2004)           Dex previous night                   200...
GR receptors in Schizophrenia, Bipolar       and Unipolar Disorder  GR and MR receptors reduced in post-mortem brains samp...
Psychiatric adverse effects ofcorticosteroids• Endogenously raised cortisol - Cushing’s  syndrome     High rates of depre...
Hypercortisolaemia and cognitive function • Cushing’ s disease - marked cognitive   impairment (Starkman et al Arch Int Me...
Primary neurocognitive battery1.   CANTAB Spatial Working Memory2.   Rey-AVLT
The effect of hydrocortisone on within-search errors in  the CANTAB spatial working memory test                           ...
Trial design
Spatial Working Memory: Improvement inbetween search error rate from baseline                                   35        ...
Correlation between baseline cortisol and spatial working      memory improvement following mifepristone                  ...
Mifepristone (RU 486) study 2
Baseline                                        Active                  Placebo    Controln                               ...
Spatial Working Memory betweensearch errors, change from baseline            Watson S et al Biol Psychiatry 2012
Relationship between the cortisol response totreatment and SWM performance at study end                Watson S et al Biol...
Clinical impact of HPA axis dysfunctionin depression• Evidence that HPA axis dysregulation in depression is  associated wi...
Corticosteroid effects on SSRIsmediated increases in cortical 5-HT                                      24
Metyrapone augmentation of     antidepressants                                  n = 63                                  An...
Antiglucocorticoid augmentation                 of antiDepressants in DepressionPsychobiologyResearch Group               ...
Questions for ADD 1.   Are the effects of metyrapone found by Jahn also      found in larger, somewhat different but more ...
ADD Recruitment: Issues      Drug        Drug                           Recovery plan put  procurement    procurement     ...
Recovery plan• Alterations to study protocol - Substantial  amendments to REC and MHRA• Adoption by PCRN – identification ...
Consort: Total Patients                              Total patients:                                    877               ...
ConclusionsGood evidence for HPA abnormalities in BipolarDisorder and MDDCortisol may contribute to the cognitive impairme...
Acknowledgements Stuart Watson, Peter Gallagher, Mel Leitch, Sasha Gartside, Allan Young, Ian Anderson, Tom Hughes, Margar...
Nicol ferrier mhrn mar13
Nicol ferrier mhrn mar13
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Nicol ferrier mhrn mar13

  1. 1. Experimental medicine – new treatments for mood disordersPsychobiologyResearch Group Professor Nicol Ferrier Newcastle University
  2. 2. HPA Axis and Stress STRESS Metabolism / energy balance-ve GR/ Hypothalamus MR CRH / AVP -ve Immunosuppression GR/ Pituitary MR ACTH -ve GR/ Adrenals MR Cognitive function Corticosteroids Corticosteroids Brain neurochemistry
  3. 3. HPA hormones- cognition and affect Hippocampus CentralCentral behavioural Inhibitioneffects 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
  4. 4. HPA axis abnormalities inaffective disorders• Alterations in HPA axis hormones• HPA Activation/feedback tests  Stress  DST  Dex/CRH• GR/MR abnormalities
  5. 5. Cortisol in Melancholia
  6. 6. Circadian secretion of cortisol in bipolar disorderCervantes, 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. 7. Cortisol levels in bipolar disorder 350 Controls (F=4.975, df=2,57, p=0.010) Bipolar patients 300 250Cortisol (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
  8. 8. Dex/CRH in Depressionvon Bardeleben U, Holsboer F. Biol Psychiatry. 1991;29(10):1042-1050.
  9. 9. HPA axis abnormalities in bipolardisorder patients (Watson et al. 2004) Dex previous night 200 180 euthymics 160 ill bipolars CRH controls 140 Cortisol nmol/l 120 100 80 60 40 20 0 1 2 3 4 5 6 7 8 9 10 11 Sample
  10. 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. 11. Psychiatric adverse effects ofcorticosteroids• 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. 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)
  13. 13. Primary neurocognitive battery1. CANTAB Spatial Working Memory2. Rey-AVLT
  14. 14. The effect of hydrocortisone on within-search errors in the CANTAB spatial working memory test 3 Hydrocortisone Errors: Mean (s.e.m.) within-search errors Placebo Hydrocortisone > Placebo P=0.007 2 Strategy (not shown): 1 Hydrocortisone < Placebo P=0.040 0 6 moves 8 movesYoung, AH, Sahakian, BJ, Robbins, TW, Cowen PJ (1999) Psychopharmacology, 145, 260-266
  15. 15. Trial design
  16. 16. Spatial Working Memory: Improvement inbetween 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
  17. 17. 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)
  18. 18. Mifepristone (RU 486) study 2
  19. 19. Baseline Active Placebo Controln 30 30 55%male 50 57 55Age 48(9.3) 48(9.5) 45(13.1)BMI 30(5.0) 29(7.4) 26.0(3.7)% BP-I 55 55Age 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 47suicide% with current suicidal ideation 31 17% who have previously had ECT 27 21% with alcohol abuse (DSM-IV) in 10 11the last 12 months% with a life time history of alcohol 7 20dependenceHDRS17 at baseline 20(5.1) 19(4.5) Watson S et al Biol Psychiatry 2012
  20. 20. Spatial Working Memory betweensearch errors, change from baseline Watson S et al Biol Psychiatry 2012
  21. 21. Relationship between the cortisol response totreatment and SWM performance at study end Watson S et al Biol Psychiatry 2012
  22. 22. Clinical impact of HPA axis dysfunctionin 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 studies3,41- Young EA et al. 2004 3 - Appelhof BC, et al 2006 2- Juruena MF, et al in press 4- Zobel AW et al. 2001
  23. 23. Corticosteroid effects on SSRIsmediated increases in cortical 5-HT 24
  24. 24. Metyrapone augmentation of antidepressants n = 63 Antidepressants = nefazadone or fluvoxamine 25(Jahn et al. 2004)
  25. 25. Antiglucocorticoid augmentation of antiDepressants in DepressionPsychobiologyResearch Group (ADD study) Newcastle, Manchester and Leeds Universities MHRN
  26. 26. 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?
  27. 27. 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
  28. 28. 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
  29. 29. Consort: Total Patients Total patients: 877 Source: Self: 310 Prim. care: 237 Sec. care: 320 N/K: 10Total 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
  30. 30. ConclusionsGood evidence for HPA abnormalities in BipolarDisorder and MDDCortisol may contribute to the cognitive impairmentsfound in mood disordersGR receptors may be a locus for the dysfunction inthe HPACortisol synthesis inhibitors and GR receptorantagonists may augment SSRIsWATCH THIS SPACE!GR receptor antagonists may be antidepressant andreverse some of the neurocognitive impairmentsfound in mood disorders
  31. 31. 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

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