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Genetic variants in FKBP5 affecting response to antidepressant drug treatment.
Pharmacogenomics. 2008 Jul; 9(7): 841-6
Kirchheiner J, Lorch R, Lebedeva E, Seeringer A, Roots I, Sasse J, Brockmöller J
INTRODUCTION: Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is a pathogenic mechanism of depression, and genetic polymorphisms in HPA axis genes have been described to influence response to antidepressant drugs. In particular, two polymorphisms in FKBP5, a co-chaperone of the glucocorticoid receptor, were strongly associated with response to therapy. We aimed to analyze whether these findings could be reproduced in a different sample of otherwise comparable inpatients with major depression. METHODS: Genotyping for the two variants within the FKBP5 gene was performed using PCR-restriction fragment length polymorphism and Taqman real-time PCR in a cohort of 179 inpatients who were monitored for the first 3 weeks of antidepressant drug treatment. The early response to antidepressant drugs was assessed as percentage of decline in Hamilton depression score after 3 weeks, responders versus nonresponders were distinguished by a 50% decrease. RESULTS: The FKBP5 variants rs3800373 and rs1360780 were highly linked, and carriers of the FKBP5 variants had a trend towards a higher chance to respond (p = 0.04; odds ratio: 1.8; 95% CI: 0.98-3.3). When analyzing drug-specific subgroups, the effect was seen mainly in the subgroups of patients treated with antidepressant drug combinations or with venlafaxine. CONCLUSION: In this study, an effect of FKBP5 variants on antidepressant drug response was confirmed in an independent cohort of depressed patients; however, with an odds ratio of 1.8 the effect size was smaller than that described earlier.
J Manag Care Pharm. 2008 Jun; 14(5): 426-41
Khandker RK, Kruzikas DT, McLaughlin TP
BACKGROUND: While much has been published on utilization of antidepressants and associated resource use, surprisingly little information is available on the relationship between a change in antidepressant agent and health care utilization. Given that many patients will not respond to initial therapy (and therefore would be candidates for switching treatment) and the array of antidepressant medications on the market, information on the impact of switching would be beneficial to both providers and policymakers. OBJECTIVE: To explore patterns of antidepressant drug use and depressionrelated and all-cause medical costs for patients who switched therapy between 2 drug classes, selective serotonin reuptake inhibitors (SSRIs) and the selective norepinephrine reuptake inhibitor (SNRI) venlafaxine. METHODS: Using an administrative claims database of 36 million members from 61 health plans, this retrospective cohort analysis examined patients who had (1) a diagnosis of major depressive disorder (MDD, International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 296.2x for MDD single episode, 296.3x for MDD recurrent episode, 300.4 for dysthymic disorder, and 311 for depressive disorder not elsewhere classified) and (2) a newly prescribed antidepressant during the year 2002. Costs were defined as amounts paid by health plans for all inpatient, outpatient, physician and pharmacy services (i.e., allowed charges after subtraction of member cost-share). Depression-related costs were defined using (1) medical claims with primary diagnosis of depression and (2) pharmacy claims for antidepressants. Using an index date of the first antidepressant claim, 12 months of pre-index and postindex data were available for all eligible patients. Switching was defined as occurring between the SSRIs and venlafaxine (i.e., patients who switched within the SSRI drug class across different SSRIs were treated as nonswitchers until they switched to venlafaxine), and there was no minimum or maximum gap in therapy. The SSRIs included fluoxetine, citalopram, sertraline, and paroxetine; the only SNRI on the market at the time was venlafaxine. Multivariate regression analyses determined predictors of switching and factors influencing overall and depression-related costs, while controlling for confounding factors. For the 12-month period following the index date (fixed length of follow-up), the study compared per-patient per-year (PPPY) costs for (1) patients who switched versus those who did not switch and (2) patients with single versus multiple trials of SSRI for the subgroup of patients who switched from an SSRI to venlafaxine. For the time periods before versus after the switch (variable lengths of follow-up), per-patient means and medians of monthly cost averages (with follow-up periods < 1 month set to 1 month for 16.5% [n = 272] of SSRI-tovenlafaxine switchers and 14.1% [n = 103] of venlafaxine-to-SSRI switchers) were calculated for the subgroup of patients who made a switch. RESULTS: A total of 48,950 patients were included in the study, with 43,653 (89.2%) treated first with SSRIs and 5,297 (10.8%) treated first with venlafaxine. Of the initial SSRI users, 1,645 (3.8%) switched to venlafaxine, and of the initial venlafaxine users, 733 (13.8%) switched to an SSRI. Mean (standard deviation [SD]) 12-month total (medical plus pharmacy) depression-related costs in 2002-2003 dollars were 118.0% higher for SSRI switchers ($1,225 [$3,438] vs. $562 [$2,153], P < 0.001) and 18.4% higher for venlafaxine switchers ($863 [$1,503] vs. $729 [$1,185], P = 0.021) as compared with non-switchers. From the pre-switch to post-switch periods, depression-related mean monthly medical costs declined by 66.4% among switchers from SSRIs ($113 [$912] vs. $38 [$347], P = 0.001) and by 61.1% among switchers from venlafaxine ($54 [$299] vs. $21 [$138], P = 0.005). Monthly mean depression-related pharmacy costs increased by 62.2% following a switch from an SSRI to venlafaxine (from $45 [$38] to $73 [$62], P < 0.001) and declined by 17.3% following a switch from venlafaxine to an SSRI (from $52 [$45] to $43 [$38], P < 0.001). After adjustment for multiple covariates including demographic characteristics, 10 selected comorbidities, and physician specialty, general linear models with logtransformed costs as the dependent variables demonstrated significant associations between switching and total costs (both all-cause and depression-related) in both the SSRI and the venlafaxine cohorts. CONCLUSIONS: Although relatively few patients switched antidepressant drug classes, patients who made a switch had higher all-cause health care costs and higher depression-related costs than patients who did not switch. Switching drug classes was associated with lower mean monthly depression-related health care costs following the switch. For those patients switching from an SSRI to venlafaxine, mean medical cost reductions offset higher pharmacy costs; for patients switching from venlafaxine to an SSRI, mean medical and pharmacy costs declined.
AAPS PharmSciTech. 2008 Jul 1;
Singh G, Ghosh B, Kaushalkumar D, Somsekhar V
The objective of the study was to investigate in vitro transdermal delivery of venlafaxine hydrochloride across the pigskin by passive diffusion and iontophoresis. For passive diffusion, experiments were carried out in Franz diffusion cell whereas for iontophoretic permeation, the diffusion cell was modified to contain both the donor and return electrode on the same side of skin. Anodal iontophoresis was carried out using a current density of 0.5 mA/cm(2). Donor concentrations used were 585.5 mg/ml (saturated solution) and 100 mg/ml. Experiments initially performed to determine the transport efficiency of venlafaxine ions showed promising results. Iontophoresis increased the permeation rate at both concentration levels over their passive counterparts (P < 0.01), but surprisingly higher steady-state flux was obtained from lower donor drug load (P < 0.01). The favorable pH of the unsaturated solutions is suggested to be the cause for this effect. Mild synergistic effect was observed when iontophoresis was carried out incorporating peppermint oil in the donor but the same was not found in passive diffusion. Highest steady-state flux obtained in the experiment was 3.279 mumol/cm(2)/h when peppermint oil (0.1%) was included in the donor. As the maintenance requirement of venlafaxine hydrochloride is approximately 9.956 mumol/h, the results suggested that the drug is a promising candidate for iontophoretic delivery.
J Clin Psychiatry. 2008 Jun 3; e1-e5
Bramness JG, Skurtveit S, Neutel CI, Mørland J, Engeland A
OBJECTIVES: Experimental studies have shown that both depression and the use of antidepressants may impair the ability to drive a motor vehicle. Population-based studies have been inconclusive. Differences in results have been shown for cyclic, sedating antide-pressants and newer, nonsedating antidepressants. The objective of the present study was to examine whether the use of antidepressants by drivers increased the risk of being involved in traffic accidents. METHOD: From April 2004 to September 2006, information on prescriptions, road accidents, and emigrations/deaths was obtained from 3 Norwegian population-based registries. Data on people between the ages 18-69 (N = 3.1 million) were linked. Exposure consisted of receiving prescriptions for any anti-depressants. Standardized incidence ratios (SIRs) were calculated by comparing the incidence of accidents during time exposed with the incidence over the time not exposed. Sedating antidepressants (tricyclic antidepressants, mianserin, and mirtazapine) were studied together as one group, and newer, nonsedating antidepressants (selective serotonin reuptake inhibitors, moclobemide, venlafaxine, and reboxetine) as another. RESULTS: During the study period, 20,494 road accidents with personal injuries occurred, including 204 and 884 in which the driver was exposed to sedating antidepressants or newer, nonsedating antidepressants, respectively. The traffic accident risk increased slightly for drivers who had received prescriptions for sedating antidepressants (SIR = 1.4, 95% CI = 1.2 to 1.6) or nonsedating antidepressants (SIR = 1.6, 95% CI = 1.5 to 1.7). The SIR estimates were similar for male and female drivers and slightly higher for young drivers (18-34 years of age) using older sedative antidepressants. SIR estimates did not change substantially for different time periods after dispensing of the prescription, for concomitant use of other impairing drugs, or for new users. CONCLUSION: There was a slightly increased risk of being involved in a traffic accident after having received a prescription for any antidepressants. In the present study, it was not possible to determine whether this increase was due to the antidepressant, the effect of the depression, or characteristics of the patients being prescribed these drugs.
Drug Dev Ind Pharm. 2008 Jun; 34(6): 569-76
Tian L, Zhang Y, Tang X
This study was performed in order to develop a sustained-release pellet formulation containing venlafaxine hydrochloride (VEN), an extremely water-soluble drug, prepared by combination of wax matrices and double-layer coatings. The influence of both double-layer polymeric coats and wax matrices on the release of VEN from sustained-release pellets was investigated. The pellets were prepared by wet mass extrusion spheronization methods and then coated with a fluidized bed coater. For the pellets coated with Eudragit NE30D alone, a coating level of nearly 40% was required to pass the dissolution test compared with commercial product, and it was accompanied by an unacceptable lag time. The application of an alcohol-soluble polymeric subcoat, Opadry I, was added before the Eudragit NE30D coating process, which resulted in a marked delay in drug release. However, a faster release was observed for the formulation coated with a high subcoat level (10%) at the end of the dissolution test. A further delay in drug release was observed when a wax matrix, octadecanol, was added to the core pellet formulation. The kinetics of drug release changed from the Higuchi model to a zero order model and the predominant mechanism controlling drug release changed from diffusion to dissolution upon increasing the amount of octadecanol within the matrix pellets. In addition, the drug release was markedly influenced by the drug to matrix ratio. In conclusion, the 40% drug-loaded core pellets with double-layer coatings (8% Opadry I and 12% Eudragit NE30D) and 20% octadecanol matrix produced the desired profile for once-daily sustained release compared with the commercial product, and these pellets remained stable during storage.
J Psychopharmacol. 2008 Jun 18;
Peritogiannis V, Antoniou K, Mouka V, Mavreas V, Hyphantis TN
Abstract Manic switching during antidepressant treatment has been reported with every class of antidepressant drugs. Serotonin-noradrenaline reuptake inhibitors (SNRIs) have been increasingly used for the treatment of unipolar and bipolar depression and are well tolerated and sufficiently effective because of their dual mechanism of action. A case of duloxetine-induced hypomania in a non-bipolar patient is presented, and a brief review of all the cases of SNRIs' induced mania and hypomania has been carried out. The available data suggest that SNRIs, especially venlafaxine, can induce mood switching in patients with bipolar depression and in certain patients with unipolar depression, but the potential of duloxetine and milnacipran to induce manic or hypomanic symptoms cannot be disregarded. Switching appears to be dose related and treatment initiation with lower doses and upward titration when needed may be preferable in selected cases and may help minimizing the risk of mood switching.
High-dose venlafaxine in delusional and severely depressed patients.
J Psychopharmacol. 2008 Jun 18;
Ruiz-Doblado S, Rueda-Villar T, Casillas-Lara L
J Psychopharmacol. 2008 Jun 26;
van den Broek WW, Mulder PG, van Os E, Birkenhäger TK, Pluijms E, Bruijn JA
Abstract With respect to the pharmacological characteristic, venlafaxine is comparable with tricyclic antidepressants (TCAs), and venlafaxine might be comparable in efficacy. We performed a systematic review investigating the relative efficacy and tolerability of venlafaxine compared with TCAs (imipramine, clomipramine, amitriptyline, nortriptyline and desipramine). Relevant double-blind randomised trials were identified from systematic searches of electronic databases. An exact analysis of the estimated odds ratios of response of the TCA relative to venlafaxine showed no overall significance of treatment effect (P = 0.38). The odds ratios were not homogenous across studies (P = 0.0213). The average dose of venlafaxine was 103.5 mg/day and for the TCA 106.1 mg/day. An exact analysis of the estimated odds ratios of the withdrawals and side effects in the trials with a TCA relative to venlafaxine showed no overall significance of withdrawal. From our review, no significant difference in treatment effect between low dose of both venlafaxine and the TCAs could be found. In our opinion, because of the heterogeneity of the odds ratios, one cannot conclude that they are of equal efficacy.
Encephale. 2008 Jun; 34(3): 280-3
Millet B
Escitalopram has shown some different pharmacologic properties compared to its racemic molecule, citalopram. When comparing with venlafaxine, similar efficacy of this drug was observed, notably when considering the frequency of responders [50% of decrease on the Montgomery and Asberg Depression rating Scale (MADRS)] and the frequency of remitters (MADRS
J Med Chem. 2008 Jul 10; 51(13): 4038-49
Mahaney PE, Gavrin LK, Trybulski EJ, Stack GP, Vu AT, Cohn ST, Ye F, Belardi JK, Santilli AA, Sabatucci JP, Leiter J, Johnston GH, Bray JA, Burroughs KD, Cosmi SA, Leventhal L, Koury EJ, Zhang Y, Mugford CA, Ho DM, Rosenzweig-Lipson SJ, Platt B, Smith VA, Deecher DC
Further exploration of the cycloalkanol ethylamine scaffold, of which venlafaxine ( 1) is a member, was undertaken to develop novel and selective norepinephrine reuptake inhibitors (NRIs) for evaluation in a variety of predictive animal models. These efforts led to the discovery of a piperazine-containing analogue, 17g (WY-46824), that exhibited potent norepinephrine reuptake inhibition, excellent selectivity over the serotonin transporter, but no selectivity over the dopamine transporter. Synthesis and testing of a series of cyclohexanol ethylpiperazines identified ( S)-(-)- 17i (WAY-256805), a potent norepinephrine reuptake inhibitor (IC 50 = 82 nM, K i = 50 nM) that exhibited excellent selectivity over both the serotonin and dopamine transporters and was efficacious in animal models of depression, pain, and thermoregulatory dysfunction.