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Primary Care Companion To the Journal... 2010Desvenlafaxine is the third serotonin-norepinephrine reuptake inhibitor (SNRI) approved by the US Food and Drug Administration for major depressive disorder (MDD). This...
OBJECTIVE
Desvenlafaxine is the third serotonin-norepinephrine reuptake inhibitor (SNRI) approved by the US Food and Drug Administration for major depressive disorder (MDD). This article summarizes data on the clinical pharmacology, efficacy, safety, and tolerability of desvenlafaxine (administered as desvenlafaxine succinate) for MDD with a focus on the 50-mg/d therapeutic dose. Additionally, the article discusses clinical practice considerations and future directions in desvenlafaxine research.
DATA SOURCES
Data relating to desvenlafaxine 50 mg/d were identified through searches of MEDLINE and publication databases of Pfizer for articles in English published before January 2009. Keywords were desvenlafaxine, O-desmethylvenlafaxine, ODV, and 50 mg.
STUDY SELECTION
Three randomized, placebo- and/or active comparator-controlled, 8-week clinical trials reported the efficacy of desvenlafaxine 50 mg/d for the treatment of MDD. The third of these studies included a post hoc pooled analysis of data from all 3 of these trials. In addition, the search retrieved an article examining pooled data from 9 trials, including 50-mg data from 2 of the 3 retrieved trials.
DATA SYNTHESIS
Desvenlafaxine is the major active metabolite of the SNRI venlafaxine. Significant improvements compared with placebo were observed on the primary efficacy measure (17-item Hamilton Depression Rating Scale total score) and most secondary measures in 2 of 3 clinical trials. An integrated analysis of registration data from 9 randomized, double-blind, placebo-controlled, 8-week studies of desvenlafaxine (50 to 400 mg/d) for MDD demonstrated no evidence of greater efficacy with doses higher than 50 mg/d. Safety results indicate that desvenlafaxine treatment is generally safe and well tolerated; findings were consistent with those for the SNRI class. The 50-mg/d dose of desvenlafaxine was associated with low rates of discontinuation due to treatment-emergent adverse events, which were similar to placebo.
CONCLUSIONS
Desvenlafaxine 50 mg/d has demonstrated efficacy, safety, and tolerability for the treatment of MDD in placebo-controlled trials. A long-term study is underway to further explore desvenlafaxine 50 mg/d for MDD.
PubMed: 20944767
DOI: 10.4088/PCC.09r00845blu -
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 -
Drug Design, Development and Therapy 2019To investigate the effects of Chinese herb Danzhi Xiaoyao pills on the pharmacokinetics of venlafaxine and its metabolites O-desmethylvenlafaxine (ODV) and...
OBJECTIVE
To investigate the effects of Chinese herb Danzhi Xiaoyao pills on the pharmacokinetics of venlafaxine and its metabolites O-desmethylvenlafaxine (ODV) and N-desmethylvenlafaxine (NDV) in beagles by using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS).
METHODS
Six beagles (half male, half female) were chosen to test, being fasted before the experiment but having free access to drinking water 1 day before being fed drugs. After oral administration of venlafaxine hydrochloride tablets (10.28 mg/kg), the blood samples were collected in succession at different points in time. After 1-week washout period, Danzhi Xiaoyao pills (0.6g/kg) were given through oral administration to the six beagles every morning until the 7th day, venlafaxine hydrochloride tablets (10.28 mg/kg) were given after feeding Danzhi Xiaoyao pills (0.6g/kg) half an hour and blood samples were collected continuously at different points. All samples were analyzed by UPLC-MS/MS, and the main pharmacokinetic parameters of venlafaxine, ODV and NDV were computed by DAS 2.0.
RESULTS
The C of the venlafaxine group (control group) and the combination group (experimental group) were (2267.26±252.89) ng/mL and (1542.64±190.73) ng/mL, respectively. The AUC of the two groups were (13,934.79±3609.23) ng·h/mL and (8001.91±2167.58) ng·h/mL, respectively. The ODV C of the two groups were (2253.80±215.81) ng/mL and (2721.37±118.20) ng/mL, and AUC were (13,974.99±2784.04) ng·h/mL and (17,539.44±1894.29) ng·h/mL, respectively. The NDV C of the two groups were (50.98±5.76) ng/mL and (58.74±12.33) ng/mL, and AUC were (179.26±34.94) ng·h/mL and (220.68±51.41) ng·h/mL, respectively. After administration of Danzhi Xiaoyao pills, the C and AUC of venlafaxine decreased significantly, indicating that the plasma exposure of venlafaxine decreased. The increase of C and AUC of ODV and NDV indicated a rise in plasma exposure.
CONCLUSION
Danzhi Xiaoyao pills can accelerate the metabolism of venlafaxine in beagles. In clinical, when venlafaxine was co-administrated with Danzhi Xiaoyao pills, dose adjustment of venlafaxine should be taken into account.
Topics: Animals; Area Under Curve; Chromatography, Liquid; Cyclohexanols; Desvenlafaxine Succinate; Dogs; Drugs, Chinese Herbal; Female; Male; Tablets; Tandem Mass Spectrometry; Venlafaxine Hydrochloride
PubMed: 31571835
DOI: 10.2147/DDDT.S221927 -
Brazilian Journal of Medical and... May 2016New generation antidepressant therapies, including serotonin-norepinephrine reuptake inhibitor (SNRIs), were introduced in the late 1980s; however, few comprehensive... (Meta-Analysis)
Meta-Analysis Review
Randomized controlled trials of serotonin-norepinephrine reuptake inhibitor in treating major depressive disorder in children and adolescents: a meta-analysis of efficacy and acceptability.
New generation antidepressant therapies, including serotonin-norepinephrine reuptake inhibitor (SNRIs), were introduced in the late 1980s; however, few comprehensive studies have compared the benefits and risks of various contemporary treatments for major depressive disorder (MDD) in young patients. A comprehensive literature search of PubMed, Cochrane, Embase, Web of Science, and PsycINFO databases was conducted from 1970 to January 2015. Only clinical trials that randomly assigned one SNRI or placebo to patients aged 7 to 18 years who met the diagnostic criteria for major depressive disorder were included. Treatment success, dropout rate, and suicidal ideation/attempt outcomes were measured. Primary efficacy was determined by pooling the risk ratios (RRs) of treatment response and remission. Acceptability was determined by pooling the RRs of dropouts for all reasons and for adverse effects as well as suicide-risk outcomes. Five trials with a total of 973 patients were included. SNRIs were not significantly more effective than placebo for treatment response but were for remission. The comparison of patients taking SNRIs that dropped out for all reasons and those taking placebo did not reach statistical significance. Significantly more patients taking SNRIs dropped out for adverse effects than those taking placebo. No significant difference was found in suicide-related risk outcomes. SNRI therapy does not display a superior efficacy and is not better tolerated compared to placebo in these young patients. However, duloxetine has a potential beneficial effect for depression in young populations, showing a need for further research.
Topics: Adolescent; Antidepressive Agents; Child; Cyclopropanes; Depressive Disorder, Major; Desvenlafaxine Succinate; Duloxetine Hydrochloride; Female; Humans; Male; Milnacipran; Placebos; Randomized Controlled Trials as Topic; Serotonin and Noradrenaline Reuptake Inhibitors; Treatment Outcome; Venlafaxine Hydrochloride
PubMed: 27240293
DOI: 10.1590/1414-431X20164806 -
Marine Pollution Bulletin Jul 2023The assessment of exposure to the antidepressant venlafaxine and its major metabolite o-desmethylvenlafaxine in Holothuria tubulosa, Anemonia sulcata and Actinia equina...
Accumulation and metabolization of the antidepressant venlafaxine and its main metabolite o-desmethylvenlafaxine in non-target marine organisms Holothuria tubulosa, Anemonia sulcata and Actinia equina.
The assessment of exposure to the antidepressant venlafaxine and its major metabolite o-desmethylvenlafaxine in Holothuria tubulosa, Anemonia sulcata and Actinia equina is proposed. A 28-day exposure experiment (10 μg/L day) followed by a 52-day depuration period was conducted. The accumulation shows a first-order kinetic process reaching an average concentration of 49,125/54342 ng/g dw in H. tubulosa and 64,810/93007 ng/g dw in A. sulcata. Venlafaxine is considered cumulative (BCF > 2000 L/kg dw) in H. tubulosa, A. sulcata and A. equina respectively; and o-desmethylvenlafaxine in A. sulcata. Organism-specific BCF generally followed the order A. sulcata > A. equina > H. tubulosa. The study revealed differences between tissues in metabolizing abilities in H. tubulosa this effect increases significantly with time in the digestive tract while it was negligible in the body wall. The results provide a description of venlafaxine and o-desmethylvenlafaxine accumulation in common and non-target organisms in the marine environment.
Topics: Animals; Venlafaxine Hydrochloride; Desvenlafaxine Succinate; Holothuria; Aquatic Organisms; Antidepressive Agents; Sea Anemones
PubMed: 37207394
DOI: 10.1016/j.marpolbul.2023.115055 -
CNS Spectrums Jun 2019This post-hoc pooled analysis evaluated categorical change in functional impairment in patients with major depressive disorder (MDD) treated with desvenlafaxine versus... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
This post-hoc pooled analysis evaluated categorical change in functional impairment in patients with major depressive disorder (MDD) treated with desvenlafaxine versus placebo and examined whether early improvement in functioning predicted functional outcomes at study endpoint.
METHODS
Data were pooled from eight randomized, double-blind, placebo-controlled studies of desvenlafaxine for the treatment of MDD, including adults who were randomly assigned to receive desvenlafaxine 50 or 100 mg/d or placebo (N=3,384). Shift tables were generated for categorical changes in functional impairment from baseline based on Sheehan Disability Scale (SDS) subscale scores. The categories were none/mild (0-3), moderate (4-6), and marked/extreme (7-10). Treatment comparisons for prespecified shifts of interest and predictive value of week 2 or 4 improvement in SDS subscale scores for functional outcome at week 8 were assessed using logistic regression.
RESULTS
Greater proportions of patients receiving desvenlafaxine 50 and 100 mg achieved improvement from baseline to week 8 for each prespecified shift endpoint versus placebo (all p ≤ 0.02). Early improvement in SDS subscale scores was a statistically significant predictor of functional outcome at week 8, both overall and for each treatment group (all p<0.0001).
CONCLUSIONS
Treatment with desvenlafaxine 50 or 100 mg/d led to significantly greater categorical improvement in functional impairment versus placebo, and improvement in SDS subscale scores significantly predicted functional outcome. Monitoring patient progress early in the course of antidepressant treatment using a functional assessment such as the SDS may help clinicians determine whether or not treatment adjustments are needed.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antidepressive Agents; Depression; Desvenlafaxine Succinate; Female; Humans; Male; Middle Aged; Quality of Life; Treatment Outcome
PubMed: 29140227
DOI: 10.1017/S1092852917000633 -
PloS One 2014Triple reuptake inhibitors (TRIs) are currently being developed as a new class of promising antidepressants that block serotonin (5-HT), dopamine (DA) and norepinephrine...
Triple reuptake inhibitors (TRIs) are currently being developed as a new class of promising antidepressants that block serotonin (5-HT), dopamine (DA) and norepinephrine (NE) transporters, thereby increasing extracellular monoamine concentrations. The purpose of this study was to investigate the effects of LPM570065, a novel TRI and a desvenlafaxine prodrug, on extracellular 5-HT, DA and NE levels in the rat striatum after acute and chronic administration relative to desvenlafaxine, using High Performance Liquid Chromatography (HPLC) and microdialysis. Acute administration was performed by providing rodents with oral solutions (0.06 mmol·kg(-1) p.o.), oral suspensions (0.06 mmol·kg(-1) p.o.) and intravenous solutions (0.04 mmol·kg(-1) i.v.) of LPM570065 and desvenlafaxine. Oral suspensions (0.06 mmol·kg(-1)·day(-1)) of the two drugs were also administered for a 14-day chronic period. HPLC analysis revealed that LPM570065 rapidly penetrated the rat striatum, converted into desvenlafaxine and exhibited larger total exposure compared with the administration of desvenlafaxine. Microdialysis revealed that acute and chronic administration of oral suspension of LPM570065 increased the 5-HT, DA and NE levels more than the relative administration of desvenlafaxine. Unlike desvenlafaxine, acute administration of an intravenous LPM570065 solution did not induce the undesirable 90% decrease in extracellular 5-HT levels. In contrast to the fully dose-dependent elevation of 5-HT induced by desvenlafaxine, the acute administration of LPM570065 showed a capped increase in extracellular 5-HT levels when combined with WAY-100635. Additionally, forced swim test demonstrated that acute and chronic administration of LPM570065 reduced the immobility time more than the relative administration of desvenlafaxine. These data suggest that LPM570065 may have greater efficacy and/or a more rapid onset of antidepressant action than desvenlafaxine and also counterbalance the harmful effects of desvenlafaxine on 5-HT neurotransmission related to 5-HT1A autoreceptors. Thus, this new class of drugs, TRIs has the potential to provide a new therapeutic mechanism for treating depression.
Topics: Animals; Antidepressive Agents; Benzoates; Cyclohexanols; Desvenlafaxine Succinate; Dopamine; Extracellular Space; Male; Microdialysis; Norepinephrine; Piperazines; Pyridines; Rats, Sprague-Dawley; Serotonin; Selective Serotonin Reuptake Inhibitors; Swimming
PubMed: 24614602
DOI: 10.1371/journal.pone.0091775 -
Journal of Neurochemistry Oct 2014Serotonin/norepinephrine reuptake inhibitors antidepressants exert their effects by increasing serotonin and norepinephrine in the synaptic cleft. Studies show it takes...
Desvenlafaxine prevents white matter injury and improves the decreased phosphorylation of the rate-limiting enzyme of cholesterol synthesis in a chronic mouse model of depression.
Serotonin/norepinephrine reuptake inhibitors antidepressants exert their effects by increasing serotonin and norepinephrine in the synaptic cleft. Studies show it takes 2-3 weeks for the mood-enhancing effects, which indicate other mechanisms may underlie their treatment effects. Here, we investigated the role of white matter in treatment and pathogenesis of depression using an unpredictable chronic mild stress (UCMS) mouse model. Desvenlafaxine (DVS) was orally administrated to UCMS mice at the dose of 10 mg/kg/day 1 week before they went through a 7-week stress procedure and lasted for over 8 weeks before the mice were killed. No significant changes were found for protein markers of neurons and astrocytes in UCMS mice. However, myelin and oligodendrocyte-related proteins were significantly reduced in UCMS mice. DVS prevented the stress-induced injury to white matter and the decrease of phosphorylated 5'-AMP-activated protein kinase and 3-hydroxy-3-methyl-glutaryl-CoA reductase protein expression. DVS increased open arm entries in an elevated plus-maze test, sucrose consumption in the sucrose preference test and decreased immobility in tail suspension and forced swimming tests. These findings suggest that stress induces depression-like behaviors and white matter deficits in UCMS mice. DVS may ameliorate the oligodendrocyte dysfunction by affecting cholesterol synthesis, alleviating the depression-like phenotypes in these mice. We examined the possible role of oligodendrocyte and myelin in the pathological changes of depression with an unpredictable chronic mild stress (UCMS) mouse model. Oligodendrocyte-related proteins in the mouse brain were specifically changed during the stress period. The depressive-like behaviors and oligodendrocyte deficits could be prevented by the administration of desvenlafaxine. Oligodendrocyte and myelin may be an essential target of desvenlafaxine for the treatment of depression.
Topics: Animals; Antidepressive Agents; Cholesterol; Cyclohexanols; Depression; Desvenlafaxine Succinate; Disease Models, Animal; Female; Mice; Mice, Inbred C57BL; Phosphorylation; Random Allocation; White Matter
PubMed: 24934403
DOI: 10.1111/jnc.12792 -
Journal of Clinical Psychopharmacology Oct 2017This post hoc analysis examined the time point at which clinically significant improvement in major depressive disorder (MDD) symptoms occurs with desvenlafaxine versus... (Meta-Analysis)
Meta-Analysis
PURPOSE/BACKGROUND
This post hoc analysis examined the time point at which clinically significant improvement in major depressive disorder (MDD) symptoms occurs with desvenlafaxine versus placebo.
METHODS
Data were pooled from 9 short-term, double-blind, placebo-controlled studies in adults with MDD randomly assigned to desvenlafaxine 50 mg/d, 100 mg/d, or placebo. A mixed-effects model for repeated-measures analysis of change from baseline score was used to determine the time point at which desvenlafaxine treatment groups separated from placebo on the 17-item Hamilton Rating Scale for Depression and psychosocial outcomes. The association between early improvement and week 8 outcomes was examined using logistic regression analyses. Time to remission for patients with early improvement versus without early improvement was assessed using Kaplan-Meier techniques. Comparisons between groups were performed with log-rank tests.
RESULTS
In the intent-to-treat population (N = 4279 patients: desvenlafaxine 50 mg/d, n = 1714; desvenlafaxine 100 mg/d, n = 870; placebo, n = 1695), a statistically significant improvement on the 17-item Hamilton Rating Scale for Depression was observed with desvenlafaxine 50 mg/d at week 1 (P = 0.0129) and with desvenlafaxine 100 mg/d at week 2 (P = 0.0002) versus placebo. Early improvement was a significant predictor of later remission. Treatment assignment, baseline depression scale scores, and race were significantly associated with probability of early improvement. On several measures of depressive symptoms and function, desvenlafaxine 50 mg/d and 100 mg/d separated from placebo as early as week 1 and no later than week 4 in patients with MDD.
IMPLICATIONS/CONCLUSIONS
These findings suggest that clinicians may be able to use depression rating scale scores early in treatment as a guide to inform treatment optimization.
Topics: Adolescent; Adult; Aged; Antidepressive Agents; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome; Young Adult
PubMed: 28817491
DOI: 10.1097/JCP.0000000000000775 -
Neuropsychopharmacology : Official... Sep 2017MicroRNAs are short non-coding molecules that play a major role in regulating gene expression. Peripheral levels of miR-1202 have been shown to predict and mediate...
MicroRNAs are short non-coding molecules that play a major role in regulating gene expression. Peripheral levels of miR-1202 have been shown to predict and mediate antidepressant response. However, it is not clear to what extent these peripheral measures reflect central neural changes in vivo. We approached this problem with the combined use of peripheral miR-1202 measures and neuroimaging. At baseline and after 8 weeks of desvenlafaxine (50-100 mg die), 20 patients were scanned with 3T magnetic resonance imaging, first at rest then during the Go/NoGo task, a classical test of response inhibition. Blood samples were collected at both time points. During resting state, lower baseline miR-1202 levels were predictive of increased connectivity from T0 to T8 between the posterior cingulate and the prefrontal, parietal, and occipital cortices. Changes in miR-1202 levels following desvenlafaxine treatment were negatively correlated with changes in activity in right precuneus within the default-mode network, and in connectivity between the posterior cingulate and the temporal and prefrontal cortices, and the precuneus. During the Go/NoGo task, baseline miR-1202 levels and changes in these levels were correlated with activity changes in different regions, including bilateral prefrontal, insular, cingulate, and temporal cortices, and left putamen and claustrum. Finally, secondary analyses in a subset of patients showed a trend for a significant correlation between miR-1202 levels and glutamate levels measured by spectroscopy. Changes in peripheral miR-1202 levels were therefore associated with changes in brain activity and connectivity in a network of brain regions associated with depression and antidepressant response. These effects may be mediated by the glutamatergic system.
Topics: Adult; Antidepressive Agents; Brain; Brain Mapping; Depressive Disorder, Major; Desvenlafaxine Succinate; Female; Humans; Inhibition, Psychological; Magnetic Resonance Imaging; Male; MicroRNAs; Motor Activity; Neural Pathways; Neuropsychological Tests; Rest; Serotonin and Noradrenaline Reuptake Inhibitors; Treatment Outcome
PubMed: 28079059
DOI: 10.1038/npp.2017.9