-
Brain, Behavior, and Immunity Jul 2020The response of patients with major depressive disorders (MDD) to antidepressant treatments have been shown to be affected by multiple factors, including disease...
INTRODUCTION
The response of patients with major depressive disorders (MDD) to antidepressant treatments have been shown to be affected by multiple factors, including disease severity and inflammation. Increasing evidence indicates that the kynurenine metabolic pathway is activated by inflammation in MDD patients and plays a role in the pathophysiology of depression. Antidepressant treatments have been reported to affect kynurenine pathway metabolite levels as well. This study investigates differential associations between the antidepressant treatment outcome to escitalopram versus desvenlafaxine with the pre-treatment and post-treatment-changes in serotonin and kynurenine pathway metabolite levels.
METHODS
The levels of serotonin and of kynurenine pathway metabolites were measured in plasma using liquid chromatography-mass spectrometry (LC-MS) in 161 currently depressed patients with MDD at baseline and after 8 weeks of treatment with either escitalopram or desvenlafaxine. Treatment response was defined conventionally by a reduction of at least 50% in the Hamilton Depression Rating Scale 21 item (HAMD-21) total score from baseline; remission was defined by reaching a post-treatment HAMD-21 score ≤7.
RESULTS
Response to escitalopram treatment was associated with higher baseline serotonin levels (p = 0.022), lower baseline kynurenine (Kyn)/tryptophan (Trp) ratio (p = 0.008) and lower baseline quinolinic acid (QuinA)/tryptophan (Trp) ratio (p = 0.047), suggesting a lower inflammation state. Greater improvement in depression symptoms as measured by percent change of HAMD-21 score from baseline was also associated with higher baseline serotonin levels (p = 0.033) in escitalopram treatment arm. Furthermore, remitters to escitalopram treatment showed significant increases in the kynurenic acid (KynA)/3-hydroxykynurenine (3HK) ratio after treatment (p = 0.015). In contrast, response to desvenlafaxine treatment was not associated with any metabolite analyzed. We also confirmed a previous report that plasma serotonin levels are lower in MDD patients compared to healthy controls (p = 0.004) and that the kynurenine plasma level is negatively associated with depression symptom severity (p = 0.047).
CONCLUSIONS
In MDD patients the antidepressant response to escitalopram was positively associated with baseline serotonin levels and inversely associated with activation of the kynurenine pathway. These results appear consistent with previous literature showing that biomarker evidence of inflammation is associated with lower response to antidepressants from the selective serotonin reuptake inhibitor class. Moreover, increases in the kynurenic acid (KynA)/3-hydroxykynurenine (3HK) ratio, which previously has been characterized as a neuroprotective index, were associated with full remission under escitalopram treatment.
Topics: Citalopram; Depressive Disorder, Major; Desvenlafaxine Succinate; Humans; Kynurenic Acid; Kynurenine; Plasma; Serotonin
PubMed: 31978524
DOI: 10.1016/j.bbi.2020.01.011 -
Journal of Child and Adolescent... Feb 2018To evaluate the short-term efficacy and safety of desvenlafaxine versus placebo in the treatment of children and adolescents with major depressive disorder (MDD).
OBJECTIVE
To evaluate the short-term efficacy and safety of desvenlafaxine versus placebo in the treatment of children and adolescents with major depressive disorder (MDD).
METHODS
Outpatient children (7-11 years) and adolescents (12-17 years) who met DSM-IV-TR criteria for MDD and had screening and baseline Children's Depression Rating Scale-Revised (CDRS-R) total scores >40 were randomly assigned to 8 weeks of treatment with placebo, low exposure desvenlafaxine (20, 30, or 35 mg/day based on baseline weight), or higher exposure desvenlafaxine (25, 35, or 50 mg/day based on baseline weight). The primary efficacy endpoint was change from baseline in CDRS-R total score at week 8, analyzed using a mixed-effects model for repeated measures. Secondary efficacy assessments included Clinical Global Impressions-Severity and Clinical Global Impressions-Improvement scales. Safety assessments included adverse events and the Columbia-Suicide Severity Rating Scale.
RESULTS
The safety population included 363 patients (children, n = 109; adolescents, n = 254). No statistical separation from placebo was observed for either desvenlafaxine group for CDRS-R total score or for any secondary efficacy endpoint. At week 8, adjusted mean (standard error) changes from baseline in CDRS-R total score for the desvenlafaxine low exposure, desvenlafaxine high exposure, and placebo groups were -23.7 (1.1), -24.4 (1.1), and -22.9 (1.1), respectively. The incidence of adverse events was similar among groups.
CONCLUSION
Low and high exposure desvenlafaxine groups did not demonstrate efficacy for the treatment of MDD in children and adolescents in this double-blind, placebo-controlled trial. Desvenlafaxine (20-50 mg/day) was generally safe and well tolerated with no new safety signals identified in pediatric patients with MDD in this study.
Topics: Adolescent; Antidepressive Agents; Child; Depressive Disorder, Major; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Psychiatric Status Rating Scales; Treatment Outcome
PubMed: 29185786
DOI: 10.1089/cap.2017.0099 -
Frontiers in Chemistry 2022We herein describe an optimal approach for the efficient synthesis of -desmethylvenlafaxine succinate monohydrate (DVS) with high yield and high purity through 5-step...
We herein describe an optimal approach for the efficient synthesis of -desmethylvenlafaxine succinate monohydrate (DVS) with high yield and high purity through 5-step reactions, including benzyl protection of the phenolic hydroxyl group, cyclohexanone condensation, deprotection, cyano reduction, dimethylation, and succinic acid salt formation from -hydroxybenzene acetonitrile as a starting material. 4-Benzyloxyphenylacetonitrile (Intermediate I) was prepared by the hydroxyl protection of the bromide benzyl--hydroxyphenylacetonitrile catalyzed by potassium carbonate with 99.83% purity and 98.92% yields. The 1, 2-nucleophilic addition of intermediate I to cyclohexanone promoted by sodium hydroxide with the homogeneous catalyst (n-Bu)NBr to the preparation of 1-[Cyano(4-benzyloxyphenyl)methyl]cyclohexanol (Intermediate II) was obtained by 99.13% purity and 99.71% yields. Cyclohexanone residues and benzyl bromide residues were trace, and tetrabutylammonium bromide residues were UNDER 0.7 ppm, which further improves the residual standards for genotoxic impurities (GIs). 1-[2-amino-1-(4-hydroxyphenyl)ethyl]cyclohexanol hydrochloride (Intermediate III) was prepared by 10% palladium-carbon under 2.0 MPa up to 98.32% purity and 94.20% yields. -desmethylvenlafaxine (ODV) was synthesized by dimethylation of intermediate III with 37% formaldehyde solution and 85% formic acid solution. The highest purity was up to 99.20% and the yield was up to 84.77%. -desmethylvenlafaxine succinate monohydrate (DVS) was formed from succinic acid and -desmethylvenlafaxine (ODV) and crystallized in a mixed solvent of acetone and water (3:1) to obtain 99.92% purity and 90.27% yields. The 5-step total yields of desvenlafaxine succinate monohydrate is 71.09%, and its crystal form has characteristic peaks at 5, 10, 21, and 26 min by XRD powder diffraction, which is consistent with the crystalline form I. Compared with conventional synthesis strategy, we revealed a novel and green process with a high total yield, high atomic economy, low environmental pollution, high operational safety, and high residual standards for genotoxic impurities (GIs), which improves drug safety.
PubMed: 36059880
DOI: 10.3389/fchem.2022.860292 -
Revista de Neurologia Mar 2017Desvenlafaxine is the third antidepressant within the group of serotonin-norepinephrine reuptake inhibitors. The latest clinical practice guidelines consulted agree that... (Review)
Review
INTRODUCTION
Desvenlafaxine is the third antidepressant within the group of serotonin-norepinephrine reuptake inhibitors. The latest clinical practice guidelines consulted agree that tricyclic antidepressants, dual (venlafaxine/duloxetine) and gabapentin/pregabalin antiepileptics, are the first-line drugs in the treatment of neuropathic pain, being tramadol, lidocaine 5% patches and capsaicin 8% patches of second-line drugs, while strong opioids constitute a third line treatment. The interaction between the binomial pain and depression is very frequent, being the psychological complication more frequent in patients with chronic pain.
DEVELOPMENT
Following a literature search, this article summarizes the most relevant pharmacological data of desvenlafaxine and its usefulness in clinical practice, as well as the specific literature of this drug in neuropathic pain and chronic pain.
CONCLUSIONS
Although evidence of desvenlafaxine in neuropathic pain is scarce, it presents some interesting pharmacokinetic properties, as it is not substrate or have activity on P-glycoprotein, and have a metabolism which practically does not depend on cytochrome P450 system, which limits the risk of pharmacokinetic interactions and potential problems associated tolerability when administered with drugs that are CYP2D6 moderate or potent inhibitors or other substrates of this isoenzyme. These characteristics make desvenlafaxine a different antidepressant especially useful in some subgroups of patients with chronic pain (as polypharmacy and patients with liver failure), where comorbid depression is frequent.
Topics: Antidepressive Agents; Biological Availability; Biotransformation; Chronic Pain; Clinical Trials as Topic; Cytochrome P-450 Enzyme System; Depressive Disorder; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Drug Interactions; Duloxetine Hydrochloride; Humans; Multicenter Studies as Topic; Neuralgia; Selective Serotonin Reuptake Inhibitors; Venlafaxine Hydrochloride
PubMed: 28229443
DOI: No ID Found -
International Journal of Molecular... Sep 2022Drug metabolizing enzyme activity is affected by various factors such as drug-drug interactions, and a method to quantify drug metabolizing enzyme activity in real time...
Drug metabolizing enzyme activity is affected by various factors such as drug-drug interactions, and a method to quantify drug metabolizing enzyme activity in real time is needed. In this study, we developed a novel radiopharmaceutical for quantitative imaging to estimate hepatic CYP3A4 and CYP2D6 activity. Iodine-123- and 125-labeled -desmethylvenlafaxine (I-ODV) was obtained with high labeling and purity, and its metabolism was found to strongly involve CYP3A4 and CYP2D6. SPECT imaging in normal mice showed that the administered I-ODV accumulated early in the liver and was excreted into the gallbladder, as evaluated by time activity curves. In its biological distribution, I-ODV administered to mice accumulated early in the liver, and only the metabolite of I-ODV was quickly excreted into the bile. In CYP3A4- and CYP2D6-inhibited model mice, the accumulation in bile decreased more than in normal mice, indicating inhibition of metabolite production. These results indicated that imaging and quantifying the accumulation of radioactive metabolites in excretory organs will aid in determining the dosages of various drugs metabolized by CYP3A4 and CYP2D6 for individualized medicine. Thus, I-ODV has the potential to direct, comprehensive detection and measurement of hepatic CYP3A4 and CYP2D6 activity by a simple and less invasive approach.
Topics: Animals; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Desvenlafaxine Succinate; Iodine Radioisotopes; Liver; Mice; Radiopharmaceuticals; Venlafaxine Hydrochloride
PubMed: 36232758
DOI: 10.3390/ijms231911458 -
Journal of Chromatography. B,... Aug 2022The majority of women have health problems that require medication after giving birth. Complications such as allergies, postpartum depression, and diabetes are often...
The majority of women have health problems that require medication after giving birth. Complications such as allergies, postpartum depression, and diabetes are often treated with drugs such as cetirizine, venlafaxine, and metformin, respectively. These treatments are considered safe during lactation, but information of the transfer of drugs to breast milk and possible effects on the infant is scarce. Therefore, this needs to be systematically investigated in larger populations. To enable the determination of drug transfer, we here describe the validation of two rapid, sensitive, and high-throughput analysis methods for 1) simultaneous quantification of cetirizine, venlafaxine, and O-desmethylvenlafaxine in human breast milk, and 2) metformin in human breast milk and plasma. In both methods, a simple protein precipitation protocol with acetonitrile and benchtop-centrifugation was used prior to compound analysis with liquid-chromatography tandem mass spectrometry. The methods had linear ranges between 0.39 - 194.5 ng/mL for cetirizine, 0.28 - 138.7 ng/mL for venlafaxine, 0.26 - 131.7 ng/mL for O-desmethylvenlafaxine, in milk, and 0.65 - 193.7 ng/mL for metformin in both milk and plasma. Intra-run and inter-run precision and accuracy were ≤ 9% for cetirizine, venlafaxine, and O-desmethylvenlafaxine in milk, and ≤ 7% for metformin in milk and plasma. Cetirizine was measured to median milk concentrations of 13 ng/mL (range: 0.65 - 65 ng/mL) in 228 donor samples from breast-feeding women.
Topics: Cetirizine; Chromatography, High Pressure Liquid; Desvenlafaxine Succinate; Female; Humans; Infant; Metformin; Milk, Human; Pregnancy; Reproducibility of Results; Tandem Mass Spectrometry; Venlafaxine Hydrochloride
PubMed: 35732105
DOI: 10.1016/j.jchromb.2022.123340 -
The Cochrane Database of Systematic... Oct 2012Although pharmacological and psychological interventions are both effective for major depression, in primary and secondary care settings antidepressant drugs remain the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Although pharmacological and psychological interventions are both effective for major depression, in primary and secondary care settings antidepressant drugs remain the mainstay of treatment. Amongst antidepressants many different agents are available. Duloxetine hydrochloride is a dual reuptake inhibitor of serotonin and norepinephrine and has been licensed by the Food and Drug Administration in the US for major depressive disorder (MDD), generalised anxiety disorder, diabetic peripheral neuropathic pain, fibromyalgia and chronic musculoskeletal pain.
OBJECTIVES
To assess the evidence for the efficacy, acceptability and tolerability of duloxetine in comparison with all other antidepressant agents in the acute-phase treatment of major depression.
SEARCH METHODS
MEDLINE (1966 to 2012), EMBASE (1974 to 2012), the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register and the Cochrane Central Register of Controlled Trials up to March 2012. No language restriction was applied. Reference lists of relevant papers and previous systematic reviews were hand-searched. Pharmaceutical company marketing duloxetine and experts in this field were contacted for supplemental data.
SELECTION CRITERIA
Randomised controlled trials allocating patients with major depression to duloxetine versus any other antidepressive agent.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data and a double-entry procedure was employed. Information extracted included study characteristics, participant characteristics, intervention details and outcome measures in terms of efficacy, acceptability and tolerability.
MAIN RESULTS
A total of 16 randomised controlled trials (overall 5735 participants) were included in this systematic review. Of these, three trials were unpublished. We found 11 studies (overall 3304 participants) comparing duloxetine with one selective serotonin reuptake inhibitor (SSRI) (six studies versus paroxetine, three studies versus escitalopram and two versus fluoxetine), four studies (overall 1978 participants) comparing duloxetine with a newer antidepressants (three with venlafaxine and one with desvenlafaxine, respectively) and one study (overall 453 participants) comparing duloxetine with an antipsychotic drug which is also used as an antidepressive agent, quetiapine. No studies were found comparing duloxetine with tricyclic antidepressants. The pooled confidence intervals were rather wide and there were no statistically significant differences in efficacy when comparing duloxetine with other antidepressants. However, when compared with escitalopram or venlafaxine, there was a higher rate of drop out due to any cause in the patients randomised to duloxetine (odds ratio (OR) 1.62; 95% confidence interval (CI) 1.01 to 2.62 and OR 1.56; 95% CI 1.14 to 2.15, respectively). There was also some weak evidence suggesting that patients taking duloxetine experienced more adverse events than paroxetine (OR 1.24; 95% CI 0.99 to 1.55).
AUTHORS' CONCLUSIONS
Duloxetine did not seem to provide a significant advantage in efficacy over other antidepressive agents for the acute-phase treatment of major depression. No differences in terms of efficacy were found, even though duloxetine was worse than some SSRIs (most of all, escitalopram) and newer antidepressants (like venlafaxine) in terms of acceptability and tolerability. Unfortunately, we only found evidence comparing duloxetine with a handful of other active antidepressive agents and only a few trials per comparison were found (in some cases we retrieved just one trial). This limited the power of the review to detect moderate, but clinically meaningful differences between the drugs. As many statistical tests have been used in the review, the findings from this review are better thought of as hypothesis forming rather than hypothesis testing and it would be very comforting to see the conclusions replicated in future trials. Most of included studies were sponsored by the drug industry manufacturing duloxetine. As for all other new investigational compounds, the potential for overestimation of treatment effect due to sponsorship bias should be borne in mind. In the present review no trials reported economic outcomes. Given that several SSRIs and the great majority of antidepressants are now available as generic formulation (only escitalopram, desvenlafaxine and duloxetine are still on patent), more comprehensive economic estimates of antidepressant treatment effect should be considered to better inform healthcare policy.
Topics: Antidepressive Agents; Citalopram; Cyclohexanols; Depression; Desvenlafaxine Succinate; Dibenzothiazepines; Duloxetine Hydrochloride; Fluoxetine; Humans; Paroxetine; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Thiophenes; Venlafaxine Hydrochloride
PubMed: 23076926
DOI: 10.1002/14651858.CD006533.pub2 -
Journal of Child and Adolescent... Feb 2018To evaluate the short-term efficacy and safety of desvenlafaxine (25-50 mg/d) compared with placebo in children and adolescents with major depressive disorder (MDD). (Comparative Study)
Comparative Study Randomized Controlled Trial
OBJECTIVES
To evaluate the short-term efficacy and safety of desvenlafaxine (25-50 mg/d) compared with placebo in children and adolescents with major depressive disorder (MDD).
METHODS
Outpatient children (7-11 years) and adolescents (12-17 years) who met DSM-IV-TR criteria for MDD and had screening and baseline Children's Depression Rating Scale-Revised (CDRS-R) total scores >40 were randomly assigned to 8-week treatment with placebo, desvenlafaxine (25, 35, or 50 mg/d based on baseline weight), or fluoxetine (20 mg/d). The primary efficacy endpoint was change from baseline in CDRS-R total score at week 8, analyzed using a mixed-effects model for repeated measures. Secondary efficacy endpoints included week 8 Clinical Global Impressions-Severity, Clinical Global Impressions-Improvement (CGI-I), and response (CGI-I ≤ 2). Safety assessments included adverse events, physical and vital sign measurements, laboratory evaluations, electrocardiogram, and the Columbia-Suicide Severity Rating Scale.
RESULTS
The safety population included 339 patients (children, n = 130; adolescents, n = 209). The primary endpoint, change from baseline in CDRS-R total score at week 8, did not statistically separate from placebo, for either desvenlafaxine (adjusted mean [standard error] change, -22.6 [1.17]) or fluoxetine (-24.8 [1.17]; placebo, -23.1 [1.18]). Week 8 CGI-I response rates were significantly greater for fluoxetine (78.2%; p = 0.017) than for placebo (62.6%); desvenlafaxine (68.7%) did not differ from placebo. Other secondary outcomes were consistent with those obtained with CDRS-R. Rates of treatment-emergent adverse events were comparable among treatment groups (desvenlafaxine, 60.0%; placebo, 70.5%; and fluoxetine, 64.3%).
CONCLUSION
Desvenlafaxine did not demonstrate efficacy for treating MDD in children and adolescents in this trial. Because neither desvenlafaxine nor the reference medication, fluoxetine, demonstrated a statistically significant difference from placebo on the primary endpoint, this was considered a failed trial and no efficacy conclusions can be drawn. Desvenlafaxine 25-50 mg/d was generally safe and well tolerated in children and adolescents in this study.
Topics: Adolescent; Antidepressive Agents; Child; Depressive Disorder, Major; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fluoxetine; Humans; Male; Psychiatric Status Rating Scales; Severity of Illness Index; Treatment Outcome
PubMed: 29189044
DOI: 10.1089/cap.2017.0100 -
Primary Care Companion To the Journal... 2010To characterize weight change during short- and longer-term treatment with desvenlafaxine (administered as desvenlafaxine succinate) for major depressive disorder (MDD).
OBJECTIVE
To characterize weight change during short- and longer-term treatment with desvenlafaxine (administered as desvenlafaxine succinate) for major depressive disorder (MDD).
METHOD
Data from 9 short-term, double-blind, placebo-controlled studies and 1 longer-term relapse-prevention trial conducted between September 2002 and January 2007 were analyzed. Adult outpatients with a primary diagnosis of MDD using criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition received fixed- or flexible-dose desvenlafaxine or placebo for 8 weeks in the short-term studies. In the longer-term study, responders to 12 weeks of open-label desvenlafaxine treatment were randomly assigned to double-blind treatment with desvenlafaxine or placebo for 6 months. Mean weight changes and incidence of potentially clinically important changes were evaluated.
RESULTS
In the short-term studies (desvenlafaxine: n = 1,834; placebo: n = 1,116), mean decreases in weight associated with desvenlafaxine were small but statistically significant compared with baseline (P < .05) and with placebo (final evaluation: -0.82 kg desvenlafaxine vs + 0.05 kg placebo; P < .001). Likewise, during the 12-week, open-label phase of the relapse-prevention study (n = 594), a small but statistically significant mean decrease in weight from baseline (-0.8 kg; P < .001) occurred. Small mean increases in weight (< 1 kg) were observed with both desvenlafaxine (n = 190) and placebo (n = 185) throughout the relapse-prevention phase, with no statistical difference between desvenlafaxine- and placebo-treated patients at the final evaluation. Less than 1% of desvenlafaxine-treated patients experienced a clinically meaningful weight change.
CONCLUSIONS
Desvenlafaxine was not associated with clinically significant weight change during short- or longer-term treatment.
PubMed: 20582292
DOI: 10.4088/PCC.08m00746blu -
PloS One 2020Desvenlafaxine (DES) and Alprazolam (ALP) are the drugs commonly prescribed together for the treatment of Major Depressive Disorders (MDD). A literature survey revealed,...
Desvenlafaxine (DES) and Alprazolam (ALP) are the drugs commonly prescribed together for the treatment of Major Depressive Disorders (MDD). A literature survey revealed, there is no method for the simultaneous determination of these two drugs. The purpose of this research was to develop and validate a simple, accurate, precise, robust, and isocratic RP-HPLC method for simultaneous determination of DES and ALP in human spiked plasma using UV-detector in short analysis time. The method utilized Hypersil BDS C18 (250 mm×4.6 mm, 5 μm) through an isocratic mode of elution using HPLC grade acetonitrile and 0.02M KH2PO4 buffer (65:35) and 0.1% Tri Fluoro Acetic acid (TFA) with pH 4.00 adjusted with 1M KOH. The flow rate was 1.00 mLmin-1 and elution of the drugs was monitored at 230nm. The elution time of DES and ALP was 4.011 and 5.182 minutes respectively. The method was linear for the concentration range 10-150 μgmL-1 for DES and 5.0-75.0 μgmL-1 for ALP. According to the validation results, the method is sensitive with Limit of Detection (LOD) 4.740 μgmL-1 and Limit of Quantification (LOQ) of 14.365 μgmL-1 for DES and LOD 1.891 μgmL-1 & LOQ 5.730 μgmL-1 for ALP. The reproducibility of results with minute deliberate variations in method parameters has proven that the method is robust. The data from stability studies show a non-significant change in drugs solutions for 2 months. The optimized method was validated as per International Conference for Harmonisation (ICH) Q2(R1) guidelines. This method can be used for the estimation of DES and ALP in plasma and can evaluate pharmacokinetic parameters of both drugs simultaneously.
Topics: Alprazolam; Chromatography, High Pressure Liquid; Desvenlafaxine Succinate; Humans; Limit of Detection; Pharmaceutical Solutions; Plasma; Reproducibility of Results
PubMed: 32941505
DOI: 10.1371/journal.pone.0238954