cipralex ecnp 2009

7/27/2019 Cipralex ECNP 2009

1/92

Emerging focal

points in depressionand anxiety

22ndECNP Congress, Istanbul

12thSeptember 2009

Chairman:

George I Papakostas, USA


2/92

2

Programme

Emerging focal points in depression and anxiety

Chairmans introductionGeorge I Papakostas,USA

Serotonergic dysfunction

implications for treatment of mood and anxiety disorders

Pierre Blier,Canada

Comorbid depression and anxietyunderstanding and treating complex patients

Borwin Bandelow,Germany

Is real-life functionality the new goal of treatment?Raymond W Lam,Canada

Integrating clinical treatment strategies formajor depressive disorder

George I Papakostas,USA

Panel discussion Panel

Chairmans conclusionGeorge I Papakostas,

USA


3/92


implications for treatment ofmood and anxiety disorders

Pierre Blier, Canada


4/92

4

Plan of the presentation

Describe abnormalities in the serotonin (5-HT) system indepression

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) anddopamine (DA) systems


5/92

5

Serotonin: overall evidence for decreasedlevels in depression and anxiety

5-HT and 5-HIAA inMDD/anxious vs controls

5-HT1Abinding in limbic areas

Blunted prolactin response to

fenfluramine Diminished 5-HT transporter

binding

Alterations in 5-HT receptorbinding

Platelet findings of 5-HT receptor/transporter alterations

5-HIAA=5-Hydroxyindoleacetic acid


6/92

6

Regulation of behavioural circuits byneuromodulatory systems

VTA

DA

Prefrontal cortex

Cognition, workingmemory, modulationof affect

Raphe

5-HT

Nucleus accumbens

Reward/pleasure

Amygdala/BNST/

hippocampus

Fear/stress response,anxiety symptoms,memory

Hypothalamus

Stress response,sleep/wake/appetiteregulation

LC

NA

Thalamus

Arousal/sleep,sensorimotor gating


7/927

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

Meta-analysis of15 studies examiningamygdala activation and5-HTTLPR genotype

In all but one of thesestudies, the short allelewas associated withincreased amygdala

activation compared tothe long allele

Munaf et al. Biol Psychiatry 2008; 63: 852857

-4.00 -2.00 0.00 2.00 4.00

Long high

activation

Short high

activation

Standard difference in means (95% CI)


8/928

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

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

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

Study

Standardised mean difference

(95% CI) % weight

Frodl 2002 -0.23 (-0.74, 0.28) 9.2

Macqueen 2003 -0.07 (-0.69, 0.55) 7.9Von Gunten 2000 -0.41 (-1.16, 0.34) 6.6

Mervaala 2000 -0.83 (-1.43, -0.22) 8.1

Rusch 2001 0.04 (-0.60, 0.68) 7.7

Vakili 2000 0.36 (-0.18, 0.91) 8.7

Ashtari 1999 -0.30 (-0.72, 0.13) 10.2

Bremner 2000 -0.99 (-1.72, -0.25) 6.7

Macqueen 2003 -1.23 (-1.97, -0.49) 6.7

Posener 2003 0.19 (-0.29, 0.68) 9.5

Sheline 2003 -0.79 (-1.26, -0.32) 9.7

Steffens 2000 -0.66 (-1.19, -0.13) 8.9

Overall (95% CI) -0.38 (-0.65, -0.11)

0 2.0-2.0

Standardised mean difference


9/929

Treatment: antidepressant effects on plasmaBDNF

BDNF is hypothesised as being a key factor inneuroplasticity

This study evaluated the pre- and post-treatment levels of

BDNF in a group of depressed patients (n=20) andcompared them with healthy controls (n=20)

All were treated with escitalopram 10 mg/day over6 weeks

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


10/9210

SSRIs positively affect BDNF

Aydemir et al. Prog Neuropsychopharmacol

Biol Psychiatry 2006; 30: 12561260

**p=0.002; ***p


11/9211

5-HT

TryptophanT3Visken

Lithium

SSRI

Postsynaptic

neuron

5-HT neuron

MAOI

Tryptophan

5-HT

(-)

MAO

Buspirone

(+)

(+)

(+)

5-HT1A 5-HT1B

(+)

Actions of various agents on theserotonin system


12/9212

Antidepressant actions at theserotonin transporter

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

Escitalopram

(S-citalopram enantiomer)

Conventional SSRIs

and SNRIs


13/9213

*p


14/9214Mnie-Filali et al. NeuroReport 2007; 18: 15531556

Different effects on neurogenesis:the case of escitalopram and citalopram

R-citalopram antagonises escitalopram-induced increase of cell proliferation

*p


15/9215

Higher SERT occupancy observed withescitalopram after multiple dosing

Kasper et al. Int Clin Psychopharmacol 2009; 24: 119125

A build-up of the R-enantiomer after repeated citalopram dosing may lead

to increased inhibition of S-enantiomer occupancy of SERT

Escitalopram Citalopram

0 20 40 60 80

100

90

80

70

60

50

40

30

20

10

0

SERToccupancy(%)

Serum S-citalopram (nmol/l)

0 20 40 60 80

100

90

80

70

60

50

40

30

20

10

0

Single dose Steady state

SERToccupancy(%)

Serum S-citalopram (nmol/l)


16/9216

5-HT NA

DOPAMINE

1 +)

D2 (-)

(-)

-) 2, D2 -) 2(+) D2 ??

Reciprocal interactions betweenmonoaminergic neurons


17/9217

5-HT2Aantagonism reverses the inhibitionof NA neurons by an SSRI

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

0

50

100

150

*

#

Control

(no co-treatment)SB 242084 Haloperidol M100907

EscitalopramVehicle

*p


18/9218

Reversal of the inhibitory effect ofan SSRI by a 5-HT2Cantagonist

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

Firing rate, spikes/sec Proportion of spikes occurring

in bursts

Percentage(SEM)ofc

orresponding

parameterincont

rolrats

EscitalopramEscitalopram +

SB 242084 0.5 mg/kg/day

Escitalopram +

SB 242084 2.0 mg/kg/day

0

20

40

60

80

100

120

140

***

*#

#

*

*

*p


19/9219

5-HT2Afor NE neurons5-HT2Cfor DA neurons

Functional connectivity


20/9220

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


21/92


implications for treatment ofmood and anxiety disorders

Pierre Blier, Canada


22/92

Comorbid depression and

anxietyunderstanding andtreating complex patients

Borwin Bandelow,

Germany


23/9223

Dissecting a controversy

Coexistent, simultaneous depression and anxiety may beviewed as mixed anxietydepression or as comorbidsyndromes, i.e. separate disorders occurring concurrently

Controversy remains over the extent to which the twodisorders intersect aetiologically and phenomenologically

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


24/92

24

Anticipatory anxiety

Nervous tension

Muscular tension

Restlessness

Tension pains

Physiological arousal

Apathy

Retardation

Withdrawal

Loss of interest

Morning depression

Poor concentration

Self confidence

Hopelessness

Fatigue

Dysphoria

Irritability

Sleep dist.

Appetite dist.

Sensitivity

(criticism)

GAD Depression

Nutt, Rickels, Stein. GAD. Dunitz, 2002

Symptom overlap


25/92

25

Comorbiditya less favourable prognosis

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. J Clin Psychiatry 2005; 66 (Suppl 8): 22292Bandelow. Depress Anxiety 2007; 24: 5361

Compared with non-comorbid cases,

depressed patients with comorbid anxiety have


26/92

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

A less favourable prognosisexample 1

Perceived mental

health = fair/poor

Work impairment

6 days/month

Social role =

high impairment

GAD+MDD (n=70)

MDD (n=358)

GAD (n=29)

Quality of life

0

10

20

30

40

50

60


27/92

27

A less favourable prognosisexample 2

MDD = Major Depression per PRIME-MD*Adjusted for sociodemographics and substance abuse Goodwin et al. Depress Anxiety 2001; 14: 244246

Adjustedoddsratiofor2-week

prevalenceofsuicidalide

ation*

No panic disorder

or MDD (n=758)

MDD/No panic

disorder (n=83)

Panic disorder/

No MDD (n=44)

Panic disorder

+ MDD (n=40)

Suicidal ideation

0

4

8

12

16

1

3.3

5.3

15.4


28/92

28

Presence of anxiety complicates diagnosis

Wittchen et al. J Clin Psychiatry 2002; 63 Suppl 8: 2434N=17,739 patients

Disorder

Percentage of patients

34.4

43.2

64.3

65.6

56.8

35.7

0% 20% 40% 60% 80% 100%

GAD

GAD+MDD

MDDCorrectly diagnosed

Not diagnosed


29/92

Treatment of

complex patientsgeneral concepts


30/92

30

Effective SSRIs (escitalopram, etc.)

SNRIs venlafaxine, duloxetine(GAD)

Tricyclic antidepressants Benzodiazepines

Pregabalin (only GAD)

Buspirone (only GAD)

Irreversible MAOIs

Moclobemide (only SAD)

Quetiapine (only GAD)

Cognitive behavioural therapy

Psychoanalysis1 study

Insufficient evidence

Typical neuroleptics

Lack of evidence/negative studies Beta blockers

Bupropion

Herbal preparations

Other psychological treatments

Hypnosis

Treatment guidelines for anxiety disorders

In God we trust.

Everybody else needs to provide evidence.

Anon.

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

Evidence from controlled studies


31/92

31

Drug treatment and cognitive behaviouraltherapy in panic disorder

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

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

Effect size (Cohens D)

1.47

1.43

2.07

0 0.5 1 1.5 2 2.5

Drugs

CBT

CBT + Drugs


32/92

32

Early detection and treatment of anxietydisorders is essential

Wittchen et al. NCS, 1999

Age of onset

Cumulativehazar

drate

Anxiety disorders

0

5

10

15

20

25

30

35

0 5 10 15 20 25 30 35 40 45 50 55 60

Major depression


33/92

33

Treatment of panic disorder associated with adecreased risk of developing depression

Hazard ratio = 0.52 both cases; *p=0.001 Goodwin & Olfson. Am J Psychiatry 2001; 158: 11461148

45%

Percentageofpatie

nts

developingMDD(%)

*

19%

Treated Untreated

0

10

20

30

40

50


34/92

34

Risk reduction seen also with treatment ofGAD

Study group: diagnoses of GAD (lifetime prevalence)(n=219), either with depression (with onset occurring afteronset of GAD) or without depression

Results suggested that pharmacological treatment ofGAD is associated with a lower risk of depression amongadults

Past use of medication was associated with a lower riskof depression, with a hazard ratio of 0.52 (p=0.001)(18.9% vs. 5.73% [p


35/92

Treatment of complex

patients escitalopram


36/92

36

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


37/92

37

Anxiety in depressionescitalopram versus paroxetine

Escitalopram

Paroxetine

Percentageofpatients

100

90

80

70

60

50

40

30

20

10

0

All

(n=451)

20

(n=281)

22

(n=254)

24

(n=201)

26

(n=166)

28

(n=120)

30

(n=84)

32

(n=67)

Baseline HAM-A total score

***

**

Complete remission (CGI-S=1)

Escitalopram

Paroxetine


Baseline HAM-A total score

100

90

80

70

60

50

40

30

20

10

0

All

(n=451)

20

(n=280)

22

(n=254)

24

(n=201)

26

(n=166)

28

(n=120)

30

(n=84)

32

(n=67)

**** ** ** ** ** ******

Complete remission of

depressive symptoms (MADRS 5)

Escitalopram vs paroxetine in relation to baseline levels of anxiety ( LOCF)*p


38/92

38

Prominent anxiety symptoms in depressiona pos t hocanalysis

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 1Hamilton Rating Scale for Depression (HAM-D24)

score of 25 Studies 2 and 4Montgomerysberg Depression Rating Scale

(MADRS) score of 2240

Studies 3 and 5MADRS score of 22 andHAM-D24depressed mood (item 1) score of 2

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


39/92

39

Summary of studies

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

Study Reference Comparison, dosage range Dose Setting

1 Ninan et al., 2003 Escitalopram 20 mg/day versus placebo Fixed Specialist

2 Wade et al., 2002 Escitalopram 10 mg/day versus placebo FixedPrimary

care

3 Burke et al., 2002Escitalopram 10 or 20 mg/day versuscitalopram 40 mg/day and placebo

Fixed Specialist

4 Lepola et al., 2003Escitalopram 1020 mg/day versuscitalopram 2040 mg/day and placebo

FlexiblePrimary

care

5 Rapaport et al., 2004

Escitalopram 1020 mg/day versus

citalopram 2040 mg/day and placebo Flexible Specialist


40/92

40

A solution for depressed patients with highinitial anxiety

Patients with high initial anxiety (MADRS item 3 score 4)

Bandelow et al. Depress Anxiety 2007; 24 (1): 5361Studies 35, ITT, OC; *p


41/92

41

Escitalopram effective against anxietysymptoms in depression

Bandelow et al. Depress Anxiety 2007; 24 (1): 5361Study 3, OC; *p


42/92

42

Escitalopram in a non-interventionalobservational naturalistic study

Patients had depressive disorder and/or anxiety and were treatedwith 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 anddepression

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


43/92

43

Response rates over 16 weeks of treatment

100

90

80

70

60

50

40

30

20

10

0

Baseline Visit 2 Visit 3 End of study

Responserate(%

)

Comorbid (n=2,371)

Depression (n=284)

Anxiety (n=188)

Response = 50% reduction in svMADRSLOCF Laux & Friede. Psychopharmakotherapie 2009; 16: 106113


44/92

44

Conclusions

Patients with comorbidity present with complexities at anumber of levels:

Diagnosisa challenge to define the primary condition

Prognosissuicide, chronicity

Treatment responsepoor, may require combination therapy

Application of evidence-based guidelines combined witha careful understanding of each individual patientsunique clinical profile is essential to achieve positive

outcomes Early treatment may improve prognosis

Escitalopram has proven efficacy in MDD, anxietydisorders, and combinations of the two


45/92

Comorbid depression andanxietyunderstanding andtreating complex patients

Borwin Bandelow,

Germany


46/92

Is real-life functionalitythe new goal of treatment?

Raymond W Lam, Canada

Wh t i d h t f th


47/92

47

What is a good enough outcome for thetreatment of depression?

Physician perspective: Symptoms

Adverse events

P ti l i i i i t d ith hi h


48/92

48

Partial remission is associated with highrelapse rate

Type of remissionRelapse

Yes No

Complete remission, n=80(HAMD 7)

51% 49%

Partial remission, n=58(HAMD = 813)

91% 9%

All proportions reflect percentage of relapse according to type of remission

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

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

Wh t th li i l il t f


49/92

49

What are the clinical milestones fortreatment of depression?

Onset of response (20% improvement from baseline)

Response (50% improvement from baseline)

Different grades of remission:

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

6 monthsNo residualsymptoms

No MADRS item >1Symptom-freeremission

6 monthsCorresponds toCGI-S = 1

MADRS 5Completeremission

Defined as Reason Useful at

Remission MADRS 12Prospectivelydefined

8 weeks

Remission MADRS 10 Commonly used 8 weeks

Pooled analysis of four trials of escitalopram vs


50/92

50

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

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

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


Response Remission Complete

remission

Symptom-free

remission

p=0.0087

p=0.0025

p=0.0082p=0.0029

0

10

20

30

40

50

60

70

80

90Escitalopram (n=699) Comparator (n=699)


51/92

51

Is remission the optimal outcome?

Remission (as measured by symptom scales) is animportant target for treatment

Residual symptoms are predictors of relapse, chronicityand suicidality

There are various remission criteria

But, does remission = health or functional recovery?

Health is a state of complete physical, mental, and social well-beingand not merely the absence of disease or infirmity.

World Health Organization

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

Wh t i d h t f th


52/92

52

What is a good enough outcome for thetreatment of depression?

Physician perspective: Symptoms

Adverse events

Patient perspective: Symptoms Adverse events Well-being Quality of life

Functioning Economic aspects

Society perspective: Functioning Economic aspects

Factors identified b depressed o tpatients


53/92

53

Factors identified by depressed outpatientsas 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 andfriends

Absence of symptoms of depression

Zimmerman et al. Am J Psychiatry 2006: 163 (1): 148150


54/92

54

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 workershave: 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): 3846Kessler et al. Health Aff 1999; 18: 163171


55/92

55

Antidepressant treatment reduces sick days

Naturalistic Austrian study

505 physicians(GPs & psychiatrists)

n=2,378 patients

Escitalopram 1020 mg/day(mean dose 12.4 mg/day)

Winkler et al. Hum Psychopharmacol 2007; 22: 245251*p


56/92

56

Presenteeism is a greater problemthan absenteeism

Absenteeism

Time spent awayfrom the job due to illness

Presenteeism Impaired job performance and productivity while at work

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

Depression has huge impact on workplace


57/92

57

Depression has huge impact on workplaceproductivity

*

*

*

*

0

10

20

30

40

50

(Missed work days) (Decreased effectiveness)


PresenteeismAbsenteeism

No depressive

symptoms (n=4,387)

Acute depressive

symptoms (n=652)

Chronic depressive

symptoms (n=501)

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


58/92

58

Measuring productivity using self-ratedscales

ScaleNumber

of ItemsMeasures

Health and WorkPerformance Questionnaire(HPQ)

30Absenteeism andpresenteeism

Endicott Work ProductivityScale (EWPS)


Work LimitationsQuestionnaire (WLQ)

25Presenteeism

8-item version available

Stanford Presenteeism Scale(SPS)

34 Presenteeism6-item version available

Sheehan Disability Scale(SDS)



59/92

59

LEAPS validation studies

High internal consistency: Cronbachs alpha = 0.89

Good construct validity: correlations between LEAPS andother scales (all p


60/92

60

Productivity loss in a working cohort withMDD

*Severity based on QIDS-SR score

Perc

entageofsamplee

ndorsing

50%

ormoreofthe

time

Doing poor

quality work

Making more

mistakes

Getting less

work done

Moderatelydepressed (n=44)

Severelydepressed (n=37)

Very severelydepressed (n=25)

0

10

20

30

40

50

60

70

80

90

100

Lam. APA, 2009

How to optimise pharmacotherapy for


61/92

61

How to optimise pharmacotherapy fordepressed workers

Choose appropriate treatments

Enhance adherence

Monitor outcomes

Manage non-responders

Lam et al. CANMAT Working with Depression Program, 2008

Remission does not always translate into


62/92

62

Feeling better Doing bettervs

Remission does not always translate intofunctional outcomes

p=ns

Percenta

geofpatientsachieving

remission(MADRS12

)

Impr

ovementinSheeha

n

DisabilityScore

*

Escitalopram

20 mg/day

Duloxetine

60 mg/day

100

70

60

50

40

30

20

10

0

90

80

*p


63/92

63

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

Side effects* that most impair work


64/92

64

Class Drug Insomnia Sedation Headache Anxiety Nausea

SSRI

Citalopram

Escitalopram

Fluoxetine

Fluvoxamine

Paroxetine

Sertraline

SNRI

Duloxetine

Desvenlafaxine

Venlafaxine

OthersBupropion

Mirtazapine >50%

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

09% 1029% 30%

Side effects that most impair workperformance


65/92

65

Conclusion

Symptom free is a realistic remission outcome, however

success rates differ among antidepressants

Recovery of functionalityespecially work functioningis important to patients (and should be for clinicians)

Remission of symptoms is not always associated withfunctional improvement

Monitoring functioning using validated scales is animportant component of care

Pharmacotherapy can be optimised to improve workfunctioning in patients with depression


66/92

Is real-life functionalitythe new goal of treatment?

Raymond W Lam, Canada


67/92

Integrating clinicaltreatment strategies formajor depressive disorder


I t d ti


68/92

68

Introduction

Dozens of pharmacological agents have so far beendeveloped and proven to be effective in the treatment ofmajor depressive disorder (MDD)

Like all existing treatments, they have their limitations Efficacy

Tolerability

Safety

H ff ti tid t ?


69/92

69Papakostas & Fava. Eur Neuropsychopharmacol 2009; 19 (1): 3440*p


70/92

70

Risks associated with residual symptoms andfailure 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,5morbidity and/or

mortality with stroke,6diabetes complications,7,8MI,9CVD,10CHF,11and HIV12

Ongoing risk of suicide13

MI=myocardial infarction;

CVD=cardiovascular disease;

CHF=congestive heart failure;HIV=human immunodeficiency virus.

1Judd 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; 9Frasure-

Smith et al. JAMA 1993;270:18191825; 10Penninx et al. Arch Gen Psychiatry

2001;58:221227;

11

Vaccarino et al. Am Coll Cardiol 2001;38:199205;

12

Ickovics etal. JAMA 2001;285:14661474; 13Judd et al. J Affect Disord 1997;45:518

Optimising the resolution of depressive


71/92

71

Optimising the resolution of depressivesymptoms

Timing First-line

Subsequent approaches

Scope Focused effect

Broad effect

Modality Monotherapy

Polypharmacy

Fi t li


72/92

72

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)?

Focused effect Targeting a specific depressive symptom

MDD with symptom predominance (lethargy, fatigue)?


73/92

First-linebroad effect

Venlafa ine ers s SSRIs remission rates


74/92

74HDRS17=17-item Hamilton Depression Rating Scale

Venlafaxine versus SSRIsremission rates

Data extracted from:Schmitt et al. Eur Arch Psychiatry Clin Neurosci 2009; 259 (6): 329339

*p


75/92

75

Escitalopram versusolder SSRIs, venlafaxine and duloxetine

Data from all randomised, double-blind, active-controlled(citalopram, fluoxetine, paroxetine, sertraline, venlafaxineXR 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

Escitalopram versus


76/92

76Data extracted from: Kennedy et al. Curr Med Res Opin 2009;25(1):161175

*p


77/92

77

sc ta op a e sus t e S sduloxetine and venlafaxineremission rates

*p


78/92

78

First-linebroad 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

1Jahn et al. Arch Gen Psychiatry 2004;61:12351244;2Coppen & 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;

5

Londborg et al. J Affect Disord 2000;61(1-2):7379;6Ji et al. Zhonguhua Yi Xue Za Zhi 2007;87(23):15851589


79/92

First-linefocused effect

Residual somnolence and fatigue in bupropion and


80/92

80

g p pSSRI remitters: pooled analysis of six RCTs

Papakostas et al. Biol Psychiatry 2006;60(12):13501355

*p


81/92

81

Fava et al. Biol Psychiatry 2006;59(11):10521060

*p


82/92

82Fava et al. Biol Psychiatry 2006;59(11):10521060

p pof severe insomnia at the end of treatment

*p


83/92

83

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

1Winokur et al. WFSBP Meeting. 2005;2Dolberg et al. Am J Psychiatry 1998;155(8):11191121;

3Manber et al. Sleep 2008;31(4):489495;4

Fava et al. APA 2008;5Dunlop et al. J Clin Psychopharmacol 2007;27(6):614619


84/92

Following treatmentfocused effect

When first-line treatment has, largely, succeeded

Targeting residual symptoms (augmentation)

Modafinil augmentation for SSRI-associatedsomnolence and fatigue: a pooled-analysis of two


85/92

85p0.05 for fatigue, n=348 Fava et al. Ann Clin Psychiatry 2007; 19(3):153159

somnolence and fatigue: a pooled-analysis of twoclinical trials

SSRIs included: sertraline, paroxetine, fluoxetine

Please refer to source publication

Other examples


86/92

86

Other examples

AD + methylphenidate > AD for apathy and fatigue1

AD + trazodone > AD for insomnia2

AD + zolpidem > AD for insomnia3

1Ravindran et al. J Clin Psychiatry 2008;69(1):8794;2

Nierenberg et al. Am J Psychiatry 1994;151(7):106910723Asnis et al. J Clin Psychiatry 1999;60(10):668676


87/92

Following treatmentbroad effect

When first-line treatment has, largely, failed

Treatment-resistant depression

Special topic area

Atypical antipsychotic augmentation in MDD:t l i f 10 d bl bli d t di


88/92

88Papakostas et al. J Clin Psychiatry 2007;68(6):826831*p


89/92

89

Other examples

Augmentation Lithium

Omega-3 FAs

T3

Buspirone Pindolol

Mecamylamine

SAMe

Testosterone

Combination Tricyclic antidepressants

Bupropion

Mirtazapine

Conclusions


90/92

90

Conclusions

First-line treatment most often easy to use and effective

Numerous strategies exist to resolve depressivesymptoms in non-responding patients

Clinicians called to make more individualised treatmentchoices for their patients Clinical features

Severity

Treatment history

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


91/92

Integrating clinicaltreatment strategies formajor depressive disorder



92/92

Emerging focalpoints in depression

and anxiety

22nd

ECNP Congress, Istanbul12thSeptember 2009

Chairman:


cipralex ecnp 2009

Documents