venlafaxine (Effexor)
One-year costs of second-line therapies for depression.

Sullivan EM, Griffiths RI, Frank RG, Strauss MJ, Herbert RJ, Clouse J, Goldman HH.

Covance Health Economics and Outcomes Services Inc., Washington, DC 20005-3934, USA. erin.sullivan covance.com

BACKGROUND: We compared patterns of medical resource utilization and costs among patients receiving a serotonin-norepinephrine reuptake inhibitor (venlafaxine), one of the selective serotonin reuptake inhibitors (SSRIs), one of the tricyclic agents (TCAs), or 1 of 3 other second-line therapies for depression. METHOD: Using claims data from a national managed care organization, we identified patients diagnosed with depression (ICD-9-CM criteria) who received second-line antidepressant therapy between 1993 and 1997. Second-line therapy was defined as a switch from the first class of antidepressant therapy observed in the data set within 1 year of a diagnosis of depression to a different class of antidepressant therapy. Patients with psychiatric comorbidities were excluded. RESULTS: Of 981 patients included in the study, 21% (N = 208) received venlafaxine, 34% (N = 332) received an SSRI, 19% (N = 191) received a TCA, and 25% (N = 250) received other second-line antidepressant therapy. Mean age was 43 years, and 72% of patients were women. Age, prescriber of second-line therapy, and prior 6-month expenditures all differed significantly among the 4 therapy groups. Total, depression-coded, and non-depression-coded 1-year expenditures were, respectively, $6945, $2064, and $4881 for venlafaxine; $7237, $1682, and $5555 for SSRIs; $7925, $1335, and $6590 for TCAs; and $7371, $2222, and $5149 for other antidepressants. In bivariate analyses, compared with TCA-treated patients, venlafaxine- and SSRI-treated patients had significantly higher depression-coded but significantly lower non-depression-coded expenditures. Venlafaxine was associated with significantly higher depression-coded expenditures than SSRIs. However, after adjustment for potential confounding covariables in multivariate analyses, only the difference in depression-coded expenditures between SSRI and TCA therapy remained significant. CONCLUSION: After adjustment for confounding patient characteristics, 1-year medical expenditures were generally similar among patients receiving venlafaxine, SSRIs, TCAs, and other second-line therapies for depression. Observed differences in patient characteristics and unadjusted expenditures raise questions as to how different types of patients are selected to receive alternative second-line therapies for depression.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10830151&dopt=Abstract venlafaxine Effexor refs
Effexor, Effexor XR

venlafaxine (Effexor)
Effects of sustained administration of the serotonin and norepinephrine reuptake inhibitor venlafaxine: I. in vivo electrophysiological studies in the rat.

Beique J, de Montigny C, Blier P, Debonnel G.

Neurobiological Psychiatry Unit, McGill University, 1033 Pine Avenue West, Quebec, H3A 1A1, Montreal, Canada.

The effect of a 21-day treatment with the dual 5-HT and NE reuptake blocker venlafaxine (delivered s.c. by osmotic minipumps) was assessed on the time required for a 50% recovery (RT(50)) of the firing activity of dorsal hippocampus CA(3) pyramidal neurons from the suppression induced by microiontophoretic applications of 5-HT and NE. The RT(50) values for 5-HT were increased by both 10 and 40 mg/kg/day regimens of venlafaxine, whereas those for NE were increased only by the 40 mg/kg/day regimen, indicative of a greater potency of venlafaxine in blocking 5-HT reuptake. The sensitivity of the postsynaptic 5-HT(1A) and alpha(2)-adrenergic receptors was altered by neither regimen of venlafaxine. Using a paradigm by which the 5-HT(1A) antagonist WAY 100635 can induce a disinhibition of firing activity of CA(3) pyramidal neurons, it was demonstrated that the high, but not the low, dose of venlafaxine led to an enhanced tonic activation of postsynaptic 5-HT(1A) receptors in the dorsal hippocampus. The duration of the suppressant effect of the firing activity of CA(3) hippocampus pyramidal neurons produced by the electrical stimulation of the ascending 5-HT pathway was significantly reduced when the frequency of the stimulation was enhanced from 1 Hz to 5 Hz in control rats and in rats treated with 10 mg/kg/day, but not with 40 mg/kg/day of venlafaxine. Hence, venlafaxine induced a desensitization of the terminal 5-HT(1B) autoreceptor only at the high dose. A 2-day treatment with 10 mg/kg/day of venlafaxine induced a suppression of the firing activity of 5-HT neurons of the dorsal raphe. The firing activity of these neurons was back to control level in rats that had been treated for 21 days with the same dose of venlafaxine. The suppressant effect of the i.v. administration of the 5-HT autoreceptor agonist LSD on the firing activity of dorsal raphe 5-HT neurons was reduced in rats that had been treated for 21 days with 10 mg/kg/day of venlafaxine. A 2-day treatment with 40 mg/kg/day of venlafaxine, unlike the 10 mg/kg/day regimen, induced a marked suppression of the firing activity of locus coeruleus NE neurons. However, in contrast to 5-HT neurons, NE neurons did not recover their firing activity after a 21-day treatment. Taken together, the results from this study indicate that the low dose of venlafaxine blocked selectively the reuptake of 5-HT, whereas the high dose blocked the reuptake of both 5-HT and NE. Moreover, an enhancement of serotonergic neurotransmission by venlafaxine was only achieved under conditions whereby the desensitization of the terminal 5-HT(1B) autoreceptor is appended to that of the somatodendritic 5-HT(1A) receptor.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10884561&dopt=Abstract venlafaxine Effexor refs
Effexor, Effexor XR

venlafaxine (Effexor)
Effects of sustained administration of the serotonin and norepinephrine reuptake inhibitor venlafaxine: II. In vitro studies in the rat.

Beique J, de Montigny C, Blier P, Debonnel G.

Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal, H3A 1A1, Quebec, Canada.

The effects of long-term administrations of a low (10 mg/kg/day) and a high (40 mg/kg/day) dose of the dual 5-HT and NE reuptake inhibitor venlafaxine (delivered s.c. by osmotic minipumps for 21 days) were assessed on the electrically-evoked release of tritium from hippocampal slices preloaded with either [(3)H]5-HT or [(3)H]NE, 48 h after the removal of the minipump. The high, but not the low, dose regimen of venlafaxine enhanced the electrically-evoked release of [(3)H]5-HT while treatment with the high dose of venlafaxine failed to alter the electrically-evoked release of [(3)H]NE. The inhibitory effect of the 5-HT(1B) agonist CP 93,129 on the electrically evoked release of [(3)H]5-HT was unaltered by the low dose regimen of venlafaxine while it was attenuated in rats treated with the high dose of venlafaxine, indicative of a functional desensitization of the terminal 5-HT(1B) autoreceptor. Unexpectedly, neither regimen of venlafaxine altered the inhibitory effect of UK 14,304 on the electrically evoked release of both [(3)H]5-HT and [(3)H]NE, indicating that neither the alpha(2)-adrenergic auto- nor heteroreceptors were desensitized. Finally, the functions of the 5-HT and NE reuptake process were assessed. None of the treatment regimens altered the basal uptake of [(3)H]5-HT from hippocampal or mesencephalic slices nor that of [(3)H]NE from hippocampal slices. Finally, the enhancing effect of 1 microM of paroxetine in the perfusion medium on the electrical release of [(3)H]5-HT was unaltered in hippocampal slices prepared from rats that had been treated for 21 days with 40 mg/kg/day of venlafaxine. Taken together, these results indicate that, in terms of alteration of the sensitivity of the terminal 5-HT(1B) autoreceptor, alpha(2)-adrenergic auto-and heteroreceptors, the effects of long-term administration of venlafaxine are no different than those observed with classical SSRI's.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10884562&dopt=Abstract venlafaxine Effexor refs
Effexor, Effexor XR

venlafaxine (Effexor)
Simultaneous stereoselective analysis of venlafaxine and O-desmethylvenlafaxine enantiomers in clinical samples by capillary electrophoresis using charged cyclodextrins.

Rudaz S, Stella C, Balant-Gorgia AE, Fanali S, Veuthey JL.

Laboratory of Pharmaceutical Analytical Chemistry, University of Geneva, Switzerland.

Capillary electrophoresis (CE) was used for the simultaneous chiral determination of venlafaxine (Vx), a new antidepressant drug and its main active metabolite. O-desmethyl venlafaxine (ODV). Among the charged cyclodextrins (CD) tested, phosphated gamma-CD was the most appropriate. Resolution of Vx and ODV was obtained with 50 mM phosphate buffer (pH 2.5) containing 20 mg/ml of phosphated gamma-CD. After optimisation of the method (including robustness), validation was carried out. Vx and ODV concentrations, as well as the enantiomeric ratio, were investigated in clinical samples. Chiral determination of Vx and ODV was performed after a simple liquid-liquid extraction (LLE). In the tested concentration range (25-500 ng/ml), coefficients of correlation were superior to 0.996. Within-day and between-day accuracy and precision were determined at three different concentrations for each enantiomer. Analyses of clinical samples (n = 16) exhibited non-racemic ratios for Vx and ODV, which suggests a stereoselective metabolism in humans.

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Effexor, Effexor XR

venlafaxine (Effexor)
Potentiation by (-)Pindolol of the activation of postsynaptic 5-HT(1A) receptors induced by venlafaxine.

Beique JC, Blier P, de Montigny C, Debonnel G.

Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal, Quebec, Canada.

The increase of extracellular 5-HT in brain terminal regions produced by the acute administration of 5-HT reuptake inhibitors (SSRI's) is hampered by the activation of somatodendritic 5-HT(1A) autoreceptors in the raphe nuclei. The present in vivo electrophysiological studies were undertaken, in the rat, to assess the effects of the coadministration of venlafaxine, a dual 5-HT/NE reuptake inhibitor, and (-)pindolol on pre- and postsynaptic 5-HT(1A) receptor function. The acute administration of venlafaxine and of the SSRI paroxetine (5 mg/kg, i.v.) induced a suppression of the firing activity of dorsal hippocampus CA(3) pyramidal neurons. This effect of venlafaxine was markedly potentiated by a pretreatment with (-)pindolol (15 mg/kg, i.p.) but not by the selective beta-adrenoceptor antagonist metoprolol (15 mg/kg, i.p.). That this effect of venlafaxine was mediated by an activation of postsynaptic 5-HT(1A) receptors was suggested by its complete reversal by the 5-HT(1A) antagonist WAY 100635 (100 microg/kg, i.v.). A short-term treatment with VLX (20 mg/kg/day x 2 days) resulted in a ca. 90% suppression of the firing activity of 5-HT neurons in the dorsal raphe nucleus. This was prevented by the coadministration of (-)pindolol (15 mg/kg/day x 2 days). Taken together, these results indicate that (-)pindolol potentiated the activation of postsynaptic 5-HT(1A) receptors resulting from 5-HT reuptake inhibition probably by blocking the somatodendritic 5-HT(1A) autoreceptor, but not its postsynaptic congener. These results support and extend previous findings providing a biological substratum for the efficacy of pindolol as an accelerating strategy in major depression.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10942853&dopt=Abstract venlafaxine Effexor refs
Effexor, Effexor XR