-
Therapeutic Drug Monitoring Jun 2018Therapeutic drug monitoring has become increasingly important in psychiatric therapy. However, it is not yet implemented as a daily routine in clinical settings. To...
BACKGROUND
Therapeutic drug monitoring has become increasingly important in psychiatric therapy. However, it is not yet implemented as a daily routine in clinical settings. To evaluate new, noninvasive procedures, we compared blood and saliva venlafaxine, quetiapine, and citalopram concentrations in samples collected from psychiatric patients.
METHODS
We collected blood and saliva samples from 75 psychiatric patients (39 venlafaxine, 19 quetiapine, and 17 citalopram). Saliva sampling was achieved by the use of cotton pads. Venlafaxine (and its metabolite O-desmethylvenlafaxine) and quetiapine were analyzed by LC-MS/MS, whereas citalopram was analyzed by HPLC.
RESULTS
We observed significant correlations between concentrations of venlafaxine (ratio saliva/serum ± SD: 18.3 ± 9.5, P < 0.01, r = 0.895) and its metabolite O-desmethylvenlafaxine (ratio saliva/serum ± SD: 4.1 ± 3.2, P < 0.05, r = 0.344), quetiapine (ratio saliva/serum ± SD: 0.2 ± 0.2, P < 0.01, r = 0.935), and citalopram (ratio saliva/serum ± SD: 2.6 ± 1.2, P < 0.05, r = 0.54) in serum and in saliva. Furthermore, measured concentrations of venlafaxine (and its metabolite O-desmethylvenlafaxine) and citalopram were higher in saliva than in serum, whereas measured concentrations of quetiapine were higher in serum than in saliva.
CONCLUSIONS
Using cotton pad saliva sampling, venlafaxine and quetiapine demonstrate high correlations between saliva and serum concentrations, whereas for O-desmethylvenlafaxine and citalopram, other methods of sampling might be preferable. Saliva therapeutic drug monitoring of psychoactive drugs might become a useful approach to achieving individual treatment regimens.
Topics: Adult; Aged; Antidepressive Agents; Antidepressive Agents, Second-Generation; Citalopram; Desvenlafaxine Succinate; Drug Monitoring; Female; Humans; Male; Mental Disorders; Middle Aged; Protein Binding; Quetiapine Fumarate; Saliva; Serotonin and Noradrenaline Reuptake Inhibitors; Venlafaxine Hydrochloride; Young Adult
PubMed: 29746434
DOI: 10.1097/FTD.0000000000000508 -
International Clinical... May 2016The chronic course of major depressive disorder (MDD) often impedes the ability of patients to achieve full remission. Return of full functioning is a critical goal of... (Meta-Analysis)
Meta-Analysis
The chronic course of major depressive disorder (MDD) often impedes the ability of patients to achieve full remission. Return of full functioning is a critical goal of antidepressant pharmacotherapy as the presence of residual depressive symptoms is associated with an increased risk of relapse. Treatment guidelines recommend selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, or atypical antidepressants as first-line treatment for moderate to severe MDD. Desvenlafaxine, administered as desvenlafaxine succinate, is an serotonin-norepinephrine reuptake inhibitor approved for the treatment of adults with MDD at the recommended dose of 50 mg/day. The aim of this integrated analysis was to assess the efficacy and safety of desvenlafaxine 50 and 100 mg/day compared with placebo in adult outpatients with MDD. The analysis used data from nine fixed-dose, short-term, placebo-controlled studies in adult outpatients diagnosed with MDD who had depressive symptoms for at least 30 days. Data from 4279 and 4317 patients were pooled for the efficacy and safety analyses, respectively. Statistically significant improvements were observed with desvenlafaxine 50 and 100 mg/day versus placebo for all efficacy endpoints assessed, including improvements in depressive symptoms, response and remission rates, as well as functional and cognitive outcomes. Treatment with desvenlafaxine 50 and 100 mg/day was generally safe and well tolerated. The findings of this integrated analysis of data from a large population of patients with MDD confirmed the antidepressant efficacy of both desvenlafaxine doses and add to previous evidence supporting the efficacy of desvenlafaxine.
Topics: Adolescent; Adult; Antidepressive Agents; Depressive Disorder, Major; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Treatment Outcome; Young Adult
PubMed: 26895080
DOI: 10.1097/YIC.0000000000000121 -
Progress in Neuro-psychopharmacology &... Jul 2018Venlafaxine and the atypical antipsychotic quetiapine are often administered concomitantly. Both drugs share several metabolic hepatic pathways. However, pharmacokinetic...
Venlafaxine and the atypical antipsychotic quetiapine are often administered concomitantly. Both drugs share several metabolic hepatic pathways. However, pharmacokinetic interactions between venlafaxine and quetiapine have not been studied yet. A therapeutic drug monitoring database containing serum concentrations of venlafaxine (VEN) and its active metabolite O-desmethylvenlafaxine (ODVEN) was analyzed. Two groups of patients were compared: venlafaxine monotherapy V (n = 153) and co-medication with quetiapine, V (n = 71). Serum concentrations of VEN, ODVEN, and active moiety, AM (VEN + ODVEN), metabolite to parent compound ratio (ODVEN/VEN) and dose adjusted serum concentrations were compared using non-parametrical tests without information on CYP2D6 genotype. The two groups did not differ in terms of the daily dosage of venlafaxine, age, or sex. Median serum concentrations in the quetiapine group showed significantly, 15.8% and 29.3% higher values for AM and ODVEN (p = 0.002, Cohen's d = 0,41; p = 0.003, d = 0,44), respectively. Dose adjusted serum concentrations of active moiety and ODVEN revealed comparable differences (p = 0.038, d = 0,32; p = 0.015, d = 0,28) with significantly higher values in the co-medicated group. Significantly higher values for ODVEN and AM suggest a reduced clearance of ODVEN and active moiety when quetiapine is co-administered. This may be a consequence of a reduced metabolism of venlafaxine to the inactive metabolite N-desmethylvenlafaxine via CYP3A4, the main metabolizing enzyme for quetiapine, and a shift towards a higher proportion of the active metabolite ODVEN. Therapeutic drug monitoring is recommended in the case of co-medication to ensure clinical efficacy and patient safety. Although the increase of AM is moderate, we consider it relevant for clinicians given the prevalence of concomitant medication of quetiapine and venlafaxine.
Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Central Nervous System Agents; Delayed-Action Preparations; Desvenlafaxine Succinate; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Quetiapine Fumarate; Retrospective Studies; Venlafaxine Hydrochloride; Young Adult
PubMed: 29702137
DOI: 10.1016/j.pnpbp.2018.04.014 -
Therapeutic Drug Monitoring Oct 2021Venlafaxine (VEN) is primarily metabolized by CYP2D6. Although several studies have reported the significant effects of CYP2D6 on VEN and O-desmethylvenlafaxine (ODV)...
BACKGROUND
Venlafaxine (VEN) is primarily metabolized by CYP2D6. Although several studies have reported the significant effects of CYP2D6 on VEN and O-desmethylvenlafaxine (ODV) pharmacokinetics in Whites, limited data are available regarding the effects of the Asian-specific CYP2D6 genotype on VEN metabolism. This study evaluated the effects of the CYP2D6*10 and CYP2D6*5 genotypes on the steady-state plasma concentrations of VEN and ODV in Japanese patients.
METHODS
This study included 75 Japanese patients with depression who were treated with VEN. Steady-state plasma concentrations of VEN and ODV were measured using liquid chromatography. Polymerase chain reaction was used to determine CYP2D6 genotypes. A stepwise multiple regression analysis was performed to analyze the relationship between independent variables (sex, age, smoking habit, and number of mutated alleles, CYP2D6*10 and CYP2D6*5), subject-dependent variables (plasma concentrations of VEN and ODV [all corrected for dose and body weight]), and the ODV/VEN ratio.
RESULTS
Significant correlations were observed between the daily dose of VEN (corrected for body weight) and plasma concentrations of VEN (r = 0.498, P < 0.001) and ODV (r = 0.380, P = 0.001); ODV plasma concentrations were approximately 3.2 times higher than VEN plasma concentrations (VEN versus ODV = 18.60 ng/mL versus 59.10 ng/mL). VEN plasma concentrations (corrected for dose and body weight) did not differ with differing numbers of CYP2D6-mutated alleles. However, the ODV/VEN ratio decreased as the number of mutated CYP2D6 alleles increased (P = 0.001).
CONCLUSIONS
This is the first study to examine the effects of CYP2D6*10 in a clinical setting. Although no effects on the plasma concentrations of VEN or ODV were observed, CYP2D6 polymorphism affects the ODV/VEN ratio. Further studies are needed to confirm the clinical relevance of these findings.
Topics: Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6; Depression; Desvenlafaxine Succinate; Genotype; Humans; Japan; Venlafaxine Hydrochloride
PubMed: 33306568
DOI: 10.1097/FTD.0000000000000854 -
The Journal of Pharmacy and Pharmacology Jun 2015To prepare new crystalline forms of the antidepressant o-desmethylvenlafaxine salt as potential new commercial forms and evaluate their physicochemical properties, in... (Comparative Study)
Comparative Study
OBJECTIVES
To prepare new crystalline forms of the antidepressant o-desmethylvenlafaxine salt as potential new commercial forms and evaluate their physicochemical properties, in particular the dissolution rate.
METHODS
A new hydrogen oxalate salt of o-desmethylvenlafaxine hydrogen oxalate (ODV-OX) was synthesized, and a polymorph screening was performed using different solvents and crystallization conditions. Crystalline forms were characterized by a combination of solid-state techniques: X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis, FT-IR spectroscopy and single crystal X-ray diffraction. The stability of all crystalline phases was tested under International Conference on Harmonisation (ICH) conditions (40°C and 75% Relative Humidity (RH)) for 1 week. Dissolution tests were performed on the hydrogen oxalate salt ODV-OX Form 1 and compared with dissolution test on the commercial form of the succinate salt of o-desmethylvenlafaxine.
KEY FINDINGS
Five crystalline forms of ODV-OX were isolated, namely three hydrated forms (Form 1, Form 2, Form 3) and two anhydrous forms (Form 4 and Form 5).
CONCLUSIONS
Comparative solubility tests on ODV-OX Form 1 and o-desmethylvenlafaxine succinate evidenced a significant increase in solubility for the hydrogen oxalate salt (142 g/l) with respect to the succinate salt (70 g/l).
Topics: Antidepressive Agents; Calorimetry, Differential Scanning; Chemistry, Pharmaceutical; Crystallization; Crystallography, X-Ray; Desvenlafaxine Succinate; Dosage Forms; Drug Stability; Humans; Hydrogen; Molecular Structure; Oxalates; Powders; Salts; Solubility; Solvents; Spectroscopy, Fourier Transform Infrared; Succinates; Technology, Pharmaceutical; Thermogravimetry
PubMed: 25644936
DOI: 10.1111/jphp.12378 -
Journal of Psychopharmacology (Oxford,... Mar 2020Major depressive disorder is characterized by the presence of at least five of nine specific symptoms that contribute to clinically significant functional impairment.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Major depressive disorder is characterized by the presence of at least five of nine specific symptoms that contribute to clinically significant functional impairment. This analysis examined the effect of desvenlafaxine (50 or 100 mg) versus placebo on symptom cluster scores and the association between early improvement in symptom clusters and symptomatic or functional remission at week 8.
METHODS
Using data from nine double-blind, placebo-controlled studies of desvenlafaxine for the treatment of major depressive disorder (=4317), the effect of desvenlafaxine 50 or 100 mg versus placebo on scores for symptom clusters based on 17-item Hamilton Rating Scale for Depression items was assessed using analysis of covariance. Association between early improvement in symptom clusters (⩾20% improvement from baseline at week 2) and symptomatic and functional remission (17-item Hamilton Rating Scale for Depression total score ⩽7; Sheehan Disability Scale score <7) at week 8 was analyzed using logistic regression. Symptom clusters based on Montgomery-Åsberg Depression Rating Scale were also examined.
RESULTS
Desvenlafaxine 50 or 100 mg was associated with significant improvement from baseline compared to placebo for all symptom clusters (<0.001), except a sleep cluster for desvenlafaxine 100 mg. For all symptom clusters, early improvement was significantly associated with achievement of symptomatic and functional remission at week 8 for all treatment groups (⩽0.0254).
CONCLUSION
Early improvement in symptom clusters significantly predicts symptomatic or functional remission at week 8 in patients with depression receiving desvenlafaxine (50 or 100 mg) or placebo. Importantly, patients without early improvement were less likely to remit.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antidepressive Agents; Depressive Disorder, Major; Desvenlafaxine Succinate; Female; Humans; Male; Middle Aged; Remission Induction; Young Adult
PubMed: 31913085
DOI: 10.1177/0269881119896066 -
Current Medical Research and Opinion Apr 2015To evaluate the effect of the serotonin-norepinephrine re-uptake inhibitor desvenlafaxine on blood pressure and incidence of new onset hypertension in pooled short-term... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To evaluate the effect of the serotonin-norepinephrine re-uptake inhibitor desvenlafaxine on blood pressure and incidence of new onset hypertension in pooled short-term studies and in two longer-term, randomized withdrawal studies.
RESEARCH DESIGN AND METHODS
Data from patients randomly assigned to desvenlafaxine 10 mg to 400 mg/day or placebo in 11 short-term (8-12 weeks), fixed-dose, double-blind, placebo-controlled studies of major depressive disorder (MDD) were pooled for analysis; two desvenlafaxine randomized withdrawal studies (36 and 46 weeks) were analyzed separately.
CLINICAL TRIAL REGISTRATION
www.clinicaltrials.gov , NCT00072774, NCT00073762, NCT00277823, NCT00300378, NCT00384033, NCT00798707, NCT00863798, NCT01121484, NCT00824291, NCT01432457, NCT00075257, NCT00887224.
MAIN OUTCOME MEASURES
Outcomes included change from baseline in supine systolic blood pressure (SSBP) and supine diastolic blood pressure (SDBP), assessed using a mixed model repeated measures (MMRM) analysis, and incidence of hypertension (defined as three consecutive second SDBP measures ≥90 mm Hg AND increase of ≥10 mm Hg from baseline and/or SSBP ≥140 mm Hg AND increase of ≥10 mm Hg), analyzed using Cochran Mantel Hanzael tests. Potential predictors of change in SSBP and SDBP at LOCF were examined by including predictor variables in a regression model.
RESULTS
In the pooled, short-term studies, mean changes from baseline over time in SSBP and SDBP were statistically significant compared with placebo for the desvenlafaxine doses of 10 mg/day or greater for SSBP (p ≤ 0.0004; MMRM) and 25 mg/day or greater for SDBP (p ≤ 0.0449; MMRM). The proportion of patients with new onset hypertension differed significantly from placebo for the 50, 200, and 400 mg/day doses (1.9%, 2.4%, 4.8%, respectively, vs 0.8%; all p ≤ 0.0244). Predictors of change in BP included baseline SDBP, baseline SSBP, dose, body mass index, gender, age, race, and history of hypertension.
LIMITATIONS
Data were pooled from studies which differed somewhat in study design and patient demographics. None of the studies were originally designed to examine treatment effects on BP. Study entry criteria limit generalization of these results to medically stable patients with a primary diagnosis of MDD.
CONCLUSIONS
Short-term desvenlafaxine treatment was associated with small but statistically significant increases in SSBP and SDBP.
Topics: Adult; Antidepressive Agents; Blood Pressure; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 25758058
DOI: 10.1185/03007995.2015.1020365 -
Psychiatry Research. Neuroimaging Jun 2023The anatomical changes that antidepressant medications induce in the brain and through which they exert their therapeutic effects remain largely unknown. We randomized... (Randomized Controlled Trial)
Randomized Controlled Trial
The anatomical changes that antidepressant medications induce in the brain and through which they exert their therapeutic effects remain largely unknown. We randomized 61 patients with Persistent Depressive Disorder (PDD) to receive either desvenlafaxine or placebo in a 12-week trial and acquired anatomical MRI scans in 42 of those patients at baseline before randomization and immediately at the end of the trial. We also acquired MRIs once in 39 age- and sex-matched healthy controls. We assessed whether the serotonin-norepinephrine reuptake inhibitor, desvenlafaxine, differentially changed cortical thickness during the trial compared with placebo. Patients relative to controls at baseline had thinner cortices across the brain. Although baseline thickness was not associated with symptom severity, thicker baseline cortices predicted greater reduction in symptom severity in those treated with desvenlafaxine but not placebo. We did not detect significant treatment-by-time effects on cortical thickness. These findings suggest that baseline thickness may serve as predictive biomarkers for treatment response to desvenlafaxine. The absence of treatment-by-time effects may be attributable either to use of insufficient desvenlafaxine dosing, a lack of desvenlafaxine efficacy in treating PDD, or the short trial duration.
Topics: Humans; Desvenlafaxine Succinate; Depressive Disorder, Major; Cyclohexanols; Double-Blind Method; Brain
PubMed: 36996664
DOI: 10.1016/j.pscychresns.2023.111634 -
Journal of Hazardous Materials Apr 2023Pharmaceutical compounds and their metabolites are found in natural and wastewater. However, investigation of their toxic effects on aquatic animals has been neglected,...
Pharmaceutical compounds and their metabolites are found in natural and wastewater. However, investigation of their toxic effects on aquatic animals has been neglected, especially for metabolites. This work investigated the effects of the main metabolites of carbamazepine, venlafaxine and tramadol. Zebrafish embryos were exposed (0.1-100 µg/L) for 168hpf exposures to each metabolite (carbamazepine-10,11-epoxide, 10,11-dihydrocarbamazepine, O-desmethylvenlafaxine, N-desmethylvenlafaxine, O-desmethyltramadol, N-desmethyltramadol) or the parental compound. A concentration-response relationship was found for the effects of some embryonic malformations. Carbamazepine-10,11-epoxide, O-desmethylvenlafaxine and tramadol elicited the highest malformation rates. All compounds significantly decreased larvae responses on a sensorimotor assay compared to controls. Altered expression was found for most of the 32 tested genes. In particular, abcc1, abcc2, abcg2a, nrf2, pparg and raraa were found to be affected by all three drug groups. For each group, the modelled expression patterns showed differences in expression between parental compounds and metabolites. Potential biomarkers of exposure were identified for the venlafaxine and carbamazepine groups. These results are worrying, indicating that such contamination in aquatic systems may put natural populations at significant risk. Furthermore, metabolites represent a real risk that needs more scrutinising by the scientific community.
Topics: Animals; Carbamazepine; Desvenlafaxine Succinate; Epoxy Compounds; Larva; Tramadol; Venlafaxine Hydrochloride; Zebrafish
PubMed: 36860067
DOI: 10.1016/j.jhazmat.2023.130909 -
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