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International Journal of Neuropsychopharmacology (2007), 10, 41–50.

Copyright f 2006 CINP ARTICLE
doi:10.1017/S1461145705006395

Effects of different doses of venlafaxine on
CINP
serotonin and norepinephrine reuptake in
healthy volunteers

Pierre Blier1,3, Élise Saint-André1, Chantal Hébert1,3, Claude de Montigny1,
Normand Lavoie2 and Guy Debonnel1
1
Department of Psychiatry, McGill University, Montréal, QC, Canada
2
Department of Urology, McGill University, Montréal, QC, Canada
3
University of Ottawa Institute of Mental Health Research, Ottawa, ON, Canada

Abstract
Venlafaxine is generally considered to be a dual 5-HT and NE reuptake inhibitor when it is used at doses
above 75 mg/d in humans. While its 5-HT reuptake-inhibiting property has been demonstrated, some
controversy still exists regarding the doses of venlafaxine required to inhibit NE reuptake. Healthy male
volunteers received, on a double-blind basis, paroxetine (20 mg/d), desipramine (100 mg/d), nefazodone
(300 mg/d), or venlafaxine (150 or 300 mg/d) in the last 5 d of a 7-d period of administration. Inhibition of
5-HT reuptake was estimated by determining the degree of depletion of whole-blood 5-HT, while that
of NE was assessed by measuring the attenuation of the systolic blood pressure increases produced
by intravenous injections of tyramine. Paroxetine, both regimens of venlafaxine, and to a lesser extent
desipramine significantly decreased whole-blood 5-HT content. Nefazodone failed to produce any
significant change. Desipramine abolished the tyramine pressor response, whereas all other drug
regimens left this parameter unaltered. Venlafaxine and paroxetine acted as potent 5-HT reuptake
inhibitors in the present study. In contrast, neither the moderate nor the high dose of venlafaxine
displayed any significant inhibiting activity in this model assessing NE reuptake in peripheral NE
terminals. The validity of the model was confirmed by the potent inhibitory action of desipramine on NE
reuptake. While the reasons for this unexpected lack of action remain unclear, venlafaxine appeared to be
an effective NE reuptake agent in depressed patients using the same approach.
Received 13 September 2005 ; Reviewed 30 October 2005 ; Revised 14 November 2005 ; Accepted 22 November 2005 ;
First published online 11 May 2006
Key words : Antidepressant, nefazodone, paroxetine, reuptake inhibition, tyramine.

Introduction reuptake sites, and at NE reuptake sites, its affinity has
generally been reported to be in the micromolar range,
Almost all tricyclic antidepressant drugs are potent
which may be considered of questionable physio-
norepinephrine (NE) reuptake inhibitors. In contrast,
logical significance (Béı̈que et al., 1998). Specifically,
their potency to inhibit the reuptake of serotonin
its activity on NE reuptake is about 10 times weaker
(5-hydroxytryptamine ; 5-HT) is more variable, ran-
than that of sertraline, which is considered a selective
ging from extremely potent for clomipramine to
5-HT reuptake inhibitor (SSRI ; Bolden-Watson and
ineffective for trimipramine (Hyttel, 1982). In contrast,
Richelson, 1993). Similar in-vitro data have been
it is acknowledged that the non-tricyclic agent
reported in human cell lines (Owens et al., 1997 ;
venlafaxine is an effective 5-HT reuptake inhibitor,
Tatsumi et al., 1997). These observations using dif-
but there remains uncertainty regarding the doses
ferent preparations and assays show considerable
necessary to inhibit the NE transporter in humans.
variability in the potency and selectivity of venla-
In synaptosomal preparations of rodent brains,
faxine, thereby raising concerns about the mechanism
venlafaxine displays only moderate affinity for 5-HT
of action of venlafaxine in the treatment of mood and
anxiety disorders.
Address for correspondence : Professor P. Blier, University of Ottawa
The in-vivo assessment of the potency of venla-
Institute of Mental Health Research, Royal Ottawa Hospital, Lady
Grey Building, Suite 2043, Ottawa, Ontario, Canada K1Z 7K4.
faxine to inhibit 5-HT and NE reuptake in the rat
Tel. : 613-722-6521 (ext. 6908) Fax : 613-761-3610 brain have, however, yielded very different results.
E-mail : pblier@rohcg.on.ca For instance, the dose of venlafaxine necessary to

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(5) history of difficult phlebotomy. venlafaxine was only three times less active ceptives . Since blood platelets can only store 5-HT through a 5-HT reuptake transporter that is Volunteers were randomly assigned to one of six nearly identical to that present on 5-HT neurons in the groups : placebo. the sustained inhibition of 5-HT reuptake (Norpramine1). 1978). The activity of the NE transporter faxine IR 300 mg/d (Effexor IR1. 42 P.. and that y90 % of the total blood 5-HT is in zodone (Serzone1) 300 mg/d. on the McGill University all subjects took one capsule in the morning and one Downloaded from https://academic. study for any of the following reasons : (1) use of pared to those of paroxetine and desipramine. In the present study. Subjects were excluded from the plasma protein binding of venlafaxine when com.. nefa- brain. the greater free fraction of venla. Presumably. including migraines. Studies A total of 37 healthy male volunteers entered examining such actions of venlafaxine in both groups the study. liver enzymes. (3) use of any psychotropic medication or 1996).. investigators and subjects remained blind to the drug administration groups. 150 mg/d (Effexor IR1. inhibit the firing rate of 5-HT neurons in anaesthetized campus. 95 % for the latter two drugs (2) orthostatic hypotension (a fall in systolic BP>10 (Ereshefsky and Dugan. 2000 . (4) regular use of any medication other faxine may allow greater brain penetration. Blier et al. Participants met the following quite different from the 100-fold greater in-vitro inclusion criteria : (1) male. females were not included to venlafaxine (Béı̈que et al. paroxetine (Paxil1) 20 mg/d. For the first 2 d. Any significant abnormality tiveness of various antidepressant drugs to inhibit upon physical examination or laboratory tests was 5-HT and NE reuptake needs to be evaluated in also a reason for exclusion. high dose). 2002). hepatitis B and HIV testing. desipramine 100 mg/d platelets. electrolytes. venlafaxine immediate release (IR) depletes whole-blood 5-HT (Artigas et al. y30 % for venlafaxine vs. resulting from 5-HT reuptake inhibition. (4) no Among the possible explanations for this discrepancy evidence suggestive of a past or present history of between in-vitro and in-vivo results is the low mental disorders. therefore.. 1996 . a physical examination. The dose of paroxetine was injection of tyramine. the effec. None of the the rodent and the human brain are similar.. 1998 . outside different medications were identical.. Tyramine penetrates peripheral the minimal effective dose for depression and was NE terminals through their NE transporters and then not meant to test its potential noradrenergic action releases NE which transiently increases BP (Hoffman reported to occur with high doses (Gilmor et al. (2) body weight in the normal range as than the potent tricyclic NE reuptake inhibitor indicated by body mass index . Tatsumi et al. 1999). urine drug screening. regimens were chosen on the basis of their clinical tolic blood pressure (BP) produced by the intravenous efficacy in depression. Thase et al. pressure (BP>140/90). 40 rats is the same as for the SSRI paroxetine (Béı̈que volunteers underwent a structured clinical interview et al. Such a suppression of firing activity is (SCID for non-patients). 1997). (3) no significant desipramine in suppressing the firing rate of NE medical illness. 1990). The was evaluated by measuring the increase in the sys. 1984). any illicit drug . high blood neurons in the locus coeruleus (Béı̈que et al. NE reuptake inhibition therefore The two venlafaxine regimens on the basis of their attenuates this response (Ghose. Prior to their inclusion in the study. antidepressant action were superior to SSRIs. healthy volunteers and in patient populations.. the faculty of medicine. complete blood count.oup. an due to the increased activation of cell body 5-HT1A electrocardiogram and laboratory tests consisting of a autoreceptors by enhanced amounts of synaptic 5-HT.. than acetaminophen or vitamins and mineral supple- Despite the fact that the 5-HT and NE systems in ments . between the ages of 18 potency of paroxetine when compared to that of and 40 years old . 2001). mmHg) . This subject was the capacity of venlafaxine and of other reference replaced to have six persons in each group. intermediate dose). being an investigational drug within 30 d of study entry . Study subjects The capsules containing placebo or one of the five Volunteers were recruited among students. at least in some studies (Kelsey. or venla- Demet et al. This dose urea and creatinine. 1999). avoid having to control for menstrual cycle or In a similar model indirectly assessing NE reuptake possible metabolic interference with oral contra- activity. subjects smoked tobacco.com/ijnp/article-abstract/10/1/41/628056 by guest on 10 June 2018 . and equivalency between these two drugs is. antidepressant agents to inhibit 5-HT reuptake was evaluated from their ability to deplete whole-blood Drug regimens content of 5-HT. There was one dropout in the high-dose of subjects are still lacking. venlafaxine group due to side-effects. hepatitis B or HIV . Puozzo and Leonard. and Lefkowitz. Subjects and methods Following randomization. 1985 .

3 ml concentrated up 5-HT are removed from the circulation. OR. the nefa. The parox. Montreal.com/ijnp/article-abstract/10/1/41/628056 by guest on 10 June 2018 .i. a standard Assessment of 5-HT reuptake analytical Hypersil column (Chromatographic Platelet 5-HT content has become widely used Sciences Company. 1984).. Quebec). it was deemed that 5 d at the same dose chloric acid was used to precipitate serum proteins. and a gold 5-HT receptors subtypes (Demet et al.2 ml per- metabolites. Following blockade of the 5-HT calculate the area under the curve and obtain ratios of reuptake process. 1978).. For the next 5 d. Pletscher.i. 5-HT/NE reuptake inhibition in healthy volunteers 43 capsule at bedtime. the low-dose venlafaxine group recovery was used to correct for methodological losses 75 mg b. search. Thus.. and the high-dose venlafaxine group during the extraction and chromatographic pro- 150 mg b. 25.d. The paroxetine group received 10 mg b. 1985 . The assessment of NE and 5-HT cedures and ensure correction for losses during quan- reuptake processes was performed at baseline (day 0) tification by HPLC.1 was fil- effective 5-HT uptake by the reuptake.i.. which 5-HT is eluted with an acetate buffer (pH 5.i. Quebec) was used for taken up by the transport system.5 ml methanol with a pH adjusted to 5. An autosampler (Hitachi model 1986). NE reuptake inhibition therefore attenuates this chemical detector for assessing 5-HT levels in response (Ghose. as a very large proportion (90–95 %) degassed for 15 min before use. hydroxide.d.. compared to the baseline level and its reduction i.i.i. The supernatant was transferred to glass Gilles Caillé at the University of Montreal using a tubes containing 2 ml of sodium acetate buffer.d. the desipramine procedure involves deproteination of blood samples group 25 mg b. on 5-HT neurons. 1998). NE acts on the Downloaded from https://academic. Blood plate. Koch and etine group received 10 mg in the morning. 1984 . Chromabec.. Pletscher. the low-dose venlafaxine group by addition of perchloric acid (4 M) in presence of 37.. One-millilitre whole-blood aliquots and on day 7 with the last dose being taken about were thawed and 0. any 5-HT present in the platelets has been 7200 L. of blood 5-HT is sequestrated in the platelets..e.d. the half-life of the drugs and that of their to make up the volume to 2 ml. it is taken up in NE neurons by the NE transporter was used as an index of the degree of 5-HT reuptake and then it produces a release of NE from its inhibition. The HPLC equipment consisted of a Waters HPLC pump (510 model . USA)..d. 1990).i. would be sufficient to achieve steady-state plasma the mix was vortexed for 1 min and centrifuged at levels (Devane. 1978 ..inhibiting tered through 0. but lack the enzymatic interference caused by catecholamines. the nefa. 1981 . (2006). 1986). Kissinger.d. Oakridge. The mobile phase con- decreases as older platelets that have previously taken taining 100 mg disodium EDTA. USA) with an Ag/AgCl lets can take up and store 5-HT in a fashion very reference electrode set at +0. an electro- for studying the activity of the 5-HT transporter on chemical detector (model 400. They were started at bedtime on samples from total blood.. intraneuronal stores (Hoffman and Lefkowitz. The method approved by Wyeth and summarized in pH was adjusted to 5.1 with 6 mol/l ammonium Debonnel et al. all subjects took one amberlite CG-50 cation exchange resin column from capsule in the morning and two capsules at bedtime. and the high-dose venlafaxine group antioxidants and application of the supernatant on an 75 mg b. working electrode.d.45 picometres membrane filters and drugs. An adapted HPLC procedure using an electro.0¡0. Taking into account these gradual working solution was added as well as acetate buffer titrations. the desipramine 5-hydroxytryptamine oxalate salt) and its per cent group 50 mg b..oup. Montreal. We used an internal standard (2 nmol/ml N-methyl- zodone group received 150 mg b. from approaches previously the day the baseline data were collected.. Blood 5-HT content measured on day 7 was Tyramine acts indirectly as a sympathomimetic agent. Korpi. whole- blood 5-HT content largely reflects platelet 5-HT con- Assessment of NE reuptake tent (Artigas et al. The plasma levels of venlafaxine 4000 rpm for 10 min with a Brinkmann Eppendorf and desmethyl venlafaxine were carried out by Dr centrifuge. and replaced by new ones that are rendered incapable of 162.d. Oregon City..d.i. and concentration automatic injection of samples and a Waters 740 data constitutes an index of the efficacy of 5-HT uptake sites module integrator was used to record chromatograms. Princeton Applied Re- serotonergic neurons (Arora et al. described was utilized (Kilts et al. 32. The zodone group received 75 mg b.5 mg b.5 ml of the internal standard 2–3 h before testing.i. A total of 0. Moreover.1). TN. platelet 5-HT content gradually 5-HT and internal standard. metanephrines system necessary to synthesize 5-HT and most of the and other metabolites of catecholamines. 1984). In turn. 1978 .5 V potential to eliminate similar to that of 5-HT neurons. They are ammonium hydroxide. 1980 . Demet et al.3 ml glacial acetic acid. Sasa et al.

These levels are consistent with those second dose of 6 mg was given. lowest and the highest metabolite/parent compound ratio still had a total level of active agents within 15 % of the mean of their respective group. The nificant elevation in BP after the test dose. 1990). ary to cause a predetermined increase in systolic BP Post-hoc analyses were conducted where appropriate (Ghose.oup. a dose total level of venlafaxine plus its metabolite was of 4 mg tyramine was administered. Pretreatment with drugs paired Student’s t test. necessary to cause a given increase in systolic BP. desmethyl laboratory tests. and a catheter was installed in an antecubital vein sation for lost time related to their participation. 2006). the mean level of period allowed us to detect the peak increase in BP. Plasma levels of the antidepressant drugs A test dose of 0. were measured as previously described. values that are fully consistent 5-HT concentrations in pmol/l compared to baseline with those reported using 20 mg/d (Gilmor et al. McGill University. Ghose and Turner. The systolic BP response to that block the high-affinity NE reuptake site. 44 P. All subjects gave informed written which automatically registered the heart rate (HR) and consent. or an increase in the dose of tyramine p<0. NE neurons (Hoffman and Lefkowitz. Either a de. the parent compound was 170 ng/ml (range 75–265) which usually occurs 2 min after a bolus injection of and that of the metabolite was 540 ng/ml (range tyramine. prevent tyramine was considered to be the difference between the increase in BP that usually follows tyramine the systolic BP measured just prior to the tyramine administration by preventing tyramine entry into load and that measured 2 min post-administration. In the six subjects were then measured every 2 min for 10 min. 1975).05. pressor response to loads of 4 mg and 6 mg tyramine. it is important to mention considered the index for the action of tyramine. and the BP and HR obtained in depressed patients (Debonnel et al. the effects of two doses of intravenous tyramine (4 mg and 6 mg) on systolic This study was carried out in accordance with the BP were assessed. as well as the systolic. The level of significance was set at tyramine. a 516–930). The differ. during which HR and BP were recorded every 10 min. Downloaded from https://academic.5 mg tyramine was then adminis- tered intravenously in order to rule out the presence In the six subjects who received 150 mg/d venlafaxine. Blier et al.4). in one arm. the two subjects who had the drug regimen (effect of tyramine measured on day 1). The BP and HR 404¡31 ng/ml (range 319–512). or measuring the dose of tyramine necess. The total level of venlafaxine plus its meta- to its baseline level. blood was drawn for 5-HT Results level measurements. Declaration of Helsinki and was approved by the The following procedure was followed at each visit : Research Ethics Board of the Royal Victoria Hospital. Subjects were given $150 (CDN) as compen- BP. 1984). These results. the subject was connected to a Criticare 508 apparatus. venlafaxine.7 (range 1. diastolic a vasoconstriction and a secondary elevation of BPs and the pulses were analysed using the two-tailed systolic BP (Ghose.. The ANOVA for repeated measures for doses of tyramine tyramine test consists of measuring the increase in and treatments were conducted on the data to assess systolic BP of patients receiving a fixed dose of the effects of the different drug regimens on the tyramine. which would not have the mean level of the parent compound was 67 ng/ml been detected by the physical examination and (range 43–97) and that of its metabolite. which causes levels. with Bonferroni’s method. that the total concentration of venlafaxine active Blockade of NE reuptake manifests itself by a decrease moieties varied by less than 2-fold in both groups of in the elevation of BP shown prior to beginning the subjects.M. Furthermore. as well as sufficient time to let BP return 369–699).com/ijnp/article-abstract/10/1/41/628056 by guest on 10 June 2018 . Following a resting period of 30 min in the supine position. is considered to be a reliable index of NE reuptake Ethics blockade. and if there was no sig.E. 1984 . vascular post-synaptic a1-adrenoceptors. of a pheochromocytoma. In the present study. n=6). Despite this apparent wide the tyramine load and that measured 2 min after was range of metabolic activity. Evaluation and statistical analysis The mean level of paroxetine was 53¡19 ng/ml Serotonin reuptake data are expressed in whole-blood (range 21–110. If the increase in BP did not bolite in this second group was 710¡67 ng/ml (range reach 30 mmHg after the 4-mg tyramine dose. was 338 ng/ml (range 235–415). After 5 min. This time who received 300 mg/d venlafaxine. All values are expressed as crease in the pressor response to the same doses of means¡S.5–7. The mean ratio of the metabolite/parent compound ence between the systolic BP measured just prior to was 4..

expressed in when the subjects were lying down immediately pmol/l. 300 mg/d venlafaxine group.=5. there was a non-significant mean 10 pmol/l p<0. t=4. all six subjects showing systolic BP than the 4-mg dose in all the groups at a decrease in this parameter after 7 d administration baseline.com/ijnp/article-abstract/10/1/41/628056 by guest on 10 June 2018 . Percentage changes of whole-blood 5-HT levels the antidepressants after 7 d administration of placebo or the various antidepressant agents.03).05.884). it was decided to assess BP and pulse at 5 d on a twice-daily regimen.f. were 2446¡377 in the placebo group.f. d. there was a mean significant drop of 13 beats/ group. Depletion of whole-blood 5-HT levels by the antidepressant drugs Effects of the antidepressant medications on the tyramine pressor response The mean concentration of 5-HT was 2446¡376 pmol/l at baseline in the placebo group and 2344¡411 The modifications in systolic BP were compared using 7 d later. p=0. d.54. 1901¡430 in the paroxetine group. In the paroxetine only in the nefazodone group (t=4. was 5-HT level (range 52–85 % .02).05 as significant. In the placebo in the desipramine group. 1344¡131 in the nefazodone group. of treatment (F=6. change in pulse (p>0.03 . 2326¡407 in min (range +2 to x27 . after ensuring that the normality variation within that 1-wk period. There were six subjects in each Despite the small number of subjects tested in each group.=5. d.51.02. range <3–79 ng/ml). This mean differ. 20 mg/d −100 300 mg/d Modifications of cardiovascular parameters by Figure 1.=5.92.63. In the desipramine group. −60 nefazodone. d. t=1.19.=5.=1. 2585¡344 before starting the tyramine infusions. p=0. * Indicates p<0. The mean desipramine level was 119¡39 ng/ Desipramine Nefazodone 20 ml (range 71–295. 925¡480).=5.001). with the 150 mg/d venlafaxine group and 2083¡254 in the five of the six subjects presenting a decrease at day 7. In the desi. there was a small but sig. d.f.001 . The last dose was given 2–3 h baseline and after the 1-wk duration of the study.=5. with five of the six subjects having a f10 % a two-way ANOVA.=5. suggesting a lack of sustained effect of All the subsequent pairwise comparisons were carried nefazodone on 5-HT reuptake (Figure 1).16). all subjects had a robust decrease in whole- other medications did not produce any significant blood 5-HT (range 45–96 % . d.f. t=2. The group.5.f. there was a mean signifi- cant increase of 14 beats/min (range x4 to +32 .046).007 .34 . and mCPP levels were low as expected −40 (mean¡S. in the paroxetine group (range +2 to +9 . p=0.E. d. The mean Downloaded from https://academic.44. p=0.45. p=0. In the 150 mg/d venlafaxine group.E.f. t=3. n=6). but not of treatmentrdose (F=1.02. 5-HT/NE reuptake inhibition in healthy volunteers 45 2002). Finally. decrease after 7 d administration (d. t=3.=5. d. data not shown). the decrease was profound and more homogeneous t=3. They received half of the indicated doses for the group. It revealed a significant source of p=0.=11.f.f.23 and ence was not statistically significant (d.f. and the numerous factors that can alter such first 2 d of administration and the full doses for the next parameters. all sub- to systolic and diastolic BPs. p<0. was of 1315¡250 ng/ml (range −80 * * Paroxetine 150 mg/d * 553–2051). prior to drawing blood. with five of the six subjects presenting an increase during the second session.f.37). those of the hydroxy- metabolite varied from 35 to 499 ng/ml (mean¡S. out using Bonferroni’s method considering a p value pramine group. The levels of nefazodone 100 mg/d 300 mg/d Venlafaxine % change in whole-blood 5-HT in the six subjects varied from 66 to 2990 ng/ml 0 (mean¡S. the increased mean diastolic pressure by 5 mmHg Figure 1). p=0. −20 Placebo * 263¡72).f. With regards Figure 1). p=0. group.oup.017). in the high-dose venlafaxine group. 0.70 respectively). see Figure 1).M. The baseline levels. Figure 1).=11. 29¡12 ng/ml.M. a metabolite with an uncharacterized biological activity. d. t=2. p<0.=5.001). although it reached statistical significance (range 8–33 % decreases.f. The 6-mg dose of nificant mean 19 % decrease in whole-blood 5-HT tyramine produced a numerically greater increase in (d.43.E.M.05 using the paired two-tailed Student’s t test. The mean concentration of des-ethyl-hydroxy. t=8. p=0. smaller than 0. and equal variance tests were passed (p=0. the only significant jects also had a marked decrease in their whole-blood difference noted among all the treatment groups. t=0. however. Similarly in the nefazodone variance of dose of tyramine (F=61.15. Figure 1). than in the last two groups (range 73–82 % .

99). Placebo Desipramine Paroxetine Nefazodone 30 100 mg/d 20 mg/d 300 mg/d Increase in systolic blood pressure by tyramine (mmHg ± S. The last dose was given process (Figure 1). 5 1.05 using the Bonferroni method as post-hoc tests following an ANOVA for repeated measures. Desipramine exerted a small. The paroxetine. The difference between the effects of the 4-mg and 6-mg doses of tyramine at baseline was significant only in the nefazodone group. Among these four antidepressant 2–3 h prior to the tyramine challenge. %. increase produced by the 4-mg dose was 12 mmHg 40 and a statistically significant further increase of Increase in systolic pressure produced 9 mmHg was produced by the 6-mg dose.45 at 4 mg and 6 mg respectively). 75 mg/d). 0 6 6 6 6 4 mg 6 mg 4 mg 6 mg Discussion Figure 3. 2 min of the intravenous injection of tyramine in a etine and venlafaxine are potent inhibitors of 5-HT bolus manner.06 and 15 5. &. Alterations of systolic blood pressures within 2 min of the intravenous injection of tyramine in a bolus manner.96). The treatments drugs. nefazodone and the low. group is indicated at the bottom of the histograms. %. inhibition of 5-HT reuptake.90. did administration. Alterations of systolic blood pressures within The results of the present study indicate that parox. &. The number of subjects studied in each reuptake.M. Prior to administration . using the Bonferroni method as and 3).and high-dose venlafaxine 10 regimens yielded non-significant t values of 0. thus indicating test– retest reliability of this paradigm over a 1-wk period.) 25 20 15 10 5 * * 6 6 6 6 6 6 6 6 0 4 mg 6 mg 4 mg 6 mg 4 mg 6 mg 4 mg 6 mg Figure 2. only desipramine exerted a significant attenu. The number of subjects studied in each group is indicated at the bottom of the histograms.15. 1. Downloaded from https://academic.E.M. whereas nefazodone They received half of the indicated doses for the first 2 d of administration and the full doses for the next was devoid of sustained inhibitory action on this 5 d on a twice-daily regimen.) 30 150 mg/d 300 mg/d the tyramine response (t=1.28 and 0. after 7 d administration. 25 The only medication that significantly altered the tyramine pressor response was desipramine (t=5.oup. * Indicates p<0. 46 P. 35 Venlafaxine Placebo administration did not significantly alter by tyramine (mmHg ± S. Prior to administration .64 respectively (Figures 2. did not produce significant alterations of the tyramine ation of the tyramine pressor response (Figures 2 pressor response. The last dose was given 2–3 hours prior to the tyramine challenge.E.e. cant. 3). Blier et al. after 7 d effective dose in depression (i. These data indicate that venlafaxine. even post-hoc tests following an ANOVA for repeated at a dose that is four times higher than its minimal measures. They received half of the indicated doses for the first 2 d of administration and the full doses for the next 5 d on a twice-daily regimen. albeit signifi.com/ijnp/article-abstract/10/1/41/628056 by guest on 10 June 2018 . 20 This drug nearly abolished the pressor response to both doses of tyramine (t values of 5.

to be occupied to produce an antidepressant response especially at the 300 mg/d regimen. the degree of depletion The robust inhibitory action of desipramine on increases over time despite venlafaxine achieving its the tyramine pressor response was expected based steady-state level within a few days (Debonnel et al. produced an 80 % respect to the baseline value with the standard error Downloaded from https://academic. a daily dose Seppala et al. (2002) showed that tory action of such plasma levels of NE reuptake is the reuptake of 5-HT was also significantly inhibited 40 % (Gilmor et al. 2002). In the case of nefazodone. for instance. Harvey et al. In The lack of inhibitory action of venlafaxine humans. because. Turcotte et al. 1994). rise in systolic BP. of 20 mg fluoxetine produced a sustained inhibition 2001 . that study has clearly shown that parameter using a 375 mg/d regimen of venlafaxine. but not 12 h after the last dose.. 2000 . if higher regimens of paroxetine instance.oup. whole-blood levels of 5-HT. 1985. Moreover.. only of y20 % with inhibitors. respectively) potently inhibit this response. however. It remains to be ficity of this drug for the NE reuptake process. nefazodone did not even they do not imply that it would necessarily alter 5-HT inhibit 5-HT reuptake despite having a higher affinity levels in the brain.. prior NE reuptake ex vivo using the plasma of patients reports have documented the lack of absolute speci. maproptiline. In the denoted atomoxetine) and reboxetine (Gobbi et al. including venlafaxine. Slater et al. 1997). Although the three sets of is conceivable. of y200 ng/ml paroxetine. would attenuate the tyr- the IC50 required to inhibit 5-HT platelet depletion was amine pressor response. in order to maintain the effectiveness of the process. In contrast. 1981 ... assessed using a labelled 5-HTT ligand and positron The assessment of whole-blood 5-HT diminutions emission tomography. Hassan et al. This is potent inhibitory action on the 5-HT reuptake process. as present study in healthy volunteers. the tyramine pressor response consistently with its taining 100 ng/ml desipramine in a human cell line in relative absence of effect at the human NE transporter vitro. (2000) estimated that after a (50 mg/d or more).. 1989 . For determined. It may appear surprising that desipramine at a 1985. given that the ex-vivo inhibi- 195 ng/ml.. their content needs an extended delay to be disorder. as port system. the advantage of this approach is tories. Figure 2). extended from 1 to 4 wk. containing 100 ng/ml paroxetine. it is estimated that y80 % of the 5-HTT have on the tyramine pressor response was unexpected. It is noteworthy using drugs that inhibit 5-HT reuptake (Meyer et al. nefazodone was devoid of effects on the 2003 .. is that they are and completely inhibit the 5-HT reuptake pump of not effective in the treatment of obsessive–compulsive platelets. it those previously published. clomipramine was reported that 200 mg nefazodone administered (which is metabolized to the potent NE reuptake twice daily inhibited by 34 % the ex-vivo platelet 5-HT inhibitor desmethyl-clomipramine).. and the non- reuptake in healthy male volunteers 2–4 h after its oral tricyclic NE reuptake inhibitors tomoxetine (now administration..com/ijnp/article-abstract/10/1/41/628056 by guest on 10 June 2018 . Nefazodone did not alter (by 18 %) when using the plasma of the patients con. However. the SSRI parox- of platelet 5-HT reuptake and a whole-blood 5-HT etine at its minimal effective dose in depression of depletion of up to 80 % (Salazar et al. and several other labora- 2006). consistently producing levels prolonged administration of desipramine in patients. on prior reports from ours. Indeed. 20 mg/d was devoid of effect in this test (Hassan et al. Gilmor et al. Indeed. unlike the SSRIs. Indeed. 1997). Indeed. The present results are thus strikingly similar to (Ki=618 nmol/l . a reserve in the number of 5-HT transporters (5-HTT) Owens et al. 1997). although improbable. Javors et al. 2000 .. Zerbe et al... Nevertheless. that its high data indicate that desipramine produces a consistent affinity for a1-adrenoceptors may have prevented a inhibition of 5-HT reuptake transporters in humans. however. In contrast. Nevertheless. In contrast. 1985). (2002) showing a 27 % inhibition of reduction of whole-blood 5-HT. it does nortriptyline itself. amitriptyline and imipramine (which that it readily permits detection if various substances are metabolized to nortriptyline and desipramine exert a sustained action on the 5-HT reuptake trans. even if a reuptake inhibitor would rapidly with the exception of clomipramine. 5-HT/NE reuptake inhibition in healthy volunteers 47 not appear to inhibit the NE reuptake process in the occupancy of 5-HTT sites in the human brain.. when the only tricyclic drug with an anti-obsessional action treatment with a dose of 75 mg/d venlafaxine is (Goodman et al. clomipramine depleted as a result of 5-HT being released and not is a potent 5-HT reuptake inhibitor and it is the being refilled through reuptake. This is presumably because there is for 5-HT than for NE reuptake sites (Ki=459 nmol/l . Perhaps the strongest clinical by reuptake inhibitors yields an underestimation of evidence that tricyclic antidepressants do not exert a the actual degree of reuptake inhibition. (2000) reported an attenuation of this 2004). that Harvey et al. the minimal effective doses of various 5-HT reuptake The attenuation was. 1989 . Owens et al. same study. This is consistent with the results relatively low dose actually produced a significant of Gilmor et al.

the venlafaxine plasma both groups of subjects (Ghose and Coppen. Wilkins et al. Biological Psychiatry 19. 345–354. BP and HR alterations.. but degree of occupancy of NE transporters is the NE prior evidence and the present report indicate that reuptake process significantly inhibited.. We volunteer/depressed patient difference is not present would like to thank Dr Gilles Caillé and his team for with amitriptyline.. P. Kregel L. it is important to emphasize here that this healthy This work was supported by Wyeth Canada. G. Melichar et al. desipramine. tyramine pressor response to document the presence it appears that these experiments did not produce any of NE reuptake inhibition was indicated by the evidence for a significant attenuation of the tyramine inhibitory action of the NE reuptake inhibitor pressor response using 375 mg/d.com/ijnp/article-abstract/10/1/41/628056 by guest on 10 June 2018 . Szabadi E. Desipramine levels were determined in For instance.0 ratio level the availability of a specific ligand of NE reuptake sites (i. These Statement of Interest approaches. de Montigny have been probably did not correspond to a threshold of NE paid consultants. In contrast. 48 P. 2001). Upon in body fluids : characterization of human plasmatic and Downloaded from https://academic. with the drug being effective in carrying out. 1579–1584. It for use in positron emission tomography studies. 75 mg/d venlafaxine and 20 mg/d paroxetine were ineffective. British Journal of 1999). in a companion nefazodone. In contrast. Figure 2). a significant attenuation was demonstrated faxine did not result in NE reuptake inhibition in at regimens of 225 and 375 mg/d venlafaxine in healthy volunteers.e. Blier NE reuptake process necessary to produce an anti. We would like to Aside from the tyramine pressor test on BP. effects for 75 mg/d venlafaxine (Bitsios et al. as done by Meyer et al.and methoxamine-evoked constriction of the dorsal hand vein. (2004) for the authors proposed that 5-HT reuptake inhibition could 5-HT reuptake process. mediated by an additional NE reuptake inhibition. men and of the SSRI sertraline due to the relatively Nevertheless. Serotonin estimating NE reuptake inhibition in the brain. In summary. level determinations... clinical action of venlafaxine superior to that of SSRIs Arora R. the main laboratory of the Royal Victoria Hospital in reduced salivary flow. however.. It is interesting to note. that in the NE-induced constriction References of the dorsal vein of the hand. 2006). 1985. Blier et al. Thase et al. 1989 . Meltzer H (1984). 5-HT reuptake inhibition was clearly Their conclusion was solely based on the observation documented with 20 mg/d paroxetine and with that the 375 mg/d venlafaxine regimen failed to 150 and 300 mg/d venlafaxine. the two regimens of venla- paper. respectively. Gelpi E (1985). the should be noted that this value was not significantly degree of occupancy of NE transporters by various different from those of the low-dose venlafaxine regi. although they demonstrate a significant degree of NE reuptake inhibition in the periphery. 1999 . Debonnel and C. under contract. and Montreal. but 100 mg/d Abdelmawla A. 1977 . tyramine-induced pupillary response. and duced significant inhibitory effects (Abdelmawla et al. Langley R. 2000 . desipramine as well as 150 mg/d venlafaxine pro. Possible bases for this healthy volunteer/depressed patient Acknowledgements difference are discussed in that paper. 1989 . such results will have to be correlated high standard deviations in all three conditions. depressed patients (Debonnel et al. presumably being serotonin uptake in the blood platelets of normal controls. The latter model would thus correspond to a Clinical Pharmacology 48. provided in Debonnel et al. SSRIs (Kelsey. as did the present desipramine and the lack of effect of paroxetine and ones using 300 mg/d. has been contracted to produce an animated pro- depressant response potentially superior to that of gramme for educational purposes for Wyeth. 2001 . Comparison of the effects of venlafaxine. The with clinical data. other thank GlaxoSmithKline and Bristol–Myers Squibb for peripheral human models have been utilized to the plasma level assays of paroxetine and nefazodone demonstrate a NE reuptake action of venlafaxine. no change prior to and following treatment).oup.. Bradshaw C (1999). All these physiological models represent attempts at Artigas F. Consequently. for that mean value nearly reaching the 1. Nevertheless. (2006).. regimens of venlafaxine will be directly measurable. remunerated speakers and have reuptake inhibition sufficient to alter the central received other research grants from Wyeth.. Watkins et al. paroxetine on noradrenaline. this not the case (Hassan et al. P. 2003). 1985). Blier. P. in order to determine at what somehow enhance the tyramine pressor response. Details of this procedure are Hassan et al. Sarrias MJ. The adequacy of the separate from the maproptiline group. Martinez E. Circadian rhythm of at doses greater than 75 mg/d. Blier is an Adjunct Professor in the cardiac NE reuptake have all reported significant Department of Psychiatry at McGill University.

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