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Primary Psychiatry. 2009;16:5 (Suppl 4):25-35
Serotonin Norepinephrine Reuptake
Inhibitors: Similarities and Differences
Richard C. Shelton, MD
ABSTRACT
FOCUS POINTS
Serotonin norepinephrine reuptake inhibitors (SNRIs) are increas-
• The serotonin norepinephrine reuptake inhibitors (SNRIs)
venlafaxine, duloxetine, milnacipran, and desvenlafaxine
all bind the serotonin and norepinephrine transporters,
but the potency with which they bind each of these—and
their selectivity ratios—differ.
• SNRIs vary in their potential to influence cytochrome P450
(CYP)-mediated drug-drug interactions, but, in general,
they interact less with CYP 450 compounds, particularly
the important isozyme CYP 2D6, than do selective serotonin reuptake inhibitors (SSRIs).
• SNRIs demonstrate efficacy that is comparable to or better
than that of tricyclic antidepressants and SSRIs in metaand pooled analyses, but there are few studies addressing
differences in efficacy within the class.
• The safety and tolerability profiles of SNRIs are similar to
those of SSRIs; however, SNRIs may be associated with
dose-related increases in blood pressure and lower rates of
sexual dysfunction compared with certain SSRIs.
ingly being used as first-line treatment for major depressive
disorder (MDD). This article discusses differences in the pharmacology and pharmacokinetics of the members of this class of
antidepressants and compares their efficacy and tolerability to
those of other agents used to treat MDD. The SNRIs have relatively
short half-lives and display linear pharmacokinetics. In general,
these drugs interact less with cytochrome P450 (CYP) compounds,
especially the important isozyme CYP 2D6, than do selective serotonin reuptake inhibitors (SSRIs), suggesting a reduced potential
for drug-drug interactions. Overall, SNRIs demonstrate efficacy
that is comparable to or better than that of tricyclic antidepressants and SSRIs. They are also effective in treating a broad range
of psychiatric illnesses associated with MDD, but additional studies
are needed to determine optimal treatment for these comorbid con-
INTRODUCTION
ditions. Although SNRIs as a class exhibit many similarities, indi-
The four medications that comprise the serotonin norepinephrine reuptake inhibitor (SNRI) class—venlafaxine,
duloxetine, milnacipran, and desvenlafaxine (administered as
desvenlafaxine succinate)—share similarities in structure and
mechanism, but differences in their pharmacology and pharmacokinetics can affect their efficacy and tolerability profiles.
Each of the SNRIs has been approved in the United States or
in other countries for the treatment of major depressive disorder (MDD), and all but the newest SNRI, desvenlafaxine,
have been approved for additional indications.1-5 This article
vidual agents differ in their pharmacokinetic and safety profiles.
Furthermore, the range of selectivity ratios observed with these
agents implies that differences in serotonergic and noradrenergic
levels may exist, which could have important clinical implications.
These factors, along with genetic variations in individual patients
and the pharmacologic profiles of concomitant medications, must
be considered when selecting an SNRI for treatment of MDD.
Dr. Shelton is James G. Blakemore Research Professor of Psychiatry and Professor of Pharmacology, and Vice Chair for Research in the Department of Psychiatry at Vanderbilt University School of Medicine in Nashville.
Disclosure: Dr. Shelton is a consultant to Eli Lilly, Evotec, Forest, Gedeon-Richter, Janssen, Merck, Otsuka, Pamlab, and Sierra; and receives grant support from Bristol-Myers Squibb, Eli Lilly, Forest, Janssen,
the National Institutes of Health, Novartis, Otsuka, Pamlab, and Pfizer. Dr. Shelton discusses unapproved/investigational uses of milnacipran for the treatment of major depressive disorder.
Acknowledgment: The author would like to thank Kathleen Dorries, PhD, and Lorraine Sweeney, BA, of Advogent for assisting in the writing and editing of this article.
Please direct all correspondence to: Richard C. Shelton, MD, Department of Psychiatry, Vanderbilt University School of Medicine, 1500 21st Avenue, South, Suite 2200, Nashville, TN 37212; Tel:
(615) 343-9669; Fax: (615) 343-9038; E-mail: [email protected].
Primary Psychiatry 16:5 (Suppl 4)
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R.C. Shelton
assesses the similarities and differences among members of the
SNRI class in pharmacology and pharmacokinetics, efficacy
in the treatment of MDD, and safety and tolerability. As
the first available SNRI, venlafaxine has been well studied
in each of these areas. There are far fewer studies assessing
milnacipran, which has not been approved by the Food and
Drug Administration for treatment of MDD (although it is
approved by drug regulatory agencies outside the US), and
desvenlafaxine, which was approved in the US in 2008.4 Few
head-to-head studies have been published to date comparing
the efficacy of the different SNRIs for any indication; thus
much of the available data comes from comparisons between
SNRIs and antidepressants of other classes.
modestly but significantly from the minimal clinical dose of
75 mg/day (~80% occupancy) to 225–450 mg/day (~85%
occupancy).14,15 Four selective serotonin reuptake inhibitors
(SSRIs) were also assessed, and all showed ~80% occupancy at
their respective minimum recommended clinical dosage.14
Duloxetine has a higher affinity for both the 5-HT and NE
transporters than venlafaxine. In vitro, duloxetine potently
inhibits 5-HT and NE uptake in rat hypothalamus and cerebral cortex.16 In ex vivo studies, administration of duloxetine
1 hour prior to sacrifice causes dose-dependent and parallel decreases of 5-HT and NE uptake in rat hypothalamus,
which is consistent with significant NE uptake blockade at
relatively low tissue concentrations.16 The ratio of binding to
the human 5-HT and NE transporters in vitro is approximately 1:10.7 In clinical studies, serotonin reuptake inhibitors
block the uptake of 5-HT in platelets and decrease whole
blood 5-HT concentrations.13,17 In a double-blind controlled
study conducted in healthy human subjects, duloxetine
reduced whole blood 5-HT versus placebo.17 In addition,
increased sympathetic tone was observed with duloxetine,
which is associated with significantly decreased whole body
NE turnover in healthy human subjects, consistent with reuptake blockade.17 In a separate study, duloxetine in doses of
20 or 60 mg/day was found to interfere with 5-HT reuptake
determined by whole blood 5-HT content in healthy human
volunteers, but did not prevent an increase in blood pressure
after infusion of intravenous tyramine, suggesting a lack of an
effect on NE reuptake at either dose.18 However, duloxetine
60 mg was observed to increase supine systolic blood pressure
in that study, indicating that this dose may reflect a threshold
dose for NE reuptake inhibition.18 Higher doses may be needed to optimally block NE uptake. In healthy human subjects,
5-HT transporter occupancy in the striatum, measured using
PET, was 81% after a single administration of duloxetine 40
mg/day and 82% occupancy after administration of 60 mg/
day,19 the dose range recommended in the prescribing information.2 5-HT transporter occupancy increased to 84% after
administration of duloxetine 60 mg/day for 7 days.19
PHARMACOLOGY AND PHARMACOKINETICS
Pharmacology
The SNRIs venlafaxine, duloxetine, milnacipran, and desvenlafaxine all bind the serotonin (5-HT) and norepinephrine (NE)
transporters, but the potency with which they bind each of these
and the selectivity ratios differ (Table 1).1-4,6-9 The estimated 5HT:NE selectivity ratios for the SNRIs are shown in comparison
to antidepressant drugs of other classes in Table 2.7-11
In radioligand binding studies in rat brain membranes, venlafaxine was shown to have a relatively low affinity for both the
5-HT and NE transporters.12 However, binding is much higher for the human 5-HT transporter than for the human NE
transporter; the 5-HT:NE ratio was estimated at 1:30 in one
study.7 In vivo studies in healthy human subjects demonstrated
that venlafaxine inhibits platelet 5-HT uptake across its dose
range, whereas it inhibits NE uptake (as measured by the pressor response to intravenous tyramine) only at higher doses (ie,
≥225 mg/day).13 Positron emission tomography (PET) studies in healthy human subjects administered venlafaxine show
that 5-HT transporter occupancy in the striatum increases
TABLE 1
PHARMACOLOGY OF SEROTONIN NOREPINEPHRINE REUPTAKE INHIBITORS1-4,6-9
Venlafaxine
Duloxetine
Milnacipran
Desvenlafaxine
Recommended dose range
IR: 75–375 mg/day1,6
ER: 75–225 mg/day1
40–60 mg/day2
100 mg/day3
50 mg/day4
Estimated 5-HT:NE selectivity ratio
1:307
1:97
1:1.69
1:148
Binding inhibition, 5-HT transporter, Ki
82±3 nM7
0.8±0.047
123±11 nM9
40.2±1.6 nM8
Binding inhibition, NE transporter, Ki
2480±437
7.5±0.37
200±2 nM9
558.4±121.6 nM8
IR=immediate release; ER=extended release; 5-HT=serotonin; NE=norepinephrine.
Shelton RC. Primary Psychiatry. Vol 16, No 5. 2009.
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Serotonin Norepinephrine Reuptake Inhibitors: Similarities and Differences
Milnacipran has a relatively high affinity for both 5HT and NE transporters as shown by in vitro and in vivo
preclinical studies.20 Cerebral microdialysis in the hypothalamus of guinea pigs showed that extracellular levels of
both 5-HT and NE were increased by milnacipran, with
a ratio of 5-HT to NE uptake of roughly 2:1.20 The ratio
of inhibition of cloned human 5-HT and NE transporter
binding by milnacipran was approximately 1:2.9
Desvenlafaxine is the primary metabolite of venlafaxine
(O-desmethylvenlafaxine [ODV]).1 Studies in animal models showed that desvenlafaxine has affinity for both 5-HT
and NE transporters.21 Cells expressing either the human
5-HT transporter or NE transporter yielded Ki values for
desvenlafaxine of 40.2±1.6 and 558.4±121.6 nM, respectively,8 in the same range as the parent compound. The ratio
of inhibition of cloned human 5-HT and NE transporter
binding by desvenlafaxine was approximately 1:14.8
None of the members of the SNRI class have shown significant binding to other transporters or receptors (eg, α1, α2, β1,
or β2 adrenergic, muscarinic, histaminergic, 5-HT, or dopamine receptors, or benzodiazepine binding sites) in preclinical
studies other than the 5-HT and NE transporters.7,8,16,22-24
Pharmacokinetics
The pharmacokinetic profiles of the four SNRIs are shown in
Table 3.1-4,6,25-29 In contrast to many SSRIs, the SNRIs have relatively short half-lives, ranging from 5 hours (venlafaxine) to 12
hours (duloxetine).1-4 Time to peak plasma concentration ranges
from 2 hours for milnacipran to 6 hours for duloxetine; steadystate plasma concentrations are achieved after 3 days for all of
the SNRIs except desvenlafaxine (4 days).1-4 The pharmacokinetics for all four SNRIs are linear (dose-proportional) over their
respective therapeutic ranges. Greater than 90% of duloxetine is
protein-bound; venlafaxine, milnacipran, and desvenlafaxine are
minimally bound to plasma proteins (Table 3).1-4,6,25-29
Like the SSRIs,30 metabolism of venlafaxine is primarily
hepatic, via the cytochrome P450 (CYP) isozymes.1 Formation
of ODV from venlafaxine is catalyzed by CYP 2D6. A clinical study has shown that patients with the CYP 2D6 poor
metabolizer phenotype had higher plasma levels of venlafaxine
and lower levels of ODV compared with CYP 2D6 extensive
metabolizers.31 The majority of the venlafaxine dose is metabolized; ~87% appears in the urine as unchanged venlafaxine (5%),
unconjugated ODV (29%), conjugated ODV (26%), and
other metabolites (27%).1 Duloxetine metabolism is primarily
via CYP 2D6 and CYP 1A2.2 The majority of the duloxetine
dose is metabolized; ~70% appears in the urine as metabolites
and ~20% in the feces; <1% of the dose remains unchanged.2
Milnacipran is metabolized hepatically, but does not appear to
involve the CYP 450 system.3,32 First pass metabolism is low33
and elimination is both renal and nonrenal; 90% of the dose
is excreted renally and 50% to 60% is unchanged.3,22,32 Unlike
venlafaxine, desvenlafaxine does not undergo extensive firstpass metabolism in the liver. Metabolism is primarily direct
conjugation through a high-capacity (glucuronidation) pathway exclusive of the CYP 450 system, and to a lesser extent,
through oxidative metabolism through N-methylation mediated by CYP 3A4.4 The pharmacokinetics of desvenlafaxine are
not affected by CYP 2D6 metabolizer phenotype.4 After oral
administration of desvenlafaxine, ~45% is excreted unchanged
in urine, 19% excreted as a glucuronide metabolite, and <5%
as the oxidative metabolite (N,O-didesmethylvenlafaxine).4
Most SSRIs are significant inhibitors of CYP 2D6, and thus
have potential for interactions with concomitant drugs that are
CYP 2D6 substrates.34,35 In studies that evaluated the effects of
venlafaxine, desvenlafaxine, duloxetine, and paroxetine on the
CYP 2D6 model substrate-drug desipramine, venlafaxine and
TABLE 2
ESTIMATED 5-HT:NE SELECTIVITY RATIOS FOR
ANTIDEPRESSANTS IN DIFFERENT DRUG CLASSES7-11
Estimated
5-HT:NE
Selectivity Ratio
Drug
Class
Source
Clomipramine
TCA
Human transporters, KD10
1:136
Trimipramine
TCA
Human transporters, KD
1:16
Imipramine
TCA
Human transporters, Ki11
1:15
Amitriptyline
TCA
Human transporters, Ki
1:7
Dothiepin
TCA
Human transporters, KD
1:5
Doxepin
TCA
Human transporters, KD
2:1
Nortriptyline
TCA
Human transporters, Ki11
8:1
Protriptyline
TCA
Human transporters, KD
14:1
Desipramine
TCA
Human transporters, Ki
35:1
Maprotiline
TCA
Human transporters, KD
523:1
Escitalopram
SSRI
Human transporters, Ki11
1:7128
Sertraline
SSRI
Human transporters, Ki11
1:5447
Citalopram
SSRI
Human transporters, Ki
1:5243
Fluvoxamine
SSRI
Human transporters, Ki
1:1844
Paroxetine
SSRI
Human transporters, Ki
1:1308
Fluoxetine
SSRI
Human transporters, Ki11
1:863
Venlafaxine
SNRI
Human transporters, Ki
1:30
Desvenlafaxine
SNRI
Human transporters, Ki
1:14
Duloxetine
SNRI
7
Human transporters, Ki
1:9
Milnacipran
SNRI
Human transporters, Ki9
1:2
Nefazodone
Atypical
Human transporters, Ki
1:1
10
11
10
10
10
11
10
11
11
11
7
8
11
5-HT=serotonin; NE=norepinephrine; TCA=tricyclic antidepressant; SSRI=selective serotonin reuptake inhibitor; SNRI=serotonin norepinephrine reuptake inhibitor.
Shelton RC. Primary Psychiatry. Vol 16, No 5. 2009.
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R.C. Shelton
EFFICACY
desvenlafaxine inhibition of CYP 2D6 have been found to be
weaker than both paroxetine and duloxetine,25,30,34,36,37 suggesting that both venlafaxine and desvenlafaxine have lower potential for drug-drug interactions with other CYP 2D6 substrates
compared with duloxetine or paroxetine (desvenlafaxine has
been found to not exert a clinically relevant effect on CYP 2D6
metabolism at the dose of 100 mg/day).4 Venlafaxine is also a
weaker inhibitor of CYP 2D6 than are fluoxetine, fluvoxamine,
and sertraline.34,38 Duloxetine inhibition of CYP 2D6 enzyme
is lower than paroxetine but greater than sertraline.25,30
CYP 450 enzymes CYP 3A4, CYP 1A2, and CYP 2C9 are
not inhibited by venlafaxine.1,34 Diazepam metabolism, which
is partially metabolized by CYP 2C19, also is unaffected by
venlafaxine.1 Desvenlafaxine exerts weak induction of CYP
3A4, which may lower plasma levels of drugs metabolized by
this enzyme (ie, midazolam).4 In vitro, desvenlafaxine does not
inhibit or induce the CYP 1A2, 2A6, 2C8, 2C9, and 2C19
isozymes.4 Duloxetine inhibits CYP 1A2; in two clinical studies,
the area under the plasma concentration-versus-time curve of
theophylline, a known CYP 1A2 substrate, increased by 7% and
20% when coadministered with duloxetine.2 Duloxetine does
not inhibit CYP 2C9, CYP 3A, and CYP 2C19.2 Milnacipran
has not been shown to interact with CYP 450 enzymes.22,29,32
Efficacy for the treatment of MDD has been demonstrated
in randomized, placebo-controlled clinical trials for all four
members of the SNRI class.39 However, the relative efficacy of
the SNRIs is unclear. Currently, few head-to-head trials have
been published comparing efficacy of antidepressants within
the SNRI class; for this reason, the comparative efficacy of the
SNRIs for treating MDD will be considered relative to other
antidepressant classes. Particularly for venlafaxine, a large number of trials with active comparators have been published, with
varying results. Multiple meta-analyses and pooled analyses have
now been performed, generally including overlapping sets of
those trials, but based on different criteria for study inclusion and
measures of clinical improvement. Meta-analyses can be useful
for generalizing across many trials, but when interpreting results
of meta-analyses, the limitations of this type of analysis must be
considered: outcomes of individual MDD trials are affected by
study design (eg, open versus blinded, inclusion of active and/or
placebo controls); number of patients enrolled; dose selection;
treatment duration; criteria for the selection of patient population; and other factors, and these sources of variability are not
controlled in the meta-analysis. For example, a meta-analysis may
TABLE 3
PHARMACOKINETIC PROFILES OF SEROTONIN NOREPINEPHRINE REUPTAKE INHIBITORS1-4,6,25-29
Venlafaxine
Duloxetine
Milnacipran
Desvenlafaxine
Half-life (t1/2), mean (range), hours
5 (3–7)
12 (8–17)
8
114
Time to peak plasma
concentration (tmax), hours
IR: 2
ER: 5.51
62
2 (dose-independent)3
7.54
Peak plasma concentration (Cmax)
IR: 225 ng/mL after
75 mg q12 hours
35.2 ng/mL after 40
mg/day for 5 days25
120 ng/mL after 50 mg dose
135 ng/mL after 75 mg dose
(Wyeth, data on file)
6
2
3
ER: 150 ng/mL after
150 mg q24 hours1
216 ng/mL after steady state
is reached (2–3 days)3
Dose vs. concentration relationship
Linear over
75–450 mg/day1,6
Dose-proportional over
therapeutic range2
Dose-proportional ≤200 mg/
day administration3
Linear and dose-proportional
over 100–600 mg/day4
Dose-response relationship
Positive over
75–375 mg/day26
No evidence of a
dose-response effect2
Some evidence of
dose-response effect,
but few doses tested27,28
No evidence of
dose-response effect4
Protein binding (%)
27%6
>90%2
13%3
30%4
Major metabolic pathways
Hepatic, CYP 2D66
Hepatic, CYP 2D6,
CYP 1A22
Glucuronic acid
conjugation; not metabolized
by CYP 4503,29
Conjugation (mediated by UGT
isoforms); minor CYP 3A4; not
metabolized by CYP 2D64
Substrate metabolic enzymes
CYP 2D6, CYP 3A4
CYP 2D6, CYP 1A2
–
CYP 3A4
Metabolic enzymes inhibited
CYP 2D6 (weak)
CYP 1A2, CYP 2D6
(moderate)
–
CYP 2D6 (weak)
Metabolic enzymes induced
–
–
–
CYP 3A4
IR=immediate release; ER=extended release; vs.=versus; CYP=cytochrome P450; UGT=UDP-glucuronosyltransferase.
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Serotonin Norepinephrine Reuptake Inhibitors: Similarities and Differences
give equal weight to results from uncontrolled, open-label trials
and randomized, double-blind, placebo-controlled trials, which
provide different levels of evidence, or to studies using low versus
high drug doses, short versus long treatment duration, and large
versus small patient populations. Furthermore, a meta-analysis
may be biased toward studies with positive results if the study
sample is generated through a search of the published literature.
SNRI efficacy for treating moderate-to-severe MDD was
compared with tricyclic antidepressants (TCAs) and SSRIs in a
meta-analysis of head-to-head clinical trials (n=15) that included
remission rates.40 The intent-to-treat (ITT) population remission
rate (17-item Hamilton Rating Scale for Depression [HAMD17]41 ≤7 or Montgomery Åsberg Depression Rating Scale
[MADRS]42 ≤12) for SNRIs (49.0%) did not differ statistically
from results observed for TCAs (44.1%), but was significantly
higher compared with SSRIs (37.7%; P<.001). Based on a difference of >10%, the authors found the remission rates for SNRIs
to be clinically superior to SSRIs. The dropout rate for SNRIs
(26.1%) was significantly lower compared with TCAs (35.7%;
P<.05) and did not differ statistically from SSRIs (28.4%).40
amine, and citalopram in a meta-analysis of remission rates in
34 randomized, double-blind trials sponsored by the manufacturer of the drug comparing venlafaxine with an SSRI.47
Remission rates (HAM-D17 ≤7 or MADRS ≤10) favored
venlafaxine over SSRIs in 28 trials while SSRIs were favored in
the remaining six studies. The meta-analytic remission rate was
higher for venlafaxine-treated patients compared with SSRItreated patients (5.9% difference [95% CI: 0.038–0.081]).
Venlafaxine efficacy for MDD also was compared with SSRIs
in several pooled analyses of clinical trials sponsored by the manufacturer of venlafaxine. Data pooled from eight trials comparing
venlafaxine IR (75–375 mg/day) or ER (75–225 mg/day) headto-head with the SSRIs fluoxetine (five trials; 20–80 mg/day),
paroxetine (two trials; 20–40 mg/day) or fluvoxamine (one trial;
100–200 mg/day) were assessed for HAM-D17 and MADRS
total score, response and remission rates, and number of MDDfree days in separate analyses.48-50 Study durations ranged from 6
to 12 weeks. In the pooled analyses (ITT population, N=2,045),
there were significantly larger changes from baseline in HAM-D17
total (–14.5) and MADRS total (–17.8) scores at week 8 (using
the last-observation-carried-forward [LOCF] approach) for venlafaxine compared with SSRIs (–12.6 and –15.9, respectively;
both comparisons, P≤.05).48 Response rates were significantly
higher for venlafaxine (HAM-D17, 64%; MADRS, 67%) than
for SSRIs (HAM-D17, 57%; MADRS, 59%) at week 8.48 Final
remission rates (HAM-D17 ≤7) for venlafaxine and SSRIs were
45% and 35%, respectively (P<.001), with an overall OR of 1.5
(95% CI: 1.3–1.9), indicating a 50% greater chance of remission
during venlafaxine treatment than during SSRI treatment.49
Taken together, these analyses are consistent across
reports and efficacy measures, and indicate that venlafaxine has superior efficacy for treating MDD compared with
SSRIs. Data available suggest that it is no less effective than
TCAs, as is reported for the SNRI class as a whole.40
Venlafaxine
Venlafaxine was compared with TCAs and SSRIs in a metaanalysis of response rates in 44 English language, randomized,
double-blind trials including ≥1 active drug43 and in a metaanalysis of effect size in 32 randomized, double-blind trials with
a venlafaxine arm and ≥1 active comparator.44 Response rates
based on the HAM-D17 and MADRS for ITT patients were
significantly higher for venlafaxine (73.7%) than for either TCAs
(57.9%) or SSRIs (61.1%; both P<.001).43 Effect size (HAMD17, MADRS, or Clinical Global Impressions [CGI] scale45) in
the second study did not show a significant difference between
venlafaxine and TCAs, but favored venlafaxine over SSRIs (–
0.17, 95% confidence interval [CI]: –0.27 to –0.08).44 Analysis
of response and remission rates in that study favored venlafaxine
over SSRIs (response: odds ratio [OR] 1.26, 95% CI: 1.02–1.58;
remission: OR: 1.43, 95% CI: 1.21–1.71) but not TCAs; however, the remission analysis included only one TCA trial. In a
recent meta-analysis of randomized controlled trials comparing
venlafaxine with TCAs (18 trials) or SSRIs (34 trials), including
both published and unpublished trials provided by the manufacturer of venlafaxine, that drug was favored over SSRIs for rates
of response (OR: 1.15, 95% CI: 1.02–1.29) and remission (OR:
1.19, 95% CI: 1.06–1.34).46 Venlafaxine response and remission
rates did not differ compared with TCAs (response: OR: 1.22,
95% CI: 0.96–1.54; remission: OR: 1.06, 95% CI: 0.74–1.63)
using the full random effects method of analysis, but venlafaxine
was favored for response rates by a conditional maximum likelihood method (OR: 1.21, 95% CI: 1.03–1.43).
Venlafaxine (immediate release [IR] and extended release
[ER], study doses ranging from 37.5–399 mg/day) was compared with the SSRIs fluoxetine, sertraline, paroxetine, fluvoxPrimary Psychiatry 16:5 (Suppl 4)
Duloxetine
Duloxetine, venlafaxine, and fluoxetine were compared indirectly in a meta-analysis of nine duloxetine, eight venlafaxine, and
22 fluoxetine studies.51 All studies were randomized trials including a placebo arm. Study durations ranged from 8 to 9 weeks for
duloxetine, 6 to 12 weeks for venlafaxine, and 5 to 12 weeks for
fluoxetine. Two of the venlafaxine studies and 13 of the fluoxetine studies were small, with <60 patients in active treatment.
There were no significant differences between duloxetine 40–120
mg/day and fluoxetine for meta-analytic effect size (HAM-D17)
compared with placebo or for response rates. The meta-analytic
effect size (0.22 [95% CI: 0.06–0.38]) and the estimated response
log OR (0.70 [95% CI: 0.26–1.14]) both favored venlafaxine
over duloxetine. A second indirect comparison of venlafaxine ER
(three trials) and duloxetine (five trials) found no significant difference between the SNRIs for response or remission rates based
on HAM-D17 or MADRS total scores.52
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May 2009
R.C. Shelton
Duloxetine and venlafaxine were compared directly in two
identically designed, randomized, double-blind trials that
were analyzed together in a pooled analysis.53 Patients received
venlafaxine (75–225 mg/day; n=337) or duloxetine (60–120
mg/day; n=330) for 12 weeks in flexible-dose studies. No significant differences were found between drugs for HAM-D17
total score, response rates, or remission rates after 6 or 12 weeks
of treatment.53 Thus, although an indirect comparison between
duloxetine and venlafaxine suggested that venlafaxine may be
favored for efficacy to treat MDD, the single head-to-head
comparison between the drugs does not support that finding.
control in two 8-week, double-blind, placebo-controlled, flexible-dose studies that were analyzed separately and pooled.59 The
venlafaxine groups from the two studies were not pooled in the
analysis because the dose ranges differed (75–150 mg/day and
75–225 mg/day, respectively). One of the individual studies
failed: neither desvenlafaxine nor venlafaxine (75–150 mg/day)
separated from placebo on the primary efficacy measure, HAMD17 total score. In the second trial, venlafaxine-treated patients
(75–225 mg/day) had significant improvement in HAM-D17
total scores compared with placebo (P=.005), but desvenlafaxinetreated patients did not. In the pooled analysis, HAM-D17 scores
for desvenlafaxine and both venlafaxine groups improved significantly compared with placebo at week 8 (all P<.01). Response
rates for the venlafaxine groups (64% and 57% for lower and
higher-dose, respectively; both P≤.033), but not desvenlafaxine
(55%), were significantly higher compared with placebo (47%).
Only the higher dose venlafaxine group (36%) had significantly
higher rates of remission compared with placebo (23%; P=.003;
desvenlafaxine, 30%; lower dose venlafaxine, 34%).
Of the four SNRIs, venlafaxine has demonstrated the
strongest efficacy for MDD, either by comparison to other
antidepressant classes, or in head-to-head trials. A recent metaanalysis of 117 randomized controlled trials comparing efficacy
of 12 new-generation antidepressants at therapeutic range for
treating MDD found that venlafaxine had significantly better
response rates compared with fluoxetine, used as a standard for
comparison of all included antidepressants (OR: 1.28, 95%
CI: 1.11–1.47), whereas duloxetine and milnacipran did not
(desvenlafaxine was not included in the analysis).60 However, as
the first SNRI, venlafaxine has been far more extensively studied, and more head-to-head trials are certainly needed to clarify
whether there are real differences in efficacy within the class.
Milnacipran
A meta-analysis of seven trials comparing milnacipran with
TCAs indicated that milnacipran and TCAs were equally effective.54 There was no significant difference between milnacipran
and TCAs for response rates based on HAM-D17 (64% and
67%, respectively) and MADRS (63% and 68%, respectively)
total scores. Remission rates based on the HAM-D17 total score
were 39% for milnacipran and 42% for TCAs (not statistically
significant).54 The efficacy of milnacipran for MDD has been
compared with SSRIs in several meta-analyses with mixed results.
In the first analysis, milnacipran was compared with fluoxetine
and fluvoxamine (one trial each).55 HAM-D17 response rates were
64% for milnacipran and 50% for the SSRIs (P=.01); remission
rates were 39% and 28% (P=.04), respectively. In an analysis of six
double-blind trials comparing milnacipran and SSRIs (fluoxetine,
fluvoxamine, paroxetine), no significant differences were found in
response rates.56 Papakostas and Fava56 included one trial57 that
had been excluded from the earlier meta-analysis because of “an
inappropriate once-daily dosage regime for milnacipran,”55 but
a sensitivity analysis showed that no one trial had a significant
effect on their results.56 The most recent and most comprehensive
analysis included all randomized, controlled trials comparing milnacipran with any other active antidepressant monotherapy.58 A
total of 16 trials were included in the analysis; seven trials included
a TCA as an active comparator and eight compared milnacipran
with an SSRI. No statistically significant differences were found
in response or remission rates between milnacipran and TCAs or
between milnacipran and SSRIs after 6–12 weeks of therapy in the
meta-analysis or in any of the trials included in the analysis.58
To date, no head-to-head trials between milnacipran and any
other SNRI have been published. Milnacipran is demonstrated
as effective as TCAs for the treatment of MDD, but unlike
venlafaxine, little data supports superiority over SSRIs.
TOLERABILITY
There are commonalities among the safety and tolerability
profiles of the four SNRIs; however, there exist some important
differences as well. Table 41-4 lists the most common adverse
drug reactions for SNRIs. In general, SNRIs are associated with
the drug reactions common to SSRIs (eg, gastrointestinal disturbances, sleep disturbance, anxiety/nervousness/agitation, sexual
dysfunction)61,62 and some related to NE reuptake inhibition
(eg, dry mouth, constipation, dizziness).63 Nausea is the most
common adverse event (AE) for three of the four SNRIs, with
incidence reported at ~20% to 40% (placebo, 7% to 12%).1,2,4
For milnacipran, nausea is not listed among the most common
AEs; it is included as a less frequent AE in the prescribing information, along with other gastrointestinal disturbances.3 The
more balanced 5-HT:NE selectivity ratio for milnacipran may
account for the lower incidence of gastrointestinal AEs.
Overall, more patients treated with SNRIs discontinue due to
AEs compared with placebo (venlafaxine versus placebo, 18%
Desvenlafaxine
Currently, there are no studies comparing desvenlafaxine with
TCAs or SSRIs, but two head-to-head studies have been published comparing desvenlafaxine with venlafaxine. Desvenlafaxine
200–400 mg/day was compared with venlafaxine as an active
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Serotonin Norepinephrine Reuptake Inhibitors: Similarities and Differences
versus 6%, respectively, in a pooled analysis64; duloxetine, 9.7%
versus 4.2%, respectively, in a pooled analysis65; desvenlafaxine
5% to 21% versus 3% to 6% in individual trials66-70; no rates of
discontinuation due to AEs are reported in placebo-controlled
trials of milnacipran71-73). Clinical trial evidence indicates that
common adverse drug reactions with SNRIs, particularly nausea,
tend to occur early in treatment and usually resolve over time.64-67
Discontinuations due to AEs increased with dose.26,65-68,70
within individual studies.77 Clinical trials often report very low
incidence rates of sexual dysfunction, but those data typically
represent spontaneous reports from patients and are spuriously
low. Clayton and colleagues78 examined the prevalence of sexual
dysfunction in a population of sexually active adult outpatients
receiving antidepressant monotherapy in primary care clinics,
based on total scores from the Changes in Sexual Function
Questionnaire. In the overall clinical population, the prevalence
of sexual dysfunction was ~40% for venlafaxine, significantly
greater compared with bupropion IR (22%), and no different
from any SSRI. In an analysis of data from four 8-week, doubleblind, placebo- and active paroxetine-controlled MDD trials,
sexual dysfunction (assessed using the Arizona Sexual Experience
Scale79) was significantly less common in duloxetine-treated
patients (46.4%) compared with paroxetine (61.4%; P<.015);
however, both groups showed significantly greater rates of sexual
dysfunction compared with the placebo group (28.8%; P=.007,
P<.001, respectively).80 A separate study compared the effects
of duloxetine and escitalopram versus placebo in the acute and
long-term treatment of patients with MDD using the Changes
in Sexual Functioning Questionnaire.81 At 8 weeks, incidence of
treatment-emergent global sexual dysfunction was significantly
greater than placebo (16.7%) for escitalopram (48.7%; P=.01)
but not duloxetine (33.3%; P=.13). Sexual dysfunction during treatment with desvenlafaxine or milnacipran has not been
Cardiovascular effects and hypertension
Earlier generation antidepressants, such as monoamine oxidase inhibitors and TCAs, are associated with adverse cardiovascular effects. Studies with SNRIs appear to show a relatively safe
cardiovascular profile. Venlafaxine does not show a significant
effect on heart rate,74 although venlafaxine causes an increase in
blood pressure that, at higher doses, may be attributed to central
inhibition of noradrenergic uptake.74 Dose-related effects of
venlafaxine (75, 225, and 375 mg/day) were studied in a doubleblind, placebo-controlled trial of outpatients with MDD.26 A
meta-analysis of data from 2,817 venlafaxine-treated patients
with MDD demonstrated a sustained increase in supine diastolic
blood pressure (≥90 mm Hg) in 4.8% for venlafaxine (placebo,
2.1%; P=.037) that was highly dose-dependent: sustained
elevated supine diastolic blood pressure was observed in 1.7%,
3.5%, 3.7%, and 9.1% of patients treated with ≤100 mg/day,
101–200 mg/day, 201–300 mg/day, and >300 mg/day venlafaxine, respectively.75 A cardiovascular safety profile of duloxetine
was compiled using data from 1,139 duloxetine-treated and 777
placebo-treated patients in eight placebo-controlled clinical trials
of MDD.76 A small mean increase in systolic blood pressure was
observed with duloxetine compared with placebo (1.0 and –1.2
mm Hg, respectively), with no apparent dose effect. Sustained
elevated blood pressure was observed in 1.3% of duloxetinetreated patients (placebo, 0.8%).76 Subgroup analyses of patients
with an elevated blood pressure at baseline showed that neither
venlafaxine nor duloxetine caused an increased risk of sustained
blood pressure elevation in those patients.75,76
No comprehensive analyses of the cardiovascular safety of
desvenlafaxine or milnacipran have yet been published. The
prescribing information reports a small increase in systolic blood
pressure for the recommended dose of desvenlafaxine (50 mg/
day) compared with a decrease for the placebo group (+1.2 mm
Hg, desvenlafaxine 50 mg; –1.4 mm Hg placebo). Sustained
increases in blood pressure were found in some patients, particularly at the highest dose studied (400 mg/day; 2.3%).4 Rates
of sustained hypertension or increased blood pressure are not
reported in the prescribing information for milnacipran.3
TABLE 4
MOST COMMON ADVERSE SNRI DRUG REACTIONS1-4
Duloxetine2
Milnacipran3
Desvenlafaxine4
Nausea
Nausea
Anxiety
Nausea
Sweating
Increased
sweating
Excessive
sweating
Hyperhidrosis
Somnolence
Somnolence
Vertigo
Somnolence
Anorexia
Decreased
appetite
Hot flush
Decreased appetite
Tremor
Constipation
Dysuria
Constipation
Nervousness
Fatigue
Anxiety
Dry mouth
Dry mouth
Insomnia
Dizziness
Dizziness
Abnormal
dreams
Specific male sexual
function disorders
Abnormal
ejaculation
Adverse reactions as defined as occurring in ≥5% of SNRI-treated patients and at least
twice the rate for placebo for venlafaxine, duloxetine, and desvenlafaxine; as defined by the
European Medicines Agency for milnacipran.
Sexual dysfunction
SNRI=serotonin norepinephrine reuptake inhibitor.
There is often confusion regarding actual rates of sexual dysfunction with antidepressant use, based on the reporting method
Primary Psychiatry 16:5 (Suppl 4)
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R.C. Shelton
assessed using a specific sexual functioning questionnaire. The
prescribing information for desvenlafaxine does list male sexual
function disorders as a common adverse reaction4; sexual dysfunction is not listed for milnacipran.3
discontinuation (P<.03). The most common discontinuation
symptoms after venlafaxine withdrawal were dizziness, excessive
sweating, irritability, dysphoria, and insomnia. Discontinuation
symptoms following abrupt withdrawal of duloxetine (20–60
mg BID or 60 mg QD) were examined in a pooled analysis of
six short-term treatment trials of 8–9 weeks duration.87 A greater
proportion of the SNRI-treated patients (44.3%) exhibited
discontinuation symptoms compared with the placebo group
(22.9%; P<.05). Discontinuation symptoms that occurred significantly more frequently after abrupt withdrawal of duloxetine
compared with placebo were dizziness (12.4%), nausea (5.9%),
headache (5.3%), paraesthesia (2.9%), vomiting (2.4%), irritability (2.4%), and nightmares (2%). Discontinuation symptoms
associated with long-term treatment of duloxetine ≤52 weeks
also were studied; no increase in incidence or severity of symptoms was reported.87 Discontinuation symptoms were examined
following discontinuation of treatment with milnacipran (100
mg/day) compared with paroxetine (20 mg/day) in patients
with MDD.88 After a 6-week treatment, abrupt withdrawal led
to discontinuation symptoms in 13% of the milnacipran group
compared with 31.8% of the paroxetine group. In those patients
who completed an additional 18-week extension, discontinuation symptoms were observed in 30% of the milnacipran
group compared with 30.3% of the paroxetine group. The most
frequently reported AE following treatment withdrawal after
24 weeks of treatment in the milnacipran group was anxiety
as compared with dizziness, anxiety, and nausea in the paroxetine group. Discontinuation symptoms have been observed in
patients with MDD who undergo abrupt discontinuation or
dose reduction of desvenlafaxine.4 These symptoms include dizziness, nausea, headache, irritability, insomnia, diarrhea, anxiety,
fatigue, abnormal dreams, and hyperhidrosis.
Weight change
Short-term SNRI treatment has been linked to a greater
incidence of weight loss compared with placebo in patients
with MDD; longer-term data show a return to baseline or small
increase in weight compared with placebo.1,4,82,83 Venlafaxine ER
treatment led to a loss of ≥5% of body weight in 7% of patients
versus 2% in placebo-treated patients in short-term, placebocontrolled, MDD trials.1 In a long-term, placebo-controlled
trial, weight loss in venlafaxine-treated patients persisted only
through the third month of treatment.83 Wise and colleagues82
examined the effect of duloxetine on body weight in an analysis
of 10 clinical studies of both acute (8–9 weeks) and long-term
duration (26, 34, and 52 weeks). During the acute phase, duloxetine-treated patients lost more weight compared with placebotreated patients, although the difference was small (–0.5 versus
0.2 kg respectively; P<.001). In those studies with an active comparator, similar reductions in mean weight changes compared
with placebo were observed with the SSRIs fluoxetine and paroxetine. Weight change during long-term treatment (34 weeks)
was not different between duloxetine 40 mg BID (0.7 kg) and
placebo (0.1 kg). However, at a higher dose of duloxetine (60 mg
QD), the mean weight change (0.9 kg) was similar to paroxetine
20 mg QD (1.0 kg) and significantly greater compared with
placebo (0.1 kg, both P<.05). Mean weight gain for milnacipran
(50, 100, or 200 mg/day) was significantly less compared with
an active comparator in two separate studies (amitriptyline,84
fluoxetine85), but no comparison of weight gain for milnacipran
versus placebo was reported. Desvenlafaxine at doses of 50, 100,
200, and 400 mg/day was associated with weight loss of –0.4,
–0.6, –0.9, and –1.1 kg, respectively, compared with no change
in the placebo group in short-term, fixed-dose, controlled studies.4 In a study of patients who responded to desvenlafaxine during an initial 12-week, open-label phase, a subsequent 6-month,
double-blind, placebo-controlled phase showed no statistical
difference in mean weight change between desvenlafaxine and
placebo at the final on-therapy assessment.4
DOSING
The recommended initial starting dose of venlafaxine ER is 75
mg/day with some patients, although a 37.5 mg capsule is available if needed. In those patients who do not respond to the 75 mg/
day dose, increases to a maximum of ~225 mg/day of venlafaxine
ER is recommended at increments of 75 mg/day at intervals not
less than 4 days.1 However, venlafaxine IR was approved in doses
≤375 mg/day, suggesting that this drug has a very wide therapeutic
dosing range. Rudolph and colleagues26 reported that for patients
treated with venlafaxine 75, 225, or 375 mg/day, higher doses
resulted in greater improvement in MDD scores (HAM-D21,
MADRS, and CGI-S). In a separate study that included venlafaxine 75, 150, and 200 mg/day dose groups, Khan and colleagues89
found that statistical separation from placebo for patient response
rates (based on HAM-D and CGI scales) was achieved earlier
in treatment with increasing dose, with significantly higher rates
compared with placebo starting at weeks 4, 3, and 2, for the three
venlafaxine dose groups, respectively.
Discontinuation symptoms
Discontinuation symptoms have been reported after abrupt
discontinuation of each of the SNRIs. Emergence of discontinuation symptoms was studied in a population of 20 outpatients
with MDD who had participated in a double-blind, placebocontrolled study of the efficacy and safety of venlafaxine (75 mg/
day).86 Seven of nine (78%) venlafaxine-treated subjects showed
discontinuation symptoms compared with only two of nine
(22%) in the placebo group during the 3 days following drug
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Serotonin Norepinephrine Reuptake Inhibitors: Similarities and Differences
The dose-response relationship of duloxetine at fixed doses of
40, 60, 80, and 120 mg/day was characterized in an analysis of
data from six double-blind, randomized, placebo-controlled clinical trials assessing efficacy using HAM-D6 scores in patients with
MDD.90 Duloxetine 40 mg/day yielded an effect size of 0.40,
whereas duloxetine 80 and 120 mg/day reached an effect size >.40.
A numerically greater effect size was found in response to duloxetine 120 mg/day as compared with duloxetine 60 and 80 mg/day,
but the difference was not statistically significant. Based on these
studies, duloxetine 60 mg/day was determined to be the optimal
effective dose for the treatment of patients with MDD.90
There is some suggestion of a dose effect for milnacipran, but
few doses have been tested.27,28,56,91,92 In a population of patients
with MDD or bipolar disorder, milnacipran 100 mg/day was
found to have a faster onset of action than milnacipran 50 mg/
day with a cumulative improved percentage of responder patients
(as defined as a 50% reduction from baseline total scores on the
HAM-D) with >80% response at 4 and 6 weeks, respectively.28
Milnacipran 150 mg/day was also found to provide significant
improvement over 75 mg/day in both response and remission
as assessed by the HAM-D in patients with MDD.27 In another
study of patients with MDD, milnacipran was shown to be effective when administered at a 50 mg/day dose during the first week,
and 100 mg/day afterward, with no relationship between MDD
scores and plasma milnacipran levels.91 The recommended dose
of milnacipran is 100 mg/day in two divided 50 mg/day doses.3
Clinical studies have demonstrated efficacy of desvenlafaxine at doses of 50–400 mg/day.66-68 No additional benefits were observed at doses >50 mg/day, but AEs and discontinuations were more frequent at higher doses.66-68 Thus,
the recommended dose of desvenlafaxine is 50 mg/day.4
factor and anxiety-psychic item.95 Venlafaxine ER also has been
shown to be efficacious in the treatment of patients with MDD
with comorbid anxiety.96 For example, in a prospective, 12-week,
randomized, double-blind, placebo-controlled trial of MDD
patients with anxiety, venlafaxine ER was shown to be superior
to fluoxetine on the Hamilton Rating Scale for Anxiety (HAMA)97 (65% versus 51%, respectively, [placebo 39%]; P<.05).96
Although no clinical trial data are available assessing effects of
desvenlafaxine on anxiety symptoms as a primary end point, data
from placebo-controlled MDD trials suggest that this SNRI can
also reduce anxiety symptoms in MDD patients. Scores on the
Covi Anxiety Scale were significantly reduced compared with placebo in an 8-week trial of desvenlafaxine (50 and 100 mg/day)70
and in a pooled analysis of two flexible-dose trials (200 and 400
mg/day)59; however, a second fixed-dose trial showed no effect of
desvenlafaxine (50 and 100 mg/day) on Covi scores.66 The efficacy of milnacipran for treating anxiety or anxiety symptoms in
MDD has not been assessed in placebo-controlled trials.
Treatment-resistant depression
Over half of all MDD patients may fail to remit with antidepressant treatment: in a meta-analysis of 2,458 patients treated
with TCAs, SSRIs, or SNRIs in 15 studies, remission rates ranged
from 37.7% for SSRIs to 49% with SNRIs.40 When MDD
patients fail to adequately respond to a first-line antidepressant,
three strategies for subsequent pharmacotherapy are available:
switch to a different drug in the same class, switch to a different
class of antidepressants, or augment with another drug.98 Results
from several randomized controlled trials suggest that switching to
venlafaxine may be more effective after SSRI failure than switching
to another SSRI. Patients with treatment-resistant depression (ie,
having a history of resistance to two successive antidepressant treatments for the current episode) treated for 4 weeks with venlafaxine
(200–300 mg/day) had HAM-D response and remission rates
of 52% and 42%, respectively, compared with 33% and 20%,
respectively, for patients treated with paroxetine (30–40 mg/day;
both P<.05).99 In a single-blind study of elderly patients with
MDD who had previously failed two rounds of antidepressant
therapy (an SSRI followed by a TCA or heterocyclic antidepressant), venlafaxine (mean dose=165 mg/day) was found to be superior to paroxetine (mean dose=26 mg/day) on CGI and HAM-D
measures (both P<.05).100 However, other randomized controlled
trials have found no advantage to switching to venlafaxine over
a second SSRI; in the second treatment step of the Sequenced
Treatment Alternatives to Relieve Depression (STAR*D) trial,101
patients who did not remit (>5 on the 16-item Quick Inventory of
Depressive Symptomatology–Clinician-Rated102) after 12 weeks
of treatment with citalopram (mean exit dose=42 mg/day) were
randomly assigned to receive sertraline (≤200 mg/day), venlafaxine (≤375 mg/day), or bupropion (≤400 mg/day) for ≤14 weeks
in an open-label trial.103 Approximately 25% of patients achieved
remission; response and remission rates did not differ among
UNMET NEEDS REGARDING
ANTIDEPRESSANT THERAPY
Management of comorbid conditions
Although MDD and anxiety are distinct illnesses, both may
occur in the same patient and share some underlying pathophysiology.93 Virtually all antidepressant classes and newer atypical
antidepressants have shown efficacy for treating anxiety disorders.93,94 SSRIs exert significant effects in the treatment of anxiety
disorders, including panic disorder, obsessive-compulsive disorder, and social phobia. Dual reuptake inhibitors are also effective
in anxiety disorders.93 Dunner and colleagues95 concluded that
the SNRI duloxetine was effective in the treatment of comorbid
anxiety symptoms associated with MDD. In pooled data from
four studies in which duloxetine 60 mg/day yielded superiority
over placebo on the HAM-D17 total depression score, duloxetine
demonstrated efficacy over placebo in treating anxiety symptoms
as well, as measured by the HAM-D anxiety/somatization subPrimary Psychiatry 16:5 (Suppl 4)
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R.C. Shelton
treatment groups. In the Treatment of SSRI-Resistant Depression
in Adolescents trial, 100 patients aged 12–18 years with a CGI-S
score of ≥4 after at least 8 weeks of treatment with an SSRI were
randomly assigned to receive venlafaxine or a second SSRI, with
or without cognitive-behavioral therapy (CBT). Response rates
were higher in patients who were treated with CBT compared
to those who did not receive CBT, but there was no significant
difference between the venlafaxine and SSRI groups.104 Currently,
duloxetine has only been assessed in switch studies with no active
or placebo comparators,105 and no studies assessing the efficacy of
milnacipran or desvenlafaxine after switch have been published.
Despite some encouraging data for venlafaxine, treatment-resistant depression is still a major unmet need as the response rates of
patients on antidepressant therapy—whether SSRI, SNRI, or an
alternative—remain insufficient.106
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15. Voineskos AN, Wilson AA, Boovariwala A, et al. Serotonin transporter occupancy of high-dose selective serotonin
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CONCLUSION
All four SNRIs have demonstrated efficacy similar to TCAs
for the treatment of MDD. The extensive efficacy data available
for venlafaxine suggests that it may be superior to SSRIs, whereas
there is no evidence yet to indicate that duloxetine, milnacipran,
or desvenlafaxine also show superior efficacy. The available data
suggest that the safety and tolerability of the SNRIs are comparable, with two notable exceptions: sustained hypertension is
observed in almost 10% of patients treated with high doses of
venlafaxine, but at much lower levels for duloxetine and desvenlafaxine; and milnacipran may be associated with fewer AEs,
and in particular, lower levels of nausea. However, because few
placebo-controlled studies of milnacipran for MDD have been
published, and because conventions for reporting AE data outside
of the US differ from those used in US prescribing information, it
is difficult to draw conclusions from the currently available data.
Additional head-to-head trials are necessary to confirm these possible differences in efficacy and safety within the SNRI class. PP
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