PG CME
Desvenlafaxine
Chittaranjan Andrade
Department of Psychopharmacology, National Institute of Mental Health and Neurosciences, Bangalore - 560 029, India
Desvenlafaxine (DV) succinate (Pristiq; Wyeth) is a recent
serotonin-norepinephrine reuptake-inhibiting (SNRI)
antidepressant drug. DV is O-desmethylvenlafaxine, the
principal active metabolite of venlafaxine, formed by the
action of CYP 2D6 on the parent drug. In February 2008, DV
(50 mg/day) was approved for the treatment of depression
by the Food and Drug Administration (FDA) in the USA.[1]
If patients receive venlafaxine, DV is formed in their bodies;
so, what is gained if venlafaxine is eliminated from the
treatment chain and DV is administered directly? A cynical
answer is that DV extends the patent life of venlafaxine.
Whereas venlafaxine went out of patent in 2008, the
extended-release formulation of the drug will go out of
patent in 2010. In India, unless a substantial advantage
for DV over venlafaxine is demonstrated, the introduction
of DV will be considered to be evergreening; i.e., merely
an incremental modification of an existing molecule.
Evergreening is not recognized for the grant of patents
under the Indian Patents Act as modified by the Parliament
in 2005.[2]
Therefore, does DV have any advantages over venlafaxine?
At present, it is too early to say. There are both positives
and negatives for DV. Positives for DV over venlafaxine are:
1. In clinical trials of patients with major depressive
disorder, assessments using a visual analogue scale
showed that DV (100-400 mg/day) has a greater efficacy
than placebo against painful symptoms associated with
depression.[1]
2. In clinical trials of patients with major depressive
disorder, assessments using the Sheehan Disability
Scale showed that DV (50-400 mg/day) has a greater
efficacy than placebo against disability associated with
depression.[1]
3. DV has demonstrated efficacy against the vasomotor
symptoms (hot flushes) of menopause.[3-5]
Address for correspondence: Prof. Chittaranjan Andrade,
Department of Psychopharmacology, National Institute of
Mental Health and Neurosciences, Bangalore - 560 029, India.
E-mail: andradec@gmail.com
DOI: 10.4103/0019-5545.58303
How to cite this article: Andrade C. Desvenlafaxine. Indian J
Psychiatry 2009;51:320-3.
320
It is likely, however, that these properties of DV constitute
a class action of all antidepressants and are not unique to
DV. More specific advantages with DV over venlfaxine are:
1. In order to maximize tolerance, clinicians usually take
7-10 days or longer to uptitrate the dose of venlafaxine to
the target of 150-225 mg/day, at which doses venlafaxine
becomes dual-acting. In contrast, DV is started at the
target dose of 50 mg/day from the very first day.[1] Should
it be considered necessary, an escalation to 100 mg/day
can be effected within 4-7 days.
2. CYP 2D6 poor metabolizers constitute about 10%
of the population. Such persons would not tolerate
standard doses of venlafaxine.[6] Unless clinicians order
blood levels or pharmacogenomic tests, they will have
no way of knowing whether a patient who develops
adverse effects with venlafaxine is a poor metabolizer
(in whom lower doses would achieve effective blood
levels with fewer adverse effects) or merely does not
tolerate standard doses of the drug (necessitating drug
withdrawal). Venlafaxine will therefore (unnecessarily)
be withdrawn in the former subgroup. In contrast, DV is
negligibly metabolized in the liver.[7,8] Therefore, genetic
variations in metabolic capacity will not influence the
tolerability of the drug or influence adverse effect-
related drug withdrawal decisions.
3. Venlafaxine is associated with an up to 10% or
greater dose-dependent risk of treatment-emergent
hypertension. In contrast, in patients who receive DV
(50-400 mg/day), there is only an approximately 1-2%
risk of sustained increase in diastolic blood pressure
to values .90 mmHg or values .10 mmHg above
baseline (as compared with a 0.5% risk in patients
receiving placebo).[1]
4. Sexual adverse effects are common with venlafaxine. In
contrast, sexual adverse effects are placebo-level with
DV 50-100 mg/day, rising to noticeably above placebo
level (more in men than in women) only with the
400 mg/day dose.[7,9] A caveat here is that sexual adverse
effects with DV were recorded based on spontaneous
reports and had not been formally evaluated in the
clinical trials available so far, and could therefore be
underestimated.
5. Venlafaxine is commonly associated with an unpleasant
drug discontinuation reaction because its (terminal)
half-life is short - about 5 h. This half-life does not vary
as a function of immediate-release vs. extended-release
formulation. As a result, the drug is substantially
Indian J Psychiatry 51(4), Oct-Dec 2009
 Andrade: PG CME: Desvenlafaxine
washed out of the body 24 h after a single missed
dose. This is why discontinuation symptoms may
emerge after even a single missed dose of venlafaxine,
and why venlafaxine is best dosed at the same time
of day each day. Whereas DV is also associated with
a discontinuation syndrome,[1] from a theoretical
perspective, because its terminal half-life is longer at
around 10 h,[1] a drug discontinuation reaction could
be less of a problem as compared with venlafaxine.
A caveat here is that, as one molecule of venlafaxine
yields one molecule of DV upon metabolism, this
putative advantage assumes that venlafaxine and DV
have subtle pharmacodynamic differences, and that
DV does not compensate pharmacodynamically for
the hiatus arising from the washout of venlafaxine.
The issue can only be resolved through a head-to-head
comparison of discontinuation symptoms between the
two drugs; these data have so far not been released.
The above notwithstanding, there are some concerns about
DV and some regards in which it has yet to establish itself
relative to venlafaxine:
1. Many doses of DV in many trials failed to separate from
placebo for the primary outcome measure. This failure
was more marked in the flexible-dose (200-400 mg/
day) studies and with the 200 mg/day dose in the fixed-
dose studies; however, failure at the primary outcome
measure was also recorded with the 50 and 100 mg/day
doses in certain fixed-dose studies. Clearcut separation
for all outcome measures with all doses in all studies,
and in both fixed- and flexible-dose designs, emerged
only in pooled analyses. However, effect sizes remained
low (around 0.30 or less) and onset of separation from
placebo was late (2-4 weeks).[10-12]
2. Data exist to suggest that venlafaxine is associated with
better treatment outcomes than the selective serotonin
reuptake inhibitors (SSRIs), and that venlafaxine may
benefit patients who fail SSRI trials. No such studies
have so far been conducted with DV.
Indian J Psychiatry 51(4), Oct-Dec 2009
DV is about 11 times more potent an inhibitor of
serotonin reuptake than of norepinephrine reuptake.[13]
Just as venlafaxine becomes a dual-acting SNRI drug only
at higher doses (e.g., 150 mg/day and above), might it
be possible that DV is merely an SSRI at lower doses?
If so, this might, at least in part, explain some of the
disappointing results with the drug in the clinical trials
conducted to date. Such a possibility is supported by the
adverse effect profile of the drug in 50-100 mg/day doses:
nausea and dizziness, which are serotonergic adverse
effects, are noticeably present whereas dysuria and
hypertension, which are noradrenergic adverse effects,
are negligible or absent.[7]
Here, it may be noted that strongly noradrenergic drugs such
as reboxetine and more balanced SNRIs such as duloxetine
and milnacipran have both found poor acceptance in
clinical practice and/or have evidenced unimpressive results
relative to SSRIs in meta-analyses. If DV is more strongly
noradrenergic than venlafaxine, this may explain the
somewhat unimpressive clinical trial results. However, as
noted above, the adverse effect profile of the drug does not
seem to suggest a noradrenergic bias.
With this background, mark True or False against each of the
following statements:
1. The dose-dependent risk of dry mouth and constipation
with DV is due to muscarinic receptor blockade.
2. Patients prescribed DV may lose weight.
3. DV results in a clinically significant increase in the QTc
interval.
4. DV inhibits CYP 2D6.
5. DV should be avoided in patients with liver disease.
6. DV should be avoided in patients with renal disease.
7. DV separates from placebo by week 1 in menopausal
women with hot flushes.
8. The 100 mg/day dose of DV optimizes safety and
adverse effects in the treatment of the vasomotor
symptoms of menopause.
321
 Andrade: PG CME: Desvenlafaxine
CME Answers
1. False; 2. True; 3. False; 4. True; 5. False; 6. False; 7. True;
8. True.
1. DV blocks the synaptic reuptake of serotonin and
norepinephrine. As norepinephrine and acetylcholine
have opposing actions, increased noradrenergic activity
simulates anticholinergic activity and results in effects
such as dry mouth and constipation. Such effects are
seen with other noradrenergic antidepressant as well,
including reboxetine, milnacipran and duloxetine.
DV does not block muscarinic receptors. In fact, with
the exception of its inhibition of the serotonin and
norepinephrine transporters, DV has negligible effects
on 96 different transporters, receptors, enzymes, ion
channels, second messengers, and other molecular
targets.[13]
2. In randomized controlled trials, treatment with DV
was dose-dependently associated with weight loss of
around 0.5-1.0 kg across an 8-week treatment period.[9]
3. In a pooled analysis of nine clinical trials, DV was shown
to slightly but (statistically) significantly increase the
QTc interval; however, the magnitude of increase was
small, clinically insignificant and could at least partly be
explained by the application of the Bazett formula for
QT correction. The Bazett formula overcorrects the QT
interval when tachycardia is present, as was the case in
the DV clinical trials.[9] In an as-yet unpublished study
of healthy female volunteers, DV did not prolong the
Fridericia-corrected QT interval.[1]
4. DV inhibits CYP 2D6, but the magnitude of inhibition is
unlikely to be of clinical significance in most patients.
In comparisons between DV and duloxetine[14] or
paroxetine,[15] it was observed that the in vivo inhibition
of CYP 2D6 was slight with DV (100 mg/day), modest with
duloxetine (60 mg/day) and pronounced with paroxetine
(20 mg/day). At doses of 400 mg/day, however, DV
may be associated with a greater degree of CYP 2D6
inhibition.[16] In the approximately 10% of subjects who
are CYP 2D6 poor metabolizers, such inhibition could
be clinically significant. Of note, CYP 2D6 is responsible
6. The Wyeth prescribing information indicates that, in mild
for the metabolism of tricyclic antidepressant (TCA),
beta-blockers, many antipsychotic drugs, opiates, anti-
arrhythmic agents, tamoxifen and, in general, about 20-
25% of the pharmacopoeia.
5. DV is only about 30% protein-bound.[7] Therefore, a
decrease in plasma protein levels associated with liver
disease is unlikely to much influence the free:bound
fraction of DV. Less than 5% of an administered dose of DV
is metabolized in the liver; the enzyme involved is CYP
3A4 and the metabolite is N, O-didesmethylvenlafaxine.[7]
About 20% of DV is conjugated by glucuronidation,[7]
a pathway that is affected only in more severe liver
disease. Thus, the liver plays a relatively minor role
in DV pharmacokinetics. The drug could therefore be
expected to be safe in liver disease. Indeed, the half-
322
life and area under the curve (AUC) are increased by
only about 30-40% in patients with moderate to severe
liver disease.[17] The Wyeth prescribing information for
DV therefore indicates that no dose adjustments are
necessary; however, caution is always advisable. In this
context, several points are worthy of note:
(a) In the DV clinical trials, doses of up to 400 mg/day
were studied for durations of up to 8 weeks.[1,7,9]
These doses would result in considerably higher
blood levels than those associated with DV doses
of 50-100 mg/day in the presence of liver disease.
As the 200-400 mg/day doses were reasonably well
tolerated by most patients,[7] it is likely that the 50-
100 mg/day doses of the drug would be safe and well
tolerated even when liver functioning is impaired.
(b) In the DV clinical trials, small but statistically
significant increases in alkaline phosphatase
and transaminase enzymes levels were
observed across an 8-week treatment period.[9]
Reassuringly, as yet unpublished data indicate
that these increases do not magnify during long-
term treatment and that the elevated enzyme
levels return to baseline after discontinuation of
DV.[9] There is a theoretical risk that this effect on
liver enzymes could assume clinical significance
in patients whose liver function has already been
compromised by other insults.
(c) Reassuringly, DV does not inhibit the effects of
CYP 1A2, CYP 2A6, CYP 2C8, CYP 2C9, CYP 2C19,
and CYP 3A4;[18] i.e., enzymes responsible for
the metabolism of about three-quarters of the
pharmacopoeia. However, as already mentioned,
clinical (50-100 mg/day) doses of DV will result in
a small degree of inhibition of CYP 2D6.[14,15] This
inhibition is too small to be of clinical importance in
persons with a healthy liver; however, it could result
in the potential for CYP 2D6 drug interactions in
those whose liver is already compromised by other
insults. The potential for drug interactions could be
even greater when the dose of DV is higher, such as
400 mg/day.[16]
to moderate renal disease, the DV AUC is increased by
42-46%; in severe and end-stage renal disease, the AUC
is increased by 108-116% and when creatinine clearance
is ,30 ml/min, clearance of DV is reduced by half. Thus,
the pharmacokinetics of DV in severe and end-stage renal
disease are akin to a doubled dose of the drug. Considering
that doses of up to 400 mg/day (i.e., up to eight times
the recommended dose of 50 mg/day) have been studied
and found safe in 8-week clinical trials, doubled DV levels
may not be of much concern. Therefore, whereas no dose
adjustments are necessary when renal disease is mild
to moderate, when renal disease is severe, halving the
daily dose or shifting to alternate-day dosing at the same
dosage level would suffice.[1]
Indian J Psychiatry 51(4), Oct-Dec 2009
 Andrade: PG CME: Desvenlafaxine
7. DV has an early onset of action against the vasomotor
symptoms of menopause; a statistically significant
advantage over placebo is apparent by the end of
week 1 itself.[3-5] This response is maintained at 12
weeks[3-5] and 26 weeks.[5] The number needed to treat
for 75% reduction in moderate to severe hot flushes is
approximately 5.
8. Speroff et al.[3] found that DV separated from placebo in
doses of 100,150 and 200 mg/day but not 50 mg/day. The
100 mg/day dose optimized the balance between efficacy
and adverse effects. Two other studies[4,5] also reported
12-week outcomes with statistically indistinguishable
improvement at doses of 100 and 150 mg/day. However,
one study[5] found that only the 150 mg/day dose remained
superior to placebo at 26 weeks, but this study had only
been powered for a 12-week treatment endpoint. It may
be noted that DV has not yet been approved for the
treatment of menopausal symptoms.
References
1. Perry R, Cassagnol M. Desvenlafaxine: A new serotonin-norepinephrine
reuptake inhibitor for the treatment of adults with major depressive
disorder. Clin Ther 2009;31:1374-404.
2. Andrade C, Shah N, Chandra S. The new patent regime: Implications for
patients in India. Indian J Psychiatry 2007;49:56-9.
3. Speroff L, Gass M, Constantine G, Olivier S, for the Study 315 Investigators.
Efficacy and tolerability of desvenlafaxine succinate treatment for
menopausal vasomotor symptoms. Obstet Gynecol 2008;111:77-87.
4. Archer DF, Seidman L, Constantine G, Pickar JH, Olivier S. A double-blind,
randomly assigned, placebo-controlled study of desvenlafaxine efficacy
and safety for the treatment of vasomotor symptoms associated with
menopause. Am J Obstet Gynecol 2009;200:172.e1-172.e10.
5. Archer DF, Dupont C, Constantine GD, Pickar JH, Olivier S; for the
Study 319 Investigators. Desvenlafaxine for the treatment of vasomotor
symptoms associated with menopause: A double-blind, randomized,
placebo-controlled trial of efficacy and safety. Am J Obstet Gynecol
2009;200:238e1-e10.
6. McAlpine DE, O’Kane DJ, Black JL, Mrazek DA. Cytochrome P450
Indian J Psychiatry 51(4), Oct-Dec 2009
2D6genotype variation and venlafaxine dosage. Mayo Clin Proc
2007;82:1065-8.
7. Lourenco MT, Kennedy SH. Desvenlafaxine in the treatment of major
depressive disorder. Neuropsychiatric Dis Treat 2009;5:127-36.
8. Preskorn S, Patroneva A, Silman H, Jiang Q, Isler JA, Burczynski ME,
et al. Comparison of the pharmacokinetics of venlafaxine extended
release and desvenlafaxine in extensive and poor cytochrome P450 2D6
metabolizers. J Clin Psychopharmacol 2009;29:39-43.
9. Clayton AH, Kornstein SG, Rosas G, Guico-Pabia C, Tourian KA.
An integrated analysis of the safety and tolerability of desvenlafaxine
compared with placebo in the treatment of major depressive disorder.
CNS Spectr 2009;14:183-95.
10. Lieberman DZ, Montgomery SA, Tourian KA, Brisard C, Rosas G,
Padmanabhan K, et al. A pooled analysis of two placebo-controlled trials
of desvenlafaxine in major depressive disorder. Int Clin Psychopharmacol
2008;23:188-97.
11. Thase ME, Kornstein SG, Germain JM, Jiang Q, Guico-Pabia C, Ninan PT.
An integrated analysis of the efficacy of desvenlafaxine compared
with placebo in patients with major depressive disorder. CNS Spectr
2009;14:144-54.
12. Tourian KA, Padmanabhan K, Groark J, Brisard C, Farrington D.
Desvenlafaxine 50 and 100 mg/d in the treatment of major depressive
disorder: An 8-week, phase III, multicenter, randomized, double-blind,
placebo-controlled, parallel-group trial and a post hoc pooled analysis of
three studies. Clin Ther 2009;31:1405-23.
13. Deecher DC, Beyer CE, Johnston G, Bray J, Shah S, Abou-Gharbia M,
et al. Desvenlafaxine succinate: A new serotonin and norepinephrine
reuptake inhibitor. J Pharmacol Expt Ther 2006;318:657-65.
14. Patroneva A, Connolly SM, Fatato P, Pedersen R, Jiang Q, Paul J, et al. An
assessment of drug-drug interactions: The effect of desvenlafaxine and
duloxetine on the pharmacokinetics of the CYP2D6 probe desipramine in
healthy subjects. Drug Metab Dispos 2008;36:2484-91.
15. Nichols AI, Fatato P, Shenouda M, Paul J, Isler JA, Pedersen RD, et al.
The effects of desvenlafaxine and paroxetine on the pharmacokinetics of
the cytochrome P450 2D6 substrate desipramine in healthy adults. J Clin
Pharmacol 2009;49:219-28.
16. Preskorn SH, Nichols AI, Paul J, Patroneva AL, Helzner EC, Guico-
Pabia CJ. Effect of desvenlafaxine on the cytochrome P450 2D6 enzyme
system. J Psychiatr Pract 2008;14:368-78.
17. Baird-Bellaire S, Patat AA, Fauchoux N, Reh C, Nichols AI, Behrle A.
Effects of chronic hepatic impairment on the pharmacokinetics and safety of
devenlafaxine succinate extended release. Clin Pharmacol Ther 2006;79:26.
18. Oganesian A, Shilling AD, Young-Sciame R, Tran J, Watanyar A, Azam F,
et al. Desvenlafaxine and venlafaxine exert minimal in vitro inhibition of
human cytochrome p450 and p-glycoprotein activities. Psychopharmacol
Bull 2009;42:47-63.
Source of Support: Nil, Conflict of Interest: None declared
323
Copyright of Indian Journal of Psychiatry is the property of Medknow Publications & Media Pvt. Ltd. and its
content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for individual use.