Depression and Cardiovascular Disease

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Depression and Cardiovascular Disease

• ulrik.fredrik.malt_at_rikshospitalet.no

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Depression and CVD

• Psychological response?
• Secondary psychological response to being ill?

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Yeah, its the heart, stupid! or.????!
Otto Dix. Fliehender Verwundeter,
Sommerschlacht 1924
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Depression and CVD

• Psychological response?
• Secondary psychological response to being ill?
• Spurious / serendipity?
• Side effect of drugs (e.g betablockers,
  steroids)?
• Somatic comorbidity (e.g. Hypothyreoidism,
  vitamine deficits etc)?
• Co-incidence of CVD and mood disorders, alcohol,
  smoking etc?
• Depression-related poor compliance with somatic
  treatment?

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Symptomatology

• Symptom profile of depressed diabetes patients
  similar to depressed non-diabetes patients
• Similar findings in most other somatic disorders
• Symptoms - or understanding -are unreliable
  sole diagnostic clues to a correct etiological
  diagnosis!

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Depression and CVD

• Psychological response?
• Secondary psychological response to being ill?
• Spurious / serendipity?
• Side effect of drugs (e.g betablockers,
  steroids)?
• Somatic comorbidity (e.g. Hypothyreoidism,
  vitamine deficits etc)?
• Co-incidence of CVD and mood disorders, alcohol,
  smoking etc?
• Depression-related poor compliance with somatic
  treatment?
• Etiological (neurobiological) association?
• Severe heart disorder elicits more severe
  depression?
• Mood causes (completely/partly)
  artheriosclerosis etc?

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Depression and cardiovascular disease

• Physiological effects of depression
• - autonomic system
• - immune system
• - hormone system
• Depression and cardio vascular disease
• -epidemiology
• -retrospective and prospective studies
• Intervention studies
• -psychological intervention
• -pharmacological intervention

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The physiological effects of depression

• Autonomic nervous system

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Autonomic nervous system and depression

• ? sympathetic ? parasympathetic activity
  increased catecholamines (e.g. NA)
• lower threshold for ischemia, ventricular
  tachycardia, ventricular fibrillation, sudden
  death in CHD pts.
• ? heart rate ? heart rate variability
• ? baroreceptor sensitivity
• ? QT tid ved depresjon

Carney et al Psychosomatic Medicine 2005 67
Suppl. 1 s29-s33
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Immunology
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• B lymphocytes (B cells) (has membrane bound
  anti-body molecule. If an antigen matches the
  membrane bound antigen, cell divides and
  differentiate into memory B cells and effector B
  cells (plasmacells). The latter produce
  antibodies (gt2000 /second?!) humoral immunity)
• T lymphocytes (T cells)
• -T helper cells (express the membrane
  glycoprotein called CD4. When activated T helper
  cells secrete numerous low-molecular-weigth
  proteins called cytokines).
• -cytotoxic T cells (express the membrane
  glycoprotein called CD8. When activated these
  cells differentiate into effector cells that can
  destroy altered self-cells including cells
  infected by virus and tumor cells)

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Cytokines

• Proteins having a role in cell-to-cell
  communication partly by regulating development of
  immune effector cells some also possess direct
  effector functions of their own (hormones
  messenger for the endocrine system cytokines
  messenger for the immune system).
• Target cell has a receptor for that cytokine
• Effect varies depending on the target cell
• Interleukins cytokines secreted by some
  leukocytes (e.g. monocytes, macrophages, B-cells,
  endothelial cells) to act upon other leukocytes

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Cytokines influence the brain !

• Cross directly blood brain barrier (e.g.
  IL-1,TNF-a, and IL-2)
• Via circumventricular organs which posesses a
  leaky BBB (e.g. pineal gland median eminence of
  hypothalamus subfornical organ area postrama,
  subcommissural organ, parts of lamina terminalis
  etc)
• Via N. vagus
• De novo synthesis by BBB cells (induced by
  peripheral immune stimuli e.g. synthesis of
  IL-1 IL-6 TNF-alfa induce expression of COX-2
  in endothelial cells of BBB)
• Infiltrating leukocytes (e.g. activated
  leucocytes during infection)

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Cytokines / cytokine receptors in the brain

• IFN-alfa
• IFN-gamma
• TNF-alfa
• IL-1
• IL-2
• IL-4
• IL-6
• IL-10

Cytokines - Neurotransmitter interaction -
Direct effects on neurons
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CNS Disease Brain immune
response Neurological
Manifestations
CHEMICAL CASCADE
Neuropeptides Cytokines
Cytokine
Balance
IL-1, IL-6
TNF Neurotransmitters
- IL-1Ra IL-4

IL-10 TGF

Signals
Neuroinflammation

-Neurotoxicity PERIPHERAL DISEASE
-Neurodegeneration
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Hormones and immunology
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Immunology and depression
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Immunology in depression

• Cytokines may lead to sickness-behaviour
  (lethargia, anorexia, paresthesia, irritability,
  social withdrawal, impaired concentration, sleep
  problems, decreased libido particularly TNF-alfa
  and IL-6 may induce depression, anxiety and
  memory impairment)
• In non-melancholic depression elevated levels of
  
• -IL-6 (mediates activation of the HPA axis),
• -NK cells (acute stage)
• -leucocytes/lymphocytes (acute stage)
• In melancholic depression
• - decreased (in vitro) production of IL-2
  IFN-g IL-10 (acute stage i.e. weakens
  anti-inflammatory response ), but normal cell
  counts

Schwarz . Dialogues in Clin Neurosciences 2003
5 139-153
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TNF-?
Depressed pts had higher sensitivity to
glucocorticoids.(baseline). Following exposure
to the stressor protocol, however, sensitivity
declined among Depressed (marked with an arrow.
In contrast, sensitivity increased among
control subjects. Miller Psychosom Med,
Volume 67(5). September/October 2005.679-687
IL-6
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Possible implications of the study

• If depressed individuals glucocorticoid
  sensitivity was diminished over the long-term
  through exposure to repeated stressors, this
  would likely facilitate the sustained expression
  of inflammatory mediators.
• This could foster a number of adverse disease
  outcomes. Among patients with cardiac disease,
  for example, it could lead to acute complications
  such as plaque rupture, thrombus formation, and
  sudden cardiac death.

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The relationship between central nervous system
correlates of depression and immune system
parameters is bidirectional, mediated by
neurohormonal and parasympathetic pathways.
Depressive symptoms primarily affect the
transition from stable CAD to acute coronary
syndromes via plaque activation and
prothrombotic processes (solid line) and may
adversely affect the initial response to injury
at early stages of coronary atherosclerosis
(dashed line).
Kop Psychosom
Med 2005 67 Suppl 1 s37-s41
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Depression and cardiovascular disease
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Regression Coefficients (B) for Depressive
Symptoms Predicting Carotid IMT in Men and
Women. Adjusted for Age, LDL Cholesterol, Body
Mass Index, and Systolic Blood Pressure in
Childhood/Adolescent (in 1980) and for LDL
Cholesterol, Body Mass Index, Systolic Blood
Pressure and Smoking Status in Adulthood at
Follow up (in 2001). Elovainio Psychosom Med,
2005 67 561-567
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Adjusted relative risks for coronary heart
disease (CHD) mortality among women by depressive
symptoms (CESD). Numbers indicate increasing
severity of depression. From   Mendes de Leon
Arch Intern Med, 1998 58(21) 2341-2348
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Depressive Symptoms and Mortality From  
Wulsin Psychosom Med, Volume
67(5). 2005.697-702
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Relative risk of incident CHD associated with
depressive symptoms. From   Thurston
Psychosom Med, Volume 68(1).January/February
2006.25-32
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Myocardial Infarction and DepressionIntervention
Trial (MIND-IT) for symptoms of depression

• 1989 patients post MI Beck Depression Inventory
  /CIDI
• Severity of left ventricular (LV) dysfunction
  (measured by LV ejection fraction) related to the
  severity of depressive symptoms during the
  hospitalization even after controlling for
  demographic factors, coronary risk factors, co-
  morbidities (including diabetes mellitus), and
  Killip class.
• van Melle et al. Eur Heart J 2005 26 2650-5
  (December)

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Clinical outcome following percutaneous coronary
intervention (PCI).
Major adverse cardiac event stratified by the
presence of negative affectivity and inhibition.
Adjusted for age, gender and stent type.
Denollet et al. Eur Heart J 2006


27171-77.
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Long- term survival after MI in relation to
Beck Depression Inventory Score during
hospitalization

Lesperance et al, Circulation 2002105104953
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Rate of depressive disorder in the first year
following MI according to LVEF for women LVEF
gt60 (n154), LVEF 45-60 (n176), LVEF 30-45
(n79), LVEF
van Melle, J. P. et al. Eur Heart J 2005
262650-2656
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Event-Free Survival Days Following Myocardial
Infarction and Relationship With Depressive
Symptoms (N494) de Jonge et al. Am J Psychiatry
2006 163138-144 (January).
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Intervention studies
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Home-based psychosocial nursing intervention in
pts with myocardial infarction

• -903 men 473 women post-MI
• - intervention or usual care one year
• Results
• Men No effect
• Women Treatment group higher cardiac
• and all-cause mortality

Frasure-Smith et al, Lancet 1997
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Enhancing Recovery in Coronary Heart Disease
clinical trial (ENRICHD)

• Post-MI patients with low social support (26),
  or major or minor depression (39 wide HAM-D
  range in population) or combination of both
• Psychosocial intervention to improve social
  support and/or depression CBT (individual,
  group) vs usual care plus sertraline if HAMD gt24
  or lt50 reduction in BDI-scores after 5 weeks.
• Randomized controlled trial 2481 pts
• Main outcome variable mortality and recurrent
  infarction rate

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Enhancing Recovery in Coronary Heart Disease
clinical trial (ENRICHD)

• CBT initiated 17 days post MI
• 11 sessions over six months, plus group therapy
  when feasible

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ENRICHED Outcome

• No effect on mortality in overall sample
• No effect on mortality in subgroups
• - Depression
• - Low social support
• - Minority
• - Non-minority
• Trend to worse outcome in women

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Psychological interventions for CHD Outcome
non-fatal MI
Rees et al, Cochrane Database of Systematic
Reviews 2005 Issue 4 (Updated Feb 2004)
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Psychological interventions for CHD Outcome
depression
Rees et al. Cochrane Database of Systematic
Reviews 2005 Issue 4 (Updated Feb 2004)
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Psychological interventions for CHD Outcome
anxiety
Rees et al. The Cochrane Database of Systematic
Reviews 2005 Issue 4 (Updated Feb 2004)
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Cochrane conclusion 2004

• Overall psychological interventions showed no
  evidence of effect on total or cardiac mortality
• but did show small reductions in anxiety and
  depression in patients with CHD.
• Similar results were seen for stress management
  interventions when considered separately.
• However, the poor quality of trials, considerable
  heterogeneity observed between trials and
  evidence of significant publication bias make the
  pooled finding of a reduction in non-fatal
  myocardial infarction insecure.

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Psychopharmacotherapy
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SSRI therapy in patients with ischemic heart
disease

• SSRIs increase HRV (5) compared with a 9
  decrease in SDNN over the 22-week study period in
  the placebo group
• SSRIs reduce platelet activity. SSRI (sertraline)
  was associated with substantially less release of
  platelet/endothelial biomarkers PF4, ßTG,
  platelet/endothelial cell adhesion molecule 1, P
  selectin, thromboxane B2, 6-keto prostaglandin
  F1a, vascular cell adhesion molecule 1, and E
  selectin.
• Correlates with plasma-concentration of the drug

Jiang W, Davidson JRT. Am Heart J 2005 150
871-881 (november) Serebruany et al. Am J
Psychiatry 2005 162 1165-70.
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Antidepressants reduces cardiac complications and
death in markedly depressed pts following MI
(ENRICHD Not RCT !)
Taylor, C. B. et al. Arch Gen Psychiatry
200562792-798.
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ENRICHDSSRIs were effective in reducing
negative cardiac events in markedly depressed
patients

• The fact that the patients received aggressive
  state-of-the-art care confirms the applicability
  of the data to contemporary MI patients.

• Taylor, C. B. et al. Arch Gen Psychiatry
  200562792-798.

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SADHARTSertraline AntiDepreassant Heart Attack
Trial

• Multicenter trial (Shapiro et al Amer Heart J
  19991371100)
• Acute coronary syndrome (74 MI 26 unstable
  angina)
• Post hospitalisation evaluated (5-30 days)
• 369 pts with major depression (DSM-IV)
• Placebo or sertraline (50-200 mg)
• Cardiac outcome (Glassman et al. JAMA 2002 288
  701-9.)
• QoL (Swenson et al Am J Cardiol 2004 931080).

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Sertraline Antidepressant Heart Attack Trial
(SADHART) Glassman et al. JAMA. 2002288701-709.

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In progress The CREATE study

• Canadian Cardiac Randomized Evaluation of
  Antidepressant and psychoTherapy Efficacy
  (CREATE) study
• 2-by-2 factorial, placebo-controlled trial
• IPT and citalopram
• Funded by the Canadian Institutes of Health
  Research (CIHR) clinical trials program

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Who should be offered intervention?
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How to identify pts in need of treatment (1)?

• In the year following MI, 18.5 suffered from
  depressive disorder (ICD-10 criteria).
• Factors associated with depression were younger
  age (OR 1.94 CI 1.38-2.74), hypercholesterolemi
  (OR 1.68 CI 1.08-2.61), the use of calcium
  channel blockers at discharge (OR 1.80 CI
  1.20-2.71), and low left ventricular ejection
  fraction (LVEF) (OR 4.14 for patients with LVEF
  lt30 CI (2.42-7.10).

Van Melle et al, Int J Card 2005 Epub, ahead of
print
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How to identify pts in need of treatment (2)?

• Validation sample (prospective)
• younger age,
• severe LV-dysfunction
• High BDI score during hospitalization
• predicted pts who would develop depression post
  MI

Van Melle et al, Int J Card 2005 Epub, ahead of
print
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The key question

• What type of therapy,
• for whom?

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Behavioral change can be considered according to
a hierarchy of behavioral challenge, ranging
from those that are least difficult (i.e., the
initiation of new practices in which there is no
preexisting habit that needs to be broken) to the
most difficult (i.e., breaking addictive habits
which satisfy physiological drives).
Rozanski Psychosom Med
2005 67 Suppl 1 s67-s73
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Physical activity and immune function

• Excersising muscles produces IL-6, but regularly
  physical excersise has anti-inflammatory effects
  (incl. reduction in CRP compared to controls)
• Mediated in part via increase in glucocorticoids?
• In mice moderate (but not excessive) excersise
  after influenza (i.e.when symptoms have
  disappeared) reduces death
• In mice, down-hill (but not uphill) running
  increased IL-1? in the cerebellum and the cortex,
  and delayed recovery
• Reviews and recent findings, see Brain,
  Behaviour and Immunity 2005 19 issue 5 (Woods
  2005 Fairey et al 2005 Nieman et al, 2005
  Starkie et al 2005 Pastva et al, 2005 Kohut et
  al, 2005) Hoffman-Goetz 2005 Carmichael et al,
  2005).

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CBT HRV-biofeedback reduce depression and
improve HRV
HF high frequency spectral bandwidths of Heart
Rate Variability BSLN Baseline AC group active
control HRV-BFB Heart rate variability
biofeedback Nolan et
al. Am Heart J 2005 149 (6) 1137.
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For men, good relationship with spouse is
associated with less carotid artery intima medial
thickening (IMT).
From   Janicki Psychosom Med, Volume
67(6).November/December 2005.889-896
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For women, good relationship with much
interaction with spouse is associated with a
trend (?) towards increased (!) carotid artery
intima medial thickening (IMT).
From   Janicki Psychosom Med, 2005
67(6).Nov/Dec.889-896

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Conclusions

• Depression is a major risk factor for mortality
  and morbidity in pts with cardiovascular disease
  independent of known risk factors such as
  smoking, obesity, passiv lifestyle and
  cholesterol.
• Psychotherapy for depression may improve mood and
  quality of life, but so far (Jan 2006) no effect
  on mortality and biological morbidity has been
  demonstrated.
• In contrast, selective serotonin reuptake
  inhibitors (SSRIs) possibly may reduce morbidity
  and mortality, but few studies make the findings
  tentative.
• Antidepressant therapy should always be combined
  with behavioural interventions (e.g. reduce
  weigth, increase excersise stop smoking). .
• Type of antidepressant therapy should be fitted
  to the needs of the individual in question.
• Different needs between the sexes?

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