ADIS DRUG EVALUATION CNS Drugs 2001; 15 (8) 643-669

1172-7047/01/0008-0643/$22.00/0

© Adis International Limited. All rights reserved.

Venlafaxine Extended-Release
A Review of its Use in the Management of Major Depression
Keri Wellington and Caroline M. Perry
Adis International Limited, Auckland, New Zealand

Various sections of the manuscript reviewed by:

M. Ansseau, Psychiatric Unit, CHU Sart Tilman, Liège, Belgium; J. Azuma, Graduate School of
Pharmaceutical Science, Osaka University, Osaka, Japan; P. Blier, Neurobiological Psychiatry Unit, McGill
University, Montréal, Quebec, Canada; C. Charlier, Laboratoire de Toxicologie Clinique, CHU Sart Tilman,
Liège, Belgium; A. Frazer, Department of Pharmacology, University of Texas Health Science Center at San
Antonio, San Antonio, Texas, USA; D. Smith, Department of Biological Psychiatry, Aarhus University
Psychiatric Hospital, Risskov, Denmark; L. Staner, Institute for Research in Neurosciences,
Neuropharmacology and Psychiatry, Centre Hospitalier de Rouffach, Rouffach, France; C.Y. Stanga,
Psychiatric Research Institute, Wichita, Kansas, USA; E. Szabadi, Department of Psychiatry, University of
Nottingham, Nottingham, England; M. Thase, Department of Psychiatry, University of Pittsburgh School of
Medicine, Pittsburgh, USA.

Data Selection
Sources: Medical literature published in any language since 1980 on Venlafaxine XR, identified using Medline and EMBASE, supplemented
by AdisBase (a proprietary database of Adis International, Auckland, New Zealand). Additional references were identified from the reference
lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company
developing the drug.
Search strategy: Medline search terms were ‘venlafaxine XR’ or ‘extended release formulation and venlafaxine’ or ‘extended-release and
venlafaxine’. EMBASE search terms were ‘venlafaxine XR’ or ‘extended release formulation and venlafaxine’ or ‘extended-release and
venlafaxine’. AdisBase search terms were ‘venlafaxine XR’ or ‘extended-release and venlafaxine’. Searches were last updated 9 Aug 2001.
Selection: Studies in patients with major depression who received venlafaxine XR. Inclusion of studies was based mainly on the methods
section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant
pharmacodynamic and pharmacokinetic data are also included.
Index terms: Venlafaxine XR, major depressive disorder, depression, pharmacodynamics, pharmacokinetics, therapeutic use.

Contents

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 644
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 648
2. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 649
2.1 Effects on Neurotransmitter Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 649
2.2 CNS and Behavioural Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 650
2.3 Cardiovascular Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 650
3. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651
3.1 Absorption and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651
3.2 Metabolism and Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651
3.3 In Patients with Renal or Hepatic Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . 652
3.4 Drug-Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652
4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 653
4.1 Comparisons with Placebo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 654
4.2 Comparisons with Venlafaxine Immediate-Release and Placebo . . . . . . . . . . . . . . . . 655
644 Wellington & Perry

4.2.1 Effects on Symptoms of Anxiety in Patients with Depression . . . . . . . . . . . . . . . . 656

4.3 Comparisons with Fluoxetine and Placebo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 657
4.4 Comparison with Paroxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 658
4.5 Meta-Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 659
5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 661
5.1 Serious Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 662
5.1.1 Overdose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 662
5.1.2 Serotonin Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663
6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663
7. Role of Venlafaxine Extended-Release in the Management of
Major Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 664

Summary
Abstract Venlafaxine inhibits presynaptic reuptake of serotonin (5-hydroxytryptamine;
5-HT) and noradrenaline (norepinephrine). Venlafaxine extended-release (XR)
has been investigated in patients with major depression and in patients with major
depression with associated anxiety in randomised, double-blind, multicentre tri-
als. A therapeutic response in patients with major depression was evident at week
2 of treatment with venlafaxine XR 75 to 225 mg/day in a placebo-controlled
trial. By week 4, the drug was significantly more effective than placebo at reduc-
ing both the Hamilton Rating Scale for Depression (HAM-D) and Montgomery-
Åsberg Depression Rating Scale (MADRS) total scores. Furthermore, cumulative
relapse rates were lower among recipients of venlafaxine XR 75 to 225 mg/day
than placebo recipients after 3 and 6 months in another trial. Venlafaxine XR 75
to 150 mg/day was significantly more effective than venlafaxine immediate-
release (IR) 75 to 150 mg/day or placebo during a 12-week study. Reductions
from baseline in all 4 efficacy parameters (HAM-D, MADRS, HAM-D depressed
mood item and the Clinical Global Impression Severity of Illness scale) were
significantly higher among patients treated with venlafaxine XR than venlafaxine
IR or placebo at week 12 (using an intent-to-treat, last observation carried forward
analysis).
Venlafaxine XR 75 to 225 mg/day was compared with fluoxetine 20 to 60
mg/day in patients with major depression in 2 randomised, double-blind, placebo-
controlled, multicentre studies. Remission rates were significantly in favour of
venlafaxine XR recipients in one study: 37, 22 and 18% of patients treated with
venlafaxine XR, fluoxetine or placebo, respectively, achieved full remission
(HAM-D total score ≤7 at end-point). In the other trial, venlafaxine XR and
fluoxetine had comparable efficacy in reducing HAM-D and Hamilton Rating
Scale for Anxiety (HAM-A) total scores compared with placebo. However, the
HAM-A response rate was significantly higher with venlafaxine XR than with
fluoxetine at week 12.
In a comparative study involving paroxetine, reductions from baseline in
HAM-D and MADRS total scores in patients given venlafaxine XR 75 mg/day
or paroxetine 20 mg/day for 12 weeks were significant, but no significant differ-
ences between treatment groups were evident.
Discontinuation rates because of unsatisfactory clinical response were similar
among patients treated with venlafaxine XR, fluoxetine or paroxetine.
Adverse events pertaining to the digestive (nausea, dry mouth), nervous (diz-

© Adis International Limited. All rights reserved. CNS Drugs 2001; 15 (8)
Venlafaxine Extended-Release: A Review 645

ziness, somnolence, insomnia) and urogenital (abnormal ejaculation) systems as

well as sweating were the most frequently reported adverse events during 8 to 12
weeks of treatment in 3 randomised, double-blind, multicentre trials. Compara-
tive studies with fluoxetine and paroxetine demonstrated a similar adverse event
profile to venlafaxine XR.
Conclusion: Venlafaxine XR has shown efficacy in the treatment of major
depression and was at least as effective as fluoxetine or paroxetine and more
effective than venlafaxine IR. Furthermore, it is effective at reducing symptoms
of anxiety in depressed patients. The incidence of adverse events in recipients of
venlafaxine XR is similar to that in patients receiving treatment with well estab-
lished selective serotonin reuptake inhibitors. As an effective and well tolerated
antidepressant, venlafaxine XR should be considered as a first-line pharmacolog-
ical treatment in patients with major depression.
Pharmacodynamic Venlafaxine and its major active metabolite O-desmethylvenlafaxine (ODV) both
Properties inhibit presynaptic reuptake of serotonin (5-hydroxytryptamine; 5-HT) and nor-
adrenaline (norepinephrine). Venlafaxine has been referred to previously as a
serotonin noradrenergic reuptake inhibitor (SNRI). Venlafaxine also weakly in-
hibits dopamine reuptake. The drug has no significant affinity for α1-adrenergic,
muscarinic cholinergic, H1 histaminergic, benzodiazepine or opioid receptors and
does not inhibit monoamine oxidase.
Venlafaxine 75 to 150 mg/day did not impair psychomotor performance to any
clinically significant degree in healthy volunteers. Although the drug impaired
vigilance, it did not affect driving ability after administration of 75 to 150 mg/day
for 2 weeks. Venlafaxine did not exacerbate the detrimental effects on psycho-
motor performance when coadministered with diazepam or alcohol. However,
the drug markedly suppressed rapid eye movement (REM) sleep and increased
wake time in healthy volunteers and patients with depression.
Although dosages ≤300 mg/day are not associated with a significant risk of
sustained diastolic blood pressure (DBP) elevation, venlafaxine extended-release
(XR) may elevate BP in some patients.
Pharmacokinetic The absolute bioavailability of venlafaxine XR (≈45%) is not affected by food or
Properties the time of administration, and plasma concentrations of the drug are not affected
by gender or age. Maximum plasma concentrations of venlafaxine and ODV
occur approximately 5.5 and 9 hours, respectively, after administration of
venlafaxine XR, and steady-state concentrations are reached within 3 days with
ongoing administration. Proportionality between the dose and plasma concentra-
tions of venlafaxine has been demonstrated. Plasma protein binding is minimal
for venlafaxine (27%) and ODV (30%).
Venlafaxine undergoes extensive cytochrome P450 (CYP) 2D6–mediated
first-pass oxidative metabolism to produce ODV. In most individuals, plasma
concentrations of ODV are approximately 2- to 3-fold higher than those of
the parent drug; in poor metabolisers (determined by genetic polymorphism
in CYP2D6 activity), venlafaxine concentrations are higher than ODV concen-
trations.
The terminal elimination half-lives of venlafaxine and ODV are 5 and 11
hours, respectively, and within 48 hours of administration, 87% of a dose of
venlafaxine is recovered in urine.
Clearance of venlafaxine is reduced and dosage adjustments are warranted in

© Adis International Limited. All rights reserved. CNS Drugs 2001; 15 (8)
646 Wellington & Perry

patients with mild to moderate renal impairment, in those undergoing

Therapeutic Efficacy
haemodialysis and in patients with hepatic cirrhosis.
The results of in vitro and volunteer studies suggest that venlafaxine has a low
potential to interfere with the metabolism of other drugs. However, concomitant
administration of venlafaxine and diphenhydramine in 9 healthy volunteers with
the CYP2D6 extensive metaboliser phenotype resulted in the oral clearance of
venlafaxine being decreased by 59% and a more than 2-fold increase in the area
under the concentration-time curve. Cimetidine also inhibited the metabolism of
venlafaxine, but not ODV, in healthy volunteers; however, the interaction may
not be of clinical significance.
The clinical potential of venlafaxine XR, administered once daily, has been in-
vestigated in patients with major depression and in patients with major depression
with associated anxiety, as defined by DSM-IV or DSM-III-R criteria, in
randomised, double-blind, multicentre trials. All studies used an intent-to-treat,
last observation carried forward analysis to determine efficacy.
Venlafaxine XR 75 to 225 mg/day produced consistent and significant reduc-
tions in all primary outcome measures compared with placebo during an 8-week
flexible dose study in patients with major depression. A therapeutic response was
evident after 2 weeks of treatment with the drug. By week 4, venlafaxine XR was
significantly more effective than placebo at reducing both the Hamilton Rating
Scale for Depression (HAM-D) and Montgomery-Åsberg Depression Rating
Scale (MADRS) total scores. Significantly fewer venlafaxine XR–treated patients
discontinued treatment because of lack of therapeutic response than placebo
recipients.
Venlafaxine XR 75 to 150 mg/day was significantly more effective than
venlafaxine immediate-release (IR) 75 to 150 mg/day or placebo during a 12-
week flexible dose study. Reductions from baseline in HAM-D total and Clinical
Global Impression Severity of Illness (CGI-S) rating scores were significantly
higher among patients treated with venlafaxine XR than venlafaxine IR at week
8. A therapeutic response to venlafaxine XR compared with that to placebo was
evident after 2 weeks with respect to reductions in HAM-D total scores and the
HAM-D depressed mood item. Furthermore, mean reductions in all primary
efficacy variables [HAM-D and MADRS total scores, HAM-D depressed mood
item and the CGI-S] were significantly greater among recipients of venlafaxine
XR than venlafaxine IR or placebo at week 12.
In a subanalysis of the 2 aforementioned flexible dose studies, venlafaxine XR
75 to 150 mg/day significantly reduced HAM-D psychic anxiety scores compared
with placebo. A pooled analysis of both studies involving the HAM-D item scores
from the anxiety somatisation cluster (psychic anxiety, somatic anxiety, somatic
gastrointestinal and somatic general items) showed that mean score reductions
were significantly higher in patients who received venlafaxine XR than placebo
or venlafaxine IR at week 12.
Venlafaxine XR has been compared with fluoxetine and placebo in patients
with major depression in 2 randomised, double-blind, placebo-controlled, multi-
centre studies. In an 8-week study, reductions in HAM-D total scores among
patients treated with venlafaxine XR 75 to 225 mg/day or fluoxetine 20 to 60
mg/day were not significantly different to those in placebo recipients. However,
whereas venlafaxine XR significantly reduced the MADRS, CGI-S and HAM-D
depressed mood scores compared with placebo, fluoxetine significantly reduced

© Adis International Limited. All rights reserved. CNS Drugs 2001; 15 (8)
Venlafaxine Extended-Release: A Review 647

only the HAM-D depressed mood item compared with placebo. Remission rates
were significantly in favour of venlafaxine XR recipients: 37, 22 and 18% of
patients treated with venlafaxine XR, fluoxetine or placebo, respectively,
achieved full remission (HAM-D total score ≤7 at end-point). Furthermore, in a
12-week flexible dose study in patients with major depression and associated
anxiety, venlafaxine XR and fluoxetine both significantly reduced HAM-D and
Hamilton Rating Scale for Anxiety (HAM-A) total scores compared with placebo.
There were no significant differences between active treatment groups in any of
the measured parameters (total scores of the HAM-D, HAM-A, Hospital Anxiety
and Depression Scale and Covi Scale or remission rates). However, the HAM-A
response rate was significantly higher (p < 0.05) with venlafaxine XR than with
fluoxetine at week 12. Reductions in HAM-A total scores in venlafaxine XR
recipients were significantly greater than those in placebo recipients after 8
weeks. Among recipients of fluoxetine, HAM-A total score reductions were
higher than those of patients given placebo only at week 12. Both venlafaxine
XR and fluoxetine significantly reduced HAM-D total scores compared with
baseline values from week 2 to week 12.
In the comparative study involving paroxetine, reductions from baseline in
HAM-D and MADRS total scores in patients given venlafaxine XR 75 mg/day
or paroxetine 20 mg/day for 12 weeks were both significant, but no significant
differences between treatment groups were evident. Similarly, there were no sig-
nificant between-group differences in response rates based on HAM-D, MADRS
or Clinical Global Impression Global Improvement (CGI-I) scales, or in the num-
ber of patients achieving remission (defined as a HAM-D score of <7).
Discontinuation rates because of unsatisfactory clinical response were similar
among patients treated with venlafaxine XR, fluoxetine or paroxetine.
According to the results from 2 meta-analyses, venlafaxine XR is associated
with a significantly higher mean success rate than the selective serotonin reuptake
inhibitors fluoxetine, fluvoxamine, sertraline, paroxetine or citalopram, or the
tricyclic antidepressants (TCAs) amitriptyline, imipramine, desipramine or nor-
triptyline. A retrospective pooled analysis also demonstrated significantly higher
rates of remission and absence of depressed mood in recipients of venlafaxine
compared with paroxetine. However, it was not specified whether patients re-
ceived venlafaxine XR or IR.
A pharmacoeconomic analysis based on the results from one of these meta-
analyses concluded that venlafaxine XR is the most cost-effective antidepressant
for the initial treatment of major depression in both inpatients and outpatients.
Tolerability Among venlafaxine XR recipients, adverse events pertaining to the digestive
(nausea, dry mouth), nervous (dizziness, somnolence, insomnia) and urogenital
(abnormal ejaculation) systems as well as sweating were the most frequently
reported adverse events during 8 to 12 weeks of treatment in 3 randomised,
double-blind, multicentre trials.
The proportion of patients withdrawing from these studies because of adverse
effects was approximately 11 and 6% in patients receiving venlafaxine XR and
placebo, respectively. Nausea (4 vs <1%), dizziness (2 vs 1%) and somnolence
(2 vs <1%) were the most common events that resulted in discontinuation of
treatment among patients in the 3 studies.
The frequency of nausea associated with venlafaxine XR was highest during
the first week of treatment and decreased thereafter.

© Adis International Limited. All rights reserved. CNS Drugs 2001; 15 (8)
648 Wellington & Perry

In one comparative study, dizziness and sweating were reported by a greater

proportion of venlafaxine XR recipients (38 and 28% of patients, respectively)
than those receiving fluoxetine (18 and 17%), whereas in another study, dizziness
and nausea were more prevalent in venlafaxine XR recipients (26 and 36%) than
those receiving fluoxetine (6 and 20%). There were no significant between-group
differences in adverse events among patients receiving venlafaxine XR or parox-
etine, although the mean duration of nausea was twice as long in paroxetine-treated
patients (10 days) than in patients treated with venlafaxine XR (5 days).
Venlafaxine can cause some cardiovascular effects in overdose but is markedly
less hazardous than the TCAs. Two patients with depression who took overdoses
of the drug during clinical trials recovered without serious complication. None-
theless, the manufacturer advises that fatalities have been reported in patients
taking overdoses of venlafaxine, predominantly in combination with alcohol or
other drugs. Serotonin syndrome has been reported in patients receiving venlafax-
ine concomitantly or within ≤16 days of discontinuation of monoamine oxidase
inhibitors. This combination is contraindicated. Serotonin syndrome has also
been seen in patients taking venlafaxine alone, although rarely.
Dosage and Venlafaxine XR is indicated for the treatment of depression as defined by DSM-
Administration IV criteria. The recommended initial dosage of the drug in patients with depres-
sion is 75mg once daily, taken with food at the same time each day. In patients
who do not improve with 75 mg/day, the dosage may be titrated in increments of
≤75 mg/day, at intervals of ≥4 days, to a maximum dosage of 225 mg/day.
Venlafaxine XR has recently been approved for the prevention of relapse and the
prevention of recurrence of depression. Although the optimum duration of treat-
ment in patients with depression has not been determined, international guide-
lines recommended that, following remission, patients receive venlafaxine XR
therapy for 16 to 20 weeks. The manufacturer recommends regular BP monitoring
during treatment. Dosage adjustments are not required in elderly patients, but are
necessary in those with renal or hepatic dysfunction. When discontinuing
venlafaxine XR after more than 1 week’s treatment, the manufacturer recom-
mends that the dosage be tapered in order to minimise the risk of discontinuation
symptoms, which include asthenia, dizziness, headache, insomnia, nausea and
nervousness.

1. Introduction Venlafaxine has been referred to previously as a sero-

Venlafaxine (1-[2-(dimethylamino)-1-(4-methoxy-
phenyl)-ethyl]cyclohexanol hydrochloride) is a
bicyclic phenylethylamine derivative that inhibits
presynaptic reuptake of serotonin (5-hydroxytryp-
tamine; 5-HT), noradrenaline (NA; norepinephrine)
and, to a lesser extent, dopamine.[1] The seroto-
nergic and noradrenergic systems are implicated
in the pathophysiology of major depression, and
there is clinical evidence that suggests a potential
therapeutic benefit from a drug that can produce
blockade of both of these reuptake processes.[2,3]
tonin noradrenergic reuptake inhibitor (SNRI).[4]
Both the immediate-release (IR) and extended-
release (XR) formulations of venlafaxine have demon-
strated efficacy in reducing symptoms of depression
in patients with major depressive disorder. Further-
more, venlafaxine has shown efficacy in reducing
symptoms of concomitant anxiety in patients with
major depression, and the XR formulation has sub-
sequently been evaluated (and approved) in patients
with generalised anxiety disorder (GAD).
Venlafaxine XR, administered once daily, has a
prolonged duration of absorption compared with

© Adis International Limited. All rights reserved. CNS Drugs 2001; 15 (8)
Venlafaxine Extended-Release: A Review 649

N CH3

OH

CH3O

N-Desmethylvenlafaxine
(1%)
CYP3A3/4 CYP2D6

CH3 H

N CH3 N CH3

OH OH

CH3O HO

Venlafaxine N, O-Didesmethylvenlafaxine
(16%)

CH3
CYP2D6 N CH3 CYP3A3/4

OH

HO

O-Desmethylvenlafaxine (ODV)
(56%)

Fig. 1. Metabolic pathway of venlafaxine to its major active metabolite O-desmethylvenlafaxine and 2 minor (marginally active)
metabolites.[14,15] CYP = cytochrome P450.

venlafaxine IR, yet both agents have equivalent total
absorption. The potential benefits of the XR formu-
lation over venlafaxine IR include increased patient
compliance and convenience, and a better benefit to
risk ratio.[5-7]
The therapeutic efficacy of venlafaxine IR in pa-
tients with major depressive disorder has been re-
viewed in Drugs previously,[8] and the use of venlafax-
ine XR in patients with GAD has previously been
reviewed in CNS Drugs.[1]
This review examines the role of venlafaxine
XR in the management of major depression with or
without associated anxiety.
2. Pharmacodynamic Properties
The pharmacodynamic properties of venlafaxine
in healthy volunteers have been comprehensively
reviewed elsewhere.[1,9,10] Thus, this section pro-
vides a brief overview of these data.
2.1 Effects on Neurotransmitter Systems
Venlafaxine has one chiral centre and exists as
a racemic mixture of R (–) and S (+) enantiomers.
The R-enantiomer inhibits reuptake of both NA
and serotonin, whereas the S-enantiomer appears
to primarily inhibit serotonin reuptake. Venlafaxine

© Adis International Limited. All rights reserved. CNS Drugs 2001; 15 (8)
650
Table I. Overview of the pharmacological activity of venlafaxine
Effects on neurotransmitter systems in vitro and in animal
studies
Showed moderate (Ki = 74 nmol/L) and low (Ki = 1.26 μmol/L)
affinity for the serotonin and NA transporters in rat brain
membranes[16]
Weakly inhibited dopamine reuptake in rat brain synaptosomes
(IC50 = 2.8 μmol/L)[11]
Suppressed histamine-induced ACTH secretion and antagonised
reserpine-induced hypothermia implying NA uptake blockade at
sympathetic nerve terminals[10]
↓ Noradrenergic responsiveness of pineal β-adrenoceptorsa[17]
↓ Noradrenergic neuronal firing rate in rat locus ceruleus[18]
↓ Serotonergic neuronal firing rate in rat dorsal raphé nucleus[18]
↓ Cyclic AMP response to NA in rat brains with selective
depletion of brain serotonin by p-chlorophenylalanine[19]
Effects on neurotransmitter systems in humans
Enhanced the growth hormone response to an infusion of
tryptophan, indicative of enhanced transmission through
postsynaptic serotonin 5-HT1A receptors[20]
↓ 5-HIAA but not serotonin, MHPG, HVA or DOPAC levels in CSF
of patients with depression (at maximum tolerated dosage; ≤375
mg/day for ≥6 weeks)[21]
Potentiated venoconstrictor responses to NA consistent with
reuptake blockade after a single 150mg oral dose[22]
↓ Duration and frequency of REM sleep and increased duration
of wake time in healthy volunteers after a single 75mg oral
dose[23]
↑ Cortisol, but not prolactin, secretion in healthy volunteers after
a single 12.5-75mg oral dose[24]
a O-desmethylvenlafaxine demonstrated similar potency in this
model.
5-HIAA = 5-hydroxyindoleacetic acid; ACTH = adrenocorticotropic
hormone; AMP = adenosine monophosphate; CSF = cerebrospinal
fluid; DOPAC = 3,4-dihydroxyphenylacetic acid; HVA = homovanillic
acid; IC50 = concentration required for 50% inhibition; Ki = inhibition
constant; MHPG = 3-methoxy-4-hydroxyphenylglycol; NA = nor-
adrenaline (norepinephrine); REM = rapid eye movement. ↑ =
increase; ↓ = decrease.
is approximately 3- to 5-fold more potent in inhib-
iting serotonin than NA reuptake in vitro.[11-13] The
drug also weakly inhibits dopamine reuptake.[11]
O-desmethylvenlafaxine (ODV, fig. 1), which predomi-
nates in plasma, is the major metabolite of venla-
faxine (section 3). ODV has similar potency to the
parent compound in inhibiting reuptake of seroto-
nin and NA, but is more than 4-fold less potent in
inhibiting dopamine reuptake.[8] Table I summa-
rises the effects of venlafaxine on neurotransmitter
© Adis International Limited. All rights reserved.
Wellington & Perry
systems. Although venlafaxine inhibits reuptake of
both serotonin and NA, the drug has a paradoxi-
cally low affinity for the serotonin and NA trans-
porters in vitro (table I).[16,18] However, venlafaxine
is a potent inhibitor of serotonin and NA reuptake in
vivo.[18,22,25] Thus, further study is required to elu-
cidate the pathway through which the drug exerts
its effects on neurotransmitters.
Venlafaxine does not inhibit monoamine oxidase
and has no significant affinity for α1-adrenergic,
muscarinic cholinergic, H1 histaminergic, benzo-
diazepine or opioid receptors.[11]
2.2 CNS and Behavioural Effects
Although venlafaxine IR 75 to 150 mg/day pro-
duced slight but significant impairment in some
psychometric tests in placebo-controlled studies
involving healthy volunteers, these results were
not considered to be clinically significant.[26-29]
Venlafaxine impaired vigilance, but not driving
ability, after administration of 75 to 150 mg/day for
2 weeks.[28] A dose-dependent improvement in at-
tention, concentration, memory, fine motor activ-
ity, reaction time performance and wakefulness
versus placebo was reported after administration of
venlafaxine 12.5 to 50mg to healthy volunteers.[30]
The differences from placebo were significant 2 hours
after venlafaxine administration and increased
over the next 6 hours.[30] Venlafaxine did not have
additive detrimental effects on psychomotor per-
formance when coadministered with diazepam[27]
or alcohol.[26]
As with selective serotonin reuptake inhibitors
(SSRIs),[31] venlafaxine markedly suppresses rapid
eye movement (REM) sleep and increases wake time
in healthy volunteers[23] and patients with depres-
sion[32,33] or narcolepsy.[34]
2.3 Cardiovascular Effects
Diastolic blood pressure (DBP) may be elevated
in some patients after high dosages of venlafaxine.[35]
Hypertension, hypotension, tachycardia and ECG
changes have been reported after overdosage with
venlafaxine (see also section 5.1.1).[36-42] According
to a meta-analysis of data from 3744 patients with
CNS Drugs 2001; 15 (8)
Venlafaxine Extended-Release: A Review 651

depression, the effects of venlafaxine on DBP are Table II. Pharmacokinetic parameters of venlafaxine extended-
release (XR) and O-desmethylvenlafaxine (ODV) in healthy volun-
highly correlated with dosage. However, dosages teers[35,46]
≤300 mg/day were not associated with a significant
Parameter Venlafaxine XR ODV
risk of sustained DBP elevation in this analysis F (%) 45 NA
(≤3.7% of patients treated with venlafaxine dosages Cmax (μg/L)a 150 260
≤300 mg/day for 6 weeks had DBP ≥90mm Hg).[43] tmax (h)a 5.5 9
Among patients who were hypertensive at base- Vss (L/kg) 7.5 5.7
line, the drug did not adversely affect control of BP; AUC24h (μg/L
h)a 1877 4331
venlafaxine is not contraindicated in hypertensive Plasma protein binding (%) 27 30
patients with well controlled BP.[35] Major metabolic pathway CYP2D6
In 18 elderly patients (aged between 65 and 86 Urinary excretion (% of dose) 87 NA

years) with depression, of whom most had serious
cardiovascular or cerebrovascular disease, the
mean DBP increased by 4.7mm Hg from 76.1 to
80.8mm Hg after administration of venlafaxine 50
to 250 mg/day (nonsignificant change). Interestingly,
an inverse relationship between baseline DBP and
end of treatment BP was observed (p < 0.0001, r =
–0.8), suggesting that BP is less likely to increase
in those with high baseline values.[44]
CL (L/h/kg) 1.3 0.4
t1⁄2β (h) 5 11
a After a 150mg dose of venlafaxine XR.
AUC24h = area under the plasma concentration-time curve from 0
to 24 hours after administration; CL = systemic clearance; Cmax =
peak plasma concentration; CYP = cytochrome P450; F = mean
oral bioavailability; NA = not applicable; t1⁄2β = terminal elimination
half-life; tmax = time to reach Cmax; Vss = apparent volume of
distribution at steady state.

3. Pharmacokinetic Properties other hand, has a tmax of about 2 hours.[49] Steady-

The pharmacokinetic properties of venlafaxine
in healthy volunteers and in patients with renal or
hepatic dysfunction have been comprehensively
reviewed recently.[1,9,10] This section provides a
brief overview of these data, with additional infor-
mation from healthy volunteers.
3.1 Absorption and Distribution
The pharmacokinetics of venlafaxine after ad-
ministration of single or multiple doses of venla-
faxine XR 75 and 150mg have been studied in
healthy volunteers.[45-47] A summary of these data
is presented in table II.
Venlafaxine XR provides a prolonged duration
of absorption compared with the IR formulation,
yet with a similar extent of absorption of the drug.[35]
The absolute bioavailability of venlafaxine XR is
approximately 45% in healthy volunteers,[45] and
it is not affected by food or the time of adminis-
tration.[47,48] Maximum plasma concentrations (Cmax)
of venlafaxine and ODV occurred approximately
5.5 and 9 hours (tmax), respectively, after adminis-
tration of venlafaxine XR.[35] Venlafaxine IR, on the
state concentrations are reached within 3 days with
ongoing administration.[35]
Proportionality between the dosage of the drug
and plasma concentrations of venlafaxine and ODV
has previously been demonstrated.[50] Venlafaxine
and ODV are minimally bound to plasma proteins
(27 and 30%, respectively).[35,49]
Both venlafaxine and ODV are excreted in
breast milk (section 6); the areas under the concen-
tration-time curve (AUCs) were approximately 3-
to 5-fold greater in breast milk than those in mater-
nal plasma.[51] Plasma concentrations of the drug
are not affected by gender or age.[35]
3.2 Metabolism and Elimination
Once absorbed from the gastrointestinal tract,
venlafaxine undergoes extensive cytochrome
P450 (CYP) 2D6–mediated oxidative metabolism
to form the major active metabolite ODV (fig.
1).[15,52-54] In most individuals, plasma concentra-
tions of ODV are approximately 2- to 3-fold higher
than those of the parent drug.[50] However, because
CYP2D6 metabolism is subject to genetic poly-

© Adis International Limited. All rights reserved. CNS Drugs 2001; 15 (8)
652
morphism, venlafaxine concentrations are higher than
ODV concentrations in poor metabolisers.[15,55,56]
Nevertheless, this phenomenon does not affect
therapeutic efficacy as venlafaxine and ODV have
similar pharmacological activities.[15] N-desmethyl
and N,O-didesmethylvenlafaxine are minor meta-
bolites of venlafaxine with limited pharmacologi-
cal activity and are generated predominantly by
CYP3A3/4 metabolism of venlafaxine (fig. 1).[52,57]
However, there have been studies that suggest the
N-demethylation of venlafaxine could be affected
by both CYP3A3/4 and CYP2C19.[54,55]
The majority (87%) of the administered dose of
venlafaxine is eliminated by renal excretion within
48 hours, primarily as unconjugated (29%) or con-
jugated (26%) ODV or inactive metabolites (27%).
Only 5 to 7% of the dose is excreted as unchanged
parent drug.[9,35] The terminal elimination half-lives
(t1⁄2β) of venlafaxine and ODV were 5 and 11 hours,
respectively, and plasma clearance values at steady
state were 1.3 and 0.4 L/h/kg, respectively.[35]
3.3 In Patients with Renal or
Hepatic Dysfunction
Dosage adjustments are recommended in patients
with renal or hepatic dysfunction (section 6).[35]
The t1⁄2β of venlafaxine was prolonged by approxi-
mately 50% and plasma clearance was reduced by
24% in patients with mild to moderate renal dys-
function [estimated creatinine clearance (CLCR) 10
to 70 ml/min (0.6 to 4.2 L/h)]. In patients undergo-
ing haemodialysis the t1⁄2β was 2.8-fold greater and
clearance was 57% lower than in individuals with
normal organ function.
In patients with hepatic cirrhosis, venlafaxine
and ODV t1⁄2β values were prolonged by 30 and
60%, respectively, and plasma clearance of these 2
entities decreased by 50 and 30% compared with
individuals with normal hepatic function.[35]
3.4 Drug-Drug Interactions
Because venlafaxine is extensively metabolised
by CYP2D6, it has the potential to interfere with
the metabolism of other drugs. However, in vitro
and volunteer studies suggest that this potential is
© Adis International Limited. All rights reserved.
Wellington & Perry
low. At steady state, venlafaxine weakly inhibited
the metabolism of single dose risperidone 1mg, a
CYP2D6 substrate, in 30 volunteers.[58] Oral clear-
ance of risperidone was decreased by 38% and the
AUC∞ was increased by 32%; however, the mean
AUC∞ of 9-hydroxyrisperidone, the active metabolite
of risperidone, was unchanged and Cmax met bioequi-
valence criteria, suggesting that this interaction is
unlikely to be of clinical significance.[58]
Diphenhydramine significantly increased plasma
concentrations of venlafaxine in 9 healthy volun-
teers with the CYP2D6 extensive metaboliser pheno-
type. Concomitant administration of venlafaxine
18.75mg twice daily and diphenhydramine 50mg
twice daily resulted in the oral clearance of venla-
faxine being decreased by 59% and a more than
2-fold increase in the AUC12h of venlafaxine (p ≤
0.05 vs venlafaxine alone). There were no signifi-
cant differences in venlafaxine pharmacokinetic pa-
rameters in volunteers with the poor metaboliser
phenotype. The oral clearance of diphenhydra-
Table III. Summary of DSM-IV criteria for the diagnosis of a major
depressive episode[68]
Five of the following symptoms must be present during the
same 2-week period and include depressed mood and/or
loss of interest or pleasure:
Depressed mood most of the day, nearly every day
Loss of interest or pleasure in daily activities
Significant bodyweight loss/gain, or increase/decrease in
appetite nearly every day
Insomnia or hypersomnia nearly every day
Psychomotor agitation nearly every day
Fatigue or loss of energy nearly every day
Feelings of worthlessness or excessive/inappropriate guilt nearly
every day
Diminished ability to think or concentrate, or indecisiveness
nearly every day
Recurrent thoughts of death, recurrent suicidal ideation without
a specific plan, a suicide attempt, or a specific plan for
committing suicide
The symptoms:
Do not meet the criteria for a mixed episode
Cause clinically significant distress or impairment in social,
occupational or other important functioning
Are not attributable to a drug of abuse, medication or a
medical condition
Are not better accounted for by bereavement
CNS Drugs 2001; 15 (8)
Venlafaxine Extended-Release: A Review
mine, in both extensive and poor metabolisers, was
reduced by 6 and 18%, respectively, after coadmini-
stration of venlafaxine and diphenhydramine (p ≤
0.05 vs diphenhydramine alone).[59] Venlafaxine,
but not ODV, weakly inhibited CYP2D6-mediated
oxidative metabolism of dextromethorphan in hu-
man hepatic microsomes.[52] However, venlafaxine
was considerably less potent than paroxetine,
fluoxetine, norfluoxetine and fluvoxamine in this
model.[52] Similar results were obtained in volun-
teers receiving single doses of venlafaxine, fluoxet-
ine, paroxetine and sertraline.[60]
Volunteer studies have confirmed that venla-
faxine does not inhibit human microsomal trans-
formation of drugs mediated by CYP1A2, CYP3A
or CYP2C9.[61-63] At steady state, venlafaxine did not
alter the single dose pharmacokinetic profiles of
drugs metabolised by CYP1A2 (caffeine[64]) or
CYP3A4 (alprazolam,[65] diazepam,[27] terfenad-
ine[66]). Furthermore, venlafaxine did not change
the pharmacokinetic disposition of ethanol in
healthy volunteers.[26]
Steady-state plasma concentrations of venlafax-
ine increased by 61% after coadministration of
venlafaxine IR 150 mg/day and cimetidine 800
mg/day in a crossover study (p < 0.001 vs venla-
faxine alone). However, plasma concentrations of
ODV were unaffected by cimetidine, and the total
concentration of the 2 pharmacologically active
moieties increased by only 13%. This suggests that
this interaction may not be clinically significant.[67]
Combined use of venlafaxine and monoamine
oxidase inhibitors (MAOIs) has resulted in seroto-
nin syndrome (section 5.1.2). Hence the combination
must be avoided (section 6).[35]
4. Therapeutic Efficacy
The therapeutic efficacy of venlafaxine XR in
the management of major depression, as defined
by DSM-IV[68] or DSM-III-R[69] criteria (table III),
has been evaluated in 5 randomised, double-blind,
multicentre studies.[7,70-73] In addition, a rando-
mised, double-blind, multicentre study examined
the effects of venlafaxine XR on symptoms of anx-
iety in depressed patients.[74] There has also been
© Adis International Limited. All rights reserved.
653
Table IV. Study design and criteria for patient selection in studies
of venlafaxine extended-release in adults with major depression
Study design
Multicentre, randomised, double-blind, placebo-controlled,
parallel group[7,70,71,73,74]
Multicentre, randomised, double-blind, parallel group[72]
Primary outcome measures
HAM-D total score[7,70-72,74]
HAM-D depressed mood item[7,70,71]
MADRS total score[7,70-72]
CGI-S[7,70-73]
CGI-I[7,74]
HAM-A total score[71,74]
Secondary efficacy parameters
Covi scale[74]
HAM-D depressed mood item[74]
HAD[74]
CGI-S[74]
CGI-I response rates[72]
HAM-D psychic anxiety item[6]
Inclusion criteria
Outpatients aged ≥18 years[6,7,70-72,74]
Depression defined by DSM-IV[6,70-72,74] or DSM-III-R[6,7] criteria
Baseline HAM-D score ≥20[6,7,70-72,74]
Baseline MADRS score ≥19[72]
Symptoms of depression for ≥1 month[6,7,70,71,74] or ≥2 weeks
before study entry[72]
Exclusion criteria
Use of any antidepressant, anxiolytic, sedative-hypnotic within
7[6,7,70,74] or 30[72] days (fluoxetine within 21,[6,7,70] 28[74] or 30[72]
days)
Use of antipsychotics or electroconvulsive therapy within 30 days
Use of a monoamine oxidase inhibitor within 14[6,7,70,71,74] or
30[72] days
History of acute suicidal tendencies, bipolar disorder or
psychotic disorder not associated with depression
CGI-I = Clinical Global Impression Global Improvement; CGI-S =
Clinical Global Impression Severity of Illness; HAD = Hospital
Anxiety and Depression Scale; HAM-A = Hamilton Rating Scale
for Anxiety; HAM-D = Hamilton Rating Scale for Depression;
MADRS = Montgomery-Åsberg Depression Rating Scale.
a subanalysis of 2 of the trials[7,70] involving pa-
tients with major depression, in which the efficacy
of venlafaxine XR on symptoms of anxiety was
examined.[6] The design and patient selection cri-
teria used in these trials are presented in table IV.
Five of the trials included a placebo group, and the
CNS Drugs 2001; 15 (8)
654
drug’s efficacy was compared with that of venla-
faxine IR,[7] fluoxetine,[71,74] and paroxetine.[72] All but
one[73] of these trials have been published in full.
Venlafaxine XR was given once daily at dosages
ranging from 75 to 225 mg/day for up to 8 to 24
weeks in flexible dose studies.[7,70,71,73,74] In these
studies, all patients received placebo during a 4- to
10-day lead-in period before double-blind treat-
ment began. A dosage of 75 mg/day was evaluated
in a single 12-week fixed dose study.[72]
In the studies that evaluated the effects of
study medication on symptoms of depression,
primary outcome measures were the change in
scores between baseline and end-point on the
Hamilton Rating Scale for Depression (HAM-D),
the Montgomery-Åsberg Depression Rating Scale
(MADRS), the Clinical Global Impression Severity
of Illness (CGI-S) and Clinical Global Impression
Global Improvement (CGI-I) scales, as well as the
reduction from baseline in the HAM-D depressed
mood item. In the studies investigating symptoms
of anxiety in patients with depression, primary
outcome measures were changes from baseline
scores in the Hamilton Rating Scale for Anxiety
(HAM-A), HAM-D psychic anxiety item and the
CGI-I scale. All studies enrolled elderly patients
(aged ≥65 years); the age range across the trials was
between 18 and 83 years. In all studies, efficacy
analyses were performed on a modified intent-to-
treat basis. This included all randomised patients
who received ≥1 dose of study medication, had ≥1
baseline evaluation of one primary efficacy vari-
able, and had ≥1 primary efficacy evaluation while
receiving treatment. The last observation was car-
ried forward for patients who discontinued treat-
ment prematurely.
4.1 Comparisons with Placebo
Venlafaxine XR produced consistent and sig-
nificant reductions in all primary outcome meas-
ures compared with placebo during an 8-week flex-
ible dose study (table V).[70] Treatment was initiated
at 75 mg/day and, if the response was inadequate,
the dosage could be increased in increments of
75 mg/day every 2 weeks to a maximum of 225
© Adis International Limited. All rights reserved.
Wellington & Perry
mg/day. The mean dosage from days 29 to 56 ranged
from 172 to 177 mg/day. A significant reduction in
the CGI-S score was evident after 2 weeks of treat-
ment with venlafaxine XR 75 mg/day, and the HAM-
D depressed mood item score was significantly re-
duced by the beginning of week 3 (p < 0.05 vs
placebo). By week 4, venlafaxine XR was signifi-
cantly more effective than placebo (p < 0.05) at re-
ducing the HAM-D and MADRS total scores.[70]
The greater therapeutic effect of venlafaxine
XR compared with placebo was maintained through-
out the remainder of the study. By week 8, the change
in baseline scores for all primary outcome measures
was approximately twice as large in the venla-
faxine XR group as in the placebo group.
The HAM-D, MADRS and CGI-I therapeutic
response rates, defined as a ≥50% reduction in
HAM-D and MADRS total scores or a score of 1 or
2 on the CGI-I rating, were significantly greater in
recipients of venlafaxine XR than those in the pla-
cebo group (p ≤ 0.005) at week 8 (table V). More-
over, the HAM-D and CGI-I therapeutic response
rates to venlafaxine XR were significantly greater
than those to placebo by week 6 (p < 0.05). Sus-
tained response rates, as determined by an improve-
ment in the HAM-D, MADRS and CGI-I scales
that, once observed, persisted until the end of treat-
ment, were significantly higher (p < 0.05) with
venlafaxine XR (37.2, 34.1 and 40.0%, respec-
tively) than with placebo (18.8, 16.5 and 24.0%)
[values estimated from graph].[70]
Remission (defined as a HAM-D score of ≤8)
was achieved in 35% of patients given venlafaxine
XR and 19% of placebo recipients. Furthermore,
significantly fewer venlafaxine XR–treated pa-
tients than placebo recipients discontinued treat-
ment because of unsatisfactory clinical response
(5 vs 22%; p ≤ 0.001).[70]
In a second flexible dose study which exam-
ined relapse prevention and was reported as an
abstract,[73] 328 patients with major depressive
disorder who responded to venlafaxine XR 75 to
225 mg/day during an 8-week, nonblind lead-in
period were randomised to continue receiving
CNS Drugs 2001; 15 (8)
Venlafaxine Extended-Release: A Review 655

Table V. Efficacy of once daily venlafaxine XR (VEN) in patients with major depression in multicentre, randomised, double-blind studies
Treatment No. of Baseline scores Results at end-point (mean change from baseline)a Response rate (% of pts)b
(mg/day) pts HAM-D MADRS HAM-D total HAM-D CGI-S MADRS HAM-D CGI-I
total depressed
mood

Thase et al.[70] (flexible dose, 8 weeks)c

VEN 75-225 91 24.1 27.9 ↓11.7*** ↓1.5*** ↓1.6*** ↓12.7*** 58** 60**
PL 100 24.1 27.9 ↓7.3 ↓0.7 ↓0.9 ↓7.3 29 37
[7] d
Cunningham et al. (flexible dose, 12 weeks)
VEN 75-150 92 24.5 26.7 ↓15.1***† ↓1.22***†e ↓2.1***† ↓16.1***† 69.4***†f NR
VEN IR 75-150g 87 24.0 26.5 ↓11.7*** ↓1.05***e ↓1.4** ↓13.2*** 53.5*f NR
PL 99 24.9 26.6 ↓9.1 ↓0.49e ↓1.1 ↓8.3 31.2f NR
[71] h
Rudolph et al. (flexible dose, 8 weeks)
VEN 75-225 95 25 28 ↓12.5 NRi NRi ↓17.5* 57 71
FLU 20-60j 103 26 29 ↓11.8 NRi NRi ↓15.2 50 62
PL 97 25 29 ↓10.2 NRi NRi ↓13.3 42 52
[72] k
McPartlin et al. (fixed dose, 12 weeks)
VEN 75 183 23 29 ↓14.7 ↓2.1 ↓2.3 ↓19.3 74.0f 79.4f
PAR 20j 178 23 29 ↓14.1 ↓1.9 ↓2.3 ↓18.3 70.8f 75.7f
a Last observation was carried forward for patients who withdrew from the study.
b Response rates were defined as ≥50% reductions from baseline in HAM-D total scores or a CGI-I score of 1 or 2.
c Patient ages ranged from 18 to 77 years (mean = 41).
d Patient ages ranged from 18 to 72 years (mean = 41).
e Mean change from week 1 because baseline values were not reported.
f Values estimated from a graph.
g Administered in 2 divided doses.
h Patient ages ranged from 18 to 80 years (mean = 40).
i Baseline values were not reported.
j Administered once daily.
k Patient ages ranged from 18 to 83 years (mean = 45).
CGI-I = Clinical Global Impression-Global Improvement; CGI-S = Clinical Global Impression-Severity of Illness; FLU = fluoxetine; HAM-D =
Hamilton Rating Scale for Depression; MADRS = Montgomery-Åsberg Depression Rating Scale; NR = not reported; PAR = paroxetine; PL
= placebo; pts = patients; VEN IR = venlafaxine immediate-release; XR = extended-release; ↓ = decrease; * p ≤ 0.05, ** p ≤ 0.01, *** p ≤
0.001 vs PL; † p < 0.05 vs VEN IR.

venlafaxine XR or to be switched to placebo for 4.2 Comparisons with Venlafaxine

up to 6 months under double-blind conditions.
Cumulative relapse rates (CGI-S score ≥4) were
lower for venlafaxine XR–treated patients than
for placebo recipients after 3 and 6 months (18.5
and 28.0% vs 43.2 and 52.4%, respectively; p <
0.001 vs placebo). Furthermore, significantly
fewer patients treated with venlafaxine XR discon-
tinued treatment because of lack of therapeutic
response (24 vs 42%; p < 0.001 vs placebo).[73]
Immediate-Release and Placebo
Venlafaxine XR was significantly more effec-
tive than venlafaxine IR or placebo in a 12-week
randomised, double-blind, multicentre study.[7]
Among patients randomised to receive venlafaxine
XR 75 to 150 mg/day (mean dosage from week 3
to 12 was 124 to 140 mg/day) or venlafaxine IR 75
to 150 mg/day (mean = 115 to 125 mg/day), mean
reductions in all primary efficacy variables (HAM-D

© Adis International Limited. All rights reserved. CNS Drugs 2001; 15 (8)
656
Venlafaxine XR
Venlafaxine IR
Placebo
70
**†
60
Reduction from baseline (%)
**†
50 **
40
*
30
20
10
0 12 (p < 0.01; actual values not reported).
HAM-D total CGI-S
Fig. 2. Efficacy of venlafaxine extended-release (XR) compared
with venlafaxine immediate-release (IR) or placebo in 278 pa-
tients with major depression. Percentage reductions from base-
line in Hamilton Rating Scale for Depression (HAM-D) total,
Montgomery-Åsberg Depression Rating Scale (MADRS) or
Clinical Global Improvement-Severity of Illness (CGI-S) scores.
Patients received venlafaxine XR 75 to 150 mg/day (n = 92),
venlafaxine IR 75 to 150 mg/day (n = 87) or placebo (n = 99) for
12 weeks in a randomised, double-blind, multicentre trial. [7]
* p ≤ 0.01, ** p ≤ 0.001 vs placebo; † p < 0.05 vs venlafaxine IR.
and MADRS total scores, HAM-D depressed mood
item and the CGI-S rating) were significantly
greater than those in placebo recipients at week 12
(table V). Reductions from baseline in HAM-D total
and CGI-S scores were significantly higher among
patients treated with venlafaxine XR than venla-
faxine IR at week 8 (–13.7 and –1.86 vs –11.1 and
–1.38, respectively; p < 0.05). Furthermore, reduc-
tions from baseline were significantly greater
among recipients of venlafaxine XR for all 4 effi-
cacy variables at week 12 (p < 0.05 vs venlafaxine
IR; table V). Figure 2 illustrates the mean percent-
age reduction from baseline at week 12 of the
HAM-D, MADRS and CGI-S scores (baseline val-
ues for the HAM-D depressed mood item were not
reported). Venlafaxine XR and IR both signifi-
cantly reduced the HAM-D depressed mood item
score compared with placebo from week 2 (p < 0.01)
to week 12 (p < 0.001). Similarly, reductions in
HAM-D total scores were significantly greater
© Adis International Limited. All rights reserved.
Wellington & Perry
among venlafaxine XR- or venlafaxine IR–treated
patients than placebo recipients at week 2 and from
week 4 to 12 (p < 0.001 and 0.05 vs placebo, respec-
**† tively). Reductions in MADRS scores were signif-
icantly higher in the active treatment groups than
** in placebo recipients from weeks 3 to 12 (p < 0.05).[7]
Response rates based on the HAM-D (table V) and
MADRS scales were significantly higher in pa-
tients treated with venlafaxine XR than in patients
treated with venlafaxine IR (p < 0.05) or placebo
(p < 0.001) at week 12. Response rates based on CGI-I
criteria were significantly higher among recipients
of venlafaxine XR than placebo during weeks 3 to
MADRS Sustained response rates based on the HAM-D
and MADRS total scores and the CGI-I scale were
significantly higher with venlafaxine XR and venla-
faxine IR than with placebo (p < 0.05).[7]
Discontinuations because of an unsatisfactory
clinical response were significantly higher (p = 0.01)
among patients given placebo (12%) than patients
given venlafaxine XR (2%) or venlafaxine IR (4%).[7]
4.2.1 Effects on Symptoms of Anxiety in Patients
with Depression
The effects of venlafaxine XR on symptoms of
anxiety in patients with major depression have
been evaluated in a separate analysis[6] of 2 of the
trials[7,70] described in sections 4.1 and 4.2.
Venlafaxine XR was significantly more effective
than placebo at reducing symptoms of anxiety in 2
randomised, double-blind, multicentre studies that
enrolled patients with depression and associated
anxiety.[6] In 1 study, among patients randomised
to venlafaxine XR 75 to 150 mg/day or venlafaxine
IR 75 to 150 mg/day, mean reductions in the HAM-D
psychic anxiety score were significantly greater
than those in placebo recipients at week 12 (table
VI). Similarly, in the other study, venlafaxine XR
75 to 225 mg/day produced significant reductions
in anxiety in patients with moderate (HAM-D
psychic anxiety score ≥2 and ≤3) or severe (HAM-
D psychic anxiety score ≥3) anxiety compared
with placebo (table VI).[6]
Response rates in both studies, defined as a re-
duction in the HAM-D psychic anxiety score to <2
CNS Drugs 2001; 15 (8)
Venlafaxine Extended-Release: A Review 657

Table VI. Efficacy of venlafaxine XR (VEN), venlafaxine immediate-release (VEN IR) and placebo (PL) for symptoms of anxiety in patients
with major depression. A subanalysis[6] of the results of 2 randomised, double-blind, placebo-controlled, multicentre studies[7,70]
Treatment No. of No. of pts Baseline scores Results at end-point (mean change Response
(mg/day) pts with severe from baseline)a rate (% of pts)b
anxiety HAM-D psychic HAM-D psychic HAM-D psychic HAM-D psychic HAM-D
(HAM-D anxiety (in all anxiety in pts with anxiety (in all anxiety in pts psychic
psychic pts)c severe anxietyc pts)c with severe anxiety
anxiety ≥3) anxietyc

Study 1[6] (flexible dose, 12 weeks)d

VEN 75-150 80 26 2.5 3.1 ↓1.6*** ↓2.3*** 74***
VEN IR 75-150e 82 41 2.4 3.1 ↓1.3*** ↓1.9* 67***
PL 90 29 2.4 3.1 ↓0.7 ↓1.4 39

Study 2[6] (flexible dose, 8 weeks)f

VEN 75-225 77 25 2.4 3.1 ↓1.2*** ↓2.1** 68***
PL 84 35 2.4 3.1 ↓0.7 ↓1.3 36
a Last observation was carried forward for patients who withdrew from the study.
b Response rates were defined as a final HAM-D psychic anxiety score of <2 in patients who had a baseline score of ≥2.
c Values estimated from a graph.
d Patient ages ranged from 18 to 72 years (mean = 41).
e Administered in 2 divided doses.
f Patient ages ranged from 18 to 77 years (mean = 41).
HAM-D = Hamilton Rating Scale for Depression; pts = patients; XR = extended-release; ↓ = decrease; * p ≤ 0.05, ** p = 0.002, *** p ≤ 0.001
vs PL.

in patients who had a baseline score ≥2, were sig-
nificantly higher with venlafaxine XR than with
placebo (table VI). Anxiety developed in 7% of
patients who received venlafaxine XR compared
with 19 and 22% of patients given venlafaxine IR
or placebo, respectively (no statistical analysis was
reported). There was no significant difference be-
tween response rates (based on the HAM-D psy-
chic anxiety item) in patients receiving venlafaxine
XR or venlafaxine IR (i.e. 74 vs 67%; table VI).[6]
Among patients with severe anxiety, a reduction in
anxiety was reported in 88% of patients receiving
venlafaxine XR, 78% of patients given venlafaxine
IR and 69% of placebo recipients (statistical anal-
ysis not reported).[6]
A pooled analysis of both studies involving
the HAM-D item scores from the anxiety somatisa-
tion cluster (psychic anxiety, somatic anxiety, so-
matic gastrointestinal and somatic general items)
showed mean score reductions in patients who
received venlafaxine XR were significantly higher
than in those receiving placebo (p < 0.001) or ven-
lafaxine IR (p < 0.05) at week 12 (fig. 3).
While this subanalysis suggests that venla-
faxine XR reduces symptoms of anxiety in depressed
patients, well designed trials using symptom-specific
instruments, such as the HAM-A, are needed to
support these findings.
4.3 Comparisons with Fluoxetine
and Placebo
Venlafaxine XR has been compared with fluox-
etine and placebo in patients with major depression
in 2 randomised, double-blind, placebo-controlled,
multicentre studies.[71,74]
There were no significant differences in mean
reductions in HAM-D or HAM-A total scores at
end-point (using a last observation carried forward
analysis) among patients randomised to venlafax-
ine XR 75 to 225 mg/day, fluoxetine 20 to 60 mg/day
or placebo for 8 weeks (table V).[71] However,
whereas venlafaxine XR significantly reduced the

© Adis International Limited. All rights reserved. CNS Drugs 2001; 15 (8)
658
4.0 **
3.5
anxiety/somatisation cluster scores
*
Mean reductions in HAM-D
3.0
2.5
2.0
1.5
1.0
0.5
0 improvements in the anxiety and depression items
Venlafaxine XR Venlafaxine IR
Fig. 3. A pooled analysis[6] from 2 randomised, double-blind,
multicentre studies[7,70] of venlafaxine extended-release (XR),
venlafaxine immediate-release (IR) and placebo in patients with
major depression with associated anxiety. A comparison of the
mean reductions from baseline in Hamilton Rating Scale for
Depression (HAM-D) item scores for the anxiety somatisation
cluster (psychic anxiety, somatic anxiety, somatic gastrointesti-
nal and somatic general items) in patients who received
venlafaxine XR 75 to 225 mg/day (n = 157, from 2 studies),
venlafaxine IR 75 to 150 mg/day (n = 82, from 1 study) or pla-
cebo (n = 174, from 2 studies). * p < 0.01, ** p < 0.001 vs
placebo.
MADRS (p = 0.013), CGI-S (p = 0.01) and HAM-
D depressed mood (p = 0.002) scores compared
with placebo, fluoxetine significantly reduced only
the HAM-D depressed mood item compared with
placebo (p = 0.044).[71]
Significantly more patients treated with venla-
faxine XR achieved full remission based on a HAM-
D total score of ≤7 at end-point (p ≤ 0.05 vs fluoxetine
or placebo). 37, 22 and 18% of patients treated with
venlafaxine XR, fluoxetine or placebo, respec-
tively, achieved full remission.[71]
Venlafaxine XR and fluoxetine demonstrated
similar efficacy in reducing symptoms of depres-
sion and anxiety in a 12-week randomised, double-
blind, multicentre study that enrolled patients with
major depression and associated anxiety (patients
with a score of ≥8 on the Covi scale).[74] Among
patients randomised to venlafaxine XR 75 to 225
mg/day or fluoxetine 20 to 60 mg/day, mean reduc-
tions in HAM-D total scores were significantly
© Adis International Limited. All rights reserved.
Wellington & Perry
greater than those in placebo recipients from week
2 to week 12 (table VII). Reductions in HAM-A
total scores (table VII) in patients given venlafax-
ine XR were significantly greater than those in pla-
cebo recipients after 8 weeks (p < 0.05). Among
fluoxetine recipients, HAM-A total score reduc-
tions were significantly higher than those of pa-
tients given placebo (table VII) at only the final
on-therapy evaluation (week 12).[74]
There were also statistically significant im-
provements in some secondary efficacy parame-
ters. Among patients receiving active treatment,
Placebo
of the Hospital Anxiety and Depression Scale and
the Covi scale were significant (p < 0.05) compared
with those in placebo recipients from week 8.
Remission rates (based on a HAM-D total score
of <8 at end-point) among patients treated with
venlafaxine XR or fluoxetine were similar (46.0
and 45.2%, respectively) and significantly higher
than placebo-treated patients (24.4%; p < 0.001).
However, remission rates among venlafaxine-
treated patients were significantly higher than
those of placebo recipients from week 3, compared
with week 8 among recipients of fluoxetine.[74]
The HAM-A response rate (table VII) to venla-
faxine XR, defined as a ≥50% reduction in HAM-A
total scores, was significantly higher than that to
placebo at weeks 3, 8, 12 and the final on-therapy
evaluation (p < 0.05). Furthermore, the HAM-A
response rate was also significantly higher (p < 0.05)
among recipients of venlafaxine XR than fluoxet-
ine at week 12, but not at the final on-therapy eval-
uation. Discontinuation of venlafaxine XR (5%) or
fluoxetine (5%) because of unsatisfactory clinical
response occurred significantly less often than that
of placebo (24%) throughout the trial.[74]
4.4 Comparison With Paroxetine
Venlafaxine XR 75 mg/day or paroxetine 20 mg/day
demonstrated similar efficacy in patients with ma-
jor depression. Reductions from baseline in HAM-
D and MADRS total scores among patients receiv-
ing venlafaxine XR or paroxetine for 12 weeks
were significant (p ≤ 0.05), but there were no sig-
CNS Drugs 2001; 15 (8)
Venlafaxine Extended-Release: A Review 659

Table VII. Efficacy of once daily venlafaxine XR (VEN) for symptoms of anxiety in patients with major depression in a 12-week, flexible dose,
multicentre, randomised, double-blind, placebo-controlled trial[74]
Treatment (mg/day) No. of Baseline scores Results at end-point (mean change Response rate (% of pts)c
ptsa from baseline)b
HAM-D HAM-A HAM-D total HAM-A total CGI-I HAM-D HAM-A HAM-D +
total total HAM-A
VEN 75-225 122 27.2 25.2 ↓15.9*** ↓13.7** 2.0*** 67.8***d 66.0*†d 66.9*d
FLU 20-60 e
119 27.2 25.2 ↓15.2*** ↓12.4* 2.0*** 65.0*** d
55.0d
54.9*d
PL 118 27.2 25.2 ↓11.1 ↓10.2 2.7*** 42.8d 43.4d 36.4d
a Patient ages ranged from 18 to 71 years (mean = 42).
b Last observation was carried forward for patients who withdrew from the study.
c Response rates were defined as ≥50% reductions from baseline in HAM-D and/or HAM-A total scores.
d Values estimated from a graph.
e Administered once daily.
CGI-I = Clinical Global Impression-Global Improvement; FLU = fluoxetine; HAM-A = Hamilton Rating Scale for Anxiety; HAM-D = Hamilton
Rating Scale for Depression; PL = placebo; pts = patients; XR = extended-release; ↓ = decrease; * p ≤ 0.05, ** p = 0.002, *** p ≤ 0.001 vs
PL; † p < 0.05 vs fluoxetine.

nificant differences between the 2 treatment TCAs amitriptyline, imipramine, desipramine or

groups in any of the outcome measures (table V).
Similarly, there were no significant between-group
differences in response rates based on the HAM-D,
MADRS or CGI-I scales, although the proportion
of responders was higher among patients receiving
venlafaxine XR (table V).[72]
Remission (defined as a HAM-D score of <7)
was achieved in 53.7% of patients given venlafax-
ine XR and 52.2% of paroxetine recipients.
Discontinuation of treatment because of unsat-
isfactory clinical response was similar among
venlafaxine XR– and paroxetine-treated patients
(i.e. 1 vs 3%).[72]
4.5 Meta-Analyses
Two meta-analyses concluded that venlafaxine
XR is associated with a significantly higher suc-
cess rate than either SSRIs[75,76] or tricyclic antide-
pressants (TCAs)[75] in the treatment of patients
with major depression.
The results of 44 randomised, double-blind,
controlled trials were combined in a meta-analysis
in order to compare the clinical success rates (de-
fined as a reduction of ≥50% in the HAM-D or
MADRS total scores measured at 6 to 8 weeks) of
venlafaxine XR, the SSRIs fluoxetine, fluvoxam-
ine, paroxetine, sertraline or citalopram, and the
nortriptyline in patients (n = 4033, including 409
inpatients and 3624 outpatients) with major de-
pressive disorder.[75] Patients included in the se-
lected trials had a baseline score of ≥15 or ≥18 on
the HAM-D or MADRS instruments, respectively.
However, neither the severity of depression nor the
dosage of antidepressants in individual trials was
taken into consideration. Furthermore, none of the
5 studies that involved venlafaxine XR were pub-
lished at the time of the analysis.
The authors of the meta-analysis concluded that
venlafaxine XR demonstrated a significantly
higher mean success rate (73.7%) than that of the
studied SSRIs or TCAs (61.1 and 57.9%, respec-
tively; p < 0.001). Furthermore, although the results
were not statistically significant, venlafaxine XR
(15.7%) was associated with a lower dropout rate
due to adverse events or lack of efficacy than the
SSRIs (25.8%) or TCAs (29.9%).[75]
In the other meta-analysis,[76] results from 8
randomised, double-blind, controlled studies (3 of
which involved venlafaxine XR and 5 of which
concerned venlafaxine IR) involving 2045 patients
were pooled in order to compare remission rates
(defined as a total score of ≤7 on the first 17 items
of the HAM-D instrument) during treatment with
venlafaxine, the SSRIs fluoxetine, fluvoxamine or

© Adis International Limited. All rights reserved. CNS Drugs 2001; 15 (8)
660 Wellington & Perry

35 Placebo
Venlafaxine XR

30

25
Incidence (% of patients)

20

15

10

0
m a
th

ip ia
Vo tion

ul g
e
no s
In nce

no vou nia

dr s

Tr s

P re r
ec es n

ed ia

al git o
ac on

po n

Va rga ce

H ilat ia
te n
ar ion
tis
Sw wn

no sth g
dy al v ia
gh n

s
o
m es

al es

os
se

Fl itin

D nc

D ara ssio

rm A bid

Im latio

er tio

Ab A tin

ei isio
on ex

as es

so sm

Bo rm en
ou

D em

gi
o n
ej ati

Ya
Ab er m

ea

Ph ns
So zin

rm sn

tl
au

le

An te

yp a

ea
yn
C nor

re th

li
N so

u
N

iz
st

at
ry

ep
A

d
D

w
no
Ab

Digestive system Nervous system Urogenital CVS RS Other adverse

system events

Fig. 4. Adverse events in patients with major depression during treatment with venlafaxine extended-release (XR). Incidence of
adverse events reported by patients during 8 to 12 weeks of treatment with venlafaxine XR 75 to 225 mg/day (n = 357) or placebo
(n = 285) in 3 randomised, double-blind, multicentre studies.[35] Adverse events presented occurred in ≥2% of venlafaxine XR
recipients (statistical analysis not reported). CVS = cardiovascular system; RS = respiratory system.

paroxetine, or placebo in patients with major de-
pression (defined as a total score of ≥20 or ≥21 on the
HAM-D or MADRS instruments, respectively).
Remission rates in patients given venlafaxine were
significantly higher (45%) than in patients given
SSRIs (35%) or placebo (25%; p < 0.001 versus
SSRIs or placebo). Onset of remission occurred 1
to 2 weeks earlier in venlafaxine recipients than in
patients given SSRIs or placebo. The study also
reported that venlafaxine dosages of ≥150mg/day
were more likely to maximise the possibility of
remission.[76]
In a retrospective pooled analysis that compared
remission rates and the absence of depressed mood
among 1026 patients with major depression treated
with venlafaxine 75 to 300 mg/day (specific formu-
lation not specified) or paroxetine 20 to 40 mg/day
for 8 weeks, venlafaxine was associated with a
higher rate of remission and absence of depressed
mood than paroxetine.[77] Remission was defined
as a score of ≤7 on the first 17 items of the HAM-D
instrument. Absence of depressed mood was de-
fined as a HAM-D depressed mood item score of 0.
Among the 554 patients treated with venlafaxine,
45% achieved remission, compared with 38% of
paroxetine-treated patients (p < 0.05). Furthermore,
39% of venlafaxine recipients had an absence of
depressed mood compared with 30% of paroxetine
recipients (p < 0.05). Response rates (defined as a
≥50% reduction from baseline in the HAM-D total

© Adis International Limited. All rights reserved. CNS Drugs 2001; 15 (8)
Venlafaxine Extended-Release: A Review
score) were also significantly in favour of venla-
faxine. By week 1, 5% of venlafaxine recipients
were deemed responders, compared with 1% of
paroxetine-treated patients (p = 0.01); by week 6,
48 vs 39% of venlafaxine or paroxetine recipients,
respectively, were deemed responders. However,
because the formulation of venlafaxine (XR or IR)
used in these patients was not reported, conclu-
sions specific to venlafaxine XR cannot be made.
Moreover, it was not reported if the data used in
the analysis were from randomised, double-blind
trials.[77]
An Italian pharmacoeconomic analysis[78] that
utilised the results from one of the meta-analyses
discussed above[75] concluded venlafaxine XR to
be the most cost-effective antidepressant for the
initial treatment of major depression in both in-
patients and outpatients.[78] Costs were valued in
Italian Lira (2001, L1000 ≈ $US0.476). Initiating
treatment with venlafaxine XR was associated
with an estimated saving of L94008 ($US44.70)
per outpatient when compared with SSRIs and a
saving of L18541 ($US8.82) when compared with
TCAs. Among inpatients, initiation of treatment
with venlafaxine was associated with savings of
L619500 ($US294.86) and L906828 ($US431.62)
when compared with SSRIs and TCAs, respec-
tively.[78]
5. Tolerability
General and comparative reviews of the tole-
rability of venlafaxine in patients with depres-
sion or other disorders have been published else-
where.[43,44,79-85]
Adverse events reported by patients with de-
pression during ≤12 weeks of treatment with venla-
faxine XR 75 to 225 mg/day (n = 357) or placebo
(n = 285) in 3 studies are presented in figure 4.[35]
The most frequently reported adverse events per-
tained to the digestive (nausea, dry mouth), nervous
(dizziness, somnolence, insomnia) and urogenital
(predominantly delayed ejaculation) systems.
Sweating was also commonly reported.[35]
Approximately 11 and 6% of patients receiving
venlafaxine XR or placebo, respectively, withdrew
© Adis International Limited. All rights reserved.
661
from these studies because of adverse events. Nau-
sea (4 vs <1%), dizziness (2 vs 1%) and somnolence
(2 vs <1%) were the most common events that
resulted in discontinuation of treatment among
patients in the 3 studies.[35]
Among 5 studies described in section 4 that de-
tailed the number of patients who discontinued
treatment because of adverse effects, 10, 13, 8, 16
and 4% of patients randomised to venlafaxine XR
(62 of 603), venlafaxine IR (12 of 96), fluoxetine
(17 of 224), paroxetine (29 of 178) or placebo (15
of 419), respectively, withdrew because of adverse
events.[7,70-72,74]
The frequency of nausea associated with
venlafaxine XR was highest during the first week
of treatment and decreased thereafter.[7,70-72,74] For
example, during the first week of treatment with
venlafaxine XR 75 to 225 mg/day, nausea was
reported by 26% of patients compared with 5% of
patients receiving placebo. However, by week 2
the incidence of nausea decreased to 14% in
venlafaxine XR recipients and for the remaining 6
weeks the incidence was similar among patients in
both groups.[70]
Comparative studies with fluoxetine[71,74] and
paroxetine[72] (sections 4.3 and 4.4) demonstrated
a similar adverse event profile to venlafaxine XR.
Dizziness and sweating were reported by signifi-
cantly (p ≤ 0.05) more venlafaxine XR recipients (38
and 28% of patients, respectively) than those re-
ceiving fluoxetine (18 and 17%) in one study,[74]
and in the other study,[71] dizziness and nausea
were more prevalent in venlafaxine XR recipients
(26 and 36%) than those receiving fluoxetine
(6 and 20%; p < 0.05).[71] There were no significant
between-group differences in adverse events among
patients receiving venlafaxine XR 75 mg/day or
paroxetine 20 mg/day.[72] However, the mean du-
ration of nausea was twice as long in paroxetine-
treated patients (10 days) as in patients treated with
venlafaxine XR (5 days).
A benefit/risk analysis[5] of a randomised, double-
blind, placebo-controlled study that compared
venlafaxine XR and venlafaxine IR,[7] and inclu-
ded both efficacy and tolerability results, found
CNS Drugs 2001; 15 (8)
662 Wellington & Perry

Venlafaxine XR
Venlafaxine IR
Placebo

Nausea

Dry mouth

Anorexia

Constipation

Diarrhoea

Dizziness

Somnolence

Abnormal dreams

Abnormal ejaculation/
orgasm (men)

Sweating

0 10 20 30 40 50
Incidence (% of patients)

Fig. 5. Tolerability of venlafaxine extended-release (XR) compared with venlafaxine immediate-release (IR) and placebo in patients
with major depression; results from a randomised, double-blind, placebo-controlled trial. Incidence of adverse events reported by
≥10% of patients who received once daily venlafaxine XR 75 to 150 mg/day (n = 97), twice daily venlafaxine IR 75 to 150 mg/day (n
= 96) or placebo (n = 100) for 12 weeks. No statistical analysis was reported.[7]

venlafaxine XR to have a significantly higher ben-
efit to risk ratio than venlafaxine IR. Benefit/risk
was evaluated using a linear measure and a ratio
measure for dizziness, insomnia, nausea, nervous-
ness, somnolence and a composite of anticholiner-
gic events. A benefit to risk ratio of at least 2 : 1 for
venlafaxine XR over venlafaxine IR was deter-
mined for nausea and dizziness (p ≤ 0.05).[5] Figure
5 compares the incidence of adverse events re-
ported by ≥10% of patients who received venlafax-
ine XR, venlafaxine IR or placebo during the 12-
week study.[7]
Treatment with venlafaxine XR may increase
DBP in some patients (section 2.3).[35] In patients
with depression, mean DBP increased by 1.2mm
Hg during 8 to 12 weeks of venlafaxine XR treat-
ment with dosages ranging from 75 to 225 mg/day.
Only 0.7% of patients (5 of 705) discontinued treat-
ment because of elevated BP.[35]
5.1 Serious Adverse Events
5.1.1 Overdose
Although venlafaxine is considerably less haz-
ardous than TCAs, overdosage of venlafaxine XR
can cause some cardiovascular effects (section 2.3).
There were 2 reports of acute overdose (6 and
2.85g) among the 583 patients with depression who
received venlafaxine XR 75 to 225 mg/day during

© Adis International Limited. All rights reserved. CNS Drugs 2001; 15 (8)
Venlafaxine Extended-Release: A Review
the clinical trials described in section 4. However,
both patients recovered without serious complica-
tion.[35] The manufacturer advises that fatalities
have been reported in patients taking overdoses of
venlafaxine, predominantly in combination with
alcohol or other drugs.[35]
5.1.2 Serotonin Syndrome
There have been reports of serotonin syndrome
in patients receiving venlafaxine concomitantly
or within ≤16 days of discontinuation of MAOIs
[isocarboxazide, phenelzine, selegiline (deprenyl),
tranylcypromine, moclobemide].[86-93] There have
also been reports of serotonin syndrome in patients
receiving venlafaxine alone.[94,95] These serious re-
actions consist of cognitive, autonomic and neuro-
muscular signs and symptoms.[92] The combined
use of venlafaxine and MAOIs is contraindicated
(section 6).[35]
6. Dosage and Administration
Venlafaxine XR is indicated for the treatment of
depression as defined by DSM-IV criteria (table
III). The recommended initial dosage of the drug
in patients with depression is 75mg once daily,
taken with food at the same time each day (either
in the morning or the evening). Some patients may
need to start with a dosage of 37.5 mg/day for 4 to
7 days to allow them to adjust to the medication.
In patients who do not improve with 75 mg/day,
the dosage may be titrated in increments of ≤75
mg/day, at intervals of ≥4 days, to a maximum dosage
of 225 mg/day. Dosage adjustments (based solely
on age) are not required in elderly patients.[14,35]
Dosage adjustments are recommended in pa-
tients with renal or hepatic dysfunction because of
altered pharmacokinetics of venlafaxine in these
patients (section 3.3). The initial dosage of venla-
faxine XR should be halved in patients with mod-
erate hepatic impairment and in those receiving
haemodialysis. In patients with renal dysfunction
(CLCR 0.6 to 4.2 L/h; 10 to 70 ml/min), the total daily
dose should be reduced by 25 to 50%. The drug
should be given after haemodialysis sessions.
Dosage individualisation may be desirable in some
patients with renal or hepatic impairment because
© Adis International Limited. All rights reserved.
663
of the wide interindividual variability in clearance
of venlafaxine XR in these patients.[35]
Venlafaxine XR has recently been approved for
the prevention of relapse and the prevention of re-
currence of depression.[96] Although the optimum
duration of treatment in patients with depression
has not been determined, international guidelines
recommended that, following remission, patients
should receive treatment for 16 to 20 weeks to pre-
vent relapse.[97,98] Furthermore, following this con-
tinuation phase, a maintenance phase should be
considered to prevent recurrence of major depres-
sive disorder.[97,98]
When discontinuing venlafaxine XR after more
than 1 week’s treatment, the manufacturer recom-
mends that the dosage be tapered in order to mini-
mise the risk of discontinuation symptoms, which
include asthenia, dizziness, headache, insomnia,
nausea and nervousness.[99-107] In clinical trials, the
dosage of venlafaxine XR was tapered by reducing
the daily dose by 75mg at weekly intervals.[35]
Concomitant use of venlafaxine XR and MAOIs
is contraindicated. A washout period of ≥14 days
is required when switching patients from an MAOI
to venlafaxine XR and a washout period of at
least 7 days is recommended when switching from
venlafaxine XR to an MAOI.[35]
Venlafaxine is associated with prolonged incre-
ases in BP in some patients (section 5); therefore,
the manufacturer recommends that patients receiv-
ing venlafaxine XR have regular BP monitoring
and that the dosage be reduced or the drug discon-
tinued in patients who experience a sustained in-
crease in BP during treatment.[35]
Although it has been demonstrated in healthy
volunteers that venlafaxine does not significantly
affect driving ability,[28] the manufacturer recom-
mends that patients wait until they are certain that
venlafaxine XR therapy will not adversely affect
their ability to drive.[35]
Venlafaxine is included in pregnancy cate-
gory C (risk cannot be ruled out) by the US Food
and Drug Administration.[35] Both venlafaxine and
ODV are excreted in human milk (section 3). A
decision should be made whether to discontinue
CNS Drugs 2001; 15 (8)
664
the drug after considering the importance of the
drug to the nursing mother.[35]
7. Role of Venlafaxine
Extended-Release in the
Management of Major Depression
Depression is a relatively common disease with
a lifetime prevalence of about 4 to 12% for men
and 12 to 26% for women in the US.[108] Depres-
sion is recurrent, affects people from all walks of
life, and generally first becomes manifest in early
adulthood. The risk of recurrence after one episode
of major depression is about 50%, and the risk in-
creases after further episodes. Furthermore, the life-
time risk of suicide in major depression is about
3.5%.[109]
The management of depression largely involves
pharmacological intervention with some degree of
supportive psychotherapy.[110] Both antidepressant
pharmacotherapy or depression-specific psycho-
therapy, as reviewed by Schulberg et al.,[111] are
effective when transferred from psychiatric to pri-
mary care settings. Psychological interventions in-
clude activating positive activities, changing neg-
ative thought patterns and behavioural problems,
such as lack of assertiveness, and educating the pa-
tient about depression and the fact that it is a dis-
ease and not a moral weakness.[112-114] A review of
meta-analyses of studies in patients with major de-
pression estimated that approximately 50% of pa-
tients who received psychological treatment may
achieve normal functioning.[111] Cognitive, behav-
ioural and interpersonal psychotherapy appeared
to be most effective.[111]
Selection of pharmacotherapy depends on the
severity and duration of symptoms, the perceived
risk for overdose, age-related physiological fac-
tors and comorbid conditions that may affect the
pharmacological profile of the drug (pharmacoki-
netics and/or pharmacodynamics), previous re-
sponses to antidepressant therapy, concurrent drug
therapy that may increase the potential for signifi-
cant drug interactions, and the ability to tolerate
adverse effects.[115]
© Adis International Limited. All rights reserved.
Wellington & Perry
For decades, the only antidepressants available
were TCAs (e.g. amitriptyline, imipramine and desi-
pramine) and MAOIs (e.g. isocarboxazid, phenel-
zine and tranylcypromine). Although both are ef-
fective classes of antidepressants, the incidence of
adverse effects associated with TCAs has been as-
sociated with poor compliance[116] and the use of
suboptimal doses,[117] and MAOIs have the potential
for severe drug-drug and drug-food interactions.[118]
TCAs have nonspecific serotonergic and nor-
adrenergic activity, as well as the potential to non-
selectively bind to muscarinic cholinergic, α 1-
adrenergic and H1 histaminergic receptors.[119] This
results in a number of adverse effects such as dry
mouth, dizziness, blurred vision, constipation,
sedation, and orthostatic hypotension.[2] Further-
more, they are potentially lethal in overdose.[120]
MAOIs, which also interact with several receptor
sites, have the potential to interact with tyramine,
causing potentially fatal hypertension. For this rea-
son, patients taking MAOIs must adhere to a strict
diet that restricts tyramine-containing foods. Addi-
tional adverse effects associated with MAOIs in-
clude hypotension, bodyweight gain and sexual
dysfunction.[2] Consequently, these factors have
been instrumental in limiting the use of TCAs and
MAOIs in patients with major depression.
The introduction of SSRIs (e.g. fluoxetine,
fluvoxamine, sertraline, paroxetine and citalopram)
was considered a major advance in the treatment of
depression because, while being comparable in
efficacy to TCAs, they have lower binding affini-
ties for receptor sites associated with the anticho-
linergic and antihistaminic effects or cardiac-
conduction disturbances typical of TCAs.[121]
Furthermore, the risk of death from either accidental
or deliberate overdose with SSRIs is much lower than
with TCAs or MAOIs.[121] As a result, they have be-
come established in the first-line treatment of uncom-
plicated unipolar depression and dysthymia.[118]
However, there is some controversy over
whether SSRIs are as effective as TCAs in treating
patients with severe depression,[120,122-124] although
a review by Hirschfeld [125] of trials in patients
CNS Drugs 2001; 15 (8)
Venlafaxine Extended-Release: A Review
with severe and melancholic depression concluded
comparable efficacy between the 2 classes of drug.
The most frequently reported adverse events as-
sociated with SSRIs involve gastrointestinal dis-
turbance, particularly nausea.[119] Other typical ad-
verse events include sexual dysfunction, insomnia,
fatigue, headache and anxiety.[121]
Venlafaxine XR, a selective inhibitor of serotonin
and NA reuptake, has proved effective in the treat-
ment of major depression in randomised, double-
blind, multicentre clinical trials. In placebo-con-
trolled trials in patients with DSM-IV–defined
major depression, venlafaxine XR, administered
once daily, was effective in improving signs and
symptoms of depression, as assessed by standard
psychiatric measures (see section 4). The efficacy
of venlafaxine XR was significantly better than
that of venlafaxine IR (p < 0.05) at reducing HAM-
D and MADRS total scores, HAM-D depressed
mood item and the CGI-S rating in patients with
major depression after 12 weeks’ treatment.[7] Fur-
thermore, venlafaxine XR was significantly more
effective than venlafaxine IR or placebo at reduc-
ing the HAM-D item scores from the anxiety
somatisation cluster among patients with major
depression. The improved efficacy of venlafaxine
XR compared with that of the IR formulation may
be associated with increased compliance and the
convenience of the once-daily regimen of venla-
faxine XR compared with the twice-daily admin-
istration of venlafaxine IR.
Venlafaxine XR demonstrated similar efficacy
to fluoxetine or paroxetine in patients with major
depression, although in one trial,[71] venlafaxine
XR was significantly more effective than fluoxetine
at reducing MADRS, but not HAM-D, total scores.
Remission rates, a secondary efficacy parameter,
were also significantly in favour of venlafaxine XR
in this study. Additionally, venlafaxine XR and
fluoxetine had comparable efficacy in reducing
HAM-D and HAM-A total scores in patients with
depression and associated anxiety.
The time to onset of action of venlafaxine XR
was similar to that of venlafaxine IR, fluoxetine
and paroxetine in patients with major depression.
© Adis International Limited. All rights reserved.
665
However, among patients with depression and as-
sociated anxiety, a significant therapeutic response
(reduction in HAM-A total scores) was evident
sooner (at 8 weeks) with venlafaxine XR than with
fluoxetine (at 12 weeks). There were no significant
between-group differences in the percentage of pa-
tients who discontinued treatment because of lack
of efficacy among recipients of venlafaxine XR,
venlafaxine IR, fluoxetine or paroxetine.
According to 2 meta-analyses,[75,76] treatment
with venlafaxine XR is associated with higher suc-
cess rates in patients with major depression than
treatment with the SSRIs fluoxetine, fluvoxamine,
paroxetine, sertraline or citalopram, or the TCAs
amitriptyline, imipramine, desipramine or nortrip-
tyline (section 4.5). However, the study found no
significant overall difference in the drop out rates
due to adverse events among the different treat-
ment groups. A retrospective pooled analysis also
demonstrated significantly higher rates of remis-
sion and absence of depressed mood in recipients
of venlafaxine compared with paroxetine. How-
ever, it was not specified whether patients received
venlafaxine XR or IR.[77] An Italian pharmaco-
economic analysis (section 4.5) that utilised the
results from the meta-analysis concluded that
initiation of treatment with venlafaxine XR in both
inpatients and outpatients with major depression is
more cost-effective than initiation of treatment
with SSRIs or TCAs.[78]
Among venlafaxine XR–treated patients, nausea
is more common at the start of treatment, but fre-
quently resolves with continued treatment (section
5). Importantly, venlafaxine does not impair psy-
chomotor performance. The percentage of patients
who discontinued treatment because of adverse
events was similar among recipients of venlafaxine
XR, venlafaxine IR, fluoxetine or paroxetine.
All of the clinical trials discussed in section 4
included patients aged ≥65 years; patient ages
ranged from 18 to 82 years. However, there have
been no trials specifically concerned with evaluat-
ing the efficacy and tolerability of venlafaxine XR
in elderly patients. Limited data from trials con-
cerning the IR formulation of venlafaxine have,
CNS Drugs 2001; 15 (8)
666
however, demonstrated that this formulation is as
effective and as well tolerated in both elderly and
young patients.[124]
In conclusion, venlafaxine XR has shown efficacy
in the treatment of major depression and was at
least as effective as fluoxetine or paroxetine and
more effective than venlafaxine IR. Furthermore,
it is effective at reducing symptoms of anxiety in
depressed patients. The incidence of adverse events
in recipients of venlafaxine XR is similar to that
in patients receiving treatment with well estab-
lished SSRIs. As an effective and well tolerated
antidepressant, venlafaxine XR should be consid-
ered as a first-line pharmacological treatment in
patients with major depression.
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