1

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

2

What is the added effect of depression on the well-being of a patient who also suffers from a chronic medical disorder?

3

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

4

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

5

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

6

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

7

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

8

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

9

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

10

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

11

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

12

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

13

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

14

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

15

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

16

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

17

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

18

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

19

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

20

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

21

SSRIs heal a SADHART:sertraline decreases myocardial instability

Glassman et al. Am Heart J 1999

0123456789

10

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)

22

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

5

JAMA 2002

23

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

24

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

25

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

26

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

27

Efficacy and tolerabilityin one drug ?

Are all antidepressants the same?

28

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

29

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

●

30

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

31

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

32

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

33

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

34

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

35

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?

36

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