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Emerging focal
points in depressionand anxiety
22ndECNP Congress, Istanbul
12thSeptember 2009
Chairman:
George I Papakostas, USA
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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
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Serotonergic dysfunction
implications for treatment ofmood and anxiety disorders
Pierre Blier, Canada
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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
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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
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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
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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)
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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
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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
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SSRIs positively affect BDNF
Aydemir et al. Prog Neuropsychopharmacol
Biol Psychiatry 2006; 30: 12561260
**p=0.002; ***p
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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
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Antidepressant actions at theserotonin transporter
Snchez. Basic Clin Pharmacol Toxicol 2006; 99 (2): 9195
Escitalopram
(S-citalopram enantiomer)
Conventional SSRIs
and SNRIs
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*p
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Different effects on neurogenesis:the case of escitalopram and citalopram
R-citalopram antagonises escitalopram-induced increase of cell proliferation
*p
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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)
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5-HT NA
DOPAMINE
1 +)
D2 (-)
(-)
-) 2, D2 -) 2(+) D2 ??
Reciprocal interactions betweenmonoaminergic neurons
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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
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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
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5-HT2Afor NE neurons5-HT2Cfor DA neurons
Functional connectivity
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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
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Serotonergic dysfunction
implications for treatment ofmood and anxiety disorders
Pierre Blier, Canada
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Comorbid depression and
anxietyunderstanding andtreating complex patients
Borwin Bandelow,
Germany
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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
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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
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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
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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
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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
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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
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Treatment of
complex patientsgeneral concepts
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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
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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
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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
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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
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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
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Treatment of complex
patients escitalopram
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Boulenger et al. Curr Med Res Opin 2006; 22 (7): 13311341*p
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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
Percentageofpatients
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
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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
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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
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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
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Escitalopram effective against anxietysymptoms in depression
Bandelow et al. Depress Anxiety 2007; 24 (1): 5361Study 3, OC; *p
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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
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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
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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
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Comorbid depression andanxietyunderstanding andtreating complex patients
Borwin Bandelow,
Germany
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Is real-life functionalitythe new goal of treatment?
Raymond W Lam, Canada
Wh t i d h t f th
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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
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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
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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
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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
Percentageofpatients
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)
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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
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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
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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
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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
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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
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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
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Depression has huge impact on workplaceproductivity
*
*
*
*
0
10
20
30
40
50
(Missed work days) (Decreased effectiveness)
Percentageofpatients
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
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Measuring productivity using self-ratedscales
ScaleNumber
of ItemsMeasures
Health and WorkPerformance Questionnaire(HPQ)
30Absenteeism andpresenteeism
Endicott Work ProductivityScale (EWPS)
25Absenteeism andpresenteeism
Work LimitationsQuestionnaire (WLQ)
25Presenteeism
8-item version available
Stanford Presenteeism Scale(SPS)
34 Presenteeism6-item version available
Sheehan Disability Scale(SDS)
5Absenteeism andpresenteeism
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LEAPS validation studies
High internal consistency: Cronbachs alpha = 0.89
Good construct validity: correlations between LEAPS andother scales (all p
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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
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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
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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
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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
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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
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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
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Is real-life functionalitythe new goal of treatment?
Raymond W Lam, Canada
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Integrating clinicaltreatment strategies formajor depressive disorder
George I Papakostas, USA
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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 ?
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69Papakostas & Fava. Eur Neuropsychopharmacol 2009; 19 (1): 3440*p
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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
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Optimising the resolution of depressivesymptoms
Timing First-line
Subsequent approaches
Scope Focused effect
Broad effect
Modality Monotherapy
Polypharmacy
Fi t li
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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)?
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First-linebroad effect
Venlafa ine ers s SSRIs remission rates
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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
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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
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76Data extracted from: Kennedy et al. Curr Med Res Opin 2009;25(1):161175
*p
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sc ta op a e sus t e S sduloxetine and venlafaxineremission rates
*p
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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
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First-linefocused effect
Residual somnolence and fatigue in bupropion and
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g p pSSRI remitters: pooled analysis of six RCTs
Papakostas et al. Biol Psychiatry 2006;60(12):13501355
*p
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Fava et al. Biol Psychiatry 2006;59(11):10521060
*p
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82Fava et al. Biol Psychiatry 2006;59(11):10521060
p pof severe insomnia at the end of treatment
*p
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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
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
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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
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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
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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
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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
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88Papakostas et al. J Clin Psychiatry 2007;68(6):826831*p
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Other examples
Augmentation Lithium
Omega-3 FAs
T3
Buspirone Pindolol
Mecamylamine
SAMe
Testosterone
Combination Tricyclic antidepressants
Bupropion
Mirtazapine
Conclusions
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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
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Emerging focalpoints in depression
and anxiety
22nd
ECNP Congress, Istanbul12thSeptember 2009
Chairman:
George I Papakostas, USA