Download Suggestion from clinicians

Duloxetine & Venlafaxine
Addition to the List
Peer Feedback:
“Only SSRIs are listed currently. Another class would be ideal for those not responding to SSRIs.
Venlafaxine would also be an option as an SNRI.” Note: replacement given was Duloxetine.
“There are no SNRIs at present. Venlafaxine can help with menopausal symptoms as well as
anxiety/depression”
Literature Review Question:
How do SNRIs compare with SSRIs for efficacy?
How often are patients non-responsive to SSRIs requiring SNRI substitution?
Literature Search:
eCPS - Psychiatric Disorders: Depression
Cochrane
Medline – ‘Venlafaxine and depression and Selective serotonin reuptake inhibitor AND review/metaanalysis’; ‘Selective serotonin reuptake inhibitor and (nonresponders or non-responsive or resistance or
resistant) and review/meta-analysis’
Systematic review of meta-analyses and large randomised pragmatic trials (2013)
Some evidence was found that was supportive of increased efficacy of the addition of NA reuptake
inhibition mostly with venlafaxine and to some extent with duloxetine, but no evidence was found for
superiority of milnacipran, and we found no studies assessing the efficacy of desvenlafaxine. The NNTs
were lowest and more likely to be of clinical significance in patients with moderate to severe depression.
The data comparing venlafaxine to pooled SSRIs was consistently supportive of increased efficacy of
dual reuptake inhibition in both remission and response rates. This evidence came from several sources
including meta-analyses of RCT summary data performed by several different research groups and
patient-level analyses performed from the manufactures trial database and randomised pragmatic trials,
thus adding strength to this finding. The data comparing venlafaxine to individual SSRIs provided mixed
outcomes. Consistent evidence supports statistically significant superior efficacy compared to fluoxetine
and paroxetine from meta-analyses. Although efficacy was generally in favour of venlafaxine compared to
fluvoxamine and sertraline, only one of the meta-analytic findings was statistically significant.
Evidence of superior efficacy of dual reuptake inhibition from duloxetine trials was limited to data from
patient level meta-analyses in patients with at least moderate to severe depression (HDRS17≥19) in
comparison to pooled SSRIs and a pragmatic study also found evidence that duloxetine may be more
effective than pooled SSRIs in more severe depression (QIDS SR≥21).
The mixed outcomes from the data mean a definitive conclusion regarding additional efficacy of the
addition of NA reuptake inhibition to that of 5-HT cannot currently be drawn. The most consistent
evidence of increased efficacy of dual reuptake inhibition comes from patients with more severe baseline
depression as this is found with both venlafaxine and duloxetine. This suggests that duloxetine and
venlafaxine would be most suitable for those patients with severe depression. The NNTs for remission of
9–14 in patients with moderate to severe depression found in these studies do suggest that any
increased efficacy in these populations is clinically significant. In contrast NNTs for remission including
patients with more moderate depression ranged from 14–50, suggesting a more limited clinical relevance
in this patient population. These findings are, however, limited to comparisons from analyses pooling all
SSRIs, and further well-designed studies comparing SNRIs to individual SSRIs, particularly escitalopram,
are still required. Some evidence from two large pragmatic studies also suggests venlafaxine may be a
more effective second step treatment than SSRIs in patients who fail to reach remission with a SSRI. With
consideration of the current limitations of the available data, we conclude it is worthwhile to continue
investigating for potentially important differences between SNRIs and SSRIs. Future studies should
include patients with at least moderate to severe depression, utilise the full therapeutic dose ranges of
antidepressants and examine a broader range of outcomes including remission of symptoms, function
and quality of life. Additional studies where noradrenaline reuptake inhibition is added to a SSRI in
patients who had not remitted during treatment with a SSRI would also be helpful.
Bradley, Andrew J., and Alan J. Lenox-Smith. "Does adding noradrenaline reuptake inhibition to selective serotonin
reuptake inhibition improve efficacy in patients with depression? A systematic review of meta-analyses and large
randomised pragmatic trials." Journal of psychopharmacology 27.8 (2013): 740-758.
Duloxetine versus other anti-depressive agents for depression (2012)
There was no evidence that duloxetine was less or more effective than any SSRI (odds ratio (OR) 1.31,
95% confidence interval (CI) 0.87 to 1.97, P 0.19; three trials, 1120 participants, when duloxetine was
compared with escitalopram; OR 0.81, 95% CI 0.46 to 1.44, P = 0.47; two trials, 222 participants, when
duloxetine was compared with fluoxetine; OR 1.12, 95% CI 0.88 to 1.43, P = 0.36; six trials, 1821
participants, when duloxetine was compared with paroxetine - Analysis 1.1; Figure 3).
The analysis of primary outcome found that duloxetine was not statistically less effective than venlafaxine
(OR 1.18, 95% CI 0.82 to 1.68, P = 0.51, one trial, 332 participants) or desvenlafaxine (OR 0.82, 95% CI
0.56 to 1.20, P = 0.30, one trial, 474 participants) (Analysis 1.2).
A total of 16 randomised controlled trials (overall 5735 participants) were included in this review.
Duloxetine did not seem to provide a significant advantage in efficacy over other antidepressive agents
for the acute-phase treatment of major depression. No differences in terms of efficacy were found, even
though duloxetine was worse than some SSRIs (most of all, escitalopram) and newer antidepressants
(like venlafaxine) in terms of acceptability and tolerability. Unfortunately, we only found evidence
comparing duloxetine with a handful of other active antidepressive agents and only a few trials per
comparison were found (in some cases we retrieved just one trial). In the absence of clear evidence of an
advantage of duloxetine over other antidepressant agents in terms of efficacy or tolerability and the higher
treatment costs per daily dose, duloxetine appears not to be a suitable option as first line treatment for
patients with major depression.
Cipriani, Andrea, et al. "Duloxetine versus other anti‐depressive agents for depression." The Cochrane Library (2012).
If at First You Don’t Succeed (2011)
If one SSRI fails, is it rational to try another, or would an SNRI be better? Venlafaxine, an SNRI, inhibits
serotonin reuptake and norepinephrine reuptake; results of meta-analyses consistently support the notion
that venlafaxine is a somewhat more effective antidepressant agent than the SSRIs as a class.[64-66]
More recently, three other SNRIs – duloxetine, milnacipran and desvenlafaxine, the major active
metabolite of venlafaxine – have also been made available.
Overall, the available data suggest that venlafaxine is an effective and useful agent after the failure of an
SSRI; whether it is markedly more effective seems doubtful. The role of newer SNRIs for treatmentresistant depression remains to be characterized as we await data from large and well conducted studies.
After a poor response to a first-line antidepressant, changing course entirely is also a good option, and
can be expected to produce a response between 18% and 60% of the time, based on the data currently
available. There currently exist scant data, either from RCTs or from recent naturalistic studies, to suggest
that any antidepressant has a unique clinical advantage in the case of SSRI nonresponse.
Connolly, K. Ryan, and Michael E. Thase. "If at first you don’t succeed." Drugs71.1 (2011): 43-64.
STAR*D (2006)
The SSRIs are common first-step treatments, given their relatively low toxicity and high tolerability. Few
randomized trials have compared the efficacy and tolerability of treatment with at least two active second
agents after the initial failure of treatment with an SSRI.6-9 Open case series — typically in symptomatic
volunteers with few psychiatric and general medical coexisting conditions10 — suggest variable response
rates (25 to 65 percent) when the first SSRI is switched to a second SSRI,11-13 to a non-SSRI (an out-ofclass switch),14-16 or to medications that inhibit the uptake of both serotonin and norepinephrine (“dualaction” agents).17-19
With regard to the commonly accepted practice of switching medications, approximately one in four
depressed patients had a remission of symptoms with sustained-release bupropion, sertraline, or
extended-release venlafaxine after either not having had a remission with or being unable to tolerate
citalopram therapy. Remission rates did not differ significantly among the three medication groups nor did
QIDS-SR-16 response rates, times to QIDS-SR-16 response, change in QIDS-SR-16 scores from
baseline to the end of the study, serious adverse events, or measures of tolerability.
These findings have important practical implications. Contrary to the belief that intolerance of one SSRI
predicts intolerance of another SSRI, sertraline was tolerated as well as sustained release bupropion,
even though 56.0 percent of patients in this trial could not tolerate citalopram. Thus, intolerance to or the
lack of efficacy of one SSRI seems not to imply intolerance or lack of efficacy of another SSRI. These
results indicate that both within-class and out-of-class medication switches are reasonable choices. As for
the dual-action agent extended-release venlafaxine, post hoc pooled analyses39,40 have suggested
slightly higher remission rates with venlafaxine than with SSRIs when used as first step treatment. No
studies, to our knowledge, have compared venlafaxine with other potentially active medications at the
second treatment step. In this study, higher remission rates were not achieved with extended-release
venlafaxine than with the more selective agents among patients who could not tolerate or who did not
have a remission with citalopram therapy.
Rush, A. John, et al. "Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for
depression." New England Journal of Medicine 354.12 (2006): 1231-1242.
Treatment Resistant Depression (2003)
The most common definition of stage 1 TRD is that of inadequate response (i.e., failure to achieve
remission) to at least one antidepressant trial of adequate dose and duration (Fava and Davidson 1996).
This definition has typically included an operational classification of the degree of treatment resistance
(Fava and Davidson 1996): 1) nonresponse (25% symptom reduction from baseline); 2) partial response
(25% to 49% symptom reduction from baseline); and 3) response without remission (50% or greater
symptom reduction from baseline without achieving remission). One of the reasons for distinguishing
between partial and nonresponse is that clinicians’ treatment approaches to partial responders seem to
differ from those used for nonresponders (Fredman et al 2000). Using such classification, a meta-analysis
of clinical trials found that, among antidepressant-treated depressed patients, partial response occurs in
12% to 15%, and nonresponse in 19% to 34% (Fava and Davidson 1996).
Fava, Maurizio. "Diagnosis and definition of treatment-resistant depression."Biological psychiatry 53.8
(2003): 649-659.
eCPS (2015)
Selective Serotonin Reuptake Inhibitors (SSRIs)
Greater tolerability and ease of dosing are key reasons SSRIs are first-choice antidepressants. Both time
to onset (2–4 weeks) and rate of response (60–70%) are comparable to tricyclic antidepressants (TCAs);
side effects mainly affect the GI tract, the CNS and sexual function. 20 SSRI therapy can increase the risk
of GI bleeding, particularly in patients with additional risk factors such as concomitant NSAID therapy or a
history of GI bleeding. SSRIs should be used with caution in patients already at higher risk for GI
bleeding.23 Unlike GI or CNS side effects, sexual dysfunction is more likely to persist during SSRI therapy,
and can involve impairment of desire, arousal and/or orgasm/ejaculation. Consider the importance of
sexual function to the patient when prescribing an antidepressant. Some non-SSRI antidepressants that
cause less sexual dysfunction (e.g., bupropion, mirtazapine, moclobemide) may be more acceptable for
some patients.20
Six SSRIs are currently available in Canada (citalopram, escitalopram, fluoxetine, fluvoxamine,
paroxetine and sertraline). Escitalopram, the stereoisomer of citalopram, has a similar side effect profile
but superior efficacy to citalopram,24 and is at least as effective as venlafaxine. 25 With the exception of
fluoxetine, all SSRIs are commonly associated with discontinuation effects when stopping therapy.
See Antidepressant Discontinuation Syndrome for more information. These effects can be severe and
protracted in a small proportion of patients. Patients should be assessed regularly during and after
treatment discontinuation for withdrawal symptoms and relapse.
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
Venlafaxine is an SNRI that has inhibitory effects on serotonin reuptake at any therapeutic dose. At
doses of >150 mg daily it also inhibits norepinephrine reuptake. Compared to SSRIs, rates of remission
have been reported to be 6–10 % higher with venlafaxine, although these results are mainly due to
venlafaxine's superiority over fluoxetine.30 , 31 Dose-related hypertension occurs rarely, and is more likely
to be seen at doses ≥225 mg. Monitor blood pressure and avoid use in patients with uncontrolled
hypertension.
Duloxetine is an SNRI that appears to exert effects on both serotonin and norepinephrine systems at the
starting dose of 60 mg daily, and has comparable efficacy to venlafaxine.32 In addition to depression,
duloxetine is indicated for neuropathic pain and for pain associated with fibromyalgia. Isolated cases of
hepatic injury have been reported but there is no requirement for routine monitoring of liver enzymes.
Desvenlafaxine, an SNRI, is the active metabolite of venlafaxine. The recommended dose is 50 mg
daily, although safety data are available for 100 mg daily. In the treatment of depression, the response
and remission rates at 8 weeks are 51–63% and 31–45%, respectively. Common adverse effects include
insomnia, somnolence, dizziness and nausea.33 , 34
Class
Selective
Serotonin
Reuptake
Inhibitors
Selective
Serotonin
Reuptake
Inhibitors
Drug
fluoxetine
Prozac,
generics
sertraline
Zoloft,
generics
Dose
Initial:b10–20
mg/day po
Usual:d20–40
mg/day po
High:c60–80
mg/day po
Initial:b25–50
mg/day po
Usual:d50–100
mg/day po
High:c150–200
mg/daypo
Adverse
Effects
Nausea,
nervousness,
anorexia,
insomnia,
sexual
dysfunction,
increased risk
of GI
bleeding.
Nausea,
tremors,
diarrhea, dry
mouth, sexual
dysfunction,
increased risk
of GI bleeding.
Discontinuation
syndrome.
Drug Interactions
SSRIs: Use with MAOIs leads to potentially fatal
reaction initially presenting with tremor, agitation,
hypomania, hyperthermia and/or hypertension.
Costa
$$
Increased risk of GI bleeding with NSAIDs,
antiplatelet agents.
Inhibitors of cytochrome P450 enzymes such as
cimetidine, clarithromycin, erythromycin, fluconazole,
indinavir, isoniazid, itraconazole, ketoconazole,
quinidine or ritonavir may increase SSRI levels.
All SSRIs inhibit certain cytochrome P450 isoenzymes
and can reduce the clearance of many drugs such as
clozapine, methadone, mexiletine, phenytoin,
pimozide or propafenone, or decrease the enzymatic
conversion of a prodrug such as clopidogrel, codeine
or tamoxifen to its active form.
Inducers of cytochrome P450 enzymes (e.g.,
carbamazepine, phenobarbital, phenytoin, rifampin)
can increase the clearance of SSRIs.
Avoid combined use with drugs associated with
prolonged QTc interval/torsades de pointes, such as
amiodarone, azithromycin, clarithromycin,
domperidone, erythromycin, haloperidol, methadone,
pimozide, quinine, sotalol, ziprasidone.
$
Class
Drug
Adverse
Effects
Dose
Serotonindesvenlafaxine Initial: 50 mg
Norepinephrine Pristiq
daily po
Reuptake
Usual: 50 mg
Inhibitors
daily po
High: 100 mg
daily po
Serotoninduloxetine
Norepinephrine Cymbalta
Reuptake
Inhibitors
Nausea, sleep
disturbance,
drowsiness,
nervousness,
dizziness, dry
mouth.
Initial/Usual: 60 Nausea,
drowsiness,
mg/day po
insomnia,
If necessary for dizziness, dry
tolerability may mouth.
start with 30
mg/day and
increase to 60
mg in 1–2 wk
Drug Interactions
Costa
Use with MAOIs may lead to potentially fatal reaction $$$
initially presenting with tremor, agitation, hypomania,
hyperthermia and/or hypertension.
Potent inhibitors of CYP3A4 may increase
desvenlafaxine levels.
Use with MAOIs may lead to potentially fatal reaction $$$$
initially presenting with tremor, agitation, hypomania,
hyperthermia and/or hypertension.
Do not use with potent inhibitors of CYP1A2 such as
ciprofloxacin, fluvoamine, ketoconazole.
High: 120
mg/day po
Serotoninvenlafaxine
Norepinephrine Effexor XR,
Reuptake
generics
Inhibitors
Initial:b37.5–75
mg/daypo
Usual:112.5–
225 mg/daypo
High:c300–375
mg/daypo
Legend:
$ < $30
$$ $30–60
Nausea, sleep
disturbance,
drowsiness,
nervousness,
dizziness, dry
mouth.
Use with MAOIs may lead to potentially fatal reaction $
initially presenting with tremor, agitation, hypomania,
hyperthermia and/or hypertension.
Inhibitors of CYP2D6 or CYP3A4 may increase
venlafaxine levels.
Dose-related
hypertension
occurs rarely,
particularly at
doses≥225
mg/day.
$$$ $60–90
$$$$ $90–120
Psychiatric Disorders: Depression; Sidney H. Kennedy, MD, FRCPC, Sagar V. Parikh, MD, FRCPC, and
Sophie Grigoriadis, MD, PhD, FRCPC; Date of revision: March 2015
eCPS – Neuropathic Pain
Note: SNRIs are also second-line treatment for neuropathic pain.
SNRI antidepressants (duloxetine, venlafaxine) and topical lidocaine can be considered second-line.