Emerging focal points in depression and anxiety

22nd ECNP Congress, Istanbul 12th September 2009 Chairman: George I Papakostas, USA

Programme
Emerging focal points in depression and anxiety
Chairmans introduction
Serotonergic dysfunction implications for treatment of mood and anxiety disorders George I Papakostas, USA Pierre Blier, Canada

Comorbid depression and anxiety understanding and treating complex patients

Is real-life functionality the new goal of treatment? Integrating clinical treatment strategies for major depressive disorder Panel discussion

Borwin Bandelow, Germany Raymond W Lam, Canada

George I Papakostas, USA Panel

Chairmans conclusion

George I Papakostas, USA

2

Serotonergic dysfunction implications for treatment of mood and anxiety disorders

Pierre Blier, Canada

Plan of the presentation

Describe abnormalities in the serotonin (5-HT) system in depression Illustrate the hyperactivity in the limbic system and the atrophy of the hippocampus in depression Explain the commonality of action of antidepressant treatments on the 5-HT system Show data on the robust impact of escitalopram on the 5-HT system Present the clinical relevance of the functional connectivity between the 5-HT, noradrenaline (NA) and dopamine (DA) systems
4

Serotonin: overall evidence for decreased levels in depression and anxiety

5-HT and 5-HIAA in MDD/anxious vs controls 5-HT1A binding in limbic areas Blunted prolactin response to fenfluramine Diminished 5-HT transporter binding Alterations in 5-HT receptor binding Platelet findings of 5-HT receptor/ transporter alterations

5-HIAA=5-Hydroxyindoleacetic acid
5

Regulation of behavioural circuits by neuromodulatory systems

Prefrontal cortex Cognition, working memory, modulation of affect

Thalamus Arousal/sleep, sensorimotor gating

VTA DA LC Raphe NA 5-HT

Amygdala/BNST/ hippocampus Fear/stress response, anxiety symptoms, memory

Hypothalamus Stress response, sleep/wake/appetite regulation Nucleus accumbens Reward/pleasure

Serotonin transporter (5-HTTLPR) genotype and amygdala activation: a meta-analysis

Meta-analysis of 15 studies examining amygdala activation and 5-HTTLPR genotype In all but one of these studies, the short allele was associated with increased amygdala activation compared to the long allele
-4.00 -2.00 Long high activation 0.00 2.00 4.00

Standard difference in means (95% CI)

Short high activation

Munaf et al. Biol Psychiatry 2008; 63: 852857

7

Hippocampal volume and depression: a meta-analysis of MRI studies

Standardised mean difference of left hippocampal volume (depressed vs control subjects)
Standardised mean difference

Standardised mean difference

Study Frodl 2002

(95% CI)

% weight

-2.0

2.0
-0.23 (-0.74, 0.28) 9.2

Macqueen 2003
Von Gunten 2000 Mervaala 2000 Rusch 2001 Vakili 2000 Ashtari 1999 Bremner 2000 Macqueen 2003 Posener 2003 Sheline 2003 Steffens 2000 Overall (95% CI)

-0.07 (-0.69, 0.55)

-0.41 (-1.16, 0.34) -0.83 (-1.43, -0.22) 0.04 (-0.60, 0.68) 0.36 (-0.18, 0.91) -0.30 (-0.72, 0.13) -0.99 (-1.72, -0.25) -1.23 (-1.97, -0.49) 0.19 (-0.29, 0.68) -0.79 (-1.26, -0.32) -0.66 (-1.19, -0.13) -0.38 (-0.65, -0.11)

7.9
6.6 8.1 7.7 8.7 10.2 6.7 6.7 9.5 9.7 8.9

Videbech & Ravnkilde. Am J Psychiatry 2004; 161 (11): 19571966

8

Treatment: antidepressant effects on plasma BDNF

BDNF is hypothesised as being a key factor in neuroplasticity This study evaluated the pre- and post-treatment levels of BDNF in a group of depressed patients (n=20) and compared them with healthy controls (n=20) All were treated with escitalopram 10 mg/day over 6 weeks

Aydemir et al. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 12561260

9

SSRIs positively affect BDNF

Mean BDNF (ng/ml) Mean HAM-D score

45 40 35
BDNF (ng/ml)

**

45 40 35 HAM-D score 30 25 20 15

30 25 20 15 10 5 0
Healthy controls (n=20) Pre-treatment Post-treatment Depressed patients (n=20)

***

10 5 0

**p=0.002; ***p<0.001 (pre-treatment vs post-treatment; Wilcoxon signed ranks test) p=0.010 (pre-treatment vs healthy controls; MannWhitney U-test) p=ns (post-treatment vs healthy control BDNF levels; MannWhitney U-test)

Aydemir et al. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 12561260

10

Actions of various agents on the serotonin system

5-HT neuron MAOI Postsynaptic neuron

SSRI
Tryptophan

MAO

5-HT

5-HT

(+)
5-HT1A

5-HT1B

Lithium
(+) (-)

(+)

Buspirone
Visken Tryptophan

(+)

T3

11

Antidepressant actions at the serotonin transporter

Conventional SSRIs and SNRIs

Escitalopram (S-citalopram enantiomer)

Snchez. Basic Clin Pharmacol Toxicol 2006; 99 (2): 9195
12

Higher efficacy (5-HT release) of escitalopram vs. citalopram

Microdialysis (frontal cortex, freely moving rats) 5-HT release
*p<0.05 compared to all citalopram doses

50,000 5-HT release AUC (% x min) * 40,000

30,000

20,000

10,000

0 CIT 2.0 CIT 4.0 CIT 8.0 ESC 1.0 ESC 2.0 ESC 3.9 R-CIT 16 mg/kg

Mrk, Kreilgaard & Snchez. Neuropharmacology 2003; 45: 167173

13

Different effects on neurogenesis: the case of escitalopram and citalopram

R-citalopram antagonises escitalopram-induced increase of cell proliferation 14 days of treatment
8,000 Number of BrdU-positive cells 7,000

6,000
5,000 4,000 3,000

2,000
1,000 0
Control Escitalopram (10 mg/kg/day) Escitalopram + R-citalopram R-citalopram (20 mg/kg/day)

*p<0.05 vs control; #p<0.05 vs escitalopram

Mnie-Filali et al. NeuroReport 2007; 18: 15531556

14

Higher SERT occupancy observed with escitalopram after multiple dosing

Escitalopram
100 90 SERT occupancy (%) 70 60 50 SERT occupancy (%) 80

Citalopram
100 90
80 70 60 50 40 30 20 10 0

40
30 20 10 0 0 20 40 60 80 Serum S-citalopram (nmol/l)
Single dose

0 20 40 60 80 Serum S-citalopram (nmol/l)

Steady state

A build-up of the R-enantiomer after repeated citalopram dosing may lead to increased inhibition of S-enantiomer occupancy of SERT
Kasper et al. Int Clin Psychopharmacol 2009; 24: 119125
15

Reciprocal interactions between monoaminergic neurons

DOPAMINE
D2 (-)

(+) D2

(-) a2, D2

(-) a2

?
NA

5-HT
(-)

a1 (+)
16

5-HT2A antagonism reverses the inhibition of NA neurons by an SSRI

150

#
100

50

0 Vehicle Control (no co-treatment)

*p<0.01 vs vehicle animals; #p<0.05 vs animals administered escitalopram alone, using a Bonferroni post hoc test

Escitalopram SB 242084 Haloperidol M100907

Dremencov, Mansari & Blier. Biol Psychiatry 2007; 61: 671678

17

Reversal of the inhibitory effect of an SSRI by a 5-HT2C antagonist

140
Escitalopram
Escitalopram + SB 242084 0.5 mg/kg/day Escitalopram + SB 242084 2.0 mg/kg/day

Percentage ( SEM) of corresponding parameter in control rats

120

100

*#
80 60 40 20 0 Firing rate, spikes/sec

* *

***

Proportion of spikes occurring in bursts

Dremencov, Mansari & Blier. J Psychiatry Neurosci 2009; 34: 223229
18

*p<0.05; ***p<0.001 vs vehicle (vehicle data not shown) #p<0.05 vs escitalopram, Bonferroni post-hoc test

Functional connectivity

5-HT2A for NE neurons 5-HT2C for DA neurons

19

Conclusion
Treatment of depression results in:
Increase in serotonin function Decrease of the hyperactivity in limbic/para-limbic structures Increase in BDNF/neurotrophin (VEGF) levels
Increase in hippocampal size and grey matter density in the brain

Escitalopram shows clinical superiority over citalopram, which may be explained by its more effective action on the serotonin transporter

20

Serotonergic dysfunction implications for treatment of mood and anxiety disorders

Pierre Blier, Canada

Comorbid depression and anxiety understanding and treating complex patients

Borwin Bandelow, Germany

Dissecting a controversy
Coexistent, simultaneous depression and anxiety may be viewed as mixed anxietydepression or as comorbid syndromes, i.e. separate disorders occurring concurrently

Controversy remains over the extent to which the two disorders intersect aetiologically and phenomenologically

Hranov. Int J Psychiatry Clin Practice 2007; 11: 171189

23

Symptom overlap
GAD Depression
Fatigue Dysphoria Irritability Sleep dist. Appetite dist. Sensitivity (criticism) Apathy Retardation Withdrawal Loss of interest Morning depression Poor concentration Self confidence Hopelessness

Anticipatory anxiety Nervous tension Muscular tension Restlessness Tension pains Physiological arousal

Nutt, Rickels, Stein. GAD. Dunitz, 2002

24

Comorbidity a less favourable prognosis

Compared with non-comorbid cases, depressed patients with comorbid anxiety have
Earlier age at onset1 More severe depressive symptoms1 Increased suicidality1,2 Increased incidence of alcohol and drug abuse1,2 More chronic course1 More social distress2 Poorer response to medication1 Higher healthcare utilisation2
1Pollack. 2Bandelow.

J Clin Psychiatry 2005; 66 (Suppl 8): 2229 Depress Anxiety 2007; 24: 5361
25

A less favourable prognosis example 1

Quality of life
60
GAD+MDD (n=70)

50
40 30 20 10 0
Perceived mental health = fair/poor Work impairment 6 days/month

MDD (n=358) GAD (n=29)

Social role = high impairment

Kessler et al. Am J Psychiatry 1999; 156 (12): 19151923. Midlife Development in the US Survey
26

A less favourable prognosis example 2

Suicidal ideation
16
Adjusted odds ratio for 2-week prevalence of suicidal ideation*
15.4

12

8
5.3

4
1

3.3

No panic disorder or MDD (n=758)

Panic disorder/ No MDD (n=44)

MDD/No panic disorder (n=83)

Panic disorder + MDD (n=40)

MDD = Major Depression per PRIME-MD *Adjusted for sociodemographics and substance abuse

Goodwin et al. Depress Anxiety 2001; 14: 244246

27

Presence of anxiety complicates diagnosis

Correctly diagnosed

MDD

64.3

35.7
Not diagnosed

Disorder

GAD+MDD

43.2

56.8

GAD

34.4

65.6

0%

20%

40%

60%

80%

100%

Percentage of patients

N=17,739 patients

Wittchen et al. J Clin Psychiatry 2002; 63 Suppl 8: 2434

28

Treatment of complex patients general concepts

Treatment guidelines for anxiety disorders

Evidence from controlled studies
Effective SSRIs (escitalopram, etc.) SNRIs venlafaxine, duloxetine (GAD) Tricyclic antidepressants Benzodiazepines

Insufficient evidence
Typical neuroleptics

Lack of evidence/negative studies

Beta blockers
Bupropion Herbal preparations Other psychological treatments Hypnosis

Pregabalin (only GAD)

Buspirone (only GAD) Irreversible MAOIs Moclobemide (only SAD)

Quetiapine (only GAD)

Cognitive behavioural therapy Psychoanalysis 1 study

In God we trust. Everybody else needs to provide evidence. Anon.

Bandelow et al. World J Biol Psychiatry 2008; 9 (4): 248312
30

Drug treatment and cognitive behavioural therapy in panic disorder

Meta-analysis of controlled comparisons (effect size, Cohens D)

CBT + Drugs

2.07

CBT

1.43

Drugs

1.47

0.5

1.5

2.5

Effect size (Cohens D)

Bandelow et al. World J Biol Psychiatry 2007; 8 (3): 175187

31

Early detection and treatment of anxiety disorders is essential

35 Anxiety disorders 30 Cumulative hazard rate 25 20 15 10 5 0 0 5 10 15 20 25 30 35 40 45 50 55 60 Age of onset Major depression

Wittchen et al. NCS, 1999

32

Treatment of panic disorder associated with a decreased risk of developing depression

50

*
45%

Percentage of patients developing MDD (%)

40 30 19% 20

10 0

Treated

Untreated

Hazard ratio = 0.52 both cases; *p=0.001

Goodwin & Olfson. Am J Psychiatry 2001; 158: 11461148

33

Risk reduction seen also with treatment of GAD

Study group: diagnoses of GAD (lifetime prevalence) (n=219), either with depression (with onset occurring after onset of GAD) or without depression Results suggested that pharmacological treatment of GAD is associated with a lower risk of depression among adults Past use of medication was associated with a lower risk of depression, with a hazard ratio of 0.52 (p=0.001) (18.9% vs. 5.73% [p<0.0001])

Goodwin & Gorman. Am J Psychiatry 2002; 159 (11): 19351937

34

Treatment of complex patients escitalopram

Anxiety in depression escitalopram versus paroxetine

Change in HAM-A total score
0
1

Mean change from baseline in HAM-A total score

-2 -4 -6

-8 -10
-12 -14 -16
Escitalopram 20 mg/day (n=228)

Paroxetine 40 mg/day (n=223)

*p<0.01 Baseline HAM-A total score: Escitalopram = 23.5; Paroxetine = 23.5

Boulenger et al. Curr Med Res Opin 2006; 22 (7): 13311341

36

Anxiety in depression escitalopram versus paroxetine

Complete remission (CGI-S=1) Complete remission of depressive symptoms (MADRS 5)
100 Escitalopram 90 80 Percentage of patients 70 60 50 40 30 20 10 0 Paroxetine Percentage of patients 90 80 70 60 50 40 30 20 Escitalopram Paroxetine

100

**

**

**

**

**

**

**

***

***

**

10
0

All 20 22 28 30 32 24 26 (n=451) (n=281) (n=254) (n=201) (n=166) (n=120) (n=84) (n=67)

Baseline HAM-A total score

24 26 28 30 32 22 All 20 (n=451) (n=280) (n=254) (n=201) (n=166) (n=120) (n=84) (n=67) Baseline HAM-A total score

Escitalopram vs paroxetine in relation to baseline levels of anxiety ( LOCF) *p<0.05, **p<0.01, ***p<0.001 (logistic regression)

Boulenger et al. Manuscript in preparation; Poster presented at Depression: Brain Causes Body Consequences, King's College, London, 23 April 2007
37

Prominent anxiety symptoms in depression a post hoc analysis

Data from 5 placebo-controlled studies All patients:
Aged 1865 years Diagnosis of MDD, as defined by DSM-IV 4-week minimum duration of depressive episode

Study-specific patient requirements included:

Study 1 Hamilton Rating Scale for Depression (HAM-D24) score of 25 Studies 2 and 4 Montgomerysberg Depression Rating Scale (MADRS) score of 2240 Studies 3 and 5 MADRS score of 22 and HAM-D24 depressed mood (item 1) score of 2
Bandelow et al. Depress Anxiety 2007; 24 (1): 5361
38

Summary of studies

Study 1 2 3 4 5

Reference Ninan et al., 2003 Wade et al., 2002 Burke et al., 2002 Lepola et al., 2003 Rapaport et al., 2004

Comparison, dosage range Escitalopram 20 mg/day versus placebo Escitalopram 10 mg/day versus placebo Escitalopram 10 or 20 mg/day versus citalopram 40 mg/day and placebo Escitalopram 1020 mg/day versus citalopram 2040 mg/day and placebo Escitalopram 1020 mg/day versus citalopram 2040 mg/day and placebo

Dose Fixed Fixed Fixed Flexible Flexible

Setting Specialist Primary care Specialist Primary care Specialist

Bandelow et al. Depress Anxiety 2007; 24 (1): 5361; Ninan et al. Poster presented at APA 2003; Wade et al. Int Clin Psychopharmacol 2002; 17: 95102; Burke et al. J Clin Psychiatry 2002; 63: 331336; Lepola et al. Int Clin Psychopharmacol 2003: 18: 211217; Rapaport et al., J Clin Psychiatry 2004; 65: 4449
39

A solution for depressed patients with high initial anxiety

Patients with high initial anxiety (MADRS item 3 score 4)
Treatment week
0 0 2 4 6 8

Mean change from baseline in MADRS total score

-5

*** #
-10

Week 8 LOCF

**
-15 Placebo (n=128) Escitalopram (n=131) Citalopram (n=132)

*
* *** # ***
#

* ***

-20

Studies 35, ITT, OC; *p<0.05; **p<0.01; ***p<0.001 vs placebo; # p<0.05 vs citalopram

Bandelow et al. Depress Anxiety 2007; 24 (1): 5361

40

Escitalopram effective against anxiety symptoms in depression

HAM-A Total score 0 Change in HAM-A score from baseline -1 -2 -3 -4 -5 -6 -7 -8 HAM-A item 1 (Anxious mood) HAM-A items 16 and 14 (Psychic anxiety)

**

* ***
Placebo (n=122) Citalopram 40 mg/day (n=125) Escitalopram 10 mg/day (n=119)

**

Escitalopram 20 mg/day (n=125)

Study 3, OC; *p<0.05; **p<0.01; ***p<0.001 vs placebo

Bandelow et al. Depress Anxiety 2007; 24 (1): 5361

41

Escitalopram in a non-interventional observational naturalistic study

Patients had depressive disorder and/or anxiety and were treated with escitalopram as per Summary of Product Characteristics 16-week duration, with 4 visits 2,911 patients 83% of those included in analysis had comorbid anxiety and depression Primary efficacy parameters:
Remission on svMADRS (short version of Montgomery-sberg Depression Rating Scales) (12) Remission on HAM-A (10)

Laux & Friede. Psychopharmakotherapie 2009; 16: 106113

42

Response rates over 16 weeks of treatment

100 90 80 70 Response rate (%) 60 50 40 30 20 10 0 Baseline
Response = 50% reduction in svMADRS LOCF

Comorbid (n=2,371) Depression (n=284) Anxiety (n=188)

Visit 2

Visit 3

End of study

Laux & Friede. Psychopharmakotherapie 2009; 16: 106113

43

Conclusions
Patients with comorbidity present with complexities at a number of levels:
Diagnosis a challenge to define the primary condition Prognosis suicide, chronicity Treatment response poor, may require combination therapy

Application of evidence-based guidelines combined with a careful understanding of each individual patients unique clinical profile is essential to achieve positive outcomes Early treatment may improve prognosis Escitalopram has proven efficacy in MDD, anxiety disorders, and combinations of the two
44

Comorbid depression and anxiety understanding and treating complex patients

Borwin Bandelow, Germany

Is real-life functionality the new goal of treatment?

Raymond W Lam, Canada

What is a good enough outcome for the treatment of depression?

Physician perspective:
Symptoms Adverse events

47

Partial remission is associated with high relapse rate

Relapse in each group of remission (partial or complete) after 48 months of follow-up (n=138)

Relapse Type of remission Yes Complete remission, n=80 (HAMD 7) Partial remission, n=58 (HAMD = 813) 51% 91% No 49% 9%

All proportions reflect percentage of relapse according to type of remission

Adapted from Pintor et al. J Affect Disord 2004; 82: 291296

48

What are the clinical milestones for treatment of depression?

Onset of response (20% improvement from baseline) Response (50% improvement from baseline) Different grades of remission:
Defined as
Remission MADRS 12

Reason
Prospectively defined

Useful at
8 weeks

Remission Complete remission

Symptom-free remission

MADRS 10 MADRS 5
No MADRS item >1

Commonly used Corresponds to CGI-S = 1

No residual symptoms

8 weeks 6 months
6 months

Wade et al. J Psychiatr Res 2009; 43: 568575

49

Pooled analysis of four trials of escitalopram vs. comparators: summary of outcomes at 6 months

Escitalopram (n=699)

Comparator (n=699)

90 80 Percentage of patients 70

p=0.0087 p=0.0025

60
50 40 30 20 10 0
Response Remission

p=0.0082

p=0.0029

Complete remission

Symptom-free remission

Comparators: Citalopram, paroxetine x 2, duloxetine Response=50% reduction in MADRS from baseline; Remission=MADRS >510; Complete remission=MADRS 5; Symptom-free remission=no MADRS item >1

Wade et al. J Psychiatr Res 2009; 43: 568575

50

Is remission the optimal outcome?

Remission (as measured by symptom scales) is an important target for treatment Residual symptoms are predictors of relapse, chronicity and suicidality There are various remission criteria But, does remission = health or functional recovery?
Health is a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity.

World Health Organization

Preamble to the Constitution of the World Health Organization, 7 April 1948

51

What is a good enough outcome for the treatment of depression?

Physician perspective:
Symptoms Adverse events Symptoms Adverse events Well-being Quality of life Functioning Economic aspects Functioning Economic aspects
52

Patient perspective:

Society perspective:

Factors identified by depressed outpatients as very important in defining remission

In rank order:
Presence of positive mental health (e.g. optimism, vigour, 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 et al. Am J Psychiatry 2006: 163 (1): 148150

53

Impact of depression on sick leave

32 days unable to work in the past year (Statistics Canada Health report) Compared to non-depressed workers, depressed workers have:
34 times more work loss days per month (ESEMed study) 23 times more short-term disability (United States survey of corporations)

Statistics Canada Health Reports, Vol. 18, No. 1, February 2007 Alonso et al. Acta Psychiatr Scand 2004; Suppl (420): 3846 Kessler et al. Health Aff 1999; 18: 163171
54

Antidepressant treatment reduces sick days

12.0 Number of sick days in 3 months 10.0 8.0

11.0

*
6.0 4.0 2.0 0.0 Before escitalopram During escitalopram
5.4

Treatment saves 5.6 sick days per patient

Naturalistic Austrian study 505 physicians (GPs & psychiatrists) n=2,378 patients Escitalopram 1020 mg/day (mean dose 12.4 mg/day)

*p<0.001

Winkler et al. Hum Psychopharmacol 2007; 22: 245251

55

Presenteeism is a greater problem than absenteeism

Absenteeism Time spent away from the job due to illness Presenteeism Impaired job performance and productivity while at work

Presenteeism is a problem for both white-collar and blue-collar workers

56

Depression has huge impact on workplace productivity

50

Percentage of patients

40

*
30

* *

20

10

0 Absenteeism (Missed work days)

No depressive symptoms (n=4,387)

Presenteeism (Decreased effectiveness)

Chronic depressive symptoms (n=501)

Acute depressive symptoms (n=652)

*p<0.001 vs. no depressive symptoms

Druss et al. Am J Psychiatry 2001; 158: 731734

57

Measuring productivity using self-rated scales

Scale
Health and Work Performance Questionnaire (HPQ) Endicott Work Productivity Scale (EWPS) Work Limitations Questionnaire (WLQ) Stanford Presenteeism Scale (SPS) Sheehan Disability Scale (SDS) Number of Items 30 25 25 34 5

Measures
Absenteeism and presenteeism Absenteeism and presenteeism Presenteeism 8-item version available Presenteeism 6-item version available Absenteeism and presenteeism

58

LEAPS validation studies

High internal consistency: Cronbachs alpha = 0.89 Good construct validity: correlations between LEAPS and other scales (all p<0.01):
QIDS-SR LEAPS total score LEAPS productivity subscale 0.70 0.57 SDSWork 0.64 0.53 HPQGlobal 0.79 0.84

% work hours missed

0.43 0.41

n=208 patients with major depressive disorder, seen at a mood disorders clinic

Lam. APA, 2009

59

Productivity loss in a working cohort with MDD

Moderately depressed (n=44) Severely depressed (n=37) Very severely depressed (n=25)

100 Percentage of sample endorsing 50% or more of the time 90 80 70 60 50 40 30 20 10 0

Getting less work done

Doing poor quality work

Making more mistakes

*Severity based on QIDS-SR score

Lam. APA, 2009

60

How to optimise pharmacotherapy for depressed workers

Choose appropriate treatments Enhance adherence

Monitor outcomes
Manage non-responders

Lam et al. CANMAT Working with Depression Program, 2008

61

Remission does not always translate into functional outcomes

Feeling better
Remission (MADRS 12) at week 24 Percentage of patients achieving remission (MADRS 12) 100 90 Improvement in Sheehan Disability Score 80 70 60 50 40 30 20 10 0 Escitalopram 20 mg/day Duloxetine 60 mg/day
p=ns

vs
16 14

Doing better
Improvement in Sheehan Disability Score at week 24
*p<0.05 vs. duloxetine

12
10 8 6 4 2 0 Escitalopram 20 mg/day Duloxetine 60 mg/day

Adapted from Wade et al. Curr Med Res Opin 2007; 23: 16051614
62

Factors that impair work functioning

Depressive symptoms Fatigue and low energy Insomnia Concentration and memory problems Anxiety (especially social anxiety) Irritability

Medication side effects Daytime sedation Insomnia Headache Agitation/anxiety Nausea and GI effects

Lam et al. CANMAT Working with Depression Program, 2008

63

Side effects* that most impair work performance

Class Drug Citalopram Escitalopram Fluoxetine SSRI Fluvoxamine Paroxetine Insomnia Sedation Headache Anxiety Nausea

Sertraline
Duloxetine SNRI Desvenlafaxine

Venlafaxine
Bupropion Others Mirtazapine 09% >50% 1029% 30%
64

Adapted from CANMAT Guidelines for Major Depressive Disorder, 2009; *Based on unadjusted rates as published in Summary of Product Characteristics.

Conclusion
Symptom free is a realistic remission outcome, however success rates differ among antidepressants Recovery of functionality especially work functioning is important to patients (and should be for clinicians) Remission of symptoms is not always associated with functional improvement Monitoring functioning using validated scales is an important component of care Pharmacotherapy can be optimised to improve work functioning in patients with depression

65

Is real-life functionality the new goal of treatment?

Raymond W Lam, Canada

Integrating clinical treatment strategies for major depressive disorder

George I Papakostas, USA

Introduction
Dozens of pharmacological agents have so far been developed and proven to be effective in the treatment of major depressive disorder (MDD) Like all existing treatments, they have their limitations
Efficacy Tolerability Safety

68

How effective are antidepressants?

Please refer to source publication

*p<0.05

Papakostas & Fava. Eur Neuropsychopharmacol 2009; 19 (1): 3440

69

Risks associated with residual symptoms and failure to achieve and sustain full remission in MDD
Greater risk of relapse/recurrence13 More chronic depressive episodes1 Shorter durations between episodes1 Continued impairment in work and relationships4 Increased association with mortality,5 morbidity and/or mortality with stroke,6 diabetes complications,7,8 MI,9 CVD,10 CHF,11 and HIV12 Ongoing risk of suicide13
et al. Am J Psychiatry 2000;157:15011504; 2Paykel et al. Psychol Med 1995;25:11711180; 3Thase et al. Am J Psychiatry 1992;149:10461052; 4Miller et al. J Clin Psychiatry 1998;59:608619; 5Murphy et al. Arch Gen Psychiatry 1987;44:473 480; 6Everson et al. Arch Intern Med 1998;158:11331138; 7Lustman et al. Diabetes Care 2000;23:934942; 8de Groot et al. Psychosom Med 2001;63:619630; 9FrasureSmith et al. JAMA 1993;270:18191825; 10Penninx et al. Arch Gen Psychiatry 2001;58:221227; 11Vaccarino et al. Am Coll Cardiol 2001;38:199205; 12Ickovics et al. JAMA 2001;285:14661474; 13Judd et al. J Affect Disord 1997;45:518
1Judd
70

MI=myocardial infarction; CVD=cardiovascular disease; CHF=congestive heart failure; HIV=human immunodeficiency virus.

Optimising the resolution of depressive symptoms

Timing
First-line Subsequent approaches Focused effect Broad effect Monotherapy Polypharmacy

Scope

Modality

71

First-line
Broad effect
Greater resolution of depressive symptoms
Response, remission, change in symptom severity

Evenly spread effect Very severe MDD (poly- or pan-symptomatic)? Targeting a specific depressive symptom MDD with symptom predominance (lethargy, fatigue)?

Focused effect

72

First-line broad effect

Venlafaxine versus SSRIs remission rates

Please refer to source publication

*p<0.05, n=6492, analysis of 31 RCTs

HDRS17=17-item Hamilton Depression Rating Scale
Data extracted from: Schmitt et al. Eur Arch Psychiatry Clin Neurosci 2009; 259 (6): 329 339

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Escitalopram versus older SSRIs, venlafaxine and duloxetine

Data from all randomised, double-blind, active-controlled (citalopram, fluoxetine, paroxetine, sertraline, venlafaxine XR and duloxetine) trials pooled [16 RCTs in total]

Study durations:
8 weeks (12 trials) 24 weeks (3 trials) 27 weeks (1 trial)

Kennedy et al. Curr Med Res Opin 2009;25(1):161175

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Escitalopram versus the other SSRIs response rates

Please refer to source publication

*p<0.05, 12 RCTs
Data extracted from: Kennedy et al. Curr Med Res Opin 2009;25(1):161175
76

Escitalopram versus the SNRIs duloxetine and venlafaxine remission rates

Please refer to source publication

*p<0.05, 4 RCTs
Data extracted from: Kennedy et al. Curr Med Res Opin 2009;25(1):161175
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First-line broad effect

AD + metyrapone > AD for depression1 Fluoxetine + folate > fluoxetine for depression2 Sertraline + T3 > sertraline for depression3 Fluoxetine + clonazepam > fluoxetine4,5
Depression Insomnia Anxiety

Paroxetine + zolpidem > paroxetine for depression, insomnia6

et al. Arch Gen Psychiatry 2004;61:12351244; & Bailey. J Affect Disord 2000;60(2):121130; 3Cooper-Kazaz et al. Arch Gen Psychiatry 2007;64:679688; 4Smith et al. Am J Psychiatry 1998;155:13391345; 5Londborg et al. J Affect Disord 2000;61(1-2):7379; 6Ji et al. Zhonguhua Yi Xue Za Zhi 2007;87(23):1585 1589
1Jahn 2Coppen
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First-line focused effect

Residual somnolence and fatigue in bupropion and SSRI remitters: pooled analysis of six RCTs

Please refer to source publication

*p<0.05, n=1,317
Papakostas et al. Biol Psychiatry 2006;60(12):13501355
80

Fluoxetine plus eszopiclone for MDD with insomnia remission

Please refer to source publication

*p<0.05, n=545
Fava et al. Biol Psychiatry 2006;59(11):10521060
81

Fluoxetine plus eszopiclone for MDD: rates of severe insomnia at the end of treatment

Please refer to source publication

*p<0.05, n=545
Fava et al. Biol Psychiatry 2006;59(11):10521060
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Other examples

Mirtazapine > SSRIs for insomnia1 Fluoxetine + melatonin > fluoxetine for insomnia2 Escitalopram + focused CBT > escitalopram for insomnia3 Escitalopram + zolpidem > escitalopram for insomnia4 Modafinil + SSRI > SSRI for somnolence5

et al. WFSBP Meeting. 2005; et al. Am J Psychiatry 1998;155(8):11191121; 3Manber et al. Sleep 2008;31(4):489495; 4Fava et al. APA 2008; 5Dunlop et al. J Clin Psychopharmacol 2007;27(6):614 619
2Dolberg
83

1Winokur

Following treatment focused effect

When first-line treatment has, largely, succeeded Targeting residual symptoms (augmentation)

Modafinil augmentation for SSRI-associated somnolence and fatigue: a pooled-analysis of two clinical trials

Please refer to source publication

SSRIs included: sertraline, paroxetine, fluoxetine

p<0.05 for somnolence; p>0.05 for fatigue, n=348 Fava et al. Ann Clin Psychiatry 2007; 19(3):153159
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Other examples
AD + methylphenidate > AD for apathy and fatigue1 AD + trazodone > AD for insomnia2 AD + zolpidem > AD for insomnia3

1Ravindran 2Nierenberg

et al. J Clin Psychiatry 2008;69(1):8794; et al. Am J Psychiatry 1994;151(7):10691072 3Asnis et al. J Clin Psychiatry 1999;60(10):668676

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Following treatment broad effect

When first-line treatment has, largely, failed Treatment-resistant depression Special topic area

Atypical antipsychotic augmentation in MDD: meta-analysis of 10 double-blind studies

Please refer to source publication

*p<0.05 for remission; p<0.05 for intolerance (d/c)

Papakostas et al. J Clin Psychiatry 2007;68(6):826831

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Other examples
Augmentation
Lithium Omega-3 FAs T3 Buspirone Pindolol Mecamylamine SAMe Testosterone

Combination
Tricyclic antidepressants Bupropion Mirtazapine

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Conclusions
First-line treatment most often easy to use and effective Numerous strategies exist to resolve depressive symptoms in non-responding patients Clinicians called to make more individualised treatment choices for their patients
Clinical features Severity Treatment history

Decision on which strategy to choose is not based on efficacy alone: safety, tolerability are important factors

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Integrating clinical treatment strategies for major depressive disorder

George I Papakostas, USA

Emerging focal points in depression and anxiety

22nd ECNP Congress, Istanbul 12th September 2009 Chairman: George I Papakostas, USA