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J Clin Psychiatry 74:4, April 2013 363
Efficacy and Safety of Levomilnacipran Sustained Release in
Moderate to Severe Major Depressive Disorder: A Randomized,
Double-Blind, Placebo-Controlled, Proof-of-Concept Study
Stuart A. Montgomery, MD; Lucilla Mansuy, MD; Adam Ruth, PhD;
Anjana Bose, PhD; Hua Li, PhD; and Dayong Li, PhD
and is recognized as the most common cause of disability during the
course of a working life.1 Effective treatment of MDD is a public health
Levomilnacipran (1S, 2R-milnacipran), a potent and selective
serotonin-norepinephrine reuptake inhibitor (SNRI) with greater
potency for inhibition of norepinephrine (NE) relative to serotonin
(5-HT) reuptake, is in clinical development for the treatment of adult
MDD. In animal models of depression, it shows a potent antidepressant-
like effect2 suggesting that it may offer therapeutic effects similar to older
tricyclic antidepressants without the accompanying safety and tolerabil-
ity issues. The sustained release (SR) formulation was developed to allow
for once-daily dosing.
Potency for inhibition of 5-HT reuptake relative to NE reuptake varies
among members of the SNRI class of antidepressants. For example, 5-HT
reuptake inhibition is 10-fold more potent than NE reuptake inhibition
for duloxetine and 30-fold more potent for venlafaxine.3 Because NE
reuptake inhibition for venlafaxine at lower doses is trivial, with mean-
ingful NE reuptake inhibition achieved only at high doses,2 venlafaxine
in effect becomes a selective serotonin reuptake inhibitor (SSRI) when
prescribed at the usual dose of 150 mg/d or less. These relative differences
make generalizing from one SNRI to another potentially misleading.
In contrast, levomilnacipran has approximately 2-fold higher potency
for NE relative to 5-HT reuptake inhibition and over 10-fold higher
selectivity for NE reuptake inhibition compared with duloxetine and
venlafaxine.2 While the general question of whether SNRIs have supe-
rior efficacy relative to SSRIs, particularly on the core symptoms of
depression, remains unresolved, the potentially greater efficacy of
SNRIs with greater inhibition of NE versus 5-HT reuptake is a more
specific area of investigation that is of particular interest in regard to
The objective of this study (EudraCT number: 2006-002404-34)
was to investigate the efficacy and safety of a flexible-dose regimen of
levomilnacipran SR compared with placebo in the treatment of MDD
over a 10-week period.
Objective: To investigate the efficacy and safety
of levomilnacipran sustained release (SR), an
antidepressant candidate in late-stage development,
in major depressive disorder (MDD).
Method: Between December 2006 and October
2007, a 10-week, randomized, double-blind, placebo-
controlled, parallel-group, multicenter, flexible-dose
trial assessed once-daily levomilnacipran SR (75 mg or
100 mg) in outpatients (18–70 years) meeting DSM-IV
criteria for a major depressive episode (duration ≥ 1
month) with a 17-item Hamilton Depression Rating
Scale (HDRS17) score > 22 and Sheehan Disability
Scale (SDS) score ≥ 10. Levomilnacipran SR dose was
increased to 100 mg/d over 12 days. The primary
efficacy measure was Montgomery Asberg Depression
Rating Scale (MADRS) score change from baseline
to week 10; secondary efficacy measures were the
HDRS17, SDS, Clinical Global Impressions-Improvement
scale, and MADRS response (≥ 50% decrease from
baseline) and remission (score ≤ 10). Safety was
evaluated according to adverse events, laboratory
investigations, and vital signs/physical findings.
Results: Efficacy analyses included 276 levomilnacipran
SR–treated patients and 277 placebo-treated patients.
Levomilnacipran SR was significantly superior to
placebo on MADRS total score change from baseline to
week 10 (least squares mean difference [LSMD] = −4.2
[95% CI, −5.7 to −2.6]; P < .0001). Statistical significance
in favor of levomilnacipran SR was demonstrated
on change from baseline to week 10 in HDRS17
total score (LSMD = −3.4 [95% CI, −4.7 to −2.2];
P < .0001) and SDS total score (LSMD = −3.4 [95% CI,
−4.6 to −2.2]; P < .0001) and subscales. Significantly
more levomilnacipran SR patients versus placebo
patients achieved MADRS response (59.1% vs 42.2%;
P < .0001) and remission (46.4% vs 26.0%; P < .0001).
Levomilnacipran SR was generally safe and well
tolerated; more levomilnacipran SR patients (9.4%)
versus placebo patients (6.5%) discontinued due to
adverse events, but more placebo patients versus
levomilnacipran SR patients discontinued overall
(24.9% vs 20.2%).
Conclusions: Levomilnacipran SR demonstrated robust
efficacy on all measures and was generally
Trial Registration: EudraCT number: 2006-002404-34
J Clin Psychiatry 2013;74(4):363–369
© Copyright 2013 Physicians Postgraduate Press, Inc.
Submitted: August 29, 2012; accepted February 1, 2013
Corresponding author: Stuart A. Montgomery, MD, PO Box 8751,
London W13 8WH, UK (email@example.com).
ajor depressive disorder (MDD) is a common, potentially dan-
gerous, and disabling disorder. It has a chronic recurrent course
Patients were recruited to participate in the study from 68 sites in
France, Finland, Latvia, Lithuania, Sweden, Germany, Estonia, Czech
Republic, Bulgaria, India, and South Africa; the study was conducted
between December 13, 2006, and October 22, 2007. The final study pro-
tocol was approved by ethics committees and appropriate authorities
for all centers involved. The study was performed in accordance with
the principles stated in the Declaration of Helsinki and Good Clini-
cal Practice guidelines, as applicable at the time; all patients provided
written, informed consent.
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J Clin Psychiatry 74:4, April 2013 369
Levomilnacipran SR in Major Depressive Disorder
head-to-head trials have been performed; as such, no valid
comparison between levomilnacipran SR and milnacipran
data can be made.
This first placebo-controlled study provides robust evi-
dence that levomilnacipran SR had significant efficacy across
all evaluated parameters and a good safety and tolerability
profile. These results suggest that levomilnacipran SR will
be a welcome addition to the antidepressant armamen-
tarium. Further studies to support the present findings are
Drug names: diazepam (Diastat, Valium, and others), duloxetine (Cymbalta),
escitalopram (Lexapro and others), milnacipran (Savella), sertraline (Zoloft
and others), venlafaxine (Effexor and others), zolpidem (Ambien, Edluar,
Author affiliations: Imperial College School of Medicine, University
of London, London, United Kingdom (Dr Montgomery); Pierre
Fabre Médicament, Toulouse, France (Dr Mansuy); Prescott Medical
Communications Group, Chicago, Illinois (Dr Ruth); Forest Research
Institute, Jersey City, New Jersey (Drs Bose, H. Li, and D. Li). Dr H. Li is
now employed by Novartis Pharmaceutical Corporation, East Hanover,
Potential conflicts of interest: In the past year, Dr Montgomery has been a
consultant to Forest, Lundbeck, Pierre Fabre, Richter, Servier, and Takeda
and a speaker or advisory board member for AstraZeneca, Lundbeck,
and Pierre Fabre. Dr Mansuy is an employee of Pierre Fabre Médicament.
Dr Ruth is an employee of Prescott Medical Communications Group, a
contractor for Forest Research Institute. Drs Bose and D. Li are employees
of Forest Research Institute; at the time of the study, Dr H. Li was an
employee of Forest Research Institute.
Funding/support: Supported by funding from Forest Research Institute, a
subsidiary of Forest Laboratories Inc (New York, New York), and Pierre Fabre
Médicament (Toulouse, France). Forest Laboratories, Inc was involved in the
study design; collection (via contracted clinical investigator sites), analysis,
and interpretation of data; and the decision to present these results.
Previous presentations: American College of Neuropsychopharmacology,
December 6–10, 2009, Hollywood, Florida ▪ American Psychiatric
Association, May 22–26, 2010, New Orleans, Louisiana ▪ Collegium
Internationale Neuro-Psychopharmacologicum, June 6–10, 2010, Hong
Kong, China ▪ New Clinical Drug Evaluation Unit, June 14–17, 2010, Boca
Raton, Florida ▪ European College of Neuropsychopharmacology, August
28–September 1, 2010, Amsterdam, The Netherlands ▪ Institute of Psychiatric
Services Annual Meeting, October 14–17, 2010, Boston, Massachusetts ▪
American Psychiatric Association, May 14–18, 2011, Honolulu, Hawaii ▪ and
New Clinical Drug Evaluation Unit, June 13–16, 2011, Boca Raton, Florida.
Acknowledgments: The authors acknowledge the late Yves Lecrubier,
MD, of the French National Institutes of Health and Medical Research
(INSERM), Hôpital Pitié-Salpêtrière, Paris, France, the principal investigator
for this study until his untimely illness made it impossible for him to
continue. Writing assistance and editorial support for the preparation of
this manuscript were provided by Carol Dyer, MS, of Prescott Medical
Communications Group, Chicago, Illinois, a contractor of Forest Research
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