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Journal of Pharmaceutical and... Jun 2024Venlafaxine (VEN) and its O-demethylated metabolite, O-desmethylvenlafaxine (ODV), are commonly prescribed serotonin-norepinephrine reuptake inhibitors, approved for the...
BACKGROUND
Venlafaxine (VEN) and its O-demethylated metabolite, O-desmethylvenlafaxine (ODV), are commonly prescribed serotonin-norepinephrine reuptake inhibitors, approved for the treatment of depression and anxiety. Both are metabolized to inactive metabolites via cytochrome P450 enzymes. While previous studies have focused on quantifying VEN and ODV, bioanalytical methods for the simultaneous measurement of all metabolites are needed to fully characterize the pharmacology of VEN and ODV.
METHODS
KEDTA plasma was spiked with VEN, ODV, N-desmethylvenlafaxine (NDV), N,O-didesmethylvenlafaxine (NODDV), and N,N-didesmethylvenlafaxine (NNDDV). Drugs and metabolites were extracted via protein precipitation and quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The multiplexed assay was validated in accordance with regulatory recommendations, and evaluated in remnant plasma samples from persons prescribed venlafaxine.
RESULTS
The analytical measuring range for venlafaxine and all four metabolites was 5-800 ng/mL. Standard curves were generated via weighted quadratic (NNDDV) or linear (VEN, ODV, NDV, NODDV) regression of calibrators. Inter-assay imprecision was between 1.9-9.3% for all levels of all analytes. Minor matrix effects were observed, and both recovery efficiency and process efficiency were >96% for all analytes. All other assay validation assessments met acceptance criteria. Drug concentrations measured from remnant plasma specimens obtained from patients with current venlafaxine prescriptions (37.5-450 mg/day) yielded NDDV, NDV, and NODDV metabolite concentrations in 6/21, 14/21, and 20/21 samples, respectively. The ratio of active to inactive analytes ranged from 0.74 to 14.5, with a median of 6.39.
CONCLUSIONS
An efficient and accurate LC-MS/MS method was developed and validated for the quantification of VEN, ODV, and all three inactive metabolites in plasma. The assay met all acceptance criteria, and may be used in future studies of the pharmacokinetics of these drugs.
Topics: Humans; Venlafaxine Hydrochloride; Chromatography, Liquid; Tandem Mass Spectrometry; Cyclohexanols; Desvenlafaxine Succinate; Selective Serotonin Reuptake Inhibitors
PubMed: 38461636
DOI: 10.1016/j.jpba.2024.116082 -
CNS Spectrums Jun 2020The value of early functional improvement at week 2 for predicting subsequent functional outcomes at week 8 was assessed in a pooled analysis of patients with major... (Randomized Controlled Trial)
Randomized Controlled Trial
Predictors of functional response and remission with desvenlafaxine 50 mg and 100 mg: a pooled analysis of randomized, placebo-controlled studies in patients with major depressive disorder.
OBJECTIVE
The value of early functional improvement at week 2 for predicting subsequent functional outcomes at week 8 was assessed in a pooled analysis of patients with major depressive disorder (MDD) treated with desvenlafaxine (50 or 100 mg/d) or placebo.
METHODS
Data were pooled from eight double-blind, placebo-controlled studies of desvenlafaxine 50 mg/d or 100 mg/d for the treatment of MDD. Optimal week-2 improvement thresholds in Sheehan Disability Scale (SDS) score, which best predicted week-8 treatment success, were determined using receiver operating characteristic (ROC) analysis. Four definitions of treatment success were established: (1) functional response, (2) functional/depression response, (3) functional remission, and (4) functional/depression remission. Odds ratios (ORs) of early improvement for prediction (based on thresholds determined in the ROC analysis) of week-8 treatment success were computed using logistic regression models.
RESULTS
Functional early improvement thresholds of 17%-32% were predictive of week-8 treatment success across treatment groups and definitions of treatment success. Optimal thresholds were higher for more stringent definitions. Negative predictive value exceeded positive predictive value, indicating that failure to achieve early functional improvement was more informative about later treatment success than was the achievement of early functional improvement. Early change in SDS was a highly significant predictor of functional response/remission (ORs, 4.981-8.737; all p < 0.0001); the interaction between treatment and early functional improvement was not significant.
CONCLUSION
Early improvement in SDS total score was predictive of functional outcomes for patients treated with desvenlafaxine 50 mg, desvenlafaxine 100 mg, or placebo.
Topics: Adolescent; Adult; Aged; Antidepressive Agents; Depressive Disorder, Major; Desvenlafaxine Succinate; Female; Humans; Male; Middle Aged; Remission Induction; Treatment Outcome
PubMed: 31060632
DOI: 10.1017/S1092852919000828 -
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 -
Journal of Environmental Sciences... Apr 2023As an active metabolite of venlafaxine and emerging antidepressant, O-desmethylvenlafaxine (ODVEN) was widely detected in different water bodies, which caused potential...
As an active metabolite of venlafaxine and emerging antidepressant, O-desmethylvenlafaxine (ODVEN) was widely detected in different water bodies, which caused potential harm to human health and environmental safety. In this study, the comparative work on the ODVEN degradation by UV (254 nm) and UV-LED (275 nm) activated sodium percarbonate (SPC) systems was systematically performed. The higher removal rate of ODVEN can be achieved under UV-LED direct photolysis (14.99%) than UV direct photolysis (4.57%) due to the higher values of photolysis coefficient at the wavelength 275 nm. Significant synergistic effects were observed in the UV/SPC (80.38%) and UV-LED/SPC (53.57%) systems and the former exhibited better performance for the elimination of ODVEN. The degradation of ODVEN all followed the pseudo-first-order kinetics well in these processes, and the pseudo-first-order rate constant (k) increased with increasing SPC concentration. Radicals quenching experiments demonstrated that both ·OH and CO· were involved in the degradation of ODVEN and the second-order rate constant of ODVEN with CO· (1.58 × 10 (mol/L) sec) was reported for the first time based on competitive kinetic method. The introduction of HA, Cl, NO and HCO inhibited the ODVEN degradation to varying degrees in the both processes. According to quantum chemical calculation, radical addition at the ortho-position of the phenolic hydroxyl group was confirmed to be the main reaction pathways for the oxidation of ODVEN by ·OH. In addition, the oxidation of ODVEN may involve the demethylation, H-abstraction, OH-addition and C-N bond cleavage. Eventually, the UV-LED/SPC process was considered to be more cost-effective compared to the UV/SPC process, although the UV/SPC process possessed a higher removal rate of ODVEN.
Topics: Humans; Desvenlafaxine Succinate; Venlafaxine Hydrochloride; Phenols; Photolysis
PubMed: 36503791
DOI: 10.1016/j.jes.2022.05.052 -
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 -
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 -
The Science of the Total Environment Jun 2023Wastewater-based epidemiology (WBE) includes the analysis of human metabolic biomarkers of xenobiotics in influent wastewater. WBE complements existing drug utilization...
Wastewater-based epidemiology (WBE) includes the analysis of human metabolic biomarkers of xenobiotics in influent wastewater. WBE complements existing drug utilization approaches and provides objective, spatio-temporal information on the consumption of pharmaceuticals in the general population. This approach was applied to 24-h composite influent wastewater samples from Leuven, Belgium. Daily samples were analysed from September 2019 to December 2019 (n = 76), and on three days of the week (Monday, Wednesday, Saturday) from January 2020 to April 2022 (n = 367). Sample analysis consisted of 96-well solid-phase extraction and liquid chromatography coupled to tandem mass spectrometry. Measured concentrations of 21 biomarkers for antidepressant and opioid use were converted to population-normalized mass loads (PNML) by considering the flow rate and catchment population. To capture population movements, mobile phone data was used. Amitriptyline, hydroxy-bupropion, norcitalopram, citalopram, normirtazapine, trazodone, O-desmethylvenlafaxine, codeine, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), methadone, morphine, O-desmethyltramadol, and tramadol were included in the temporal assessment since concentrations were above the lower limit of quantification. The PNML of most biomarkers increased (with 3-119 %) throughout the sampling period. The population disruption during the COVID-19 pandemic led to a major change in the socio-demographics of the catchment area, resulting in temporal differences in the PNML of the different biomarkers. As such, higher PNML were observed during the different lockdown phases, which were characterized by the outflow of university students and a decreasing commuting in and out the catchment area. The effects of the fluctuating socio-demographics of the catchment population were further evidenced by the different week-weekend pattern of PNMLs over the course of the sampling campaign. Mean parent/metabolite ratios (i.e., citalopram/norcitalopram, tramadol/O-desmethyltramadol, venlafaxine/O-desmethylvenlafaxine, and methadone/EDDP) remained relatively stable throughout the entire sampling campaign (RSD% below 25 % for all ratios, except for methadone/EDDP) and therefore were not affected by this population change.
Topics: Humans; Wastewater; Tramadol; Citalopram; Desvenlafaxine Succinate; Pandemics; COVID-19; Communicable Disease Control; Methadone; Biomarkers; Pharmaceutical Preparations; Demography; Water Pollutants, Chemical
PubMed: 36842581
DOI: 10.1016/j.scitotenv.2023.162342 -
Therapie 2021Venlafaxine is the third most frequently prescribed antidepressant in France the last decade, with about 400,000 daily doses. Therapeutic drug monitoring (TDM) of this... (Review)
Review
Venlafaxine is the third most frequently prescribed antidepressant in France the last decade, with about 400,000 daily doses. Therapeutic drug monitoring (TDM) of this medication, by measuring the active moiety venlafaxine (V) and O-desmethylvenlafaxine (ODV), is recommended (level of recommendation 2). However, this antidepressant seems to be the one for which clinicians most often use TDM, much more frequently than escitalopram, which is more prescribed and for which TDM is also recommended. The main goal of this review is to provide an update on the TDM of venlafaxine: its therapeutic interval, its level of recommendation and the origin of its "success". From the literature does not enable to define a therapeutic interval for the active moiety V+ODV, that is to say a steady-state trough concentration allowing a clinical response without toxicity. Nevertheless, a target concentration from 100 to 400μg/L is certainly relevant for the majority of patients without any pharmacodynamic resistance ; though a greater concentration could result in an earlier response or could be required for a clinical response in a minority of patients. A patient with no clinical response despite a concentration greater than 1000μg/L should be proposed another antidepressant. Measurement of the ODV/V ratio is also a useful tool, values below 0.3 usually reflecting a slow metabolizer phenotype for cytochrome P-450 2D6, which is more at risk of adverse effects. Research for this phenotype probably explains many prescriptions for TDM.
Topics: Antidepressive Agents; Cytochrome P-450 CYP2D6; Desvenlafaxine Succinate; Drug Monitoring; Humans; Pharmaceutical Preparations; Venlafaxine Hydrochloride
PubMed: 33551091
DOI: 10.1016/j.therap.2021.01.052 -
Psychological Medicine Oct 2021Network analysis (NA) conceptualizes psychiatric disorders as complex dynamic systems of mutually interacting symptoms. Major depressive disorder (MDD) is a... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Network analysis (NA) conceptualizes psychiatric disorders as complex dynamic systems of mutually interacting symptoms. Major depressive disorder (MDD) is a heterogeneous clinical condition, and very few studies to date have assessed putative changes in its psychopathological network structure in response to antidepressant (AD) treatment.
METHODS
In this randomized trial with adult depressed outpatients (n = 151), we estimated Gaussian graphical models among nine core MDD symptom-domains before and after 8 weeks of treatment with either escitalopram or desvenlafaxine. Networks were examined with the measures of cross-sectional and longitudinal structure and connectivity, centrality and predictability as well as stability and accuracy.
RESULTS
At baseline, the most connected MDD symptom-domains were fatigue-cognitive disturbance, whereas at week 8 they were depressed mood-suicidality. Overall, the most central MDD symptom-domains at baseline and week 8 were, respectively, fatigue and depressed mood; in contrast, the most peripheral symptom-domain across both timepoints was appetite/weight disturbance. Furthermore, the psychopathological network at week 8 was significantly more interconnected than at baseline, and they were also structurally dissimilar.
CONCLUSION
Our findings highlight the utility of focusing on the dynamic interaction between depressive symptoms to better understand how the treatment with ADs unfolds over time. In addition, depressed mood, fatigue, and cognitive/psychomotor disturbance seem to be central MDD symptoms that may be viable targets for novel, focused therapeutic interventions.
Topics: Adult; Affect; Antidepressive Agents; Cognitive Dysfunction; Cross-Sectional Studies; Depressive Disorder, Major; Desvenlafaxine Succinate; Escitalopram; Fatigue; Female; Humans; Longitudinal Studies; Male; Normal Distribution; Psychopathology; Suicide
PubMed: 32312344
DOI: 10.1017/S0033291720001002 -
PloS One 2020RDoC conceptualises psychopathology as neurobiologically-rooted behavioural psychological "constructs" that span dimensionally from normality to pathology, but its...
Exploring the utility of RDoC in differentiating effectiveness amongst antidepressants: A systematic review using proposed psychometrics as the unit of analysis for the Negative Valence Systems domain.
BACKGROUND
RDoC conceptualises psychopathology as neurobiologically-rooted behavioural psychological "constructs" that span dimensionally from normality to pathology, but its clinical utility remains controversial.
AIM
To explore RDoC's potential clinical utility by examining antidepressant effectiveness through Negative Valence Systems (NVS) domain constructs.
METHOD
A systematic review was conducted on Web of Science, MEDLINE, EMBASE and PsycINFO for antidepressant trials that included psychometric instruments assessed by Watson, Stanton & Clark (2017) to represent NVS constructs of Acute Threat, Potential Threat and Loss.
RESULTS
221 citations were identified; 13 were included in qualitative synthesis, none for quantitative analysis. All suffered from significant bias risks. 9 antidepressants were investigated, most within 1 construct, and most were found to be effective. Paroxetine, citalopram and fluvoxamine were found to be effective for Acute Threat, fluoxetine, desvenlafaxine and sertraline for Potential Threat, and sertraline, fluvoxamine, fluoxetine and desvenlafaxine effective for Loss. Nefazodone was found to be ineffective for acute fear.
CONCLUSION
Preliminary evidence supports RDoC NVS constructs' clinical utility in assessing antidepressant effectiveness, but lack of discriminant validity between Potential Threat and Loss supports their recombination into a single Distress construct. Finding of effectiveness within "normal" construct levels support the utility of a dimensional approach. Testable hypotheses were generated that can further test RDoC's clinical utility.
Topics: Algorithms; Antidepressive Agents; Citalopram; Clinical Trials as Topic; Depressive Disorder; Desvenlafaxine Succinate; Fluoxetine; Fluvoxamine; Humans; Paroxetine; Psychometrics; Sertraline; Treatment Outcome
PubMed: 33326436
DOI: 10.1371/journal.pone.0243057