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Depression in patients with medical co morbidities -an overlooked problem?
DR JUNAID SALEEMM.B.B.S, F.C.P.S (MED)
CONSULTANT MEDICAL SPECIALISTHEART’S INTERNATIONAL HOSPITAL
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What is the added effect of depression on the well-being of a patient who also suffers from a chronic medical disorder?
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Depression…
• Often co-occurs with other medical disorders
• Worsens functional impairment
• Decreases adherence to prescribed treatments
• Is associated with adverse health behaviours
• Amplifies physical symptoms
• Increases mortality
• Is costly for the individual and society as a whole
Moussavi et al. Lancet 2007; 370: 851–858; Prince et al. Lancet 2007; 370: 859–877; DiMatteo et al. Arch Intern Med 2000; 160 (14): 2101–2107; Ciechanowski et al. Arch Intern Med 2000 160 (21):3278–3285
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Prevalence of major depression inchronic medical illness
NHDS, NAMCS, NHAMCS. Sutor et al. Mayo Clin Proc 1998; 73 (4): 329–337; Jiang et al. CNS Drugs 2002; 16 (2):111–127
51%
42%
27%
25%
23%
17%
12%
11%
Parkinson's disease
Cancer
Diabetes
MI
Stroke
CAD
HIV
Alzheimer's disease
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Poorer mean health scores with co morbidity
No chronic
condition
Asthma only
Angina only
Arthriti
s only
Diabetes only
Depression only
Depression and
arthriti
s
Depression and
angina
Depression and
asthma
Depression and
diabetes≥2 chronic
conditions
Depression and ≥2
chronic conditions
100
80
60
40
20
0
Mea
n he
alth
sco
re (0
–100
)
90.6
80.3 79.6 79.3 78.972.9
67.1 65.8 65.458.5
71.8
56.1
Moussavi et al. Lancet 2007; 370: 851–858
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Depression alone is costly
IMS Knowledgelink; Berto et al. J Ment Health Policy Econ 2000; 3: 3–10
Global drug costs by therapy area Depression treatment: cost distribution
5 10 15 20 25 30 35
Calcium antagonists
Erythropoietins
Oral anti-diabetics
Anti-epileptics
All other antineoplastics
Antidepressants and moodstabilisers
Antipsychotics
Antiulcerants
Cholesterol and triglyceride regulators
World sales (US dollars) –12 month period to Q2 2008
00
20
40
60
80
100
Dire
ct c
osts
(%)
Drugs
Consultations
Hospital admissions
Other
A B C D E F G
Study
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Mechanisms of depression & medical co morbidity (1)
• Depression occurs independently of the medical disorder
• Adjustment disorder with depressed mood,
precipitated by the stress of the medical condition
• Medical condition precedes the depression and is felt to have a pathophysiological relationship
• Substance-induced depression
• alcohol, drug, or a prescription medication produces depression
• Depressive symptoms that are a normal response to being
severely ill
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Mechanisms of depression & medical co morbidity (2)
Ellison et al. Mood Disorders in Later Life. Informa 2009
Primary medical illness/condition
Premorbid coping skills, cognitive set,
and personality traits
Pathologic mood state
e.g., depression
Social supports
Neuroendocrine, immune dysfunction, inflammatory change
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Depression in medical inpatients
0
2
4
6
8
10
12
14
Community Primary care Medical inpatients
Perc
ent o
f pop
ulat
ion
(%)
Katon & Sullivan. J Clin Psych 1989; 51 (s6): 3
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Diabetes mellitus and depression
• Patients with diabetes are twice as likely to experience depression as those
without
• both Type 1 and Type 2 diabetes
• The prevalence of depression among people with diabetes ranges from 8.5 to
32.5%
• Having diabetes and depression may be associated with higher risk of suicide,
with some reports of a 10-fold increased risk of suicide and suicidal ideation
Rosenthal et al. Diabetes Care 1998; 21: 231–235; Goodnick et al. J Clin Psychiatry 1995; 56 (4): 128–136; Gavard et al. Diabetes Care 1993; 16 (8): 1167–1178; Lustman et al. Diabetes Care 2000; 23 (7): 934–942;
Goldston et al. J Am Acad Child Adolesc Psychiatry 1994; 33 (2): 240–246; Goldston et al. J Am Acad Child Adolesc Psychiatry 1997; 36 (11): 1528–1536
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Behaviour (1) Depression decreases adherence to medical regimens
• Adversely influences expectations and benefits of
treatment efficacy
• Increases withdrawal and social isolation
• Reduces cognitive (executive) functioning and memory
• Influences dietary choices and reduces motivation to exercise and follow
self-management regimens
• e.g. checking blood glucose
DiMatteo et al. Arch Intern Med 2000; 160 (14): 2101–2107
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Behaviour (2)Depression decreases medication adherence in diabetes
Lin et al. Diabetes Care 2004; 27 (9): 2154–2160
0
10
20
30
40
Oral hypoglycaemic
Lipid loweringmeds
ACE inhibitors
Non
-adh
eren
t day
s (%
)
DepressedNon-depressed
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Depression and diabetics with HbA1c >8%
n=4,225; Adjusted for demographics, medical comorbidity, diabetes severity, diabetes type and duration, treatment type, HbA1c and clinic Katon et al. Diabetes Care 2004; 27 (4): 914–920
0
10
20
30
40
50
60
None Minor Major
p<0.01 vs none
Perc
ent w
ithH
bA1c
>8%
(%)
Depression group
p<0.001 vs none
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Risk factors (1)Depression is associated with increased smoking
n=4,225; Adjusted for demographics, medical comorbidity, diabetes severity, diabetes type and duration, treatment type, HbA1c and clinic
0
5
10
15
20
None Minor Major
Perc
ent
smok
ing
(%)
p<0.01 vs none
Depression group
p<0.001 vs none
Katon et al. Diabetes Care 2004; 27 (4): 914–920
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Risk factors (2)Depression and increased BMI (>30 kg/m2)
n=4,225; Adjusted for demographics, medical comorbidity, diabetes severity, diabetes type and duration, treatment type, HbA1c and clinic
01020304050607080
None Minor Major
Perc
ent w
ith
BM
I >30
kg/
m2 (
%) p<0.01 vs none
Depression group
p<0.001 vs none
Katon et al. Diabetes Care 2004; 27 (4): 914–920
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Weight changes with antidepressantsRisk factor minimization
Vieweg et al. Am J Med 2008; 121 (8): 647–655
Weight burden scale -0.5 0 +0.5 +1.0 +1.5 +2.0
Potential weight change/year (lb)
0–5 0 1–5 6–10 11–15 >15
Drug class
AntidepressantsSSRITCAMAOISNRIOther
BupropionFluoxetine
CitalopramDuloxetine
EscitalopramFluvoxamineNefazodoneSelegilineSertraline Trazodone Venlafaxine
DesipramineNortriptylineParoxetineProtriptyline
AmitriptylineDoxepin
ImipramineMirtazapinePhenelzine
Tranylcypromine
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Risk factors (3)Depression and the risk of DM complications
• Incidence of coronary artery disease was 3 times more common over a 10-year period in diabetics who were
initially depressed vs
non-depressed1
• Risk of development of retinopathy was associated with:2
• Duration of Type 1 diabetes
• Time spent in poor glucose control
• Time spent in major depression
• Meta-analysis of 27 studies showed a significant association between depression and a range of diabetes
complications3
• e.g., diabetic retinopathy, nephropathy, neuropathy,
macrovascular complications, sexual dysfunction
1. Carney et al. Psychosom Med 1988; 50: 627–633; 2. Kovacs et al. Diabetes Care 1997; 20: 45–51; 3. DeGroot et al. Psychosom Med 2001; 63: 619–630
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Depression increases mortality rate in diabetes by two-fold
Kaplan-Meier survival estimate
0.8
1.0
0.9
0 24 48 72 96 120 144
Kap
lan-
Mei
er e
stim
ate
Survival time (weeks)
Non-depressed patients
Depressed patients
Katon et al. Diabetes Care 2005; 28 (11): 2668–2672
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Cardiovascular disorders– myocardial infarction (MI)
• MDD may occur in 31% of patients admitted for acute MI
• MDD was the best single predictor of MI, angioplasty and death during the
12 months following cardiac catheterization
• Patients with history of MI and MDD were 3–5 times more likely to die within
6 months of discharge compared to non-depressed patients following MI
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Depression associated with increased mortality post MI
Cox model hazard ratio for 6-month mortality associated with depression: 5.74 (95% CI: 4.61–6.87) p=0.0006
Time after MI (months)
Perc
ent
mor
talit
y (%
)
0
5
10
15
20
25
0 1 2 3 4 5 6
Depressed (n=35)
Non-depressed (n=187)
Frasure-Smith et al. JAMA 1993; 270: 1819–1825
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SSRIs heal a SADHART:sertraline decreases myocardial instability
Glassman et al. Am Heart J 1999
0123456789
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Baseline Week 2 Week 16 Endpoint
PVCs/100
Couplets/10
NSVT
Vent
ricul
ar a
rrhy
thm
ias
(eve
nts
per 2
4 ho
urs)
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SSRIs heal a SADHART
Patients treated with sertraline had 22% fewer adverse cardiac events, 60% fewer deaths
Heart rate
PR (ms)
VT
SDNN (ms)
Deaths
Sertraline
65/64
167/167
20/14
100/104
2
Placebo
65/66
172/173
21/23
109/103
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JAMA 2002
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20
25
30
35
40
45
Baseline Week 2 Week 7
Roose et al. Am J Psychiatry 1998
Left
vent
ricul
ar
ejec
tion
frac
tion
LVEF improved 7% in study of 12 depressed CHD patients with baseline LVEF <50%
SSRIs heal a sick heart:fluoxetine increases LVEF
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Depression after coronary artery disease is associated with heart failure
May et al. J Am Coll Cardiol 2009; 53 (16): 1440–1447
Days to heart failure admission
0.5
1.0
0.7
0 1,000 2,000 3,000 4,000 5,000
Even
t-fre
e su
rviv
al
0.6
0.9
0.8
No depression diagnosis
Depression diagnosis
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Behavior of co morbid depression patients:Self-management of cardiovascular disorders
• More likely to drop out of exercise programmes1
• Less likely to adhere to low-dose aspirin than
non-depressed controls2
• Smokers are 40% less likely to succeed in quitting smoking over a 9-year period
compared to
non-depressed smokers3
• Patients with history of depression compared to non-depressed are more likely to
develop depression with smoking cessation4
1. Blumenthal et al. Psychosom Med 1982; 44 (6): 529–536; 2. Carney et al. Health Psychol 1995; 14 (1): 88–90; 3. Anda et al. JAMA 1990; 264 (12): 1541–1545; 4. Dierker. Am J Psychaitry 2002; 159: 947–953
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Post-stroke depression (PSD)
• Depression is one of the most frequent co-morbid psychiatric
disorders in stroke patients
• About 40% of patients with stroke will develop depression during the
first 2 years after the acute event
• PSD peaks within 3–6 months after the stroke
Starkstein et al. Expert Opinion 2008; 9: 1291–1298
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Efficacy and tolerabilityin one drug ?
Are all antidepressants the same?
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Cipriani et al. Lancet 2009
• Independently funded meta-analysis• Acute treatment phase• Comparison of 12 antidepressants
in adults treated for MDD• 117 randomised clinical trials
(25,928 participants)
Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis
Cipriani et al.Lancet 2009; 373: 746–758
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Cipriani et al- Meta analysis of 12 anti depressants Superior combination of efficacy and acceptability
Adapted from Cipriani et al. Lancet 2009; 373 (9665): 746–758(Source: Patrick et al. J Fam Pract 2009; 58 (7): 365–369)OR=odds ratio, using fluoxetine as the reference medication
0.800.850.900.951.001.051.101.151.201.25
0.8 0.9 1.0 1.1 1.2 1.3 1.4
Acce
ptab
ility
(O
R)
Efficacy (OR)
Fluvoxamine
Citalopram
Bupropion
VenlafaxineMirtazapine
Sertraline
Escitalopram
Paroxetine
Fluoxetine
Duloxetine
●
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Escitalopram in the prevention of PSD:Study design
Robinson et al. JAMA 2008; 299 (20): 2391–2400
739 patients assessed for eligibility
176 randomised
563 Excluded254 Did not meet inc. criteria168 Unwilling to participate141 Other
58 Randomised to PBO51 Received PBO7 Did not receive PBO
59 Randomised to ESC51 Received escitalopram7 Did not receive escitalopram
59 Randomised to PST48 Received PST11 Did not receive PST
5 Lost to follow-up 7 Lost to follow-up 3 Lost to follow-up
58 Included in analysis 59 Included in analysis 59 Included in analysis
PBO=placebo; ESC=escitalopram; PST=problem-solving therapy
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Escitalopram prevents depression onset in stroke patients
Robinson et al. JAMA 2008; 299 (20): 2391–2400
Compared to placebo: Escitalopram was 4.5 times
more likely to prevent depression
Problem Solving Therapy was 2.2 times more likely to prevent depression
No. at risk
Escitalopram 59 46 44 42 38PST 59 49 46 41 38Placebo 58 43 39 34 33
1.0
0.8
0 3 6 9 12
Prop
ortio
n w
ithou
tde
pres
sion
0.6
0.4
0.2Escitalopram
Month
Problem-solving therapy (PST)Placebo
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The benefit in context
7.2 stroke patients would need to be treated with escitalopram to prevent 1 case of depression
Compare with another preventive intervention in which 40 male patients with hypercholesterolaemia would need to be treated with
pravastatin for 5 years to prevent 1 myocardial infarction
Robinson et al. JAMA 2008; 299 (20): 2391–2400; Shepherd et al. N Engl J Med 1995; 333 (20): 1301–1307
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Metabolism of antidepressantsAn important consideration in comorbidity
Second generation antidepressant
Enzymes involved in biotransformation Isozymes inhibited
Bupropion CYP2B6 CYP2D6 (moderate)
Citalopram CYP2C19, CYP2D6, and CYP3A4 CYP2D6 (weak)
Duloxetine CYP2D6 and CYP1A2 CYP2D6 (moderate)
Escitalopram CYP2C19, CYP2D6, and CYP3A4 CYP2D6 (weak)
Fluoxetine CYP2D6, CYP2C9, CYP2C19, and CYP3A4 CYP2D6 (strong), CYP2C9 (moderate), CYP2C19 (weak to moderate), CYP3A4 (weak to moderate), CYP1A2 (weak)
Fluvoxamine CYP1A2 and CYP2D6 CYP1A2 (strong), CYP2C19 (strong), CYP2C9 (moderate), CYP3A4 (moderate), CYP2D6 (weak)
Mirtazapine CYP2D6, CYP1A2, and CYP3A4 None known
Nefazodone CYP3A4 CYP3A4 (strong), CYP2D6 (weak)
Paroxetine CYP2D6 and CYP3A4 CYP2D6 (strong), CYP1A2 (weak), CYP2C9 (weak), CYP2C19 (weak), CYP3A4 (weak)
Reboxetine CYP3A4 CYP2D6 ( weak)
Sertraline CYP2C9, CYP2C19, CYP2D6, and CYP3A4 CYP2D6 (weak to moderate), CYP1A2 (weak), CYP2C9 (weak), CYP2C19 (weak), CYP3A4 (weak)
Venlafaxine CYP2D6 and CTP3A4 CYP2D6 (weak)
Spina et al. Clin Therapeutics 2008; 30 (7): 1206–1227
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Case: Treatment choice
• 48 year-old female - nurse • 12 months of symptoms:
• Diarrhea, irritability, restlessness• Constant worry, e.g., called police because her husband
was 20 min late from work
• Further questioning resulted in additional symptoms:• Loss of interest in daily activities• Poor concentration – poor sleep
• GP diagnosed her with generalized anxiety disorder and MDD
• Treatment with diazepam – helped on her feelings of anxiety, but she felt “dull” and still depressed with increased severity
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Questions to the case
• Diagnosis: • Is the diagnosis right? Additional examination?
• Treatment strategy:• Any need for change in therapy?• Why - how - what - when?
• Follow-up: • When will you see her again and how will you monitor
her progress?• Treatment length?
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Conclusions
• Depression co-existing with medical co morbidities is often
down-prioritized or unrecognized
• Addressing the further exacerbation of disability due to
depression needs to be a treatment priority
• In these patients, antidepressant choice has more
far-reaching implications than simply resolving the
depression
• Reducing the stigma of depression would help alert all that
depression is at least as damaging as other diseases