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The Primary Care Companion For CNS... 2011The primary objective was to evaluate the long-term safety of desvenlafaxine (administered as desvenlafaxine succinate) during open-label treatment in adult outpatients...
BACKGROUND
The primary objective was to evaluate the long-term safety of desvenlafaxine (administered as desvenlafaxine succinate) during open-label treatment in adult outpatients with a primary DSM-IV diagnosis of major depressive disorder (MDD).
METHOD
Depressed adult outpatients (≥ 18 years) who had completed 8-week, double-blind therapy (desvenlafaxine, venlafaxine extended release, or placebo) in a phase 3 study of desvenlafaxine for MDD received up to 10 months of open-label treatment with flexible-dose desvenlafaxine (200 to 400 mg/d). Safety assessments included physical examination, measurement of weight and vital signs, laboratory determinations, and 12-lead electrocardiogram recordings. Adverse events (AEs) and discontinuations due to AEs were monitored throughout the trial. The primary efficacy outcome was mean change from baseline on 17-item Hamilton Depression Rating Scale (HDRS-17) total score. The trial was conducted from August 2003 to March 2006.
RESULTS
The safety population included 1,395 patients who took at least 1 dose of open-label desvenlafaxine. Treatment-emergent AEs were reported by 1,238 of 1,395 patients (89%) during the open-label, on-therapy period. Treatment-emergent AEs reported by 10% or more patients were headache, nausea, hyperhidrosis, dizziness, dry mouth, insomnia, upper respiratory infection, nasopharyngitis, and fatigue. Adverse events were the primary reason for study discontinuation in 296 of 1,395 patients (21%). Ten patients (< 1%) had serious AEs that were considered possibly, probably, or definitely related to the study drug during the on-therapy period. No deaths occurred during the study.
CONCLUSIONS
Desvenlafaxine can be safely administered for up to 12 months. No new safety findings were observed in this study.
TRIAL REGISTRATION
clinicaltrials.gov Identifier: NCT01309542.
PubMed: 21977353
DOI: 10.4088/PCC.10m00977blu -
PloS One 2014Adult hippocampal neurogenesis has been linked to the effects of anti-depressant drugs on behavior in rodent models of depression. To explore this link further, we...
Adult hippocampal neurogenesis has been linked to the effects of anti-depressant drugs on behavior in rodent models of depression. To explore this link further, we tested whether the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine impacted adult hippocampal neurogenesis differently than its primary active SNRI metabolite desvenlafaxine. Adult male Long Evans rats (n = 5-6 per group) were fed vehicle, venlafaxine (0.5 or 5 mg) or desvenlafaxine (0.5 or 5 mg) twice daily for 16 days. Beginning the third day of drug treatment, the rats were given a daily bromodeoxyuridine (BrdU; 50 mg/kg) injection for 5 days to label dividing cells and then perfused 2 weeks after the first BrdU injection to confirm total new hippocampal cell numbers and their phenotypes. The high desvenlafaxine dose increased total new BrdU+ cell number and appeared to accelerate neuronal maturation because fewer BrdU+ cells expressed maturing neuronal phenotypes and more expressed mature neuronal phenotypes in the dentate gyri of these versus vehicle-treated rats. While net neurogenesis was not increased in the dentate gyri of rats treated with the high desvenlafaxine dose, significantly more mature neurons were detected. Our data expand the body of literature showing that antidepressants impact adult neurogenesis by stimulating NPC proliferation and perhaps the survival of neuronal progeny and by showing that a high dose of the SNRI antidepressant desvenlafaxine, but neither a high nor low venlafaxine dose, may also accelerate neuronal maturation in the adult rat hippocampus. These data support the hypothesis that hippocampal neurogenesis may indeed serve as a biomarker of depression and the effects of antidepressant treatment, and may be informative for developing novel fast-acting antidepressant strategies.
Topics: Animals; Antidepressive Agents; Biomarkers; Body Weight; Cell Count; Cell Differentiation; Cyclohexanols; Dentate Gyrus; Desvenlafaxine Succinate; Male; Neurogenesis; Pyramidal Cells; Rats
PubMed: 24896246
DOI: 10.1371/journal.pone.0098530 -
International Journal of Molecular... Nov 2018Myocardial infarction (MI) in animal models induces cognitive deficits as well as the activation of caspase in the limbic system; both can be blocked by 2 weeks of...
Myocardial infarction (MI) in animal models induces cognitive deficits as well as the activation of caspase in the limbic system; both can be blocked by 2 weeks of treatment following MI using tricyclic antidepressants or selective serotonin uptake blockers. Here we used three different treatment schedules to test the short- and long-term effects of the combined serotonin-norepinephrine reuptake inhibitor desvenlafaxine on post-MI-associated cognitive deficits and caspase activation. MI was induced in 39 young adult rats, and 39 rats served as sham-operated controls. Desvenlafaxine (3 mg/kg/day, i.p.) or saline was administered according to one of three schedules: (1) for 2 weeks, starting right after surgery; (2) for 16 weeks, starting 2 weeks after surgery; (3) for 16 weeks, starting right after surgery. Behavior was tested 2 weeks (social interaction, passive avoidance) and 16 weeks (forced swimming, Morris water maze) after surgery. Caspase-3 and caspase-6 activities were measured 16 weeks after surgery. At 2 and 16 weeks post-surgery, saline-treated MI rats displayed performance deficits compared to desvenlafaxine-treated rats, regardless of the treatment schedule. Caspase-3 activity was higher in the amygdala (medial and lateral) and hippocampal CA3 region in untreated MI rats, whereas caspase-6 activity was higher in the CA1 region. Caspase-6 activity correlated positively with deficits in the Morris water maze. These results indicate that, independently of treatment schedules, various treatment schedules with desvenlafaxine can prevent MI-associated cognitive deficits and decrease caspase activities in the limbic system.
Topics: Animals; Avoidance Learning; Behavior, Animal; Caspases; Cicatrix; Cognition Disorders; Desvenlafaxine Succinate; Male; Maze Learning; Myocardial Infarction; Norepinephrine; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Social Behavior; Spatial Memory; Swimming
PubMed: 30486235
DOI: 10.3390/ijms19123748 -
The Primary Care Companion For CNS... Jan 2019
Topics: Aged, 80 and over; Antidepressive Agents; Anxiety Disorders; Depressive Disorder, Treatment-Resistant; Desvenlafaxine Succinate; Diagnosis, Differential; Humans; Male; Tardive Dyskinesia
PubMed: 30664338
DOI: 10.4088/PCC.18l02362 -
The Journal of Mental Health Policy and... Dec 2015Private health insurance plays a large role in the U.S. health system, including for many individuals with depression. Private insurers have been actively trying to...
BACKGROUND
Private health insurance plays a large role in the U.S. health system, including for many individuals with depression. Private insurers have been actively trying to influence pharmaceutical utilization and costs, particularly for newer and costlier medications. The approaches that insurers use may have important effects on patients' access to antidepressant medications.
AIMS OF THE STUDY
To report which approaches (e.g., tiered copayments, prior authorization, and step therapy) commercial health plans are employing to manage newer antidepressant medications, and how the use of these approaches has changed since 2003.
METHODS
Data are from a nationally representative survey of commercial health plans in 60 market areas regarding alcohol, drug abuse and mental health services in 2010. Responses were obtained from 389 plans (89% response rate), reporting on 925 insurance products. For each of six branded antidepressant medications, respondents were asked whether the plan covered the medication and if so, on what copayment tier, and whether it was subject to prior authorization or step therapy. Measures of management approach were constructed for each medication and for the group of medications. Bivariate and multivariate analyses were used to test for association of the management approach with various health plan characteristics.
RESULTS
Less than 1% of health plan products excluded any of the six antidepressants studied. Medications were more likely to be subjected to restrictions if they were newer, more expensive or were reformulations. 55% of products used placement on a high cost-sharing tier (3 or 4) as their only form of restriction for newer branded antidepressants. This proportion was lower than in 2003, when 71% of products took this approach. In addition, only 2% of products left all the newer branded medications unrestricted, down from 25% in 2003. Multivariate analysis indicated that preferred provider organizations were more likely than other product types to use tier 3 or 4 placement.
DISCUSSION
We find that U.S. health plans are using a variety of strategies to manage cost and utilization of newer branded antidepressant medications. Plans appear to be finding that approaches other than exclusion are adequate to meet their cost-management goals for newer branded antidepressants, although they have increased their use of administrative restrictions since 2003. Limitations include lack of information about how administrative restrictions were applied in practice, information on only six medications, and some potential for endogeneity bias in the regression analyses.
CONCLUSION
This study has documented substantial use of various restrictions on access to newer branded antidepressants in U.S. commercial health plans. Most of these medications had generic equivalents that offered at least some substitutability, reducing access concerns. At the same time, it is worth noting that high copayments and administrative requirements can nonetheless be burdensome for some patients.
IMPLICATIONS FOR HEALTH POLICY
Health plans' pharmacy management approaches may concern policymakers less than in the early 2000s, due to the lesser distinctiveness of today's branded medications. This may change depending on future drug introductions.
IMPLICATIONS FOR FURTHER RESEARCH
Future research should examine the impact of plans' pharmacy management approaches, using patient-level data.
Topics: Antidepressive Agents; Citalopram; Cost Control; Cost Sharing; Desvenlafaxine Succinate; Drug Costs; Drug Utilization; Duloxetine Hydrochloride; Fluvoxamine; For-Profit Insurance Plans; Health Care Surveys; Health Services Accessibility; Humans; Insurance Coverage; Insurance, Pharmaceutical Services; Preferred Provider Organizations; Private Sector; Selegiline; United States; Venlafaxine Hydrochloride
PubMed: 26729008
DOI: No ID Found -
BMJ (Clinical Research Ed.) Jan 2013To examine the effect of attending a medical school with an active policy on restricting gifts from representatives of pharmaceutical and device industries on subsequent...
OBJECTIVE
To examine the effect of attending a medical school with an active policy on restricting gifts from representatives of pharmaceutical and device industries on subsequent prescribing behavior.
DESIGN
Difference-in-differences approach.
SETTING
14 US medical schools with an active gift restriction policy in place by 2004.
PARTICIPANTS
Prescribing patterns in 2008 and 2009 of physicians attending one of the schools compared with physicians graduating from the same schools before the implementation of the policy, as well as a set of contemporary matched controls.
MAIN OUTCOME MEASURE
Probability that a physician would prescribe a newly marketed medication over existing alternatives of three psychotropic classes: lisdexamfetamine among stimulants, paliperidone among antipsychotics, and desvenlafaxine among antidepressants. None of these medications represented radical breakthroughs in their respective classes.
RESULTS
For two of the three medications examined, attending a medical school with an active gift restriction policy was associated with reduced prescribing of the newly marketed drug. Physicians who attended a medical school with an active conflict of interest policy were less likely to prescribe lisdexamfetamine over older stimulants (adjusted odds ratio 0.44, 95% confidence interval 0.22 to 0.88; P=0.02) and paliperidone over older antipsychotics (0.25, 0.07 to 0.85; P=0.03). A significant effect was not observed for desvenlafaxine (1.54, 0.79 to 3.03; P=0.20). Among cohorts of students who had a longer exposure to the policy or were exposed to more stringent policies, prescribing rates were further reduced.
CONCLUSION
Exposure to a gift restriction policy during medical school was associated with reduced prescribing of two out of three newly introduced psychotropic medications.
Topics: Antidepressive Agents; Antipsychotic Agents; Case-Control Studies; Central Nervous System Stimulants; Cyclohexanols; Desvenlafaxine Succinate; Dextroamphetamine; Drug Industry; Gift Giving; Health Care Sector; Humans; Interprofessional Relations; Isoxazoles; Marketing of Health Services; Organizational Policy; Paliperidone Palmitate; Practice Patterns, Physicians'; Psychotropic Drugs; Pyrimidines; Schools, Medical; United States
PubMed: 23372175
DOI: 10.1136/bmj.f264 -
Molecules (Basel, Switzerland) Jan 2023The objective of this work was to evaluate the efficiency of a solar photocatalytic process using g-CN as photocatalyst on the degradation of pharmaceutical compounds...
The objective of this work was to evaluate the efficiency of a solar photocatalytic process using g-CN as photocatalyst on the degradation of pharmaceutical compounds detected in hospital wastewater treatment plant secondary effluents. A compound parabolic collector pilot plant, established in the secondary effluent stream of the Ioannina city hospital wastewater treatment plant, was used for the photocatalytic experiments. The analysis of the samples before and after the photocatalytic treatment was accomplished using solid phase extraction (SPE), followed by UHPLC-LTQ/Orbitrap HRMS. Initial effluent characterization revealed the presence of ten pharmaceutical compounds. Among these, amisulpride, O-desmethyl venlafaxine, venlafaxine and carbamazepine were detected in all experiments. Initial concentrations ranged from 73 ng L for citalopram to 2924.53 ng L for O-desmethyl venlafaxine. The evolution of BOD and COD values were determined before and after the photocatalytic treatment. All detected pharmaceuticals were removed in percentages higher than 54% at an optimum catalyst loading ranging between 200 and 300 mg L. The potential of the catalyst to be reused without any treatment for two consecutive cycles was studied, showing a significant efficiency decrease.
Topics: Waste Disposal, Fluid; Venlafaxine Hydrochloride; Water Pollutants, Chemical; Hospitals; Desvenlafaxine Succinate; Pharmaceutical Preparations
PubMed: 36770837
DOI: 10.3390/molecules28031170 -
British Journal of Clinical Pharmacology Jan 2019CYP2D6*9, CYP2D6*10 and CYP2D6*41 are the most frequent reduced-function CYP2D6 alleles in Caucasians. Despite lacking in vivo evidence, they are collectively classified...
Significantly lower CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine metabolic ratio in carriers of CYP2D6*41 versus CYP2D6*9 or CYP2D6*10: a study on therapeutic drug monitoring data from 1003 genotyped Scandinavian patients.
AIMS
CYP2D6*9, CYP2D6*10 and CYP2D6*41 are the most frequent reduced-function CYP2D6 alleles in Caucasians. Despite lacking in vivo evidence, they are collectively classified with an enzyme activity score of 0.5. Thus, the aim of this study was to compare the functional impact of CYP2D6*9, CYP2D6*10 and CYP2D6*41 on CYP2D6 metabolism in a large patient population.
METHODS
A total of 1003 patients (mainly Caucasians) with data on CYP2D6 genotype and serum concentrations of venlafaxine and metabolites were included from a therapeutic drug monitoring service in Oslo, Norway. The O-desmethyl-to-N-desmethyl-venlafaxine metabolic ratio (MR) was applied as CYP2D6 biomarker and compared (Mann-Whitney) between carriers of CYP2D6*9-10 (merged) and CYP2D6*41, either combined with CYP2D6*1 or non-coding (null) alleles. MR subgroup estimates were obtained by multiple linear regression for calculations of CYP2D6*9-10 and CYP2D6*41 activity scores.
RESULTS
MR was significantly lower in carriers of CYP2D6*41 than CYP2D6*9-10 (P < 0.002). The majority of CYP2D6*41/null carriers (86.7%) had MR in the observed range of CYP2D6null/null carriers compared with the minority of CYP2D6*9-10/null carriers (17.4%). CYP2D6 genotype explained 60.7% of MR variability in the multivariate analysis providing subgroup estimates of 9.54 (95% CI; 7.45-12.20), 3.55 (2.06-6.10), 1.33 (0.87-2.05) and 0.47 (0.35-0.61) in carriers of CYP2D6*1/null (n = 269), CYP2D6*9-10/null (n = 17), CYP2D6*41/null (n = 30) and CYP2D6null/null (n = 95), respectively. Based on these estimates, the calculated activity score of CYP2D6*41 was 0.095 compared to 0.34 for CYP2D6*9-10.
CONCLUSIONS
CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine ratio is significantly lower in Scandinavian carriers of CYP2D6*41 vs. CYP2D6*9-10. Thus, these alleles should be differentiated when classifying CYP2D6 phenotype from genotype.
Topics: Aged; Alleles; Antidepressive Agents, Second-Generation; Cyclohexanols; Cytochrome P-450 CYP2D6; Desvenlafaxine Succinate; Drug Monitoring; Female; Genotype; Humans; Male; Middle Aged; Norway; Retrospective Studies; Venlafaxine Hydrochloride
PubMed: 30312494
DOI: 10.1111/bcp.13788 -
Journal of Pharmaceutical and... May 2016(±)-Venlafaxine, a bicyclic antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI) class, is prescribed for the treatment of depression and anxiety...
(±)-Venlafaxine, a bicyclic antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI) class, is prescribed for the treatment of depression and anxiety disorders. As is the case with other antidepressants, its precise mechanisms of action are still unknown. Pharmacometabonomic approaches allow for the detection of diverse metabolites, unlike classic methods for analysing drug interaction based on single metabolites and linear pathways. This provides a global view of the state of homeostasis during treatment and an insight into the mechanisms of action of a drug. Accordingly, the final outcome of treatment is characterised by the network of reactome pathways derived from the on-target and off-target effects of the drug. Regarding antidepressants, the drug network may be located in the gut-microbiome-brain-liver-kidney-immune-cardiovascular system axis (GMBLKICA), implying that neurotransmitters participate as signalling molecules in bidirectional communication. If their bioavailability is increased, this communication and the state of homeostasis may be disrupted. With a pharmacometabonomic approach using NMR in combination with different chemometric methods, a determination was made of subtle changes in the metabolic profile (metabotype) of urine and faeces in normal Wistar rats following a single administration of pharmacological doses of (±)-venlafaxine hydrochloride. Based on the drug-response metabotypes observed, (±)-venlafaxine had effects on gut microbial co-metabolites and osmolytes. Hence, it can be hypothesized that bidirectional communication in the multiorgan axis was perturbed by this drug, and very likely by its active metabolite, (±)-desvenlafaxine. This disrupted signalling could be related not only to therapeutic and adverse effects, but also to the lag period in treatment response.
Topics: Animals; Antidepressive Agents; Brain; Depression; Desvenlafaxine Succinate; Feces; Female; Magnetic Resonance Imaging; Metabolomics; Neurotransmitter Agents; Norepinephrine; Rats; Rats, Wistar; Selective Serotonin Reuptake Inhibitors; Urine; Venlafaxine Hydrochloride
PubMed: 26895493
DOI: 10.1016/j.jpba.2016.01.044 -
Basic & Clinical Pharmacology &... Oct 2017Venlafaxine is a commonly used antidepressant agent. We aimed to provide detailed information on the associations between venlafaxine dose and concentrations of... (Comparative Study)
Comparative Study
Venlafaxine is a commonly used antidepressant agent. We aimed to provide detailed information on the associations between venlafaxine dose and concentrations of venlafaxine, by patient age and sex. From a therapeutic drug monitoring (TDM) database located at Odense University Hospital, Denmark, we identified all adults for whom the treating physician had requested clinical advice on the TDM result for venlafaxine between 2002 and 2012. We identified 1077 TDM samples of venlafaxine from 334 males and 743 females (median age 45 years), and the median daily dose was 225 mg. Median plasma concentration of venlafaxine and o-desmethylvenlafaxine (ODV) was 306 nmol/L and 861 nmol/L, respectively. The median dose-corrected serum level for venlafaxine was 1.49 nmol/L/mg., while the dose-corrected serum level of men and women were 1.21 nmol/L/mg and 1.60 nmol/L/mg, respectively. The dose-corrected sum of venlafaxine and ODV was 8.91 nmol/L/mg (IQR 6.56-12.26) versus 5.52 nmol/L/mg (IQR 4.16-7.52) for patients above 64 years and below the age of 65 years, respectively. Dose-corrected plasma concentrations of venlafaxine and ODV are increased to a clinically significant degree in patients above the age of 64, and initiation of venlafaxine therapy in the elderly should be made cautiously and supported by drug measurements.
Topics: Adult; Age Factors; Aged; Antidepressive Agents, Second-Generation; Biotransformation; Databases, Factual; Denmark; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Male; Methylation; Middle Aged; Patient Selection; Risk Assessment; Risk Factors; Sex Factors; Venlafaxine Hydrochloride
PubMed: 28397349
DOI: 10.1111/bcpt.12796