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

University of Ottawa, Ottawa, Ontario, Canada
The International Journal of Neuropsychopharmacology (Impact Factor: 4.01). 03/2007; 10(1):41-50. DOI: 10.1017/S1461145705006395
Source: PubMed


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.

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Available from: Pierre Blier, Sep 03, 2015
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    • "nlafaxine group had an average in - crease in SBP of 7 . 4 mmHg at rest and 1 . 9 mmHg after standing and DBP of 4 . 2 mmHg at rest and 3 . 2 mmHg after standing . This probably indicates the presence of some NA blockade effects at low doses , despite Stahl et al . ( 2005 ) considering a dose below 150 mg / day to be too low to have NA effects and Blier et al . ( 2007 ) finding no NA effects at doses of 300 – 600 mg / day ."
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    ABSTRACT: It is generally thought that venlafaxine raises blood pressure at higher doses; however, some studies have found no effect or a decrease in blood pressure. The aim of this study was to evaluate the cardiovascular (CV) effects of 3 weeks of dosing with venlafaxine, pregabalin and placebo on young healthy adults. Fifty-four participants, of mean age 23.1 years (sd 4.68), 29 male, were randomised into three parallel groups. Each group received one of the three drugs, dosed incrementally over a 3-week period to reach daily doses of 150 mg/day venlafaxine and 200 mg/day pregabalin. Blood pressure sphygmomanometer measurements, heart rate measurements, and orthostatic challenges recorded continuously beat-to-beat were performed weekly over this period and 5 days after treatment cessation. Results showed resting systolic blood pressure (SBP) and resting and standing diastolic blood pressure (DBP) and heart rate (HR) were significantly raised by venlafaxine compared with the pregabalin and placebo groups. SBP drop on standing was larger, the resulting overshoot was smaller, and recovery was slower on venlafaxine. HR recovery was significantly impaired by venlafaxine. CV changes were observed after only 1 week of dosing at 112.5 mg/day. These effects of venlafaxine are likely to be due to its action of noradrenergic reuptake inhibition. Copyright © 2013 John Wiley & Sons, Ltd.
    Full-text · Article · Nov 2013 · Human Psychopharmacology Clinical and Experimental
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    • "Duloxetine is tenfold more potent for serotonin reuptake inhibition than norepinephrine reuptake inhibition while venlafaxine and desvenlafaxine show 30-fold higher potency for inhibiting serotonin versus norepinephrine reuptake [5]. For venlafaxine, meaningful norepinephrine inhibition is only achieved at high doses [6], so it primarily acts as a selective serotonin reuptake inhibitor (SSRI) when prescribed at the usual dose of 150 mg/day or less. Compared with duloxetine [4], venlafaxine [4], or desvenlafaxine [7], levomilnacipran has over tenfold higher selectivity for norepinephrine versus serotonin reuptake inhibition. "
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    ABSTRACT: Levomilnacipran (1S, 2R-milnacipran) is a potent and selective serotonin (5-HT) and norepinephrine (noradrenaline) reuptake inhibitor approved for the treatment of major depressive disorder in adults. The objective of this study was to evaluate the longer-term safety and tolerability of levomilnacipran extended-release (ER). Patients who completed double-blind treatment/down-taper in one of three lead-in levomilnacipran ER studies were eligible for this 48-week open-label extension. Safety evaluations included assessment of treatment-emergent adverse events (TEAEs), physical examinations, laboratory and vital sign measures, and suicidality, summarized using descriptive statistics for the safety population. The completion rate was 47 %; median treatment duration was 280 days. The most frequent reasons for discontinuation were withdrawal of consent (14 %) and adverse events (AEs; 13 %). TEAEs were reported by 712 (86 %) patients; most were mild/moderate and occurred early in treatment. The most common TEAEs were headache (22 %) and nausea (16 %); 36 (4 %) patients had ≥1 serious AEs. No clinically meaningful changes occurred in mean liver enzyme, metabolic, hematologic, urinalysis, or serum values; potentially clinically significant high AST or ALT values (≥3 × upper limit of normal) occurred in five patients. Vital sign changes occurred early and remained relatively stable. Mean increases for pulse rate (9.1 beats per minute [bpm]), and supine systolic (3.9 mmHg) and diastolic (3.3 mmHg) blood pressure were noted. The increase in the mean QT interval corrected using the Bazett formula (10.9 ms) was consistent with heart rate increase (12.8 bpm); there was no meaningful change in mean QT interval corrected using the Fridericia formula (-1.3 ms). Other than tachycardia and heart rate increases, ECG-related TEAEs were low (<0.5 %). No new or inconsistent safety/tolerability findings were discovered during longer-term evaluation.
    Full-text · Article · Sep 2013 · Clinical Drug Investigation
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    • "Following blockade of this reuptake process, there is a depletion of whole-blood 5-HT levels, due to the inability of 5-HT to enter platelets. As whole-blood 5-HT levels are also decreased by selective serotonin reuptake inhibitors (SSRIs) such as paroxetine (Blier et al., 2007; Petersen et al., 1978) which are known to affect the neuronal serotonin transporter, this method provides an indirect measurement of neuronal 5-HT reuptake activity. "
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    ABSTRACT: Nomifensine potently inhibits the reuptake of norepinephrine and dopamine in vitro. It is one of few antidepressants with marked potency to block dopamine reuptake that has ever been used clinically. Acute and sustained administration of nomifensine was investigated on the firing of monoaminergic neurons to understand its mechanism of action. In vivo extracellular recordings of locus coeruleus, ventral tegmental area and dorsal raphe nucleus neurons were obtained from male Sprague-Dawley rats. The intravenous injection of nomifensine in the locus coeruleus and ventral tegmental area yielded ED(50) values of 40 +/- 1 and 450 +/- 41 microg/kg, respectively, suggesting that nomifensine directly acted upon dopamine and norepinephrine neurons, since these values are proportional to its affinities for norepinephrine and dopamine transporters. There was no effect on 5-HT neurons. Nomifensine (5 mg/kg/day, subcutaneous, using minipumps) potently and significantly inhibited dopamine neuronal firing in the ventral tegmental area after 2 days, with recovery to normal after the 14-day treatment due to D(2) autoreceptor desensitization. Norepinephrine neuronal firing in the locus coeruleus was significantly decreased after 2 and 14 days. A significant increase in dorsal raphe nucleus 5-HT neuronal firing was seen after a two-day regimen, and remained elevated after 14 days. Desensitization of the 5-HT(1A) receptor on 5-HT neurons of the dorsal raphe nucleus occurred after two days of nomifensine administration. Nomifensine likely treated depression by acting on dopamine, norepinephrine and 5-HT neurons, highlighting the importance of the functional connectivity between these three monoaminergic systems.
    Full-text · Article · Nov 2009 · Journal of Psychopharmacology
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