venlafaxine (Effexor)
Effects of venlafaxine on p90Rsk activity in rat C6-gliomas and brain.

Khawaja XZ, Storm S, Liang JJ.

Wyeth Neuroscience, CN 8000, Princeton, NJ, USA. khawajx wyeth.com

The intracellular actions of the antidepressant, venlafaxine, were studied in C6-gliomas using a phosphoproteomics approach. Long-term pre-treatment of C6-gliomas with venlafaxine followed by an acute challenge with isoproterenol (a beta-adrenoceptor agonist), resulted in increased p90Rsk phosphorylation (three-fold) versus control levels (isoproterenol alone). The effect of venlafaxine pre-treatment on p90Rsk activity was dose-dependent (EC(50)=3.75nM) in C6 gliomas. In rat brain sections, intense immunoreactive phospho-p90Rsk labeling was observed for both neurons and glia, especially in cortical layers II/III and hippocampal formations. In vivo studies demonstrated an intense but similar distribution pattern of phospho-p90Rsk staining after chronic venlafaxine dosing of rats compared to naives and no region-specific drug effect was observed in vivo. In conclusion, our findings suggest that some of the centrally-mediated benefits of venlafaxine in depression may be due to its intracellular properties especially on the neuro-glial circuitry and MAPK/p90Rsk-dependent pathways at an early stage.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15531096&dopt=Abstract venlafaxine Effexor refs
Effexor, Effexor XR

venlafaxine (Effexor)
An open treatment trial of venlafaxine for elderly patients with dysthymic disorder.

Devanand DP, Juszczak N, Nobler MS, Turret N, Fitzsimons L, Sackeim HA, Roose SP.

Late Life Depression Clinic and the Department of Biological Psychiatry, New York State Psychiatric Institute, 1051 Riverside Drive, Unit 126, New York, NY 10032, USA. dpd3 columbia.edu

Treatment response and side effects of venlafaxine were evaluated in an open-label trial of elderly outpatients with dysthymic disorder (DD). Patients received flexible dose (up to 300 mg/d) venlafaxine (Effexor XR) for 12 weeks. Of 23 study patients, 18 completed the trial. Fourteen (60.9%) were responders in intent-to-treat analyses with the last observation carried forward, and 77.8% were responders in completer analyses. Nearly half the sample (47.8%) met criteria for remission. In the intent-to-treat sample, increased severity of depression at baseline was associated with superior response, and the presence of cardiovascular disease was associated with poorer response. Venlafaxine open-label treatment was associated with fairly high response rates and generally good tolerability in elderly patients with DD. These results indicate that in elderly patients with DD, placebo-controlled trials of a dual reuptake inhibitor such as venlafaxine would be needed to assess its efficacy or to compare its efficacy to that of other antidepressants.

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Effexor, Effexor XR

venlafaxine (Effexor)
Extended release of a novel antidepressant, venlafaxine, based on anionic polyamidoamine dendrimers and poly(ethylene glycol)-containing semi-interpenetrating networks.

Yang H, Lopina ST.

Department of Chemical Engineering, 302A Whitby Hall, The University of Akron, Akron, Ohio 44325-3906, USA.

The multiple daily administration of venlafaxine, a novel third-generation antidepressant, was reduced based on polyamidoamine and polyethylene glycol (PEG)-containing semi-interpenetrating network (IPN), respectively. Venlafaxine was covalently linked to water-soluble G2.5 anionic polyamidoamine dendrimer via a hydrolyzable ester bond. Semi-IPN hydrogels were prepared by crosslinking acrylamide in the presence of PEG, and venlafaxine with predetermined amounts was loaded in situ. Dendrimer-venlafaxine conjugate and semi-IPNs were characterized by proton nuclear magnetic resonance and Fourier transform infrared, respectively. The effect of PEG concentration and molecular weight was studied and discussed for an optimal controlled release.

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Effexor, Effexor XR

venlafaxine (Effexor)
Effects of venlafaxine on ethanol withdrawal syndrome in rats.

Saglam E, Uzbay IT, Kayir H, Celik T, Beyazyurek M.

Department of Pharmacology, Maltepe University 81530, Istanbul, Turkey.

The present study was designed to investigate the effects of venlafaxine, a serotonin and noradrenaline reuptake inhibitor (SNRI), on ethanol withdrawal syndrome in rats. Adult male Wistar rats (187-319 g) were used for the study. Ethanol (7.2%, v/v) was given to rats by a liquid diet for 21 days. Control rats were pair-fed an isocaloric liquid diet containing sucrose as a caloric substitute to ethanol. Venlafaxine (5, 10, 20 and 40 mg/kg) and saline were injected to rats intraperitoneally just before ethanol withdrawal. After the 2nd, 4th and 6th hour of ethanol withdrawal, rats were observed for 5 min, and withdrawal signs that included locomotor hyperactivity, agitation, stereotyped behaviour and wet dog shakes were recorded or rated. A second series of injections was given at the 6th hour after the first one, and rats were then tested for audiogenic seizures. Venlafaxine produced some inhibitory effects on locomotor hyperactivity, stereotypic behaviours and wet dog shakes. However, a two-way anova of the data did not indicate any significant effect. It reduced the incidence of the audiogenic seizures at the 6th hour of ethanol withdrawal. Venlafaxine (20 mg/kg) also prolonged the latency of the seizures significantly. Our results suggest that acute venlafaxine treatment has limited beneficial effects on ethanol withdrawal syndrome in rats.

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Effexor, Effexor XR

venlafaxine (Effexor)
Implication of 5-HT(2) receptor subtypes in the mechanism of action of antidepressants in the four plates test.

Nic Dhonnchadha BA, Ripoll N, Clenet F, Hascoet M, Bourin M.

EA 3256, Neurobiologie de l'anxiete et de la depression, Faculte de Medecine, 1 rue Gaston Veil, BP 53508, 44035, Nantes Cedex 01, France.

RATIONALE. The selective serotonin reuptake inhibitors (SSRIs) and the serotonin and noradrenaline reuptake inhibitors (SNRIs) increase synaptic levels of serotonin, leading to an increased activation of a multitude of specific postsynaptic 5-HT receptors. However, it is not yet known which 5-HT receptor subtypes mediate the therapeutic effects of antidepressants. METHODS. The effects of the SSRI, paroxetine and the SNRI, venlafaxine were evaluated in the mouse four plates test (FPT). RESULTS. Paroxetine administered intraperitoneally (IP) (0.5, 2-8 mg/kg) potently augmented the number of punished passages accepted by mice in this paradigm. The effects of paroxetine (8 mg/kg) were not reversed by the selective 5-HT(2C) receptor antagonist, RS 10-2221 (0.1 mg/kg and 1 mg/kg) or the selective 5-HT(2B/2C) receptor antagonist SB 206553 (0.1 mg/kg and 1 mg/kg), at doses which lack an effect when administered alone. In contrast, the selective 5-HT(2A) receptor antagonist, SR 46349B (0.1 mg/kg and 1 mg/kg) completely abolished the paroxetine-induced increase in punished passages. The acute administration of venlafaxine induced an anxiolytic-like effect in the FPT at the doses of 2-16 mg/kg. This effect was reversed by the 5-HT(2B/2C) receptor antagonist as did SR 46349B, for both doses administered. Our results strongly suggest that activation of 5-HT(2A) receptors is critically involved in the anxiolytic activity of paroxetine, whereas the 5-HT(2A) and 5-HT(2B) receptors are involved in the anti-punishment action of venlafaxine in the FPT. The co-administration of selective 5-HT(2A, 2B, 2C) receptor agonists (DOI, 0.06 mg/kg and 0.25 mg/kg; BW 723C86, 0.5 mg/kg and 2 mg/kg and RO 60-0175, 0.06 mg/kg and 0.25 mg/kg), respectively, was subsequently investigated. The effects of sub-active doses of paroxetine (0.25 mg/kg and 1 mg/kg) were augmented by BW 723C86 and RO 60-0175 receptor agonist challenge. The anti-punishment effects of venlafaxine (0.25 mg/kg and 1 mg/kg) were potentialised only by DOI co-administration. CONCLUSION. These results indicate that the co-administration of 5-HT(2) receptor agonists with paroxetine and venlafaxine may provide a powerful tool for enhancing the clinical efficacy of these antidepressants.

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Effexor, Effexor XR