Drug Evaluation

Desvenlafaxine: a new
antidepressant or just another one?
Chi-Un Pae
The Catholic University of Korea College of Medicine, Holy Family Hospital, Duke University
1. Introduction Medical Center, Department of Psychiatry and Behavioral Sciences, Bucheon, Kyounggi-Do,
2. Pharmacokinetics Republic of Korea
3. Pharmacodynamics
Desvenlafaxine (DVS) is a serotonin-norepinephrine reuptake inhibitor (SNRI)
4. Clinical data
with a different pharmacokinetic and pharmacodynamic profile to venlafaxine.
5. Major depressive disorder (only It was approved in February 2008 by the United States Food and Drug
FDA-approved indication) Administration for the treatment of major depressive disorder (MDD) based
6. Potential indications on a number of randomized, placebo-controlled clinical trials demonstrating
7. Dosing efficacy and safety for patients with MDD. Current evidence indicates that
DVS has proven efficacy, acceptable safety and tolerability profiles, convenient
8. Switching from venlafaxine XR
or other antidepressants
once-daily dosing and minimal impact on cytochrome P450 enzyme system
and adverse event-prone neuroreceptors. As with all monoamine-based
9. Discontinuation symptoms
antidepressants, DVS has mixed efficacy results from individual studies,
10. Safety and tolerability unestablished dosing strategies and limited long-term data, and comparative
11. Expert opinion and conclusion efficacy/safety with other existing antidepressants should be further investi-
gated. Preliminary evidence also suggests the clinical usefulness of DVS in
the treatment of vasomotor symptoms of menopause, anxiety symptoms and
painful physical symptoms, although only MDD is the approved indication.

Keywords: antidepressant, anxiety, depression, desvenlafaxine, menopause, SNRI, venlafaxine

Expert Opin. Pharmacother. (2009) 10(5):875-887

1. Introduction

Major depressive disorder (MDD) affects about 16% of individuals in the USA
in their lifetime and has a chronic and deteriorative clinical course also impacting
on public health costs  [1-3]. Several new antidepressants have emerged in the past
two decades, replacing older ones, to improve efficacy and safety in the treatment
of MDD. Selective serotonin reuptake inhibitors (SSRIs) have now become the
drugs of choice in the treatment of MDD.
However, the antidepressant response rates are inadequate, ranging from 50%
to 60% in clinical practice. In addition, as seen in results from the Sequenced
Treatment Alternatives to Relieve Depression (STAR*D) trial sponsored by
National Institute of Mental Health (NIMH)  [4,5], approximately 30% of patients
who did not remit after treatment with one SSRI, recover after switching to
another SSRI or different class. Hence there is an unmet need for faster, better
and safer medications to treat MDD, for which the development of new anti-
depressants may help in the development of more effective and ideal treatment
options for clinicians  [6]. In fact, current data with limited evidence indicate
that advanced formulation of antidepressants (e.g., different release formulations,
paroxetine- and paroxetine-controlled release; different isomers, citalopram and
escitalopram) may improve adherence, adverse events and even efficacy issues such
as faster onset of action  [7,8]. Therefore, new formulations of antidepressants have
significant implications for clinical practice and, as such, desvenlafaxine (DVS)
will be of interest to clinicians in practice.
DVS is a serotonin-norepinephrine reuptake inhibitor (SNRI). Recently
(February 2008) a number of registry clinical trials demonstrated the efficacy and

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Desvenlafaxine
safety of DVS for MDD treatment, leading to an approval
from the FDA  [9-13]. In addition, it showed clinical
potential for the treatment of vasomotor symptoms associated
with menopause  [14], chronic pain symptoms, and some
rheumatologic disorders such as fibromyalgia.
The action mechanisms of DVS rely mainly on inhibition
of reuptake of serotonin and norepinephrine, and regulation
of hypothalamic-pituitary-adrenal (HPA) asix, while it has
minimal effects on muscarinic, cholinergic, histaminic H1,
α1-adrenergic receptors, and cytochrome P450 enzymes  [15-18].
The purpose of this review is to provide clinicians with
updated information on DVS regarding its currently available
preclinical and clinical data, since clinicians’ familiarity with
new treatment options will positively impact on patient care
and advanced treatment options.
2. Pharmacokinetics
Data suggest potential differences in pharmacokinetics
between venlafaxine and DVS in healthy subjects including
extensive and poor metabolizers via CYP450 2D6  [19]. More
specifically, seven extensive metabolizers and seven poor
metabolizers were randomly assigned to receive either venla-
faxine XR 75 mg or DVS 50 mg. Following administration
of venlafaxine, the ratio of plasma venlafaxine to DVS was
greater in poor CYP450 2D6 metabolizers compared with
extensive metabolizers  [18,19]. By contrast, DVS levels were
not statistically different between poor metabolizers and
extensive metabolizers.
Most antidepressants, including venlafaxine, are metabolized
by the cytochrome (CYP) 450 2D6 enzyme system. However,
DVS is metabolized largely independently of the CYP450
2D6 enzyme system  [19]. In fact, an open-label, randomized
crossover study in 20 healthy subjects was done to examine
the effect of multiple oral doses of DVS 100 mg and parox-
etine 20 mg on the pharmacokinetics of a single oral dose of
desipramine 50 mg in healthy adults  [15]. Administration of
DVS showed only mild inhibition of the pharmacokinetics
of desipramine AUC (26% increase), indicating that it has
minimal to no interaction with CYP450 2D6 substrates. By
contrast, administration of paroxetine produced strong inhi-
bition in desipramine AUC (276% increase). Elimination of
DVS is primarily by Phase II metabolism to form a
glucuronide conjugate metabolite and by renal excretion of
unchanged DVS  [20]. DVS has relatively low plasma protein
binding (30%) at therapeutic concentration  [21]. In summary,
CYP450 3A4 and also CYP450 2D6 are not significant
metabolic pathways to DVS, while the principal pathway is
Phase II glucuronidation. Hence, DVS is expected to have a
low risk of drug–drug interaction since it is largely metabo-
lized extraneous to CYP450 and weak protein-binding
property. However, the risk of combination of DVS with
other psychotropic agents has not yet been systematically
evaluated. Dosage adjustment of DVS has to be considered
in combination with other medications involved in the
876 Expert Opin. Pharmacother. (2009) 10(5)
pathways of CYP450 2D6 and 3A4 as well as for those who
have renal and hepatic impairments.
DVS is well absorbed (80%) and the mean terminal-phase
elimination half-life ranges from 9 to 15 h  [20]. Mean time
to peak plasma concentrations (Tmax) is about 7.5 h after
oral administration  [20]. Food has little impact on the
pharmacokinetics of DVS, indicating that it can be taken
without regard to meals  [18]. The steady-state concentration
of DVS may be expected within 3 – 4 days with once-daily
dosing  [18]. Data have indicated that once-daily dosing of
DVS provides a stable concentration profile over the dose
interval  [20]. Animal studies have shown a possibility of
influence on pharmacokinetics of DVS by gender and/or
sex-steroid hormones  [22].
3. Pharmacodynamics
Deecher and colleagues found that an administration of
DVS alone (30 mg/kg subcutaneously) in ovariectomized
female rats selectively elevated norepinephrine concentra-
tions (116%), while both norepinephrine (97%) and serotonin
(78%) concentrations were elevated when it was administrated
with a 5-HT1A receptor antagonist  [17]. No significant
increases in dopamine levels were observed with or without
concomitant 5-HT1A receptor antagonism.
Competitive radio-ligand binding assays in vitro have shown
the affinities of DVS for human monoamine transporters  [17,23].
DVS inhibited competitive binding interactions at both human
serotonin transporter (hSERT; Ki = 40 nM) and human
norepinephrine transporter (hNET; Ki = 558 nM), while
demonstrating its weak affinity for human dopamine (DA)
transporter (hDAT; Ki = 25 μM).
The affinity for muscarinic, cholinergic, H1-histaminergic,
or α1-adrenergic receptors of DVS has been known to be
negligible in vitro  [17]. DVS is also devoid of monoamine
oxidase (MAO) inhibitory activity.
4. Clinical data
4.1 Strength
DVS is available as 50- and 100-mg tablets; no other
formulation is available at present.
4.2 Overview on clinical data
The efficacy and safety of DVS in the treatment of MDD
has been well established through a series of short-term
(8-week) randomized, double-blind, placebo-controlled clinical
trials (RCTs) They include three fixed-dose (at doses of
50, 100, 200, and 400 mg/day) RCTs  [9,10,12], one flexible-dose
(100 – 200 mg/day) RCT  [11] and one pooled analysis
(200 – 400 mg/day)  [13].
In such similarly designed RCTs, mean changes in the
17-item Hamilton Depression Rating Scale (HAMD-17)
total scores from baseline was the primary efficacy measure.
Other efficacy measures included improvement in scores of

the Montgomery Åsberg Depression Rating Scale (MADRS),
Clinical Global Impressions Scale-improvement (CGI-I) and
severity (CGI-S), Covi Anxiety Scale (CAS), Visual Analog
Scale-Pain Intensity (VAS-PI), Sheehan Disability Scale (SDS)
and the World Health Organization Five-Item Well-Being
Index (WHO-5).
The data from two randomized double-blind, placebo-
controlled clinical trials show that DVS 50 mg/day is
significantly more effective than placebo for the treatment of
MDD. Unpublished long-term RCTs also indicated that DVS
was significantly more effective than placebo in preventing
relapse and recurrence of MDD. Relapse-prevention studies
using the 50 mg/day dose have not been conducted yet.
Relapse prevention is not an approved indication for DVS at
this time, however. Safety and tolerability were assessed by
Treatment Emergent Adverse Events (TEAE; defined as
those with an incidence of 5% or more and at least twice
that of placebo), Discontinuation Emergent Signs and
Symptoms checklist (DESS), physical examination and routine
laboratory studies.
The most common TEAE included nausea, dizziness,
insomnia, hyperhidrosis, constipation, somnolence, decreased
appetite, anxiety and specific male sexual function disorders
in such RCTs. Overall safety and tolerability of DVS
were similar to SSRIs and other SNRIs. However, the
efficacy and safety of DVS for the MDD in the child–
adolescent and elderly populations has not yet been
systematically investigated and established. Pediatric trials
are being designed, however.
5.Major depressive disorder
(only FDA-approved indication)
5.1 Short-term efficacy (all 8-week)
5.1.1 Individual studies
Published RCTs supported the short-term efficacy of DVS
in patients with MDD  [9-13]. In the study by DeMartinis
et al.  [9], adult outpatients with MDD were randomly
assigned to either DVS 100 mg/day (n = 114), 200 mg/day
(n = 116), 400 mg/day (n = 113), or placebo (n = 118) for
8 weeks. Two doses of DVS (100 and 400 mg/day) were
found to be superior to placebo, based on the assessment of
the primary efficacy measure (changes in HAMD-17 total
scores from baseline), while DVS 200 mg/day was not. After
8 weeks of treatment, response (≥ 50% reduction in
HAMD-17 total scores from baseline) and remission (≤ 7 in
HAM-D total scores at end point) rates were 35.0%
and 19.0% for placebo, 51.0% (p = 0.017) and 30.0%
(p = 0.093) for DVS 100 mg/day, 45.0% (p = 0.142)
and 28.0% (p = 0.126) for DVS 200 mg/day, and 48.0%
(p = 0.046) and 32.0% (p = 0.035) for DVS 400 mg/day
respectively, indicating that only DVS 400 mg/day was
positive to both response and remission rates at end point,
which were secondary end points. Hence, DVS 200 mg/day
failed to separate from placebo with regard to changes in
Expert Opin. Pharmacother. (2009) 10(5)
Pae
primary efficacy and rates of response and remission.
However, all doses were found to be efficacious in other
secondary efficacy measures in improvement of CGI-I and
MADRS scores. VAS-PI results for DVS 100 mg/day were
superior to placebo (p = 0.002) but not for the higher
doses. All does were effective in improvement of functional
impairment measured by SDS and WHO-5 scores.
In the second RCT published by Septien-Velez  [10],
outpatients with MDD (n = 375) were randomly assigned
to 8 weeks of treatment with DVS 200 mg/day (n = 124),
DVS 400 mg/day (n = 125), or placebo (n = 126). The
changes in primary efficacy measure was greater for both doses
of DVS 200 mg/day (-50.8%, p = 0.002) and 400 mg/day
(-48.0%, p = 0.008) versus placebo (-36.8%). A significant
separation from placebo in primary efficacy measure started
at week 4 for both doses of DVS and was sustained throughout
the study.
Response rates, a secondary measure, were 60,56 and 38%
for DVS 200 mg/d, DVS 400 mg/d and placebo, respectively,
with significant between-group differences (p < 0.001,
p = 0.005). However, DVS 400 mg (34%, p = 0.066) did
not separate from placebo in remission rate, another secondary
measure, while DVS 200 mg/day (37%, p = 0.017) showed
clear superiority to placebo (23%). In addition, both doses
of DVS proved to be superior to placebo in all secondary
efficacy measures such as improvement in scores of CGI-I,
CGI-S, MADRS and VAS-PI.
Subsequent RCTs were conducted with flexible-dose  [11]
and fixed-dose  [12] design. In a flexible-dose RCT  [11],
247 patients with MDD were randomly assigned to either
DVS (n = 121, 100 – 200 mg/day) or placebo (n = 117) for
8 weeks. After treatment, no significant differences were
found in HAMD-17, CGI-S or CGI-I scores between the
DVS and placebo groups, although the DVS group had
significantly greater improvement in MADRS (p = 0.047)
and VAS-PI (p = 0.008) scores than the placebo group.
DVS also failed to separate from placebo in other efficacy
measures including SDS and WHO-5 scores. In addition,
various responder rates based on the scores of HAMD-17
(43% vs 34%), MADRS (45% vs 35%), CGI-I (51% vs 45%)
and SDS (33% vs. 25%) were not significantly different
between DVS and placebo groups.
In a recently published fixed-dose RCT  [12], the efficacy
of DVS 50 mg/day (n = 158) or DVS 100 mg/day (n = 157)
versus placebo (n = 159) was investigated in patients with
MDD. DVS 50 mg/day showed significantly greater changes
in the primary efficacy measure (-50.0%, p = 0.018) compared
with placebo, while DVS 100 mg/day failed to separate
from placebo (-41.3%, p = 0.065). In a reduction of
MADRS total scores, similar trend was seen in both doses.
However, DVS 100 mg/day was associated with significant
improvements in the total scores of HAMD-6 (p = 0.038)
and VAS-PI (p = 0.041) versus placebo. Both doses did not
reach a statistically significant difference in improvement of
CGI-S and CGI-I scores.
877
Desvenlafaxine
Finally, in a flexible-dose RCT  [24] (Phase II study), patients
with MDD were randomized to receive DVS 200 – 400 mg/day
(n = 117) or placebo (n = 118). Similarly, as seen in the
previous flexible-dose study (100 – 200 mg/day)  [11], DVS
failed to separate from placebo on the reduction in primary
efficacy measure at end point, although it has shown a supe-
riority to placebo in the improvements of the MADRS,
CGI-I, CGI-S and HAMD-6 scores. Additional observed-case
analysis has demonstrated superiority of DVS to placebo in
the primary efficacy measure.
5.1.2 Pooled studies
To overcome an under-power of individual RCTs  [9,10], a
post hoc pooled analysis was recently published  [13]. A total
of 713 patients (n = 226 for DVS 200 – 400 mg/day,
n = 127 for venlafaxine XR 75 – 150 mg/day, n = 115 for
venlafaxine XR 150 – 225 mg/day, and n = 245 for
placebo) were analyzed after excluding subjects with incomplete
data. A significant difference in the primary efficacy measure
between DVS (-35.4%, p < 0.05) and placebo (-30.2%) was
observed at week 3 and maintained throughout the treat-
ment period (-55.9%, p < 0.001) over placebo (-46.7%).
The primary efficacy results of the two venlafaxine XR
groups (75 – 150 mg/day, -30.9% and -55.3%, respectively;
150 – 225 mg/day, -38.1% and -58.0%, respectively) were
similar to the DVS treatment group. All other secondary
efficacy measures including improvement in CGI-I, CGI-S,
MADRS, CAS and VAS-PI scores for DVS-treated patients
were statistically superior to placebo-treated patients. At end
point, the observed differences were 8% and 7% in response
and remission rates, respectively, favoring the DVS group
over the placebo group without statistical differences.
A recent, unpublished, pooled study  [25] has supported
the previous pooled study  [13]. Five 8-week RCTs of DVS
were pooled (DVS 50, 100, 200, or 400 mg/day, total
n = 1342; placebo, total n = 631). All doses of DVS showed
significantly greater improvement on the HAMD-17 total
scores compared with placebo (50 mg/day: -2.2, p < 0.001;
100 mg/day: -2.4, p < 0.001; 200 mg/day: -2.2, p < 0.001;
and 400 mg/day: -2.3, p < 0.001), which was replicated in
the pooled data set of all doses (-2.3; p < 0.001). In the
pooled data set of all doses, DVS was found to have signifi-
cantly more responders (55,55 and 61%) and remitters
(34%) based on various criteria (HAMD-17, MADRS and
CGI-I) compared with placebo (responders, 42,40 and 46%;
remitters, 25%). No dose–response relationship in efficacy
across a broad range of doses (50 – 400 mg/day) was found
in the analysis.
Analysis of individual depressive symptoms was done
with the same data set  [26], where DVS was found to be
associated with statistically significant improvement in most
items of HAMD-17 with the exception of the items of
insomnia/early, insomnia/middle, gastrointestinal symptoms,
loss of weight, and insight. In addition, statistically significant
improvements (p < 0.05) were consistently seen at all doses
878 Expert Opin. Pharmacother. (2009) 10(5)
of DVS in the items of depressed mood, feelings of guilt,
work and activities, psychomotor retardation, psychic anxiety,
and general somatic symptoms.
Improvements in well-being and functional outcome
measures (WHO-5) in patients treated with DVS were also
found  [27]. Data included patients treated with fixed doses
of DVS (50, 100, 200, or 400 mg/day; n = 1205) or
placebo (n = 551) in four 8-week RCTs. Significant improve-
ment (p < 0.05) compared with placebo was also found for
the pooled data set and the individual dose groups for each
of the WHO-5 individual items (good spirits, calm/relaxed,
active/vigorous, fresh/rested, and interested in activities).
Table 1 shows a summary of published short-term
(8-week) RCTs in patients with MDD.
5.1.3 Long-term efficacy
There has been no available published study of DVS with
long-term treatment in which the 50-mg dose was used.
There is one long-term (6-month) study in adults with
MDD for prevention of relapse using doses of 200 or
400 mg/day) which were presented at scientific meetings.
The efficacy of DVS on relapse prevention in MDD was
conducted in an open-label design for 12 weeks with a
flexible dose of DVS (200 – 400 mg/day). Responders at
12 weeks entered into a 6-month RCT. Primary efficacy end
point was time to relapse. The DVS group (24%, p < 0.0001)
experienced significantly fewer relapses than the placebo
group (42%)  [28]. Another observation open-label, flexible-
dose extension study (a mean dose of > DVS 300 mg/day
for 12 months)  [29] also demonstrated long-term efficacy of
DVS in patients with MDD (n = 104). Continuous and
sustained improvement in depressive symptoms was observed,
showing an observed difference of approximately 10 points
in HAMD-17 total score from baseline.
It is prudent to think that acute episodes of MDD may
usually require continuous and maintenance treatment for
several months or for a more sustained period. However, at
present, available evidence on the long-term efficacy of DVS is
limited and, in particular, DVS 50 mg/day and 100 mg/day
doses showing short-term efficacy have not been investigated yet.
Hence we need more data for DVS in long-term efficacy issues.
6. Potential indications
6.1 Vasomotor symptoms-related to menopause
Animal studies have supported that DVS would be effective
also in vasomotor instability by reducing experimentally
elevated tail-skin temperature (TST)  [30]. In the first paradigm,
acute treatment with subcutaneous desvenlafaxine at 30 and
60 mg/kg reduced naloxone-induced opiate withdrawal TST
elevation by 62% and 72% respectively in morphine-dependent
(MD) ovariectomized female rats. Subchronic treatment with
subcutaneous desvenlafaxine 60 mg/kg for 9 days attenuated
naloxone-induced TST elevation by 66%. In the second
paradigm, desvenlafaxine restored the usual diurnal variation
 Table 1. A summary of published randomized, double-blind, placebo-controlled clinical trials of desvenlafaxine in patients with major depressive disorder.

Studies DeMartinis et al., 2007 [9] Septien-Velez et al., Liebowitz et al., Liebowitz et al., Lieberman et al.,
2007 [10] 2007 [11] 2008 [12] 2008 [13]

Trial duration (weeks) 8 8 8 8 8

Completion/randomization (number) 360/480 280/375 184/247 353/474 574/738
Drugs compared PBO (n = 118) vs DVX (n = 114; 1 PBO (n = 126) vs DVX PBO (n = 117) vs PBO (n = 159) vs PBO (n = 250) vs DVX
00 mg/day) vs. DVX (n = 116; (n = 124; 200 mg/d) vs DVX (n = 121; DVX (n = 158; 50 mg/d) (n = 239; 200-400 mg/d)
200 mg/d) vs. DVX (n = 113; DVX (n = 125; 400 mg/d) 100-200 mg/d) vs DVX (n = 157; vs VFX ER (n = 128;
400 mg/d) 100 mg/d) 75-150 mg/d) vs VFX ER
(n = 121; 150-225 mg/d)
Primary efficacy measures*
HAMD-17 PBO = 15.3 vs DVX 100 mg = 12.8‡ PBO = -9.3 vs DVX PBO = 15.1 vs PBO = -9.5 vs PBO = -11.9 vs DVX
vs DVX 200 mg = 13.3 (NS) vs DVX 200 mg = -12.6‡ vs DVX = 14.1 (NS) DVX 50 mg = -11.5§ vs 200-400 mg = -14.3‡
400 mg = 12.5‡ DVX 400 mg = -12.1‡ DVX 100 mg = -11 (NS)
Secondary efficacy measures*
CGI-I PBO = 2.8 vs DVX 100 mg = 2.3‡ vs PBO = 2.7 vs DVX PBO = 2.7 vs PBO = 2.6 vs DVX PBO = 2.0 vs DVX
DVX 200 mg = 2.5§ vs DVX 400 mg 200 mg = 2.2§ vs DVX = 2.5 (NS) 50 mg = 2.3 vs DVX 200-400 mg = 2.3‡
= 2.4§ DVX 400 mg = 2.3§ 100 mg = 2.3 (all NS)
CGI-S PBO = -1.0 vs DVX 100 mg = -1.5‡ PBO = -1.5 vs DVX PBO = 3.3 vs PBO = -1.2 vs DVX PBO = -1.6 vs DVX
vs DVX 200 mg = -1.3 (NS) vs DVX 200 mg = -2.1‡ vs DVX = 3.1 (NS) 50 mg = -1.5 vs DVX 200-400 mg = -2.0‡
400 mg = -1.5‡ DVX 400 mg = -1.9§ 100 mg = -1.4 (all NS)
MADRS PBO = -9.9 vs DVX 100 mg = -13.6‡ PBO = -11.5 vs DVX PBO = 19.5 vs PBO = -12.3 vs DVX PBO = -14.3 vs DVX

Expert Opin. Pharmacother. (2009) 10(5)

vs DVX 200 mg = -13.5‡ vs DVX 200 mg = -15.8‡ vs DVX = 16.8 § 50 mg = -15.0§ vs DVX 200-400 mg = -18.3‡
400 mg = -15.2‡ DVX 400 mg = -15.1‡ 100 mg = -14.3 (NS)
HAMD-6 Not provided Not provided PBO = 8.3 vs PBO = -5.1 vs DVX Not provided
DVX = 7.5 (NS) 50 mg = -6.4‡ vs DVX
100 mg = -6.1§
CAS Not provided Not provided PBO = 5.2 vs PBO = -1.2 vs DVX PBO = -1.5 vs DVX
DVX = 4.9 (NS) 50 mg = -1.5 vs DVX 200-400 mg = -1.8§
100 mg = -1.4 (all NS)
*Values at end point or mean changes from baseline to endpoint.
‡p < 0.01 vs PBO;

§p < 0.05 vs PBO;

Reference [25] is pooled analysis of two studies (references [1] and [2]).
CAS: Covi Anxiety Scale; CGI-I: Clinical Global Impression – Improvement Score; CGI-S: Clinical Global Impression – Severity Score; DVX: Desvenlafaxine succinate; HAMD-6: 6-Item Hamilton Depression Rating Scale;
HAMD-17: 17-Item Hamilton Depression Rating Scale; MADRS: Montgomery-Asberg Depression Rating Scale; NS: Not significant; VAS-PI: Visual Analog Scale – Pain Intensity; VFX ER: Venlafaxine extended release;
SDS: Sheehan Disability Scale; WHO-5: World Health Organization 5-item Well-Being Index.

879
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Desvenlafaxine

Table 1. A summary of published randomized, double-blind, placebo-controlled clinical trials of desvenlafaxine in patients with major depressive
disorder (continued).

Studies DeMartinis et al., 2007 [9] Septien-Velez et al., Liebowitz et al., Liebowitz et al., Lieberman et al.,
2007 [10] 2007 [11] 2008 [12] 2008 [13]

VAS-PI PBO = -5.9 vs DVX 100 mg = -13.9‡ PBO = -8.6 vs DVX PBO = 22.6 vs PBO = -7.9 vs DVX PBO = -10.3 vs DVX
vs DVX 200 mg = -5.4 (NS) vs DVX 200 mg = -17.1‡ vs DVX = 15.6 ‡ 50 mg = -10.7 (NS) vs 200-400 mg = -15.9‡
400 mg = -10.1 (NS) DVX 400 mg = -13.8§ DVX 100 mg = -12.7§
SDS PBO = -5.6 vs DVX 100 mg = -8.6‡ Not provided Total score not provided; PBO = -6.6 vs DVX Not provided
vs DVX 200 mg = -7.5‡ (NS) vs DVX each domain (all NS) 50 mg = -9.0 § vs DVX
400 mg = -8.7‡ 100 mg = -7.8 (NS)
WHO-5 PBO = 4.4 vs DVX 100 mg = 6.7‡ vs Not provided PBO = 11.3 vs PBO = 5.2 vs DVX Not provided
DVX 200 mg = 6.2‡ vs DVX DVX = 12.2 (NS) 50 mg = 6.7 § vs DVX
400 mg = 6.8‡ 100 mg = 6.1 (NS)
*Values at end point or mean changes from baseline to endpoint.
‡p < 0.01 vs PBO;

Expert Opin. Pharmacother. (2009) 10(5)

§p < 0.05 vs PBO;

Reference [25] is pooled analysis of two studies (references [1] and [2]).
CAS: Covi Anxiety Scale; CGI-I: Clinical Global Impression – Improvement Score; CGI-S: Clinical Global Impression – Severity Score; DVX: Desvenlafaxine succinate; HAMD-6: 6-Item Hamilton Depression Rating Scale;
HAMD-17: 17-Item Hamilton Depression Rating Scale; MADRS: Montgomery-Asberg Depression Rating Scale; NS: Not significant; VAS-PI: Visual Analog Scale – Pain Intensity; VFX ER: Venlafaxine extended release;
SDS: Sheehan Disability Scale; WHO-5: World Health Organization 5-item Well-Being Index.

(i.e., lowering of TST during active/dark phase as measured
by telemetry) in a dose-dependent fashion in ovarianectomy-
induced TST dysregulation. More specifically, acute oral
administration of desvenlafaxine 10 mg/kg produced no
statistically significant changes in TST, whereas 30 mg/kg
caused an immediate decrease in TST with a significant mean
change of -2.2°C. The highest dose of desvenlafaxine 100 mg/kg
also significantly decreased TST (mean change of -2.4°C).
These experiments replicated earlier work by demonstrating
increases of serotonin and norepinephrine concentrations in
the preoptic area of the hypothalamus (a key region of
the brain involved in temperature regulation) as a result of
coadministration of desvenlafaxine with a 5-HT1A receptor
antagonist. Hence, preliminary evidence indicates that DVS
directly impacts thermoregulatory dysfunction, suggesting
the potential use of DVS for the treatment of vasomotor
symptoms associated with menopause  [14].
Several RCTs have demonstrated potential efficacy of
DVS in vasomotor symptoms associated with menopause
according to the manufacturer. One such trial has recently
been made available in a public database  [14]. DVS was
compared with placebo for the treatment of vasomotor
symptoms in which 707 healthy, postmenopausal women
experiencing 50 or more moderate-to-severe hot flushes per
week were enrolled in the study. DVS 50, 100, 150, or
200 mg/day or placebo was compared for 52 weeks. Primary
efficacy measures were mean changes in average daily
number of moderate-to-severe hot flushes and in daily
hot flush severity score from baseline at weeks 4 and 12. A
significantly greater reduction in average daily number
of hot flushes was found at weeks 4 (p = 0.013) and 12
(p = 0.005) for DVS 100 mg/day compared with placebo,
reaching a 64% decrease from baseline at week 12. The 75%
responder rate was significantly higher for DVS 100 mg/day
(50%, p = 0.003; number needed to treat = 4.7) at week 12
compared with placebo (29%). Average daily severity of hot
flushes was also significantly lower in the DVS 100 mg/day
group compared with placebo at week 12 (p = 0.020).
These data are in line with the available evidence supporting
the efficacy of venlafaxine in the treatment of menopausal-related
symptoms  [31] and previous preclinical study  [30].
Unpublished pooled RCT data (n = 843, DVS 100 mg/day,
150 mg/day, or placebo)  [32] were also presented at a recent
scientific meeting and showed that DVS significantly
improved mood in those with higher than average Profile of
Mood States (POMS) score. Other unpublished data have also
supported these findings  [33]. According to the manufacturer,
three additional positive studies (6-month and 12-month
trials, and active controlled study) and subanalysis data for
vasomotor symptoms associated with menopause have been
analyzed, and some data were preliminarily presented at scientific
meetings. Vasomotor symptoms is not an approved indication
for DVS in the USA; however, in February 2009, DVS was
approved for both MDD and vasomotor symptoms in Mexico.
Vasomotor symptom studies in the USA are still continuing.
Expert Opin. Pharmacother. (2009) 10(5)
Pae
In 2006, the manufacturer submitted New Drug Applications
(NDA) to the FDA for DVS as a nonhormonal agent for
the treatment of moderate-to-severe vasomotor symptoms
associated with menopause. If approved, it will be the first and
only nonhormonal medication indicated for the treatment
of moderate-to-severe vasomotor symptoms associated with
menopause in the USA.
6.2 Painful somatic symptoms
As the individual flexible-dose and fixed-dose RCTs have shown
efficacy of DVS on reduction of VAS-PI scores, unpublished
pooled study data (DVS: n = 1048, 100 – 400 mg/day;
placebo: n = 718)  [34] have also confirmed the usefulness of
DVS for treating painful physical symptoms of MDD as
measured by the same scales and its response criteria. In
fact, venlafaxine XR has also established its utility for
patients with multi-somatoform disorder in a recent RCT
and randomized open-label studies  [35,36]. These findings
may reflect substantial usefulness of DVS for patients with
multiple somatic complaints prevailing in clinical practice as
well as for MDD patients with predominant physical
symptoms. In addition, the manufacturer has revealed that
Phase III trials to evaluate the efficacy and safety of DVS
in fibromyalgia and neuropathic pain have also been
underway  [37]. In this context, other SNRIs (duloxetine  [38,39]
and milnacipran  [40,41]) have shown efficacy on fibromyalgia
through a number of RCTs. Milnacipran (early 2009) and
duloxetine (mid 2008) have been recently approved for the
treatment of fibromyalgia. DVS is not approved for use in
any pain syndromes in the USA.
6.3 Anxiety symptoms
A pooled analysis has suggested the potential utility of DVS
in the treatment of anxiety in patients with MDD  [13]. In
fact, another unpublished pooled analysis  [26] has also shown
that DVS has proven its efficacy in reduction of psychic and
somatic anxiety as measured by HAMD-17. The efficacy of
DVS in the treatment of anxiety symptoms has been shown
also in other pooled analyses of five RCTs (DVS 50, 100,
200, or 400 mg/day; n = 1342 vs placebo, n = 631)  [42] and
seven RCTs (DVS 100 – 400 mg/day; n = 1186 vs placebo,
n = 797)  [43]. These data have clearly established that DVS
effectively improves anxiety symptoms in patients with
MDD across a wide range of doses. Hence, we may expect
that the potential usefulness of DVS may expand to patients
with anxiety disorders and anxiety symptoms comorbid with
medical illnesses since venlafaxine XR has indication for
various anxiety disorders (i.e., generalized anxiety disorder
and social anxiety disorder) approved by the FDA. DVS is
not approved for use in any anxiety disorder in the USA.
7. Dosing
Overall, doses of 50 – 400 mg/day have been shown to be
effective in clinical studies, though no additional benefit was
881
Desvenlafaxine
demonstrated at doses < 50 mg/day, and adverse events and
rates of discontinuation due to adverse events were more
frequent at higher doses.
Two fixed-dose  [9,12] and two flexible-dose  [11,24] trials partly
failed to separate from placebo in the primary efficacy measure.
In detail, DVS 100 mg/day  [12] and 200 mg/day  [9] gave
mixed results, and all flexible-dose (100 – 200 mg/day  [11]
and 200 – 400 mg/day  [24]) clinical trials showed divergent
results. However, interestingly, DVS showed much better
results considering the data based on the reduction in
MADRS scores, in which only 100 mg/day of DVS  [12]
failed to show superior efficacy compared with placebo;
while results from other fixed-doe RCTs have been positive
across all doses (50, 100, 200 and 400 mg/day). This
discrepancy may require some speculation; for instance,
proper titration, high placebo rates, characteristics of efficacy
measures, basal depression severity, illness duration, treatment
duration and other covert clinical factors such as comorbidity
etc. may subtly affect DVS trial outcomes  [44]. Since all
pooled analyses  [13,25] have demonstrated clear efficacy for
DVS as measured by reduction in HAMD-17 total scores, we
may assume the discrepancy could account for under-power
of the individual studies.
Taking all evidence together, the manufacturer’s recom-
mended dose for DVS (50 mg/day) seems to be appropriate
since doses of 50 – 400 mg/day were shown to be effective
but produced mixed results in primary and secondary efficacy
measures according to titration method or administered
doses in aforementioned RCTs. The available data indicate
no additional benefits of the use of DVS with doses higher
than 50 mg/day. However, further investigation is needed as
to whether or not nonresponders to DVS 50 mg/day with a
proper trial period would show improvement with increased
dosage. Dosage changes should occur at intervals of at least
1 week, although it has not yet been systematically investi-
gated. The mean daily doses ranged from 179 to 195 mg/day
in one flexible-dose RCT  [11], and from 324 to 373 mg/day
in another  [24]. Thus it would be prudent for clinicians to
determine carefully, at their discretion, the appropriate dose
for individual patients based on different clinical factors
and situations along with clinicians’ preference. Finally,
patients should also be periodically reassessed to determine
the most effective maintenance doses based on clinicians’
discretion and patient response, since no defined doses for
maintenance and continuation phase treatments have yet
been systematically studied.
8.Switching from venlafaxine XR or
other antidepressants
Unpublished studies have shown efficacy  [45] and tolerabil-
ity  [46] of switching from venlafaxine XR to DVS in patients
with MDD. In a secondary, post hoc analysis, switching
data  [45] were analyzed among subjects switched to open-label
DVS from placebo (n = 176), venlafaxine XR (n = 175) or
882 Expert Opin. Pharmacother. (2009) 10(5)
DVS (n = 143) who completed 8 weeks of RCT and
participated in a 10-month, open-label extension study
treated with DVS (200 – 400 mg/day). Efficacy variables
included the mean changes in HAMD-17 total scores from
baseline as well as response rates based on criteria by scores
or reduction on CGI-I, HAMD-17 and MADRS. As for
mean change in HAMD-17 total scores, switching to DVS
maintained the improvement of responders and was associ-
ated with significant benefits among those who initially did
not respond (-5.7 in double-blind study to -7.3 in open-
label study in previously venlafaxine XR-treated group; and
-4.7 to -7.8 in previously DVS-treated group); the biggest
change was found in patients who had not responded to
placebo (from -3.9 to -10.8).
Other switching tolerability data  [46] were investigated
among patients previously treated with placebo (n = 186)
and subjects previously treated with venlafaxine XR (n = 183)
who entered the open-label extension study. Rates of
nausea, treatment-emergent adverse events (TEAEs), and
discontinuation at the first month after switch were
compared between treatment groups. By week 2 after
switch, the rate of nausea was significantly higher in
previously venlafaxine XR-treated patients than in previo-
usly placebo-treated patients (p = 0.03); it did not differ
significantly between the groups at end point (2% for
both). Rates of TEAEs and discontinuation rates showed
a similar trend. These data confirm that switching from
venlafaxine XR to DVS can be tolerable with retaining
efficacy, although more practical issues in switching strategies
need to be verified.
9. Discontinuation symptoms
Common taper-emergent discontinuation symptoms of
DVS include nausea, dizziness, abnormal dreams, headache,
diarrhea, irritability, insomnia, infection and withdrawal
symptoms  [9,12]. A pooled analysis (8 weeks to 6 months)  [47]
for patients (n = 259, DVS 50 mg/day; n = 239, DVS
100 mg/day; n = 39, DVS 200 mg/day; n = 34, DVS
400 mg/day vs n = 319, placebo) who were assessed by
discontinuation-emergent signs and symptoms checklist
(DESS) has also supported the emergence of discontinua-
tion symptoms of DVS. In this study, discontinuation from
all doses of DVS was significantly associated with discon-
tinuation symptoms as measured by DESS  [47]. It ought
to be noted, therefore, that gradual dose reduction and
proper administration of minor tranquilizers should be
considered owing to the possibility of discontinuation symp-
toms when quitting current DVS regardless of short-term or
long-term use.
10. Safety and tolerability
In a number of clinical trials, the overall TEAEs profile of
DVS was similar to those of contemporary SSRIs and SNRIs

as well as to its former formulation, venlafaxine  [44]. In the
short-term RCTs  [9-12,24], the frequently reported TEAEs
included nausea, dry mouth, somnolence, hyperhidrosis,
insomnia, dizziness, constipation, fatigue, decreased appetite,
tremor, vomiting, mydriasis, anorgasmia and erectile dys-
function. Such TEAEs usually occurred during an early
phase of the treatment (the first 2 – 3 weeks) and faded
over time.
The highest frequent TEAEs resulting in early discontinuation
of DVS in short-term RCTs were reported as nausea and
insomnia, in particular nausea (usually developed within the
first week), which was ranked the first reason in four short-
term RCTs  [9,10,12,24] as shown in SNRIs and SSRIs  [48].
Higher discontinuation rates due to TEAEs were likely to be
associated with fixed-dose design  [9,10] rather than with
flexible-dose design  [11] initiated with a lower dose. In
addition, among such fixed-dose RCTs  [9,12], the discontinu-
ation rates due to TEAEs were numerically greater in high-
dose groups than in low-dose groups. In fact, at the
recommended dose of 50 mg/day, the discontinuation
rate due to TEAEs for DVS (3.3%) was similar to the
rate for placebo (2.6%)  [12]. For the 100 mg/day of
DVS, the discontinuation rate due to TEAEs ranged from
7.4% to 12.7%, while the range was 2.6 – 3.3% for
placebo  [9,12]. A recent pooled analysis (DVS, n = 1365;
placebo, n = 636)  [49] including five short-term RCTs  [9-12,24]
has also supported the findings from individual RCTs (4%
with 50 mg/day, 9% with 100 mg/day, 15% with 200 mg/day,
and 18% with 400 mg/day doses with DVS groups vs
4% with the placebo group). These discontinuation rates
for DVS doses of 50 and 100 mg/day are similar to those
of currently available SNRI (duloxetine, 8%) and SSRI
(paroxetine, 6.1%)  [48].
DVS treatment was associated with significant mean
increases in systolic (s) and diastolic (d) blood pressure
(BP; 1 – 4 mmHg) as well as pulse rate (1 – 4 bpm) in
short-term RCTs (50 – 400 mg/day) compared with
placebo, which showed small dose-related association  [9,10,12].
A pooled study (DVS, n = 1365; placebo, n = 636)  [50]
has also confirmed these data showing significant mean
increases in sBP and dBP (1 – 3 mmHg). Hence, hyperten-
sion should be controlled before initiating treatment with
DVS, and blood pressure should be monitored regularly
during treatment.
A small but significant mean decrease (-1 to -2 kg) in
weight changes was found in short-term RCTs  [9-12,24],
which was supported by pooled analysis (DVS, n = 1211;
placebo, n = 803)  [51].
There are no adequate and well-controlled studies of DVS
in pregnant and breastfeeding women. DVS has been
classified as a category C drug for pregnancy. Teratogenic
and non-teratogenic effects of DVS are still questionable.
Hence, DVS should be used only if the potential benefits
outweigh and justify the potential risks during pregnancy
and breastfeeding.
Expert Opin. Pharmacother. (2009) 10(5)
Pae
Two absolute contraindications include hypersensitivity
to DVS, venlafaxine hydrochloride or any derivatives in
the DVS formulation, as well as current or recent (within
14 days) treatment with a monoamine oxidase inhibitor  [18].
Cases with suicide ideation, suicide attempt and completed
suicide were reported during short-term RCTs, although it
was found to be unrelated to DVS  [9-11]. These findings
may recall the FDA public health advisory reminder and
black box warning to healthcare providers that clinicians
should carefully monitor patients receiving DVS for possible
worsening of depression or suicidality, especially at the
beginning of therapy or when the dose is increased or
decreased. Table 2 summarizes TEAEs from available published
studies  [9-13].
In summary, DVS was shown to be generally safe and
tolerable. In most cases, TEAEs were transient and mild to
moderate in severity. DVS was also associated with few
clinically nonsignificant laboratory, vital sign and ECG
changes. Dose relationship was partly found in the develop-
ment of TEAEs but is not yet conclusive. Starting with a
low dose of DVS may improve tolerability and decrease the
absolute incidence of common TEAEs  [9].
11. Expert opinion and conclusion
Advanced formulations for current antidepressants are still
under development. Several formulations with different
release, orally disintegrating tablets and different isomers
have already been available in the market. The use of these
advanced formulations has been found to be useful for
enhancing patients’ satisfaction with the treatment and
compliance. In this regard, DVS is the isolated major
active metabolite of venlafaxine and was developed as a
slow-release tablet formulation. Unlike venlafaxine, DVS
is not metabolized by CYP 450 enzyme pathways and
is associated with minimal inhibition of CYP enzymes.
This feature results in a comparatively low risk of drug–
drug interaction and consistent intra-individual and inter-
individual pharmacokinetic profiles, compared with the
previous formulation, venlafaxine.
Although pooled analyses of DVS demonstrated better
confirmative evidence than individual studies of DVS,
current evidence delivers some concerns about mixed results
in primary efficacy measures that may be caused by different
methodologies among individual studies. The response and
remission rates ranged from 40% to 60% and from 23% to
37%, respectively, similar to those seen in treatment with
other SNRIs and SSRIs  [9-12,24,52].
The recommended dose is 50 mg/day based on the efficacy
and safety data set. TEAEs are also similar to those of ven-
lafaxine, with the most common being insomnia, somnolence,
dizziness and nausea. However, concerns about lipid profile,
hepatic enzymes and cardiovascular parameters should be
studied further. Discontinuation symptoms potentially related
to DVS should also be considered in primary practice. The
883
884
Desvenlafaxine

Table 2. Number (%) of treatment-emergent adverse events (TEAEs; defined as those with an incidence of ≥ 5% and at least twice the rate of placebo).

TEAEs Liebowitz et al., 2008 Lieberman et al., 2008* Liebowitz et al., 2007

Placebo (n = 152) DVX 50 mg/day DVX 100 mg/day Placebo (n = 245) DVX 200 – 400 mg/day Placebo (n = 117) DVX 100 – 200 mg/day
(n = 151) (n = 148) (n = 231) (n = 121)

Any TEAEs 107 (70) 127 (84) 113 (76) - - 93 (79) 112 (93)
Nausea 17 (11) 25 (17) 23 (16) 30 (12) 87 (38) 10 (90) 36 (30)
Dry mouth 6 (4) 15 (10) 23 (16) 10 (4) 47 (20) 14 (12) 31 (26)
Constipation 5 (3) 14 (9) 16 (11) 7 (3) 32 (14) 7 (6) 20 (17)
Decreased 7 (5) 8 (5) 15 (10) 3 (1) 23 (10) 2 (2) 16 (13)
appetite
Sweating 4 (3) 10 (7) 14 (10) 10 (4) 45 (20) 4 (3) 9 (7)

Expert Opin. Pharmacother. (2009) 10(5)

Fatigue 5 (3) 9 (6) 10 (7) 10 (4) 21 (9) 8 (7) 13 (11)
Anxiety 1 (1) 5 (3) 7 (5) 2 (1) 13 (6) 6 (5) 6 (5)

*Pooled data of references [9] and [10]. Common TEAEs between three studies were included only (i.e., somnolence was not reported in the study of Liebowitz et al. (2008) and then this TEAE was omitted in the table).
Most AEs reported were rated as mild to moderate in severity.
 Pae

notable identified potential advantage of DVS over venlafaxine
or other antidepressant agents at this point is the apparently
reduced risk for pharmacokinetic drug interactions and possible
usefulness for menopause-related symptoms.
More investigations about the relationship of titration
strategies, basal depression severity, illness duration and
comorbidity with DVS will be useful in determining proper
use of DVS in clinical practice. In addition, the long-term
role of DVS has not yet been elucidated, so adequate
continuous and maintenance treatment data for DVS will
be mandatory. RCTs consistently demonstrated a potential
of DVS for treating vasomotor symptoms associated with
menopause  [26,34]. An additional and interesting application
should be if DVS were to have differential effects for
depressed female patients with or without menopause  [14,32,33].
Reflecting the action mechanism of DVS and increasing
evidence regarding the effect of SNRIs on chronic pain and
somatic symptoms  [38-41,53-55], further studies should be
conducted for patients with pain-related disorders and
predominant somatic symptoms. So far there have been no
randomized, double-blind studies comparing DVS with
other SNRIs or SSRIs in the treatment of MDD. Findings
from recent comparison studies of former formulation
venlafaxine XR with duloxetine  [56] and escitalopram  [57]
may show valuable implications for future clinical trial
direction. Such comparison studies would address the question
of whether DVS will be able to differentiate itself in a very
competitive market.
In the near future, complete analyses of additional data
sets by the manufacturer of DVS and continuous adequately
powered, well-designed RCTs across the world will contribute
to a better understanding of the exact role of DVS in the
treatment of MDD, pain and somatic symptoms.
Declaration of interest
This work was supported by a grant from the Medical Research
Center, Korea Science and Engineering Foundation, Republic
of Korea (R13-2002-005-04001-0). The manufacturer of
desvenlafaxine, Wyeth, did not contribute to any part of
this work.
Pae has received a research grant from GlaxoSmithKline
Korea, GlaxoSmithKline, AstraZeneca Korea, Janssen Phar-
maceuticals Korea, Eli Lilly and Company Korea, the Korean
Research Foundation, Otsuka Korea Pharmaceuticals, Wyeth
Korea, the Catholic Medical Center, and the Korean Institute
of Science and Technology Evaluation and Planning; has
received honoraria and is on the speaker’s bureaus of Glaxo-
SmithKline Korea, Lundbeck Korea, AstraZeneca Korea,
Janssen Pharmaceuticals Korea, Eli Lilly and Company
Korea, McNeil Consumer and Specialty, Inc. and Otsuka
Korea Pharmaceuticals, Inc.

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Affiliation
Chi-Un Pae1,2 MD PhD
†Author for correspondence
1The Catholic University of Korea College
of Medicine,
Holy Family Hospital,
Department of Psychiatry,
2 Sosa-Dong, Wonmi-Gu,
Pucheon, Kyounggi-Do 420-717
Republic of Korea
Tel: +82 32 340 2114; Fax: +82 26 442 2789;
E-mail: pae@catholic.ac.kr
2Duke University Medical Center,
Department of Psychiatry and Behavioral Sciences,
2218 Elder Street,
Durham, NC 27705, USA
887