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.
"In vivo, in human subjects, venlafaxine inhibits 5-HT reuptake in platelets across the clinical dose range, but inhibits NE reuptake (as measured by the pressor response to intravenous tyramine) only at higher doses (!225 mg/day) (Harvey et al., 2000; Debonnel et al., 2007). Similarly, duloxetine inhibits 5-HT reuptake at 20 mg/day (Turcotte et al., 2001) and 60 mg/day (Turcotte et al., 2001; Chalon et al., 2003) but does not inhibit NE reuptake at these doses (again using the pressor response to tyramine [Turcotte et al., 2001]). "
[Show abstract][Hide abstract] ABSTRACT: Levomilnacipran (LVM; F2695) is the more active enantiomer of the serotonin/norepinephrine (5-HT/NE) reuptake inhibitor (SNRI) milnacipran and is currently under development for the treatment of major depressive disorder. LVM was benchmarked against two other SNRIs, duloxetine and venlafaxine, in biochemical, neurochemical and pharmacological assays. LVM exhibited high affinity for human NE (Ki=92.2 nM) and 5-HT (11.2 nM) transporters, and potently inhibited NE (IC50=10.5 nM) and 5-HT (19.0 nM) reuptake (human transporter) in vitro. LVM had 2-fold greater potency for norepinephrine relative to serotonin reuptake inhibition (i.e. NE/5-HT potency ratio: 0.6) and 17 and 27 times higher selectivity for NE reuptake inhibition compared with venlafaxine and duloxetine, respectively. LVM did not exhibit affinity for 23 off-target receptors. LVM (i.p.) increased cortical extracellular levels of 5-HT, and NE (minimal effective doses: MEDs = 20 and 10 mg/kg, respectively). In anti-depressive/anti-stress models, i.p. LVM diminished immobility time in the mouse forced swim (MED=10 mg/kg) and tail suspension (MED = 2.5 mg/kg) tests, and reduced shock-induced ultrasonic vocalizations in rats (MED = 5 mg/kg). Duloxetine and venlafaxine were less potent (MEDs ≥ 10 mg/kg). At doses active in these three therapeutically-relevant models, LVM did not significantly affect spontaneous locomotor activity. In summary, LVM is a potent, selective inhibitor of NE and 5-HT transporters with preferential activity at the former. It is efficacious in models of anti-depressive/anti-stress activity, with minimal potential for locomotor side effects.
"Some literature suggests patients may require up to 450 mg for efficacy (Thase et al., 2006, Mbaya et al., 2002). As VEN's Ki for serotonin is much lower than for noradrenaline (Béı¨que et al., 1998), it is possible participants on lower doses of VEN had minimal noradrenergic reuptake inhibition even at doses as high as 300 mg/day (Debonnel et al., 2007). Extending to treatment phase of the study to 10 or 12 weeks would have enabled higher doses of VEN be reached and included in the analysis. "
[Show abstract][Hide abstract] ABSTRACT: Predicting differential antidepressant efficacy remains an elusive goal in major depressive disorder (MDD). The aims of this study were three-fold. Firstly, to examine if psychomotor retardation symptoms (item 8 on the 17-item Hamilton Depression Rating Scale) improve preferentially to venlafaxine (VEN) over escitalopram (ESC) treatment. Secondly, whether the 18 item CORE psychomotor signs scale predicted antidepressant remission. Finally, to investigate the role of two norepinephrine transporter gene (NET) polymorphisms (rs2242446 and rs5569) on antidepressant efficacy. Adults with Diagnostic and Statistical Manual of Mental Disorders, 4th ed. MDD (n=113) were treated with ESC or VEN prospectively for 8 weeks and rated serially with the Hamilton Depression Rating Scale. In a subsample (n=51) of patients from one of the three recruitment sites, the CORE psychomotor signs scale was also administered at baseline. Participants treated with VEN had significantly greater reduction in psychomotor retardation symptoms than those treated with ESC. The CORE scale did not predict antidepressant response or remission. Neither NET polymorphism moderated antidepressant efficacy. Findings suggest possible preferential utility of a selective serotonin and noradrenaline reuptake inhibitor in cases of MDD presenting with greater psychomotor retardation. The moderate to small sample size makes a type II error risk possible, and the negative findings need to be interpreted with caution. The positive finding of preferential efficacy of VEN for psychomotor retardation symptoms has potential translational utility.
International clinical psychopharmacology 03/2013; 28(3). DOI:10.1097/YIC.0b013e32835f1b9f · 2.46 Impact Factor
"However, for discussion purpose, it is important to emphasize the dose-dependent effects of venlafaxine on cytokines such as IL-6, a molecule involved in the acute phase response and in the control of Th1/Th2 differentiation towards a Th2 polarization : at low dose venlafaxine appears to reduce serum levels of IL-6  , while at higher dose it seems to rather increase levels of IL-6 . These data could be related to the peculiar pharmacodynamics of venlafaxine: the effects on neurotransmission and receptors expression do not seem to differ much from those of SSRIs, at least at low dose [310- 312]; nevertheless at higher dose venlafaxine acts as a real SNRI: while at low dose the molecule mainly blocks the reuptake of 5-HT, at high dose the molecule blocks the reuptake of 5-HT and NE to the same extent . Duloxetine, another SNRI, in contrast to venlafaxine has a greater affinity for the NE transporter, blocking to the same extent the reuptake of NE and 5-HT at standard dose . "
[Show abstract][Hide abstract] ABSTRACT: Neurotransmitters and hormones regulate major immune functions, including the selection of T helper (Th)1 or Th2 cytokine responses, related to cell-mediated and humoral immunity, respectively. A role of imbalance and dynamic switching of Th1/Th2 system has been proposed, with relative displacement of the immune reserve in relation to complex interaction between Th1/Th2 and neuro-hormonal balance fluctuations, in the pathogenesis of various chronic human diseases, probably also including psychiatric disorders. Components of the stress system such as norepinephrine (NE) and glucocorticoids appear to mediate a Th2 shift, while serotonin (5-HT) and melatonin might mediate a Th1 shift. Some antidepressants would occur affecting these systems, acting on neurotransmitter balance (especially the 5-HT/NE balance) and expression levels of receptor subtypes, which in turn affect cytokine production and relative Th1/Th2 balance. It could be therefore hypothesized that the antidepressant-related increase in NE tone enhances the Th2 response, while the decrease in NE tone or the increase in 5-HT tone enhances the Th1 response. However, the neurotransmitter and Th1/Th2 balance modulation could be relative, aiming to restore physiological levels a previous imbalance in receptor sensitivity and cytokine production. The considerations on neuro-immunomodulation could represent an additional aid in the study of pathophysiology of psychiatric disorders and in the choice of specific antidepressants in specific clusters of symptoms, especially in comorbidity with internal pathologies. Furthermore limited data, reviewed here, have shown the effectiveness of some antidepressants as pure immunomodulators. However, these considerations are tentative and require experimental confirmation or refutation by future studies.
DNA research: an international journal for rapid publication of reports on genes and genomes 06/2012; 10(2):97-123. DOI:10.2174/157015912800604542 · 3.05 Impact Factor
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