New Approaches to Major Depressive Disorder Management: SNRI

New Approaches to Major Depressive
Disorder Management: SNRI
Prof. Mak Ki Yan
Honorary Professor
Department of Psychiatry
The University of Hong Kong

Under nder-diagnosis diagnosis & under-treatment under treatment of
depressive disorders
♦

Unmet Needs in the Depression Treatment
♦ Despite availability of many antidepressants...
• 25-35% of depressed patients in clinical trials
achieve remission on existing single-drug
• 30-45% of depressed patients show partial or
no response at all*
• Slow onset of action (at least 2-4 weeks)
• Tolerability hindering adherence
• Limited painful physical symptoms (PPS)
efficacy
Simon GE, et al. N Engl J Med. 1999;341(18):1329-1335;
*Fava, M & Davidson, KG Psychiat Clin N Am, 1996, 19 (2): 179-2000

Phenelzine
Isocarboxazid
The Evolution of Antidepressants
1950s 1960s 1970s 1980s 1990s 2000s
Tranylcypromine
Dual
Single
Imipramine
Clomipramine
Nortriptyline
Amitriptyline
Desipramine
Fluoxetine
Sertraline
Paroxetine
Fluvoxamine
Citalopram
Bupropion
Nefazodone
Mirtazapine
Venlafaxine
Duloxetine
Milnacipran
Reboxetine
Escitalopram

TCAs vs SSRIs:
Meta-Analysis Meta Analysis of 25 Studies
Altamura et al, 1989
Amore et al, 1989
Arminen et al, 1992
Byrne, 1989
de Jonge et al, 1991
de Wilde and Doogan, 1982
Dick and Ferrero, 1983
DUAG, 1986
DUAG, 1990
Feighner et al, 1989
Geretsegger et al, 1995
Ginestet, 1989
Gueifi et al, 1983
Guy et al, 1984
Kasper et al, 1990
Klok et al, 1981
Laursen et al, 1985
Manna et al, 1989
Moller et al, 1993
Nathan et al, 1990
Nielsen et al, 1991
Ottevanger, 1995
Staner et al, 1995
Stuppaeck et al, 1994
Timmerman et al, 1987
Favors TCAs Favors SSRIs
-2 -1 0 1 2
♦ Pooled random model effect size=-0.2263 (95% CI=-0.4008 to -0.0519)
TCAs=tricyclic antidepressants. SSRIs=selective serotonin reuptake inhibitors.
Anderson IM. Depress Anxiety. 1998;7(suppl 1):11-17.

Advantage of TCAs Over SSRIs Is
Limited to “Dual Dual Reuptake” Reuptake Compounds
Effect Size
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
0.1
0.2
X
All TCAs (n=25)
p=.01
SNRI TCAs (n=15)
p=.02
SNRI=serotonin and norepinephrine reuptake inhibitor.
NRI=norepinephrine reuptake inhibitor. Meta-analysis of 25 studies.
Anderson IM. Depress Anxiety. 1998;7(suppl 1):11-17.
X
X
NRI TCAs (n=10)
p=.48

Dual Action Antidepressants May Offer
Increased Efficacy in Treating Depression
♦ Evidence suggests that
clomipramine, a TCA
with effects on
5-HT and NA, has
a more rapid and
effective result than
the SSRI paroxetine 1
♦ This study was
replicated with another
SSRI, citalopram 2 ,
and the results
were consistent
Group Average HAM-D Score
25
20
15
10
5
0
Paroxetine
Clomipramine
*p

Synergistic Effects of Norepinephrine-
Norepinephrine
Serotonin Combinations
Remission
Response
Partial Response
Nonresponse
Desipramine+
Fluoxetine
(n=13)
7 (54%)
1 (8%)
Fluoxetine
(n=14)
χ 2 (treatment group by level of response)=24.01; df=6; p=.0005.
0
5 (38%)
1 (7%)
5 (36%)
1 (7%)
7 (50%)
Desipramine
(n=12)
Remission=75% improvement and MADRS ≤9; response: 50-74% improvement;
partial response: 25-49% improvement; nonresponse:

Remission With Venlafaxine
and SSRIs
Remission Rate
100
80
60
40
20
23
Thase ME. Br J Psychiatry 2001.
0
Placebo NNT (VEN vs SSRI) range from 10-15.
SSRIs
Venlafaxine
p

Remitters:HAMD
Remitters:
Number of subjects (%)
45
40
35
30
25
20
15
10
5
0
Mirtazapine vs. SSRIs Meta-Analysis
Meta Analysis
HAMD 17
Mirtazapine (n=1402)
SSRIs (n=1405)
*
7/ MADRS
17 ≤ 7/ MADRS ≤ 12
12 (ITT, LOCF)
* p ≤ 0.05, ** p ≤ 0.001
**
NNT (MIRT vs SSRI) range from 12-20
**
1 2 4 6
Weeks
Thase ME. World Congress of Biological Psychiatry, Sydney, Australia, Feb 2004
*

Remission Rate (%) HAM-D < 7
Bupropion vs. SSRIs: Pooled Analysis of Seven
RCTs
60
50
45
40
35
30
25
20
15
10
5
0
*PBO < SSRI = BUP
NNT (BUP vs SSRI) > 1,000,000
* *
PBO (N=524) SSRI** (N=758) BUP (N=748)
**Sertraline (N=358), fluoxetine (N=348), and paroxetine (N=52)
Thase ME, et al. J Clin Psych. 2005 Aug;66(8):974-81.

Duloxetine vs. SSRI Therapy: A Pooled Analysis of
Six Fixed Dose Studies
Remission Rate (%) HAM-D < 7
60
50
40
30
20
10
0
All Patients
NNT (DUL vs SSRI) = 22
28%
PBO
(N=507)
*
38%
SSRI*
(N=423)
*
43%
DLX
(N=697)
SSRI: Fluoxetine and paroxetine (20 mg/day)
Patients with HAM-D > 19
NNT (DUL vs SSRI) = 11
p

Duloxetine: A relatively balanced and potent
dual reuptake inhibitor
♦ A relatively balanced and potent
dual reuptake inhibitor of both
serotonin (5-HT) and
norepinephrine (NE), based on
preclinical data 1
• Balanced means approximately
equal affinity for 5-HT and NE
reuptake transporters 1
• Although the mechanism of the
antidepressant action of
Cymbalta in humans is not fully
known, it is believed to be
related to its potentiation of
serotonergic and noradrenergic
activity in the central nervous
system
1. Bymaster FP, et al. Neuropsychopharmacology. 2001;25(6):871-880.
Serotonin Reuptake Transporter (Blocked)
5-HT
NE
Theoretical Representation
Dual reuptake inhibitor
Norepinephrine Reuptake Transporter (Blocked)

Affinity & 5-HT/NE 5 HT/NE Dual Reuptake Inhibition In Vitro
Inhibition of binding to human monoamine uptake transporters (K i*, nM)
Drug NE 5-HT NE/5-HT (1=balance)
Duloxetine 7.5 0.8 9
Venlafaxine 2483 82 30
Fluoxetine 1022 7 146
Paroxetine 132 0.4 330
Sertraline 715 0.9 794
Citalopram >10000 9.5 >1050
♦ Duloxetine is a weak inhibitor of dopamine reuptake.
♦ Duloxetine strongly inhibits 5-HT and NE reuptake; it has a low affinity
for adrenergic, histaminic, or muscarinic receptors.
Bymaster FP, et al. Neuropsychopharmacology. 2001;25:871-880.

Brannan SK, et al. J Psych Res 2005;39:161-172.

Brannan SK, et al. J Psych Res 2005;39:161-172.

Improvement
Once-daily Once daily Duloxetine Significantly Improves HAMD 17
Item-10 Item 10 (Psychic Anxiety) in Depressed Patients by
Week 1
Mean Change from Baseline
(HAMD17 Item 10, Psychic Anxiety)
0.0
-0.2
-0.4
-0.6
-0.8
-1.0
0 1 2 3 4 5 6 7 8 9
***
***
***
1. Hirschfeld RM, et al. Depress Anxiety. 2005;21:170-177.
Weeks
***
***
***
Duloxetine
60 mg QD
(n=244)
Placebo
(n=251)
***p≤.001
vs. placebo
MMRM
Pooled data from 2
studies

Improvement
Once-Daily Once Daily Duloxetine Significantly Improves
Major Depressive Disorder by Week 2
Mean Change from Baseline
(HAMD-17 Total Score)
0
-2
-4
-6
-8
-10
-12
Weeks
0 1 2 3 4 5 6 7 8 9
***
***
***
Brannan SK, et al. J Psych Res 2005;39:161-172.
***
***
Duloxetine
60 mg QD
(n=244)
Placebo
(n=251)
*** p < .001
vs. placebo
MMRM
Pooled data from 2
studies

Higher Remission
Once-Daily Once Daily Duloxetine Increases Probability of
Achieving Remission of Major Depressive
Disorder
Estimated Probability of
Remission at 9 Weeks (%)
50
40
30
20
10
***
44
16
0
Trial 1
• Remission = HAMD17 total score

Improvement
Efficacy in Elderly Depressed Patients
Treated with Duloxetine
HAMD17 Total Score
LS Mean Change
0
-1
-2
-3
-4
-5
-6
-7
-8
-9
-10
Weeks Duloxetine
0 1 2 3 4 5 6 7 8 60 mg QD
(N=201)
MMRM
Placebo
(N=102)
MMRM
***
***
***
Duloxetine
LOCF
Placebo
LOCF
***p ≤ .001
vs. placebo
Raskin J, et al. Presented at the 18 th Annual Meeting of the American Association for Geriatric Psychiatry; San Diego, CA; March 3-6, 2005.

Chief Complaint of Patients With Depression in
Primary Care Usually Is Physical
31%
Other
♦ 69% of patients reported only physical symptoms
as the reason for their physician visit 1
♦ N=1146 patients with major depression
Simon GE, et al. N Engl J Med. 1999;341(18):1329-1335
69%
Physical symptoms 1

Frequency
50
40
30
20
10
0
Painful Symptoms Correlate
With Depression
Limb pain
Backaches
Joint/articular pain
Gastrointestinal disturbances
Headaches
Any pain
Normal Mood Major Depressive Disorder (MDD)
Ohayon MM, Schatzberg AF. Arch Gen Psychiatry. 2003;60(1):39-47.

Treatment Effect Size
1.4
1.2
1
0.8
0.6
0.4
0.2
0
SSRIs: Low Improvement Effect
Size on Physical Symptoms
Baseline 1 Month 3 Months 6 Months 9 Months
Greco T, et al. J Gen Intern Med. 2004;19(8):813-818.
Non-somatic
depressive
symptoms
Positive
well-being
Non-painful
physical
symptoms
Painful
physical
symptoms

Higher Remission
Higher Remission Rates in Depressed Patients
with Duloxetine Compared with SSRI or Placebo
Remission at 8 Weeks (%)
60
50
40
30
20
10
0
All Randomized
Patients
*
43
*
38
28
Patients with
HAMD 17 ≥19
(n=697) (n=423) (n=507) (n=429) (n=245) (n=289)
Thase ME, et al. Presented at the 156 th Annual Meeting of the APA; San Francisco, CA; May 17-22, 2003.
*p

Long-term Long term Treatment with Duloxetine
Prevents Relapse of Depression
Therapy # Patients # Relapsed Fisher’s Exact Test P-value
PLACEBO 137 39 (28.5%)
DLX60QD 132 23 (17.4%)
0.042
Perahia DG, et al. B. J. Psych. Accepted.
PLACEBO
DLX60QD
Log-rank Test: p=0.004
Stratified Log-rank Test: p=0.002

High Rates of Estimated Response and Remission with Duloxetine
in Long-Term Long Term Open-Label Open Label Treatment of Major Depressive Disorder
Improvement
Estimated Probability (%)
100
90
80
70
60
50
40
30
20
10
0
Weeks
0 10 20 30 40 50
• Response is defined as > 50% decrease in the HAMD17 total score from baseline.
• Remission is defined as a HAMD17 total score < 7.
Raskin J, et al. J Clin Psychiatry 2003;64:1237-1244.
Duloxetine
80 mg/day or
120 mg/day
(n=1279)
MMRM
Response
Remission

Sustained Hypertension vs Placebo in
Depressed Patients Treated with Duloxetine
Development of Sustained Hypertension (acute treatment)
Duloxetine 40 mg/day (N=174)
n (%)
0 (0.0)
Duloxetine 60 mg/day (N=244) 2 (0.8)
Duloxetine 80 mg/day (N=354) 6 (1.7)
Duloxetine 120 mg/day (N=344) 6 (1.7)
Total
Duloxetine (N=1116) 14 (1.3)
Placebo (N=757) 6 (0.8)
♦Over longer-term treatment (34-weeks), the incidence of sustained
hypertension was similar for duloxetine 80 or 120 mg/day and placebo
(5.7%, 7.1%, and 6.2% respectively)
*Sustained hypertension is defined as 3 consecutive assessments of either systolic blood pressure > 140 mm Hg and a > 10 mm Hg
increase from baseline; or diastolic blood pressure > 90 mm Hg and a > 10 mm Hg increase from baseline.
Thase ME, et al. J Clin Psychopharmacol 2005; 25(2):132-140.
Hudson JI, et al. Hum Psychopharmacol Clin Exp. 2005; 20:327-341.
p = .37 (NS)
Data on file, Lilly Research Laboratories.

Summary
♦ Dual 5-HT and NE effects have advantages in
MDD efficacy
♦ For MDD, full remission is the ultimate goal of
treatment and dual action appears to increase
the likelihood of remission
♦ Remission improved physical & social
functioning, with reduced risk of relapse &
DALYs
♦ Efficacy in treating physical (including pain)
symptoms