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Pharmacoepidemiology and Drug Safety May 2022The effect of the inclusion of a more expensive me-too medicine in a hospital drug formulary (HDF) on both in- and out-of-hospital utilization, and the contextual...
BACKGROUND
The effect of the inclusion of a more expensive me-too medicine in a hospital drug formulary (HDF) on both in- and out-of-hospital utilization, and the contextual factors which influence this type of induction is rarely studied. Accordingly, this work aimed to quantify the effect of the decision of a hospital of including a more expensive me-too antidepressant in its HDF.
METHODS
A controlled longitudinal study was carried out in a Regional Health Service of Spain. We performed a segmented regression analysis with control group. We used the following dependent variables: defined daily doses (DDD) per 1000 inhabitants per day, DDD per 100 bed days, and cost per DDD.
RESULTS
At a hospital level, the modification in the formulary led to utilization changes: (1) an increase in immediate consumption of the newly included me-too drug; and, (2) an annual 25.96% [95% CI: 2.96%-48.95%] decrease in the adjusted trend of the already existing parent antidepressant. The adjusted trend of the cost per DDD of the sum of all medications in the therapeutic group increased by 20.03% annually [95% CI: 3.24%-36.82%]. In the out-of-hospital setting utilization changes were: (1) the adjusted trend of the newly included me-too drug rose by 12.14% annually [95% CI: 4.97%-19.30%]; and, (2) that of the parent drug underwent a negative change in trend of 4.18% annually [95% CI: 0.00%-8.36%].
CONCLUSIONS
The inclusion of a more expensive me-too drug in the HDF led to increased consumption of this more expensive me-too drug both in- and out-of-hospital.
Topics: Antidepressive Agents; Drug Prescriptions; Drug Utilization; Hospitals; Humans; Longitudinal Studies
PubMed: 34965012
DOI: 10.1002/pds.5405 -
Bulletin of Experimental Biology and... Dec 2021We studied the role of JNK in the regulation of the metabolism of xenobiotic venlafaxine by liver cells under in vitro conditions. The inhibitory role of this protein...
We studied the role of JNK in the regulation of the metabolism of xenobiotic venlafaxine by liver cells under in vitro conditions. The inhibitory role of this protein kinase in the biotransformation of this psychotropic agent by hepatocytes was demonstrated. JNK inhibitor added to the liver homogenate containing antidepressant enhanced and accelerated the formation of the only pharmacologically active venlafaxine metabolite O-desmethylvenlafaxine in the cell suspension. The results show the promise of studying modifiers of activity of intracellular signaling molecules (in particular, mitogen-activated protein kinases) to develop a fundamentally new approach to control the transformation of xenobiotics and to create a new class of pharmaceutical, target regulators of drugs metabolism.
Topics: Animals; Biotransformation; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Hepatocytes; JNK Mitogen-Activated Protein Kinases; Liver; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Oximes; Quinoxalines; Signal Transduction; Venlafaxine Hydrochloride; Xenobiotics
PubMed: 34855082
DOI: 10.1007/s10517-021-05352-8 -
Clinical Drug Investigation Dec 2021Low adherence to treatment is associated with poorer clinical outcome and greater healthcare resources utilization (HRU). Limited data are available on the extent of... (Observational Study)
Observational Study
BACKGROUND AND OBJECTIVE
Low adherence to treatment is associated with poorer clinical outcome and greater healthcare resources utilization (HRU). Limited data are available on the extent of adherence to each individual antidepressant. The goal of this study was to compare the adherence rate to desvenlafaxine versus usual care with selective serotonin reuptake inhibitors (SSRI) and/or other serotonin-norepinephrine reuptake inhibitors (SNRI), in subjects with major depressive disorder (MDD).
METHODS
Retrospective, multi-centric, observational study including 574 outpatients with MDD. Data were collected from mental and primary care centers. Adherence, persistence, effectiveness, and HRU was evaluated through multivariate regression models.
RESULTS
At 12-months, adjusted adherence rate was higher with desvenlafaxine versus SNRI/SSRI, 67.9% versus 59.9% (OR 1.66, 95% CI 1.07-2.59, p = 0.024). Remission rate was numerically higher with desvenlafaxine versus SNRI/SSRI, 55.9% versus 50.1% (OR 1.35, 95% CI 0.93-1.98, p = 0.118), as well as treatment response, 76.5% in desvenlafaxine group versus 70.8% in SNRI/SSRI group (OR 1.25, 95% CI 0.82-1.90, p = 0.300). Medical visits use was higher in SNRI/SSRI than in desvenlafaxine group [9.8 (4.8) versus 9.1 (6.0), p = 0.019].
CONCLUSIONS
Desvenlafaxine is significantly associated with a higher adherence rate at 12 months compared to usual care based on SSRI or other SNRI. This suggests that desvenlafaxine could improve disease management having a positive impact on disease-associated costs.
Topics: Antidepressive Agents; Depressive Disorder, Major; Desvenlafaxine Succinate; Humans; Retrospective Studies; Selective Serotonin Reuptake Inhibitors
PubMed: 34741760
DOI: 10.1007/s40261-021-01086-7 -
Anticonvulsant effects of desvenlafaxine on modulating brain monoamine and oxidative stress in mice.Brazilian Journal of Biology = Revista... 2021Desvenlafaxine succinate (DVS) inhibits serotonin reuptake selectively and is approved for major depressive disorders. This research investigated influence of DVS on...
Desvenlafaxine succinate (DVS) inhibits serotonin reuptake selectively and is approved for major depressive disorders. This research investigated influence of DVS on modulating brain monoamine and oxidative stress in mice. The antiepileptic potential of DVS (10, 20, or 30 mg/kg/i.p.) in pentylenetetrazole (PTZ; 85 mg/kg) with i.p. route of administration, strychnine (STR; 75 mg/kg) with i.p. route, pilocarpine (400 mg/kg) with s.c. route and maximal electroshock MES-induced convulsion in mouse models. The activities of oxidative stress, i.e. superoxide dismutase (SOD), glutathione (GSH) and lipid peroxidation (LPO) as well as gamma-aminobutyric acid (GABA) in the brains of PTZ-induced convulsive mice. Treatment with DVS increased the latency to develop siezures and declined mortalities in rodents against PTZ, STR and pilocarpine-induced convulsions. Results of MES-leaded siezures revealed that DVS reduced tonic hind limb extension duration and mortalities significantly. Brain, SOD, GSH and GABA level were significantly (P<0.01) increased and LPO reduced significantly (P<0.01) after DVS treatment. Furthermore, the DVS did not show any motor coordination signs in the rotarod test. We demonstrated that the role of DVS in convulsion genesis in mice under control condition and attenuate the PTZ-induced oxidative damage.
Topics: Animals; Anticonvulsants; Brain; Depressive Disorder, Major; Desvenlafaxine Succinate; Mice; Oxidative Stress
PubMed: 34468514
DOI: 10.1590/1519-6984.246194 -
Canadian Journal of Psychiatry. Revue... Jan 2022Major depressive disorder (MDD) is a common and burdensome condition that has low rates of treatment success for each individual treatment. This means that many patients...
BACKGROUND
Major depressive disorder (MDD) is a common and burdensome condition that has low rates of treatment success for each individual treatment. This means that many patients require several medication switches to achieve remission; selecting an effective antidepressant is typically a sequential trial-and-error process. Machine learning techniques may be able to learn models that can predict whether a specific patient will respond to a given treatment, before it is administered. This study uses baseline clinical data to create a machine-learned model that accurately predicts remission status for a patient after desvenlafaxine (DVS) treatment.
METHODS
We applied machine learning algorithms to data from 3,399 MDD patients (90% of the 3,776 subjects in 11 phase-III/IV clinical trials, each described using 92 features), to produce a model that uses 26 of these features to predict symptom remission, defined as an 8-week Hamilton Depression Rating Scale score of 7 or below. We evaluated that learned model on the remaining held-out 10% of the data ( = 377).
RESULTS
Our resulting classifier, a trained linear support vector machine, had a holdout set accuracy of 69.0%, significantly greater than the probability of classifying a patient correctly by chance. We demonstrate that this learning process is stable by repeatedly sampling part of the training dataset and running the learner on this sample, then evaluating the learned model on the held-out instances of the training set; these runs had an average accuracy of 67.0% ± 1.8%.
CONCLUSIONS
Our model, based on 26 clinical features, proved sufficient to predict DVS remission significantly better than chance. This may allow more accurate use of DVS without waiting 8 weeks to determine treatment outcome, and may serve as a first step toward changing psychiatric care by incorporating clinical assistive technologies using machine-learned models.
Topics: Antidepressive Agents; Depressive Disorder, Major; Desvenlafaxine Succinate; Humans; Machine Learning; Treatment Outcome
PubMed: 34379019
DOI: 10.1177/07067437211037141 -
Journal of Clinical PsychopharmacologyHeterogeneity has been documented in trajectories of symptom change during antidepressant treatment for major depressive disorder (MDD). It is unclear whether distinct... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE/BACKGROUND
Heterogeneity has been documented in trajectories of symptom change during antidepressant treatment for major depressive disorder (MDD). It is unclear whether distinct trajectories of change exist for functioning during antidepressant treatment.
METHODS/PROCEDURES
This analysis explored distinct trajectories of functioning in MDD and tested whether they corresponded to trajectories of symptom change. Data were from 4317 patients and were pooled from 9 randomized placebo-controlled trials. Growth mixture modeling was used to identify trajectories of Hamilton Rating Scale for Depression (HRSD) and Sheehan Disability Scale (SDS) for placebo- and desvenlafaxine-treated patients.
FINDINGS/RESULTS
Three trajectories were identified for symptoms (HRSD) in patients receiving placebo (mean reduction baseline to week 8, -18.4 [most favorable] to -2.6 points [least favorable]). Four HRSD trajectories were identified for patients receiving desvenlafaxine (mean reduction from baseline to week 8, -17.2 [most favorable] to -2.6 points [least favorable]). Four trajectories were identified for functioning (SDS) in patients receiving placebo (mean reduction baseline to week 8, -13.6 [most favorable] to -0.8 points [least favorable]), and 3 for desvenlafaxine (-12.8 to -1.4 points, respectively). Percentages of agreement between most favorable HRSD and SDS trajectories were 75% (placebo) and 85% (desvenlafaxine), and for least favorable trajectories were 88% (placebo) and 80% (desvenlafaxine).
IMPLICATIONS/CONCLUSIONS
Distinct trajectories of change based on symptoms and functioning were identified among patients with MDD receiving desvenlafaxine and among patients with MDD receiving placebo. Differentiating subpopulations of patients has the potential to provide a more personalized treatment of patients with MDD.ClinicalTrials.govIdentifiers: NCT00072774; NCT00277823; NCT00300378; NCT00384033; NCT00798707; NCT00863798; NCT01121484; NCT00824291; NCT01432457.
Topics: Antidepressive Agents; Depressive Disorder, Major; Desvenlafaxine Succinate; Humans; Precision Medicine; Treatment Outcome
PubMed: 34183490
DOI: 10.1097/JCP.0000000000001435 -
The World Journal of Biological... Mar 2022Therapeutic Drug Monitoring (TDM) represents one of the most promising tools in clinical practice to optimise antidepressant treatment. Nevertheless, little is still...
BACKGROUND
Therapeutic Drug Monitoring (TDM) represents one of the most promising tools in clinical practice to optimise antidepressant treatment. Nevertheless, little is still known regarding the relationship between clinical efficacy and serum concentration of venlafaxine (VEN). The aim of our study was to investigate the association between serum concentration of venlafaxine + O-desmethylvenlafaxine (SCVO) and antidepressant response (AR).
METHODS
52 depressed outpatients treated with VEN were recruited and followed in a naturalistic setting for three months. Hamilton Depression Rating Scale-21 was administered at baseline, at month 1 and at month 3 to assess AR. SCVO was measured at steady state. Linear regression analysis and nonlinear least-squares regression were used to estimate association between SCVO and AR.
RESULTS
Our results showed an association between AR and SCVO that follows a bell-shaped quadratic function with a progressive increase of AR within the therapeutic reference range of SCVO (i.e. 100-400 ng/mL) and a subsequent decrease of AR at higher serum levels.
DISCUSSION
This study strongly suggests that TDM could represent a more appropriate tool than the oral dosage to optimise the treatment with VEN. Specifically, highest efficacy might be achieved by titrating patients at SCVO levels around 400 ng/mL.
Topics: Humans; Aged; Desvenlafaxine Succinate; Venlafaxine Hydrochloride; Outpatients; Antidepressive Agents; Drug Monitoring; Cyclohexanols; Antidepressive Agents, Second-Generation
PubMed: 34096828
DOI: 10.1080/15622975.2021.1938668 -
The Science of the Total Environment Jul 2021Exposure of aquatic organisms to antidepressants is currently well documented, while little information is available on how wild organisms cope with exposure to these...
Exposure of aquatic organisms to antidepressants is currently well documented, while little information is available on how wild organisms cope with exposure to these pharmaceutical products. Studies on antidepressant metabolism in exposed organisms could generate information on their detoxification pathways and pharmacokinetics. The goal of this study was to enhance knowledge on the metabolism of venlafaxine (VEN)-an antidepressant frequently found in aquatic ecosystems-in Mytilus galloprovincialis, a bivalve that is present worldwide. An original tissue extraction technique based on the cationic properties of VEN was developed for further analysis of VEN and its metabolites using targeted and non-targeted approaches. This extraction method was assessed in terms of recovery and matrix effects for VEN metabolites. Commercial analytical standards were applied to characterize metabolites found in mussels exposed to 10 μg/L VEN for 3 and 7 days. Targeted and non-targeted approaches using liquid chromatography (LC) combined with high-resolution mass spectrometry (HRMS) were implemented to screen for expected metabolites based on the literature on aquatic species, and for metabolites not previously documented. Four venlafaxine metabolites were identified, namely N-desmethylvenlafaxine and O-desmethylvenlafaxine, which were clearly identified using analytical standards, and two other metabolites revealed by non-target analysis. According to the signal intensity, hydroxy-venlafaxine (OH-VEN) was the predominant metabolite detected in mussels exposed for 3 and 7 days.
Topics: Animals; Chromatography, Liquid; Desvenlafaxine Succinate; Ecosystem; Mytilus; Venlafaxine Hydrochloride; Water Pollutants, Chemical
PubMed: 34030260
DOI: 10.1016/j.scitotenv.2021.146387 -
The Cochrane Database of Systematic... May 2021Major depressive disorders have a significant impact on children and adolescents, including on educational and vocational outcomes, interpersonal relationships, and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Major depressive disorders have a significant impact on children and adolescents, including on educational and vocational outcomes, interpersonal relationships, and physical and mental health and well-being. There is an association between major depressive disorder and suicidal ideation, suicide attempts, and suicide. Antidepressant medication is used in moderate to severe depression; there is now a range of newer generations of these medications.
OBJECTIVES
To investigate, via network meta-analysis (NMA), the comparative effectiveness and safety of different newer generation antidepressants in children and adolescents with a diagnosed major depressive disorder (MDD) in terms of depression, functioning, suicide-related outcomes and other adverse outcomes. The impact of age, treatment duration, baseline severity, and pharmaceutical industry funding was investigated on clinician-rated depression (CDRS-R) and suicide-related outcomes.
SEARCH METHODS
We searched the Cochrane Common Mental Disorders Specialised Register, the Cochrane Library (Central Register of Controlled Trials (CENTRAL) and Cochrane Database of Systematic Reviews (CDSR)), together with Ovid Embase, MEDLINE and PsycINFO till March 2020.
SELECTION CRITERIA
Randomised trials of six to 18 year olds of either sex and any ethnicity with clinically diagnosed major depressive disorder were included. Trials that compared the effectiveness of newer generation antidepressants with each other or with a placebo were included. Newer generation antidepressants included: selective serotonin reuptake inhibitors; selective norepinephrine reuptake inhibitors (SNRIs); norepinephrine reuptake inhibitors; norepinephrine dopamine reuptake inhibitors; norepinephrine dopamine disinhibitors (NDDIs); and tetracyclic antidepressants (TeCAs).
DATA COLLECTION AND ANALYSIS
Two reviewers independently screened titles/abstracts and full texts, extracted data, and assessed risk of bias. We analysed dichotomous data as Odds Ratios (ORs), and continuous data as Mean Difference (MD) for the following outcomes: depression symptom severity (clinician rated), response or remission of depression symptoms, depression symptom severity (self-rated), functioning, suicide related outcomes and overall adverse outcomes. Random-effects network meta-analyses were conducted in a frequentist framework using multivariate meta-analysis. Certainty of evidence was assessed using Confidence in Network Meta-analysis (CINeMA). We used "informative statements" to standardise the interpretation and description of the results.
MAIN RESULTS
Twenty-six studies were included. There were no data for the two primary outcomes (depressive disorder established via clinical diagnostic interview and suicide), therefore, the results comprise only secondary outcomes. Most antidepressants may be associated with a "small and unimportant" reduction in depression symptoms on the CDRS-R scale (range 17 to 113) compared with placebo (high certainty evidence: paroxetine: MD -1.43, 95% CI -3.90, 1.04; vilazodone: MD -0.84, 95% CI -3.03, 1.35; desvenlafaxine MD -0.07, 95% CI -3.51, 3.36; moderate certainty evidence: sertraline: MD -3.51, 95% CI -6.99, -0.04; fluoxetine: MD -2.84, 95% CI -4.12, -1.56; escitalopram: MD -2.62, 95% CI -5.29, 0.04; low certainty evidence: duloxetine: MD -2.70, 95% CI -5.03, -0.37; vortioxetine: MD 0.60, 95% CI -2.52, 3.72; very low certainty evidence for comparisons between other antidepressants and placebo). There were "small and unimportant" differences between most antidepressants in reduction of depression symptoms (high- or moderate-certainty evidence). Results were similar across other outcomes of benefit. In most studies risk of self-harm or suicide was an exclusion criterion for the study. Proportions of suicide-related outcomes were low for most included studies and 95% confidence intervals were wide for all comparisons. The evidence is very uncertain about the effects of mirtazapine (OR 0.50, 95% CI 0.03, 8.04), duloxetine (OR 1.15, 95% CI 0.72, 1.82), vilazodone (OR 1.01, 95% CI 0.68, 1.48), desvenlafaxine (OR 0.94, 95% CI 0.59, 1.52), citalopram (OR 1.72, 95% CI 0.76, 3.87) or vortioxetine (OR 1.58, 95% CI 0.29, 8.60) on suicide-related outcomes compared with placebo. There is low certainty evidence that escitalopram may "at least slightly" reduce odds of suicide-related outcomes compared with placebo (OR 0.89, 95% CI 0.43, 1.84). There is low certainty evidence that fluoxetine (OR 1.27, 95% CI 0.87, 1.86), paroxetine (OR 1.81, 95% CI 0.85, 3.86), sertraline (OR 3.03, 95% CI 0.60, 15.22), and venlafaxine (OR 13.84, 95% CI 1.79, 106.90) may "at least slightly" increase odds of suicide-related outcomes compared with placebo. There is moderate certainty evidence that venlafaxine probably results in an "at least slightly" increased odds of suicide-related outcomes compared with desvenlafaxine (OR 0.07, 95% CI 0.01, 0.56) and escitalopram (OR 0.06, 95% CI 0.01, 0.56). There was very low certainty evidence regarding other comparisons between antidepressants.
AUTHORS' CONCLUSIONS
Overall, methodological shortcomings of the randomised trials make it difficult to interpret the findings with regard to the efficacy and safety of newer antidepressant medications. Findings suggest that most newer antidepressants may reduce depression symptoms in a small and unimportant way compared with placebo. Furthermore, there are likely to be small and unimportant differences in the reduction of depression symptoms between the majority of antidepressants. However, our findings reflect the average effects of the antidepressants, and given depression is a heterogeneous condition, some individuals may experience a greater response. Guideline developers and others making recommendations might therefore consider whether a recommendation for the use of newer generation antidepressants is warranted for some individuals in some circumstances. Our findings suggest sertraline, escitalopram, duloxetine, as well as fluoxetine (which is currently the only treatment recommended for first-line prescribing) could be considered as a first option. Children and adolescents considered at risk of suicide were frequently excluded from trials, so that we cannot be confident about the effects of these medications for these individuals. If an antidepressant is being considered for an individual, this should be done in consultation with the child/adolescent and their family/caregivers and it remains critical to ensure close monitoring of treatment effects and suicide-related outcomes (combined suicidal ideation and suicide attempt) in those treated with newer generation antidepressants, given findings that some of these medications may be associated with greater odds of these events. Consideration of psychotherapy, particularly cognitive behavioural therapy, as per guideline recommendations, remains important.
Topics: Adolescent; Antidepressive Agents; Bias; Child; Citalopram; Depressive Disorder, Major; Desvenlafaxine Succinate; Duloxetine Hydrochloride; Female; Fluoxetine; Humans; Male; Mirtazapine; Network Meta-Analysis; Paroxetine; Selective Serotonin Reuptake Inhibitors; Sertraline; Suicidal Ideation; Venlafaxine Hydrochloride; Vilazodone Hydrochloride; Vortioxetine
PubMed: 34029378
DOI: 10.1002/14651858.CD013674.pub2 -
Journal of Clinical PsychopharmacologyThe aim of this study was to investigate the potential dose-dependent CYP2D6 inhibition by bupropion (BUP) in patients with depression. (Comparative Study)
Comparative Study
PURPOSE
The aim of this study was to investigate the potential dose-dependent CYP2D6 inhibition by bupropion (BUP) in patients with depression.
METHODS
Patients combining BUP with venlafaxine were included from a therapeutic drug monitoring (TDM) database at the Diakonhjemmet Hospital (Oslo, Norway). The O/N-desmethylvenlafaxine metabolic ratio measured in TDM samples was used as a biomarker for CYP2D6 phenotype and was compared between patients treated with BUP 150 mg/d and 300 mg/d or greater. In addition, reference groups of venlafaxine-treated patients genotyped as CYP2D6 poor metabolizers (PMs, no CYP2D6 activity) and normal metabolizers (NMs, fully functional CYP2D6 activity) were included.
FINDINGS
A total of 221 patients were included in the study. The median O/N-desmethylvenlafaxine metabolic ratio was significantly higher in patients treated with BUP 150 mg/d (n = 59) versus 300 mg/d or greater (n = 34, 1.77 vs 0.96, P < 0.001). In CYP2D6 NMs (n = 62) and PMs (n = 66), the median metabolic ratios were 40.55 and 0.48, respectively. For patients treated with BUP 150 mg/d, 11 (19%) of the 59 patients were phenoconverted to PMs, whereas this was the case for 17 (50%) of the 34 patients treated with BUP 300 mg/d or greater.
CONCLUSIONS
Bupropion exhibits a clear dose-dependent CYP2D6 inhibitory effect during treatment of patients with depression. This finding is of clinical relevance when adjusting dosing of CYP2D6 substrates during comedication with BUP. Half of the patients treated with high-dose BUP are converted to CYP2D6 PM phenotype. Because of the variability in CYP2D6 inhibition, TDM of CYP2D6 substrates should be considered to provide individualized dose adjustments during comedication with BUP.
Topics: Adult; Aged; Aged, 80 and over; Antidepressive Agents, Second-Generation; Bupropion; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Depression; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Drug Monitoring; Female; Genotype; Humans; Male; Middle Aged; Retrospective Studies; Venlafaxine Hydrochloride; Young Adult
PubMed: 33905640
DOI: 10.1097/JCP.0000000000001387