Differential physiological effects of a low dose and high doses of venlafaxine in major depression

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DOI: 10.1017/S1461145705006413 · Source: PubMed
Abstract
Venlafaxine is an antidepressant drug with demonstrated serotonin (5-HT) and norepinephrine (NE) reuptake blockade properties in electrophysiological and microdialysis experiments in laboratory animals. In healthy volunteers, its 5-HT reuptake-inhibiting potential has also been clearly documented, but not its NE reuptake blockade action. This double-blind study compared the effects of a low dose (75 mg) and of a forced titration of high (up to 375 mg in 1 wk) daily doses of venlafaxine. Forty-four patients with major depression according to DSM-IV criteria were assessed bi-weekly for the first 2 wk and weekly for the next 2 wk. Inhibition of 5-HT reuptake was estimated using the depletion of whole-blood 5-HT, while that of NE was assessed using the attenuation of the systolic blood-pressure elevations produced by intravenous injections of tyramine. Forty-two patients completed the study. Both the low and the high doses of venlafaxine decreased the levels of 5-HT to the same extent: the reduction was of about 55% after 1 wk and of 75% after 4 wk. The 75 mg/d dose of venlafaxine did not alter the tyramine pressor response, whereas, in patients receiving the higher regimens of venlafaxine, there was a significant attenuation of the pressor effect of tyramine. There was no significant difference between the two treatment arms regarding the modifications of the depression scores. The present data showed that, at its minimal effective dose in depression (75 mg/d), venlafaxine acted as a selective 5-HT reuptake inhibitor, whereas when administered at higher doses (225 and 375 mg/d), it acted as a dual 5-HT and NE reuptake inhibitor.
Differential physiological effects of a low
dose and high doses of venlafaxine in
major depression
Guy Debonnel
1
,E
´
lise Saint-Andre
´
1
, Chantal He
´
bert
1
,
3
, Claude de Montigny
1
,
Normand Lavoie
2
and Pierre Blier
1
,
3
1
Department of Psychiatry, McGill University, Montre
´
al, QC, Canada
2
Department of Urology, McGill University, Montre
´
al, QC, Canada
3
University of Ottawa Institute of Mental Health Research, Royal Ottawa Hospital, Ottawa, ON, Canada
Abstract
Venlafaxine is an antidepressant drug with demonstrated serotonin (5-HT) and norepinephrine (NE)
reuptake blockade properties in electrophysiological and microdialysis experiments in laboratory
animals. In healthy volunteers, its 5-HT reuptake-inhibiting potential has also been clearly documented,
but not its NE reuptake blockade action. This double-blind study compared the effects of a low dose
(75 mg) and of a forced titration of high (up to 375 mg in 1 wk) daily doses of venlafaxine. Forty-four
patients with major depression according to DSM-IV criteria were assessed bi-weekly for the first 2 wk
and weekly for the next 2 wk. Inhibition of 5-HT reuptake was estimated using the depletion of whole-
blood 5-HT, while that of NE was assessed using the attenuation of the systolic blood-pressure elevations
produced by intravenous injections of tyramine. Forty-two patients completed the study. Both the low and
the high doses of venlafaxine decreased the levels of 5-HT to the same extent : the reduction was of about
55% after 1 wk and of 75 % after 4 wk. The 75 mg/d dose of venlafaxine did not alter the tyramine pressor
response, whereas, in patients receiving the higher regimens of venlafaxine, there was a significant at-
tenuation of the pressor effect of tyramine. There was no significant difference between the two treatment
arms regarding the modifications of the depression scores. The present data showed that, at its minimal
effective dose in depression (75 mg/d), venlafaxine acted as a selective 5-HT reuptake inhibitor, whereas
when administered at higher doses (225 and 375 mg/d), it acted as a dual 5-HT and NE reuptake inhibitor.
Received 13 September 2005; Reviewed 30 October 2005; Revised 14 November 2005; Accepted 22 November 2005;
First published online 11 May 2006
Key words : Norepinephrine reuptake, serotonin reuptake, tyramine.
Introduction
Venlafaxine has been used in humans since 1987 and
shown to be efficacious in major depression at doses
of 75–375 mg/d, possibly exerting a dose-dependent
effect (Guelfi et al., 1995, Goldberg and Finnerty, 1988;
Schweizer et al., 1988, 1991). Subsequently, it was
postulated that this non-tricyclic antidepressant drug
exerts a greater antidepressant action than selective
serotonin reuptake inhibitors (SSRIs). This issue still
remains controversial as venlafaxine has not always
been used at doses in its upper therapeutic range
when it is expected to inhibit norepinephrine (NE)
reuptake (Clerc et al., 1994 ; Poirier and Boyer, 1999;
Thase et al., 2001). Since venlafaxine is an effective
5-HT reuptake inhibitor, as all other SSRIs, it is poss-
ible that its NE reuptake inhibition could account for
this difference. However, the doses at which NE re-
uptake inhibition occurs in humans with venlafaxine
have not been clearly established (see Blier et al., 2006
for a review).
The main problem with establishing the NE
reuptake-inhibiting properties of various agents in
the brain is the lack of a direct method. Several ap-
proaches have been used to assess NE reuptake in the
periphery but some have yielded a significant inhibi-
tory action at its minimal effective dose of 75 mg/d,
for which there is no clinical evidence of superiority
over the effectiveness of SSRIs (Abdelmawla et al.,
1999; Bitsios et al., 1999; Melichar et al., 2001). Thus far,
the most consistent approach has been the tyramine
Address for correspondence : Professor P. Blier, University of Ottawa
Institute of Mental Health Research, Royal Ottawa Hospital, Lady
Grey Building, Suite 2043, Ottawa, Ontario, Canada K1Z 7K4.
Tel. : 613-722-6521 (ext. 6908) Fax : 613-792-3935
E-mail : pblier@rohcg.on.ca
International Journal of Neuropsychopharmacology (2007), 10, 51–61. Copyright f 2006 CINP
doi:10.1017/S1461145705006413
ARTICLE
CINP
pressor test. In brief, it consists of injecting a small
bolus of tyramine intravenously and measuring the
ensuing increase in systolic blood pressure (BP) that
results from the release of NE from peripheral NE
terminals (Hoffman and Lefkowitz, 1990). Since tyr-
amine penetrates into NE terminals via a NE reuptake
transporter that is identical to that present in the brain,
an attenuation of this response by drugs that block NE
reuptake has been used as an index of NE reuptake
inhibition (Ghose, 1984). Thus far, repeated adminis-
tration of amitriptyline, desipramine, nortriptyline,
clomipramine, maproptiline, tomoxetine (now de-
noted atomoxetine), and reboxetine, all of these drugs
blocking NE reuptake, have been shown to be effective
in this paradigm (Blier et al., 2006; Chalon et al., 2003;
Gobbi et al., 2003; Harvey et al., 2000; Hassan et al.,
1985, 1989; Slater et al., 2000; Turcotte et al., 2001;
Zerbe et al., 1985). In contrast, the SSRIs fluoxetine,
paroxetine, sertraline, and the atypical agent nefazo-
done, are inactive in this model at doses that are ef-
fective in major depression (Blier et al., 2006; Bowsher
et al., 1988 ; Harvey et al., 2000; Hassan et al., 1985,
1989). In contrast, venlafaxine was reported to have
only a marginal effect, if any, at doses of 300 and
375 mg/d in healthy volunteers (Blier et al., 2006;
Harvey et al., 2000). Since it has been documented that
depressed patients are more sensitive to the tyramine
pressor response than healthy volunteers (Ghose and
Turner, 1975), it was deemed crucial to assess the effect
of venlafaxine in patients with major depression.
The present study was thus aimed at confirming the
5-HT reuptake blockade of venlafaxine at its minimal
effective dose in depression (75 mg/d), and at possibly
documenting a NE reuptake inhibitory action with
ascending doses in depressed patients. To this end,
patients with unipolar major depression were given,
on a double-blind basis, either 75 mg/d for 28 d or a
higher regimen, achieving 225 mg/d at day 5 and
maintained at 375 mg/d from days 8 to 28. The effects
of the treatments on the 5-HT reuptake process were
assessed from their capacity to decrease whole-blood
5-HT, and the degree of NE reuptake blockade was
estimated from the attenuation of the tyramine pressor
response.
Material and methods
Patients
Forty-six in- and outpatients treated at the Allan
Memorial Institute of the Royal Victoria Hospital in
Montreal were screened for the study, following a
telephone pre-screen for outpatients. Male and female
patients aged between 18 and 65 yr, diagnosed as
suffering from major depression according to DSM-
IV-R criteria (APA, 1987) by two evaluators using the
SCID (Spitzer and Williams, 1988) and presenting an
initial global score >20 on the 21-item Hamilton
Depression Rating Scale (HAMD; Hamilton, 1960)
were enrolled after they agreed and signed and in-
formed consent form.
Exclusion criteria included evidence of significant
physical illness found either during physical examin-
ation or in the laboratory data (EEG, EKG, renal,
hepatic and haematological tests), mental retardation,
pregnancy or absence of adequate contraceptive
method in women with childbearing potential, con-
current use of psychotropic medication such as
neuroleptics, lithium or regular use of high doses of
benzodiazepines, current treatment with an anti-
hypertensive medication or patients for whom a BP of
o150/90 was found during the physical examination
and patients with a score <20 on the HAMD, after the
1-wk drug-free period.
Medication
Patients were only included if they had not been treated
for the current episode of depression or if they had
been receiving an adequate dose of antidepressant for
less than 1 wk, or if they were receiving a dose of anti-
depressant lower than that considered as adequate
(e.g. the equivalent of y150 mg/d for a tricyclic anti-
depressant drug). For the latter patients agreeing to
participate in the study, their current antidepressant
medication was discontinued. They were then entered
into the screening period, during which results of
the physical examination and laboratory tests were
obtained.
At the end of the drug-free period, allowing for
complete elimination of their prior medication,
patients randomized in the high-dose group, received
at days 1 and 2, one capsule of venlafaxine (Effexor
IR
1
) 25 mg t.i.d. (75 mg/d); at days 3 and 4, one
capsule of 50 mg t.i.d. (150 mg/d) and at days 5–7, one
capsule of 75 mg t.i.d. (225 mg/d). From day 8 to day
28, they received one capsule of 50 mg and one cap-
sule of 75 mg t.i.d. (375 mg/d). The patients random-
ized to the low dose of venlafaxine received one
capsule of 25 mg t.i.d. from day 1 to the end of the trial.
From day 8 to day 28, these patients also received one
placebo capsule three times a day to maintain the
blind with the high-dose group. All capsules were
identical in appearance. The first group of patients,
therefore, received the full dose of 75 mg/d venlafax-
ine during the 4 wk of the trial, whereas the second
52 G. Debonnel et al.
group received the maximal dose of 375 mg/d venla-
faxine during the last 3 wk of the trial. No other
psychotropic medication was allowed except for
clonazepam and chloral hydrate prescribed as re-
quired, for severe anxiety or marked insomnia.
Assessment of 5-HT reuptake
Determinations of whole-blood 5-HT levels largely
reflect platelet 5-HT contents because within blood
vessels, a very large (>90%) proportion of 5-HT is
sequestrated from the extracellular milieu into platelets
through the reuptake and storage mechanisms (Demet
et al., 1978). Blood samples were obtained at 08:00
hours on days 1, 7 and 28 and frozen at x75 xC until
the end of the study, at which time, measurements
were carried out. The method used to determine 5-HT
levels is summarized in Blier et al. (2006). Plasma
levels of venlafaxine and O-desmethyl-venlafaxine
were determined on days 7 and 28 in the laboratory of
Dr Gilles Caille
´
at the University of Montre
´
al using a
method approved by Wyeth.
In brief, a sensitive technique using reversed-phase
chromatography with ultraviolet detection was
adapted from that reported by Troy et al. (1994).
Pure powder samples of venlafaxine, O-desmethyl-
venlafaxine and WY-45818-B, the acting internal stan-
dard (IS), were provided by Wyeth–Ayerst Canada
Inc. (St-Laurent, Que
´
bec). Stock solutions of 10 mg %
(100 mg/ml) of venlafaxine, O-desmethyl-venlafaxine
and WY-45818-B hydrochloride were prepared and
stored at 4 xC. At room temperature, 1 ml of plasma
was added to 200 ml of a 0.5 mg % of IS solution (1 mg)
and completed to 2.5 ml with H
2
O. After adding 100 ml
of 10
N NH
4
OH at pH 10.7, the tubes were briefly
vortexed and then, extracted with 6 ml ether. The
tubes were shaken for 10 min on an Eberbach shaker
set at low speed and then centrifuged for 10 min at
2500 rpm. The organic layer was transferred to a clean
15 ml glass conical tube containing 280 ml of 0.25
N
HCl. After the tubes were vortexed for 1 min and
centrifuged for 5 min at 2500 rpm, the organic layer
was aspirated and discarded. The aqueous phase was
washed with 5 ml ether. This ether phase was also as-
pirated and discarded. To the remaining aqueous
phase was added 120 ml of 0.4
M NH
4
H
2
PO
4
. The tubes
were vortexed and a 150 ml aliquot of this aqueous
sample was injected into the HPLC system. The HPLC
consisted of a Waters Model 501 solvent delivery
system (Oregon City, OR, USA) attached to a Shimadzu
autosampler (Model SIL-9A, Dallas, TX, USA), along
with a tunable UV/VIS absorbance detector set at
229 nm (Spectroflow 757 ; Kratos, Chestnut Ridge, NY,
USA) and a Shimadzu Model C-R6A Chromatopac
integrator. The compounds of interest were separated
on a chromatographic column packed with 5 m
M C8
material (reversed-phase column ; 12.5r0.46 cm i.d.;
Hichrom, Theale, Berks, UK). The mobile phase con-
sisted of 0.01
M NH
4
H
2
PO
4
:acetonitrile (77 :23, v/v)
pumped at a flow rate of 1.1 ml/min. Chromato-
graphic analysis was conducted at ambient tempera-
tures (22–25 xC) and under these HPLC conditions, the
observed retention times were approximately 5.8, 17.7
and 25.2 min for O-desmethyl-venlafaxine, venlafax-
ine and WY-45818-B respectively.
Calibration curves were obtained with drug-free
plasma that was spiked with increasing concentrations
of venlafaxine and O-desmethyl-venlafaxine (10, 25,
50, 100, 250 and 500 ng/ml). The linearity of these
calibration curves was determined by a weighted
least-squares regression analysis. The coefficients of
determination (r
2
) varied from 0.9948 to 0.9999 and
0.9979 to 0.9995 for venlafaxine and O-desmethyl-
venlafaxine respectively. Between-run precision and
accuracy were determined from quality-control
samples spiked with three different concentrations of
venlafaxine and O-desmethyl-venlafaxine. A total of
10 replicates of each concentration of each substance
were assayed. The within-run precision and accuracy
were determined on seven replicates. Their corre-
sponding back-extrapolated concentrations were all
calculated from one calibration curve covering the
10–500 ng/ml concentration range for both products.
The between- and within-run coefficients of variation
were small with percentages ranging from 2 to 10%
and 1 to 5 % respectively for both substances. The
between- and within-run accuracies were also very
good, with nominal percentages of venlafaxine and
O-desmethyl-venlafaxine varying from 99 to 109 %.
The short-term stability of venlafaxine and O-
desmethyl-venlafaxine was verified with samples kept
at room temperature for 5 h.
Assessment of NE reuptake
The tyramine test (Ghose and Turner, 1975) consists of
measuring the transient increase in BP, after a tyramine
load. It can be carried out either by determining the
dose of tyramine required to induce a fixed increase in
systolic BP (i.e. 30 mmHg), or by measuring the effect
of fixed doses of tyramine. Since each patient was used
as his/her own control in our experimental paradigm,
the second method was used, but an estimate of the
ED
30
value was also extrapolated using regression
analysis. BP and heart rate alterations induced by
tyramine were assessed at days 1 (before ingestion of
5-HT/NE reuptake inhibition and venlafaxine 53
any venlafaxine administration), 7 and 28. Details of
the procedure are provided in Blier et al. (2006). All
investigators, including those administering the test,
were blind to the treatment arm the patients had been
assigned to.
Psychiatric evaluations
During the first 2 wk, patients were evaluated twice a
week (i.e. on days 4, 7, 10 and 14) using the HAMD,
the Montgomery–Asberg Depression Rating Scale
(MADRS; Montgomery and Asberg, 1979) and the
Clinical Global Improvement scale (CGI; Guy, 1976).
These scales were completed by two of the investi-
gators following a semi-structured interview (Spitzer
and Williams, 1988). During the last 2 wk, the same
assessments were carried out on a weekly basis.
Statistical analyses
The drug plasma levels were measured in ng/ml and
the 5-HT reuptake data were assessed in whole-blood
5-HT concentrations in pmol/l. The latter results were
illustrated in percentage changes from the respective
baseline levels. These results were analysed using the
two-tailed Student’s t test. The systolic BP response to
tyramine was considered as the difference between the
systolic BP measured just prior to the tyramine load
and that measured 2 min post-administration. Two-
way ANOVA for repeated measures for doses of
tyramine and treatments were conducted on the data
to assess the effects of the different drug regimens on
the pressor response to loads of 1–6 mg tyramine, as
well as for depression scores. Post-hoc analyses were
conducted where appropriate with Tukey’s tests.
Estimated doses of 30 (ED
30
) were analysed using one-
way ANOVA followed by the Student–Newman–
Keuls method for pairwise multiple comparisons. All
values are expressed as means¡
S.E.M., unless other-
wise stated. The level of significance was set at
p<0.05. One-way ANOVAs were used to compare
the clinical efficacy of the low and high doses of
venlafaxine.
Results
Patient characteristics
Forty-four patients were randomized in the trial, 42 of
which completed the 4-wk study. Demography and
clinical data for the population are summarized in
Table 1. There was no statistically significant differ-
ence between the two groups of patients, in terms of
age, sex, or severity of the disease. However, it must
be noted that, even if this did not reach statistical
significance, the ratios of female/male patients were
different in the two groups, with the usual 2/1 ratio in
the low-dose group, whereas this ratio was nearly in-
verted in the high-dose group.
Plasma levels of active compounds
Plasma levels of venlafaxine, as well as that of its
active metabolite O-desmethyl-venlafaxine, were as-
sessed at day 7 and at day 28. Plasma levels were
significantly higher in the high-dose group of patients
(Figure 1). Plasma levels of venlafaxine were stable
over time for the low-dose group, whereas they sig-
nificantly increased between day 7, when the patients
were receiving 225 mg/d, and day 28 when the
patients had been on 375 mg/d for the past 21 d.
Tolerability
Venlafaxine was generally well tolerated in both
groups of patients: only two patients withdrew from
the study before the end of the trial, but not because of
side-effects (one lost to follow-up and one due to pro-
tocol violation). The most common side-effect for both
groups was nausea which occurred in about four out
of five patients in the low-dose group and in about half
of the high-dose group, but not necessarily to intoler-
able levels as reflected in the zero dropout rate for
side-effects. This was followed by headache, insomnia,
dry mouth and constipation. The main difference be-
tween the two groups was vasodilatation, which oc-
curred in about half of the patients in the high-dose
group and was not present in the low-dose group.
Table 1. Demographics of patients randomized
Venlafaxine
p value
Low dose
(n=22)
Mean (¡
S.D.)
High dose
(n=22)
Mean (¡S.D.)
Age (yr) 42¡11 41¡10 0.75
Gender
Male 7 (32 %) 13 (55 %)
Female 15 (68 %) 9 (41 %) 0.13
Weight (kg) 67.0¡13.3 70.5¡10.5 0.34
BMI 23.7¡4.1 25.0¡3.2 0.26
Baseline scores
HAMD 33¡434¡5 0.53
MADRS 37¡535¡6 0.32
HAMD, Hamilton Depression Rating Scale ; MADRS,
Montgomery–Asberg Depression Rating Scale.
54 G. Debonnel et al.
Sweating and sexual dysfunction were only reported
by patients receiving the high dose of venlafaxine
(Table 2).
Determination of whole-blood 5-HT levels
Following a 7-d treatment, whether with the low or the
high dose of venlafaxine, there was a reduction of
whole-blood 5-HT content. Initial 5-HT levels
(1365¡177 and 1702¡192 pmol/l in the low- and
high-dose groups respectively) were reduced by
slightly more than 50%. There was no significant dif-
ference between the two groups. At day 28, whole-
blood 5-HT content was further reduced by more than
75% (Figure 2), a significant reduction compared to
that of day 28. Again, at day 28, there was no differ-
ence between the two groups of patients.
Assessment of NE reuptake activity
The activity of NE transporters was first assessed by
injecting ascending doses of tyramine and stopping the
procedure when a systolic BP increase of 25 mmHg
was obtained at any given dose (Figure 3). At baseline,
all 20 male patients received up to 4 mg tyramine since
none of them had a 25 mmHg increase with the 3-mg
dose. Only 15 of these 20 male patients received the
6-mg dose of tyramine whereas all 32 males studied
in parallel in the healthy volunteer study received the
Table 2. Side-effects reported spontaneously by the patients
randomized into the study (the low-dose regimen
consisted of 75 mg/d given on a three times daily basis
throughout the trial and the high-dose regimen was
initiated at 75 mg/d and titrated to 225 mg/d at day 5
and 375 mg/d at day 8)
Side-effect Low dose High dose
Nausea 18 (82 %) 12 (55 %)
Headache 13 (59 %) 9 (41 %)
Insomnia 11 (50 %) 12 (55 %)
Dry mouth 7 (32 %) 10 (45 %)
Constipation 6 (27 %) 11 (50 %)
Anorexia 4 (18 %) 5 (23 %)
Abdominal pain 4 (18 %) n.r.
Somnolence 4 (18 %) 7 (32 %)
Tremor 4 (18 %) n.r.
Anxiety 3 (14 %) n.r.
Asthenia 3 (14 %) 4 (18 %)
Blurred vision 3 (14 %) 5 (23 %)
Hypertension 3 (14 %) 3 (14 %)
Vasodilation n.r. 12 (55 %)*
Dizziness n.r. 8 (36 %)*
Sweating n.r. 6 (27 %)*
Sexual dysfunction n.r. 5 (23 %)
n.r., None reported.
* p<0.05 when compared to the low-dose group.
1000
800
*
*
Plasma levels of venlafaxine +
desmethyl venlafaxine (ng/ml)
600
400
200
0
Day 7 Day 28
Figure 1. Plasma levels of venlafaxine and O-desmethyl-
venlafaxine at days 7 and 28 in depressed patients
receiving the low dose (% ; 75 mg/d throughout the study)
or the high dose (& ; 75 mg/d at days 1 and 2, 150 mg/d
at days 3 and 4, 225 mg/d at days 5–7, and 375 mg/d
at days 8–28) of venlafaxine. The samples were collected
2–3 h following the last dose of venlafaxine.
100
80
*
*
Decrease (% ± S.E.M.) of whole-blood 5-HT
60
40
20
0
Day 7 Day 28
Figure 2. Decreases of the whole-blood 5-HT level
[compared to pre-treatment values (100 %)] in depressed
patients receiving the low dose (% ; 75 mg/d) or the
high dose (& ; 375 mg/d) of venlafaxine, at days 7 and 28.
* p<0.001 (using ANOVA for repeated measures: F=91.48,
d.f.=2).
5-HT/NE reuptake inhibition and venlafaxine 55
6-mg dose of tyramine using the same protocol (Blier
et al., 2006). The results clearly demonstrate a healthy
volunteer/depressed patient difference in the dose of
tyramine necessary to increase systolic BP in males.
In contrast, three of the 24 female patients already
presented such an increase after receiving only 2 mg
tyramine. Amongst female patients at baseline, 21/24,
17/24 and 9/24 received 3, 4, and 6 mg tyramine
respectively. These results thus show a differential
male/female responsiveness to tyramine in the patient
population. The difference was statistically significant
at 2 and 3 mg tyramine (d.f.=42, t=2.25, p=0.028, and
d.f.=39, t =2.78, p=0.008 respectively).
A two-way ANOVA on the tyramine data, followed
by Tukey’s multiple comparisons, revealed that a
6-mg dose of tyramine produced a significantly
greater effect (p<0.05) than all other doses, as well as
the 4-mg dose from the 1-mg dose of tyramine in both
the low- and the high-dose groups. The pressor re-
sponses remained unaltered at the various doses of
tyramine in the low regimen of venlafaxine after 7 d
and 28 d treatment, as indicated by multiple post-hoc
comparisons. In contrast, they were significantly
attenuated in the high-dose group (Figure 3). ANOVA
followed by Tukey’s test showed that there was a
significant difference between day 1 and days 7 and
28 results, but not between those obtained at days 7
and 28. This inhibitory activity of venlafaxine on NE
reuptake was supported by the observation that
higher doses of tyramine could be given at days 7 and
28 [prior to : with 2 mg (22/22), with 3 mg (21/22),
with 4 mg (19/22), with 6 mg (14/22); following 7
days: with 2 mg (22/22), with 3 mg (22/22), with 4 mg
(22/22), with 6 mg (19/22); following 28 days: all
21 subjects received the 6-mg dose of tyramine]. The
attenuation of the pressor response in the high-
dose group (Figure 3) therefore represents an under-
estimation of the NE reuptake blockade capacity of
venlafaxine because several patients did not receive
the higher doses of tyramine at baseline.
These data were then used to estimate the dose of
tyramine necessary to induce a 30 mmHg increase of
systolic BP (Figure 4). A one-way ANOVA showed the
low-dose group (patients receiving 75 mg/d venla-
faxine from day 1 onwards), there was no difference
in the dose of tyramine required at baseline, and at
40
30
20
10
0
12346 12
Dose of tyramine
Day 1
Increase in blood pressure (mmHg)
Day 7 Day 28
Low dose of venlafaxine
346 12346
40
30
20
10
0
12346 12
Dose of tyramine
Day 1 Day 7 Day 28
High dose of venlafaxine
346 12346
Figure 3. Increases of the systolic blood pressure (BP)
following the bolus injection of tyramine intravenously in
depressed patients immediately before, and 7 and 28 d
following venlafaxine administration. Because some
patients already presented systolic BP increases of
25 mmHg or more at baseline, not all 22 subjects in each
group received the five doses of tyramine. In the
high-dose group, all 21 patients received 6 mg tyramine
at day 28.
12
10
8
6
ED
30
values (mg of tyramine ± S.E.M.)
4
0
1714
Day
75 mg/d
375 mg/d
225 mg/d
21 28
Figure 4. Responses to the tyramine pressor test at days 0,
7 and 28 in depressed patients receiving the low dose
(# ; 75 mg/d throughout the study) or the high dose
($ ; 75 mg/d at days 1 and 2, 150 mg/d at days 3 and 4,
225 mg/d at days 5 and 6, and 375 mg/d at days 7–28) of
venlafaxine. The ED
30
was extrapolated for each patient
from the results obtained following the intravenous
administration of a dose of 1, 2, 3, 4 and 6 mg tyramine
(see Methods section).
56 G. Debonnel et al.
days 7 or 28. In patients in the high-dose group, a
dose-dependent increase of the ED
30
of tyramine
was observed. At day 7, when the patients had been
titrated up to 225 mg/d for the last 2 d, there was a
33% increase in the ED
30
of tyramine, whereas at day
28, following a 3-wk treatment with 375 mg/d venla-
faxine, the ED
30
of tyramine was increased by 65%.
While the means of days 7 and 28 were statistically
greater than the baseline value, the difference between
data for days 7 and 28 was not statistically significant.
A significant correlation was found between the
plasma levels of venlafaxine plus O-desmethyl-
venlafaxine and the increase in the amount of
tyramine necessary to increase the systolic BP by
30 mmHg at day 28 (Figure 5).
Antidepressant response
In both groups of patients, venlafaxine induced a
significant reduction of the severity of depressive
symptoms (p<0.001 using a two-way ANOVA). There
was no significant difference between the two groups,
regarding the efficacy of venlafaxine as an anti-
depressant as determined by changes on the HAMD,
the MADRS and the CGI scores (data not shown). None
of the biological parameters were significantly corre-
lated with clinical improvement (data not shown).
Discussion
The results of the present study indicate that venla-
faxine acted as an effective 5-HT reuptake inhibitor
throughout its effective dose range in major de-
pression in the 4 wk of the trial duration. At 75 mg/d,
venlafaxine did not seem to inhibit NE reuptake based
on its inability to attenuate the tyramine pressor
response at any time-point. In contrast, venlafaxine
produced a dose-dependent inhibition of NE reuptake
at doses of 225 and 375 mg/d after 7 and 28 d of
treatment respectively. The clinical improvements in
this 4-wk trial were the same in the low dose and in the
forced titration groups.
O-desmethyl-venlafaxine, the main metabolite of
venlafaxine, possesses similar uptake blockade
properties as the parent compound (Muth et al., 1991).
For this reason, the levels of both compounds were
assessed and combined in the present study. This
determination also served to ensure that the patients
were taking their medication assiduously. The plasma
levels of venlafaxine and O-desmethyl-venlafaxine
were in general fairly well correlated with the doses
administered. As illustrated in Figure 1, the low dose
of 75 mg/d induced stable levels of y200 ng/ml at
days 7 and 28, confirming that venlafaxine moieties
reach steady-state levels within a week. In fact, with
half-lives of about 6 h and 12 h, for venlafaxine and its
desmethylated metabolite, they probably reached
steady-state levels within 48 h (Klamerus et al., 1996).
For the patients receiving the higher doses, the plasma
levels were much higher. At day 7, they reached
y700 ng/ml, a little more than three times the level
observed in the low-dose group, in keeping with the
ratio of the doses currently administered (75 mg and
225 mg). At day 28, even if the levels were higher than
those observed at day 7 (700 vs. 900 ng/ml), they were
not increased in a linear fashion. The plasma levels
determined herein were, nevertheless, about twice as
high as those reported by Harvey et al. (2000) with the
same doses. This is probably due to the present levels
having been determined at the peak level whereas
those in the study of Harvey et al. (2000) were deter-
mined at the trough level.
In both groups of patients, the treatment with ven-
lafaxine induced the same reduction of whole-blood
5-HT content : it was decreased by more than 50%
after 1 wk of treatment and by 75% after 4 wk of
treatment (Figure 2). The lack of difference between
the two groups clearly suggests that even at the lower
dose of 75 mg/d, venlafaxine induced a complete
suppression of the reuptake of 5-HT and that a plateau
effect was already reached. The fact that the level of
ED
30
values (mg of tyramine)
r
2
= 0.25
0
0
4
8
12
16
20
200 400 600 800 1000 1200 1400 1600
Plasma levels of venlafaxine+
O
-desmethyl-
venlafaxine (ng/ml)
Figure 5. Correlation between the dose of tyramine,
administered intravenously, necessary to increase systolic
blood pressure by 30 mmHg and the plasma levels of
venlafaxine plus its active metabolite in patients who had
been receiving 75 mg/d venlafaxine for 28 d, or 375 mg/d
for the last 21 d of the 28-d treatment period. The medication
was given in three divided doses with the last one being
given 2–3 h before carrying out the test. The 95 %
confidence interval of the correlation (r=0.50) was
between 0.23 and 0.70 and the p value was 0.001 using
a two-tailed test.
5-HT/NE reuptake inhibition and venlafaxine 57
suppression was not above 55 % after 1 wk is a conse-
quence of the physiology of platelets (Celada et al.,
1994). Platelets can take up, store and release 5-HT in a
fashion similar to that of 5-HT neurons. They do not
possess, however, the enzymatic system necessary to
synthesize 5-HT (Pletscher et al., 1968). Therefore, any
5-HT present in the platelets has previously been taken
up by their 5-HT transporters. The physiological role
of the 5-HT contained in the platelets is believed to be
an aid in homeostasis, in the case of a traumatic injury
through platelet aggregation and local vasoconstriction
(Feinstein and Fraser, 1975; Houston and Vanhoutte,
1986). In the absence of injury, 5-HT is presumably
released at a low rate, and with sustained blockade of
5-HT reuptake, the gradual reduction of the whole-
blood 5-HT therefore corresponds to the elimination of
old platelets and the appearance of new ones with
their 5-HT reuptake transporters blocked since their
maturation from their precursor megakaryocytes. This
process then largely corresponds to the progressive
decrease in the total blood 5-HT levels observed in the
present study.
The most interesting finding in this study is the
result of the tyramine pressor tests. In the group of
depressed patients receiving 75 mg/d venlafaxine, the
estimated dose of tyramine required to increase BP by
30 mmHg was unchanged, either at day 7 or at day 28
(Figure 4). In contrast, for patients receiving high
doses of venlafaxine, a significant increase was ob-
served. At day 7, the daily dose of venlafaxine of these
patients had been progressively increased and they
had received 225 mg/d venlafaxine for 2 d. At that
time, the ED
30
of tyramine was increased by y30%,
whereas at day 28, after 3 wk of treatment at 375 mg/d
venlafaxine, the ED
30
dose was increased by more than
60%. These results indicate that, in depressed patients,
75 mg/d venlafaxine does not produce relevant bind-
ing to the NE transporter. Therefore, it acts as an SSRI,
whereas the clinically meaningful NE reuptake block-
ade property of venlafaxine appears only when the
dose is increased, in keeping with the reported differ-
ential affinities of venlafaxine for the 5-HT and the NE
reuptake sites.
These results, taken together with those obtained in
the study carried out with healthy volunteers using
the same paradigm, indicate that the tyramine pressor
response to venlafaxine is different in depressed
patients and in healthy volunteers. In fact, after 1 wk of
repeated administration of venlafaxine at 300 mg/d in
healthy volunteers and 225 mg/d in patients, yielding
nearly identical plasma levels of y700 ng/ml, the
tyramine pressor response was significantly attenuated
only in the patient population. This difference may
stem in part from the observation that the tyramine
pressor response is greater in depressed patients than
in healthy volunteers within genders (Ghose and
Turner, 1975). The present results comparing male
healthy volunteers and depressed patients are thus
consistent with this report. In addition, female patients
presented greater pressor responses than the male
patients at baseline. The latter difference did not,
however, contribute to the greater effect of venlafaxine
in the higher regimen group since there were more
females in the low regimen group (Table 1). The
greater sensitivity of patients to the tyramine pressor
test could be attributable to a variety of factors. First, it
is conceivable that the releasable pool of NE is greater
in patients with depression than in healthy volunteers,
and, therefore, a greater amount of NE would be
released in response to the same doses of tyramine,
thereby producing a more pronounced elevation of
systolic BP. There is some evidence in this regard with
depressed patients excreting more NE than healthy
controls (Dajas et al., 1984). However, since similar
degrees of elevation in systolic BP were achieved in
healthy volunteers and patients, albeit with different
doses of tyramine, it is unlikely that this factor played
a major role in the attenuation of the increases pro-
duced by venlafaxine. Second, it is possible to consider
a putative role of adrenergic receptors mediating the
pressor response to tyramine as being more sensitive
in patients than in healthy volunteers. Again, for the
same reason mentioned above, i.e. the attainment of
similar increases in BP, it is unlikely that this factor
may explain the attenuations in depressed patients
and the lack of alterations in healthy volunteers.
Finally, a difference in the reuptake transport system
of NE must be considered. Two possibilities can be
envisaged for this explanation. First, if depressed
patients had a lower density of NE transporter sites,
a physiologically significant inhibition of NE reuptake
could be more readily achieved with the same levels of
venlafaxine. In support of this possibility are the data
of a post-mortem study showing a down-regulation
of the density of NE transporters in the locus coeruleus
of depressed patients who had committed suicide
(Klimek et al., 1997). Second, it is also possible to en-
visage the presence of anomalies of the NE reuptake
transport system to explain the action of venlafaxine in
depressed patients. For instance, a single amino-acid
mutation in the sequence of the NE transporter has
been shown to render subjects totally insensitive to
the tyramine pressor effect (Shannon et al., 2000).
Although such anomalies are rare, and the ones thus
far studied have not been associated with depression
(Owen et al., 1999), it is still conceivable that anomalies
58 G. Debonnel et al.
could be present in modulatory elements of the NE
transporter, thereby conferring to venlafaxine a great-
er capacity to inhibit the activity of the NE transporter.
Although observed under open-labelled conditions, it
is interesting to note that for 12 patients who had
failed to respond to a combination of a SSRI and a
tricyclic antidepressant drug that potently blocks NE
reuptake, eight responded favourably to venlafaxine
in a treatment-resistant study (de Montigny et al.,
1999). It is thus possible that venlafaxine might in-
teract with the NE transport system in a manner that
is different from that of the tricyclics, especially in
depressed patients. In support of this possibility, it
was recently reported that long-term administration
of a tricyclic, but not venlafaxine, down-regulates NE
reuptake sites (Gould et al., 2005).
Both groups of patients responded equally well to
venlafaxine, as shown by a 60 % decrease on the
MADRS and HAMD scores, after 4 wk of treatment.
This might appear unexpected given several reports
suggesting that higher doses of venlafaxine could
induce a greater antidepressant effect than SSRIs
(Clerc et al., 1994 ; Poirier and Boyer, 1999 ; Thase et al.,
2001). The sample size of the present study was,
however, small and powered only to detect differences
in the biochemical/physiological parameters, not in
clinical effectiveness. If one expects that, at low doses,
venlafaxine is acting as a SSRI, it would still induce the
50–60 % response rate usually seen with this class of
medication. In addition, since women tend to respond
better to SSRIs, and since there were more females in
the low- than in the high-dose group, this unequal
distribution could have contributed to bring the group
on the low dose of venlafaxine to a faster clinical
response (Kornstein, et al., 2000; Quitkin et al., 2001;
Young, 2001). Moreover, the study was of short dur-
ation (4 wk) and it is therefore possible that a differ-
ence between the two groups might have emerged
at weeks 6 or 8, as observed in the fluoxetine/venla-
faxine comparison study by Clerc et al. (1994).
Consequently, the probability to obtain a significant
clinical difference between the two groups in the
present study was slim.
In conclusion, the present data suggest that, in
keeping with numerous previous clinical studies,
venlafaxine produces a significant antidepressant ef-
fect within 4 wk of treatment, even when administered
at a dose of 75 mg/d. The data also support that, at a
low dose of 75 mg/d, venlafaxine is acting as a SSRI
and that at higher doses, its NE reuptake blockade
property gradually manifests itself. This progressive
synergy of effects could explain previous data
suggesting that higher doses of venlafaxine may be
effective in treatment-resistant depression for patients
having failed to respond to other types of anti-
depressant treatments, including SSRIs (de Montigny
et al., 1999 ; Nierenberg et al., 1994; Poirier and Boyer,
1999).
Acknowledgements
This work was supported by Wyeth Canada. We thank
Dr Gilles Caille
´
and his team for carrying out, under
contract, the venlafaxine plasma level determinations.
P. Blier is an Adjunct Professor in the Department of
Psychiatry at McGill University.
Statement of Interest
G. Debonnel, C. de Montigny and P. Blier have been
paid consultants, remunerated speakers and have
received other research grants from Wyeth. P. Blier
has been contracted to produce an animated pro-
gramme for educational purposes for Wyeth.
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5-HT/NE reuptake inhibition and venlafaxine 61
    • "Opisane zjawisko – niezależnie od tego, czy ma dobre uzasadnienie teoretyczne – jest często obserwowane w codziennej praktyce. Wenlafaksyna to lek o co najmniej podwójnym mechanizmie działania (Davidson, 2002; Debonnel et al., 2007; Owens et al., 2008). W dawkach niższych działa głównie serotoninergicznie (Voineskos et al., 2007), w wyższych – serotoninergicznie i noradrenergicznie. "
    [Show abstract] [Hide abstract] ABSTRACT: Venlafaxine is a drug with at least two significant antidepressant mechanisms of action. Selective serotonin reuptake inhibition (5-HT) is observed even when low doses are used and noradrenalin reuptake inhibition can be seen when doses are higher. The cut-off point is usually a daily dose of 225 mg although a change from one mechanism of action into dual action is usually of spectral nature. It is possible that in daily doses higher than 375 mg, the drug exhibits dopaminergic effects, but such large doses are not recommended by the manufacturer. Using higher doses is associated with greater antidepressant efficacy. One should remember, however, that a change of dosage can be related to a different profile of adverse effects (which also depends on patient's individual sensitivity). The serotoninergic effects are also perceived as sedating, causing excessive drowsiness or even apathy. The noradrenergic effects can, however, evoke the feeling of excessive agitation and sleep disorders. Moreover, the perception of a given action, as indifferent or troublesome to functioning, depends on the time of a day at which it occurs. The sleep-inducing action is perceived as positive by patients in the evening and agitation may be considered positive in the morning. It seems that the time of using venlafaxine may affect the subjective drug tolerance. The article presents two cases that represent this viewpoint. It is not entirely clear why the action of the drug is experienced as the strongest by patients soon after administration (a specific placebo effect cannot be excluded). Despite this, subjective venlafaxine tolerance is undoubtedly associated with the manner of administration. Physicians should take this into consideration.
    Full-text · Article · Apr 2015
    • "SLC6A2 and SLC6A4 Variants … Pharmacopsychiatry tor of effect. Far more useful is the serum concentration of the active moiety [5] which, regarding VEN, is comprised of the parent compound and its almost equally active major metabolite O-desmethylvenlafaxine (ODV [6]). Low serum concentrations are assumed to act as a selective 5-HT reuptake inhibitor (sSRI) while higher levels exert the sSNRI effect [3]. "
    [Show abstract] [Hide abstract] ABSTRACT: Objective: The effects of genetic variants in genes encoding the target structures of antidepressants on the therapeutic efficacy of antidepressant drugs have been investigated with unconclusive results. One possible confounding factor in most studies was the fact that drug serum concentrations had not been determined. Methods: Within a clinical setting, 56 inpatients suffering from depressive episodes in the context of either major depressive disorder or bipolar affective disorder were studied. Response to venlafaxine was assessed after 4 weeks of treatment and correlated to serum concentration and functional variants in genes encoding the norepinephrine (SLC6A2; rs28386840) and the serotonin transporter (SLC6A4; [5-HTTLPR], rs25531). Symptom change was evaluated using the Clinical Global Impression-Improvement (CGI-I) scale. Results: No association between therapeutic response, venlafaxine serum concentration (active moiety) and rs28386840 was found. In carriers of the high expressing SLC6A4 genotype (lAlA-), a poor response to venlafaxine was found significantly more often. In subsamples stratified for serum concentration this held true for patients with serum concentrations between 201 and 400 ng/mL (n=21), while in patients with sub- (≤ 200 ng/mL; n=12) and supra-recommended (> 400 ng/mL; n=23) concentrations, no significant differences were observed. Discussion: The observed association is consistent with findings of some previous studies, whereas others showed differing results highlighting the need for further investigations.
    Full-text · Article · Oct 2014
    • "From the pharmacodynamic point of view, VEN essentially acts as a serotonin reuptake inhibitor under low daily doses (75 mg/day), and becomes a dual-acting antidepressant under a daily dose of > 150 mg/day. Indeed, VEN is more potent as a serotonin reuptake inhibitor than as a noradrenaline reuptake inhibi- tor [5,[14][15][16]. Additionally, VEN is also a weak inhibitor of dopamine reuptake; however, it does not inhibit monoamine oxidase and has no significant affinity for α 1 -adrenergic, muscarinic cholinergic, H 1 histaminergic, benzodiazepine, or opioid receptors [5, 17] . "
    [Show abstract] [Hide abstract] ABSTRACT: Abstract Venlafaxine (VEN) is an antidepressant agent widely used nowadays as an alternative to selective serotonin reuptake inhibitors (SSRIs), particularly for the treatment of SSRI-resistant depression. As the co-administration of antidepressant drugs with other medications is very common in clinical practice, the potential risk for pharmacokinetic and/or pharmacodynamic drug interactions that may be clinically meaningful increases. Bearing in mind that VEN has exhibited large variability in antidepressant response, besides the individual genetic background, several other factors may contribute to those variable clinical outcomes, such as the occurrence of significant drug-drug interactions. Indeed, the presence of drug interactions is possibly one of the major reasons for interindividual variability, and their anticipation should be considered in conjugation with other specific patients' characteristics to optimize the antidepressant therapy. Hence, a comprehensive overview of the pharmacokinetic- and pharmacodynamic-based drug interactions involving VEN is herein provided, particularly addressing their clinical relevance.
    Full-text · Article · Jun 2014
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