The relationship between inflammatory markers and response to ECT in depression

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The relationship between inflammatory markers and
response to ECT in depression

• Gavin Rush, Aoife ODonovan, Ann Maria McCrohan,
  Isabelle DeGardelle, Cliona OFarrelly, Kevin
  Malone, J V Lucey
• ECT department St. Patricks Hospital, Dublin 8,
  Ireland.
• Department of Psychiatry and Mental Health
  Research St. Vincents University Hospital,
  Dublin 4, Ireland.

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ECT department

• Accredited with excellence by ECTAS
• Mental Health Commission Rules for the
  administration of ECT (Dr J V Lucey)
• Patient attitudes to electroconvulsive therapy.
  Psychiatric Bulletin Jun 200731212-214
• Consent to ECT Patient experiences in an Irish
  ECT clinic. Psychiatric Bulletin (In press)
• Electroconvulsive therapy International
  guidelines, clinical governance and patient
  selection. Ir J Psych Med 2007 24(3)103-107

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Depression and inflammation

• CNS and immune system bidirectional
  communication
• ?immune system role in neuropathological
  processes
• Initial studies suggested anti-inflammatory
  effects (downregulated T and B cell proliferation
  and reduced NK cell response)
• 1999 Maes Inflammatory response system model of
  major depression peripheral immune activation,
  through the release of pro-inflammatory
  cytokines, is responsible for the behavioural,
  neuroendocrine and neurochemical alterations that
  are associated with depression
• Macrphage theory of depression / Cytokine theory
  of depression (Smith, Leonard, Yirmiya)
• (for review see Cytokines and major depression.
  Progress in Neuro-psychopharmacology biological
  research. 29(2005)201-217

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Cytokines

• Messenger molecules released from immunocompetent
  cells (eg. macrophages, lymphocytes)
• Regulate immune response
• Pro- and anti-inflammatory
• HPA
• Cortisol low stimulate pro-, high
  immunosupressant
• Neurotransmitters modulate CRH (hypothalamus)
  Ach, DA, NA, 5-HT

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• Parasympathetic vagal nucleus may downregulate
  immune function and cytokine production through
  Ach signalling by vagal nerve.
• Physical and psychological stress increase
  pro-inflammatory cytokine levels

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Therapeutic use of cytokines

• IFN-alpha used for hep C infection can lead to
  depression which resolves on stopping treatment

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Anti-depressant and cytokines

• Data suggestive of role
• Plasma cytokine profiles in depressed patients
  who fail to respond to selective serotonin
  reuptake inhibitor therapy. Journal of
  Psychiatric Research. OBrien S M, Scully P, et
  al. 2006. Failure of SSRI to reduce IL-6 leads to
  non-response
• SSRI reduce depressive symptoms caused by
  IFN-alpha administration

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ECT and cytokines the relationship to date

• 2 studies
• Raised Plasma Levels of Tumor Necrosis Factor a
  in patients with depression Normalisation during
  Electroconvulsive therapy. Hestad K A, Tonseth S,
  et al. Journal of ECT19(4)183-188
• Electroconvulsive therapy increases plasma levels
  of interleukin-6. Kronfol Z, Lemay L, et al.
  Annals New York Academy of Sciences 1990
  594463-465.

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Hypothesis

• ECT is associated with an increase in
  pro-inflammatory cytokines (IL-6) in the
  immediate period post ECT and with a
  statistically significant reduction on completion
  of treatment which correlates with symptom
  reduction

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Method

• 35 consecutively recruited patients referred to
  ECT for management of depression were included.
• Patients with known or suspected concomitant
  disease known to have an inflammatory component
  excluded
• Patients on immunosuppressant drugs excluded

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Procedure

• Interview Consent, MINI, Hamilton Depression
  Rating Scale
• 8 a.m. morning of first ECT baseline cortisol,
  ACTH, CRP and IL-6 (T1)
• Repeat 1 hour after ECT (T2)
• Repeat 1 week after ECT at 8a.m. (T3) along with
  a repeat Hamilton Depression Rating Scale

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Blood testing

• High-sensitivity IL-6 kits (Biosource) All
  samples analysed in duplicate
• High-sensitivity CRP analysis (Immunology
  Laboratory, St. Vincents University Hospital)
• Standard ACTH and cortisol (Endocinology
  Laboratory, St Vincents University Hospital)

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Results
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Demographics

• Mean age 55.6years (range 34-77)
• 23 females, 12 males
• Mean number of total hospital admissions 6 (
  range 035)
• Mean number bouts of mood disorder 8.4 (mean
  1-39)
• Mean attempts of suicide 1.03 (range 0-8)

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Variable Mean Std Dev
T1 HDRS 34 8.743
T3 HDRS 14 11.547
IL-6 T1 1.3 1.823
IL-6 T2 3.6 3.3
IL-6 T3 1.3 1.03
Cortisol T1 504 157.4
Cortisol T2 644 140.6
Cortisol T3 531 156.8
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Variable Mean Std Dev
ACTH T1 24.9 10.7
ACTH T2 35.8 22.7
ACTH T3 25.3 16
CRP T1 3.12 3.2
CRP T2 2.8 2.7
CRP T3 3.5 4.2
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T1-T2

• Paired sample t test
• Significant increase in IL-6 (t-4.973, df 26,
  plt0.001)
• Significant increase in cortisol (t-3.245, d.f.
  23, p0.004)
• Significant increase in ACTH (t-2.465. df 29,
  p0.02)
• Non-significant reduction in CRP (t1.248, df
  20, p0.226)

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T1-T3

• Significant reduction in Hamilton score (t8.567,
  df 31, plt0.001)
• Non-significant change in IL-6 concentration
  (t-0.07, df31, p0.994)
• Non-significant increase in cortisol (t-0.805,
  df 29, p.427)
• Non-significant change in ACTH (t-0.043, n32,
  p0.966)
• Non-significant increase in CRP (t-0.499, df
  20, p0.623)

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• No correlation between T1 Hamilton and T1 IL-6
  concentrations (Pearson correlation -0.125)

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Discussion

• Hypothesis unproven
• Unable to find evidence that IL-6 reduction is
  necessary for improvement in mood with ECT
  treatment

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Next step

• Obtain control data (healthy group)
• Examine influence of diagnosis (BPAD vs uni vs
  recurrent depressive disorder)
• Examine influence of ECT parameters
• Examine relationship with anti-inflammatory
  cytokine (IL-10) and regulatory cytokine TGF-beta
• Any suggestions??

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Declaration of Interest

• This study was part financed by a research
  scholarship sponsored by Lundbeck Ltd.