Major Depressive Disorder: Between Diagnosis and Compliance

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Major Depressive Disorder Between Diagnosis
and Compliance

• Koen Demyttenaere
• UPC KuLeuven
• Campus Gasthuisberg
• Belgium

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Effective management of depression ?

• Making the right dia-gnosis
• Offering patients appropriate care
• Adequate pharmacotherapy and/or psychotherapy
• Helping patients to comply with care

3
DSM-IV criteria for at least 2 weeks

• Depressed mood
• Diminished pleasure / interest
• Weight loss / gain
• Insomnia / hypersomnia
• Psychomotor agitation / retardation
• Fatigue / loss of energy
• Worthlessness / guilt
• Concentration problems
• Suicidal ideation

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Who makes the diagnosis ?
confidential
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Recurrent suicidal ideation in primary care
patients with MDD

• 28 of patients diagnosed with MDD by primary
  care physicians report recurrent thoughts of
  death / suicidal ideation !
• In 11/28 (39) this was not acknowlegded by the
  general practitioner

Demyttenaere K and Pitchot W, DEPRYM study
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Sheehan Disability Scale (SDS) (Sheehan, 1983)
Work
The symptoms have disrupted your work
Mildly
Markedly
Moderately
Extremely
Not at all
0
1
2
3
4
5
6
7
8
9
10
Social Life
The symptoms have disrupted your social life
Mildly
Markedly
Moderately
Extremely
Not at all
0
1
2
3
4
5
6
7
8
9
10
Family Life/Home Responsibilities
The symptoms have disrupted your family life/home
responsibilities
Mildly
Markedly
Moderately
Extremely
Not at all
0
1
2
3
4
5
6
7
8
9
10
8
Diagnosis clinically significant impairment
Sheehan Disability Scale
9
Diagnosis clinically significant impairment
Sheehan Disability Scale
Serious
Moderate
Number of areas
disability

disability

where disability

(cut off 7)

(cut off 4)

3

22

72

2

23

16

1

23

7

0

32

5



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Baseline diagnostic status

• In the FINDER study, discrepancies do exist
  between
• Observer rating
• clinical diagnosis of depression where treatment
  with an antidepressant is recommended
• Self rating
• Self rating scales as screening for diagnosis
• Hospital Anxiety and Depression Scale (HADS) with
  subscale for anxiety disorders and for depression
• 0-7 no case (-)
• 8-10 doubtful case (?)
• gt11 probable case ()

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Baseline diagnostic status

• Total number of included patients meeting
  clinical depression 3468
• Depression caseness based on HADS
• 66 probable depression
• 19 doubtful depression
• But 65 are probable case for anxiety disorder
• 15 no case
• But 41 are probable case for anxiety disorder

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Baseline diagnostic status
74
66
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Patients enrolled by general practitioners
75
60
14
Patients enrolled by psychiatrists
73
72
15
ESEMeD study of individuals being prescribed
antidepressants (last 12 M)
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Prevalence () of Psychotropic Use by
Sociodemographic Factors
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Who gets antidepressants ? ESEMeD study

• Logistic regression analysis
• OR C.I.
• Any pain 1.99 1.48 - 2.68
• Age group 2.19 1.12 - 4.27
• 6.52 3.36 -12.66
• Help seeking 13.58 9.87-18.67
• MDE past/present 2.04 1.48 - 2.68
• 4.99 3.39 - 7.35
• Anxiety past/present 1.70 1.16 - 2.51
• 2.12 1.39 - 3.25

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Long term evolution of MDD
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Symptomatic Outcome Quantitative approach

• Continuous definitions
• Endpoint severity
• Decrease in depression rating scale score
• Percentage decrease in depression rating scale
  score
• Categorical definitions
• Non-response
• Partial response 20 to 40 decrease
• Response 50 decrease
• Partial remission
• Remission HAMD 7 or less (2 weeks to 6
  months)
• MADRS 12 or less (2 weeks to 6 months)
• Residual / subsyndromal depressive symptoms
• Asymptomatic
• Recovery remission for ge 6 months

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Risk of recurrence in first episode depression
100
87
82
82
81
80
75
80
74
71
68
66
62
58
Cumulative probability of recurrence ()
60
52
43
40
28
20
13
0
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1
0.5
Time from study entry (years)
Lavori et al 1994
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of follow-up weeks spent at 4 severity
levels - a prospective 12 year study -
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Diagnostic status and outcome
Weeks to first prospective relapse to any
depressive episode (major, minor or dysthymic
Median Weeks Well
Asymptomatic Recovery, 13 Episodes 224.0
Asymptomatic Recovery, 3 Episodes 79.0
Residual SSD Recovery, 13 Episodes 34.0
Residual SSD Recovery, 3 Episodes 28.0

A. B. C. D.
1.0
0.8
Survival distribution function
0.6
0.4
0.2
0.0
0
50
100
150
200
250
300
350
400
450
500
Weeks to first prospective relapse to any
depressive episode (major, minor
or dysthymic)
Judd et al 1998
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Differential mortality

• Suicide accounts for 1619 of deaths in
  psychiatric samples
• MDD and all deaths (review 19661996)
• 51 positive studies
• 23 negative studies
• 26 mixed studies

Wulsin et al 1999
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Differential mortality

• Community sample, ? 40 years, 9 year period
• Ambulatory care, all ages, 9 year period

Gender Men Women
Recent relative risk 1.67 1.21
Past relative risk 1.92 1.16
Bruce et al 1994
Index episode Hazard ratio 95 CI
AD Age Male
1.52 1.10 1.90
1.201.92 1.091.12 1.512.39
Bingefors et al 1996
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Differential mortality

• Community sample, women ? 67 years, 7 yrs

35
30
25
Mortality ()
20
15
10
5
0
Depressive symptoms
Whooley et al 1998
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The attacks begin not infrequently after the
illness or death of near relatives We must
regard all alleged (psychic) injuries as possible
sparks for the discharge of individual attacks,
but the real cause of the malady must be sought
in permanent internal changes In spite of the
removal of the discharging cause, the attack
follows its independent development. But finally,
the appearance of wholly similar attacks on
wholly dissimilar occasions or quite without
external occasion shows that even there where
there has been external influence, it must not
be regarded as a necessary presupposition for the
appearance of the attack
Kraepelin 1921
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Time to recurrence
1.0
0.9
0.8
Cumulative survival
0.7
0.6
0.5
Time 1
0.4
0.3
Time 2
Time 3
Time 15
0.2
Time 4
Time 5
0.1
Time 10
0.0
0
5
10
15
20
25
Time to recurrence (years)
Kessing et al 1998
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From precipitated to spontaneous episodes

• First episode 57 (43-91) major life
  eventLater episode 32 (13-56) major life
  event (meta-analysis Post 1992)
• initially searching for stressors/life events
• later episodes acceptance autonomous illness

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Correlation between hippocampal volume and
duration of untreated depression
38 Female Outpatients With Recurrent Depression
in Remission
6000
R2.28 P.0006 N38
5500
5000
Total Hippocampal Volume (mm3)
4500
4000
3500
3000
0
1000
2000
3000
4000
Days of Untreated Depression

• There was a significant inverse relationship
  between total hippocampal volume and the length
  of time depression went untreated

Sheline YI, et al. Am J Psychiatry.
2003160(8)1516-1518.
Reprinted with permission from APA.
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What is a good enough outcome?

• Physician perspective
• Symptoms
• Adverse events
• Patient perspective
• Symptoms
• Adverse events
• Wellbeing
• Quality of life
• Functioning
• Economic aspects
• Society perspective
• Functioning
• Economic aspects

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Factors identified by depressed outpatients as
very important in defining remission

• Rank order
• Presence of positive mental health (e.g.
  optimism, vigor, self-confidence)
• Feeling like your usual, normal self
• Return to usual level of functioning at work,
  home or school
• Feeling in emotional control
• Participating in and enjoying relationships with
  family and friends
• Absence of symptoms of depression

Zimmerman M et al., Am J Psychiatry 2006
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Sick leave in depression

• ESEMeD study
• Work loss days (absenteism presenteism) 5
  days
• Naturalistic study in a working population
  (Austria)
• Days on sick leave 3 months prior to and 3 months
  during escitalopram treatment were compared in
  2378 patients (949 men and 1376 women)
• 807 of these patients received additional
  assessments clinical global impression of
  severity (CGI-S) and improvment (CGI-I)

Winkler D. et al. Hum. Psychopharmacol. 2007 In
press.
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Treatment with an antidepressant (escitalopram)
reduces sick leave

Mean no. of days on sick leave
Timepoint in study
p lt 0.001 n 2378
Winkler D. et al. Hum. Psychopharmacol. 2007 In
press.
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Number of sick days a distribution
Winkler et al. Hum Psychopharmacol 2007 22 (4)
245251
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Socio-economic factors and remission
Remission rate
male
32,3
female
29,9
alone
30,5
couple
31,2
no income
33
unemployment
17,5
self-employed
40
worker
36
employee
39
middle management
34
retired
34
16
no degree
low qualification
26
higher secundary
32
higher non university
34
university
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1397 patients with MDE, treated with
antidepresssants for 6 months Primary care or
psychiatric outpatient care (OREON study)
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Prediction of Remission at 6 months follow-up
(FINDER study)
Demyttenaere K et al., submitted
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Distribution of SDS occupational impairment
scores mild impairment in remitters
In psychiatric care, 58 of remitted pts have
only mild impairment
In primary care, 82 of remitted pts have only
mild impairment
Remission
No remission
1397 patients with MDE, treated with
antidepresssants for 6 months Primary care or
psychiatric outpatient care (OREON study)
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Labor force activity in a community survey (N
37.580)
Waghorn G and Chant D, 2007
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I never promised you a rose garden
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Benefits and costs of disability leave

• Benefits
• Removal from occupational stresses and of
  under-performing
• More time and opportunity to engage in activities
  conducive to recovery
• Costs
• Inactivity, retreating to bed
• Isolation, without the usual social contacts
  afforded by the workplace
• Development of a secondary anxiety pattern
  whereby patient becomes more apprehensive about
  returning to work
• The longer the disability leave, the less likely
  it is that the patient will ever return to
  gainful employment

Bilsker D et al., Can J Psychiatry 2006
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Sustaining the link between the patient and the
workplace

• Encourage the patient in active coping with
  difficulties at work
• Encourage the patient to maintain lines of
  communication, rather than avoiding contact out
  of shame (supervisor, co-workers, human resources
  etc.)
• Collaborative decision making concerning the
  duration of disability leave
• Disseminate self-management material

Bilsker D et al., Can J Psychiatry 2006
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Are subjects in trials representative of patients
in routine clinical practice ?

• Outpatient practice N 346
• - 31 (bipolar disorder)
• - 22 (psychotic features)
• -159 (insufficient symptom severity)
• - 17 (substance abuse in the prior 6 months)
• - 2 (suicidal ideation)
• - 74 (comorbid anxiety disorder)
• - 1 (depression duration less than 4 weeks)
• - 2 (another comorbid axis I disorder)
• - 1 (borderline personality disorder)
• - 1 (dysthymic disorder)
• -7 (depression duration more than 24 months)
• 29 patients would have been included

Zimmerman M et al., Am J Psychiatry 2002, 159
469-473
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Acute phase Follow-up schedules and
therapeutic effect of antidepressants

• 6 week trials
• 15 studies cohort with weekly visits
• 19 studies skip week 5 cohort
• 7 studies skip weeks 3 and week 5 cohort
• Reductions in HRDS scores from week 2 to week 6
  in patients with active Rx
• 5.87 for weekly cohort
• 5.05 for skip week 5 cohort
• 4.29 for skip weeks 3 and 5 cohort
• Reductions in HRDS scores from week 2 to week 6
  in patients with placebo
• 4.24 for weekly cohort
• 3.33 for skip week 5 cohort
• 2.49 for skip weeks 3 and 5 cohort

Posternak MA and Zimmerman M, 2007
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Long-term Relapse prevention with ADs

• 31 RCT (4410 patients)
• Continuing Rx with ADs reduced the odds of
  relapse by 70
• Relapse 41 versus 18
• Effect maintained up to 36 months

Geddes JR, 2003
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Long-term Adherence to treatment

• Medicaid database of 4052 patients
• Cox proportional hazards model (dependent
  variable time to relapse/recurrence)
• Discontinued early (4M) RR 1.77
• Substance abuse RR 1.60
• Prior hospitalization RR 1.31
• N comorbidities RR 1.09

Melfi CA et al., 1998
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Long-term Antidepressant dose reduction and the
risk of relapse in MDD

• 5 studies
• Davidson 1984, Rouillon 1991, Frank 1993, Ferreri
  1997, Franchini 1998
• Continuation between 20 weeks and 3 years
• Pooled relapse rates were 25.3 for full dose
  continuation and 15.1 for reduced dose
  continuation
• RR 1.62 (62 higher risk of relapse)

Papakostas GI et al., 2007
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• COMPLIANCE

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Patient profile
Days missed
Time
1
4
1
3
3
2
5
3
5
2
24.00
20.00
16.00
12.00
8.00
4.00
0
5
60
10
15
20
25
30
35
40
45
50
55
Days
50
Adherence Frequency Distribution
Poor (28.8)
Partial (28.7)
Good (42.5)
30
25.8
25
19.7
20
of Patients Respondingto Treatment
16.7
15
12.1
12.1
10
6.1
4.5
4.5
5
3.0
1.5
0
10
20
30
40
50
60
70
80
90
100
Days of Adherence ()
Demyttenaere K et al., Int Clin Psychopharmacol
1998
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Duration of antidepressant use in first and
recurrent episode patients (Belgium)
Survival Function in first episode patients
Survival Function in recurrent episode patientsn
1,0
1,0
0,8
0,8
0,6
0,6
Cum Survival
Cum Survival
0,4
0,4
0,2
0,2
0,0
0,0
1.000
800
600
400
200
0
1.400
1.200
1.000
800
600
400
200
0
duree
duree
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Negative views on the action of psychotropic drugs
Benkert O et al., 1997

• one no longer has control over oneself 27
• they deliver you over to the doctor 31
• no one knows exactly how they act 32
• they have severe side effects 36
• they lead to dependency 37
• they sedate instead of curing 37
• they dont eliminate the cause of the illness
  49

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Conclusions

• making the right diagnosis
• and
• helping patients to accept the treatment
• are
• probably
• as
• important
• as
• the choice of the treatment itself