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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 -
Neuropsychiatric Disease and Treatment 2009Major depressive disorder (MDD) is among the most incapacitating conditions in the world. The emergence of the selective serotonin reuptake inhibitor (SSRI) and...
Major depressive disorder (MDD) is among the most incapacitating conditions in the world. The emergence of the selective serotonin reuptake inhibitor (SSRI) and serotonin norepinephrine reuptake inhibitors (SNRI) antidepressants has improved the treatment of MDD. Desvenlafaxine succinate (DVS) is the succinate salt of the isolated major active metabolite of venlafaxine, O-desmethylvenlafaxine: it is the third SNRI to become available in the United States, and was approved in 2008 by the US Food and Drug Administration (FDA) for the treatment of MDD. Early investigations showed therapeutic efficacy for doses between 50 and 400 mg/day; however in doses above 100 mg/day there were incremental increases in side effects. Nausea was the most frequent adverse effect. Hence the recommended dosing for DVS is in the 50 to 100 mg range. Desvenlafaxine is excreted in urine, it is minimally metabolized via the CYP450 pathway, and is a weak inhibitor of CYP2D6. A reduced risk for pharmacokinetic drug interactions is a potential advantage over other SNRI. Further head-to-head trials involving comparisons of DVS in the 50 to 100 mg dose range with currently available SSRI and SNRI antidepressants are required. Evidence for relapse prevention is available in the 200 to 400 mg dose range, but this needs to be demonstrated in the 50 to 100 mg dose range, as well as health economic measures and quality of life evaluations.
PubMed: 19557107
DOI: 10.2147/ndt.s3360 -
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 -
The Primary Care Companion For CNS... 2015The purpose of this post hoc analysis was to evaluate the incidence and timing of taper/posttherapy-emergent adverse events (TPAEs) following discontinuation of...
OBJECTIVE
The purpose of this post hoc analysis was to evaluate the incidence and timing of taper/posttherapy-emergent adverse events (TPAEs) following discontinuation of long-term treatment with desvenlafaxine (administered as desvenlafaxine succinate).
METHOD
This was a phase 4, randomized, double-blind, placebo-controlled study conducted at 38 research centers within the United States between March 2010 and February 2011. Adult outpatients with major depressive disorder (MDD; DSM-IV-TR criteria) who completed 24 weeks of open-label treatment with desvenlafaxine 50 mg/d were randomly assigned to 1 of 3 groups for the double-blind taper phase: desvenlafaxine 50 mg/d for 4 weeks (no discontinuation), desvenlafaxine 25 mg/d for 1 week followed by placebo for 3 weeks (taper), or placebo for 4 weeks (abrupt discontinuation). The primary endpoint, Discontinuation-Emergent Signs and Symptoms Scale (DESS) score over the first 2 weeks of the taper phase, was described previously. Secondary assessments included incidence and timing of TPAEs (any adverse event that started or increased in severity during the double-blind phase) and the percentage of patients who could not continue the taper phase due to discontinuation symptoms. The Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16) assessed MDD status.
RESULTS
A total of 480 patients enrolled in the open-label phase; the full analysis set included 357 patients (taper, n = 139; abrupt discontinuation, n = 146; no discontinuation, n = 72). TPAEs occurred in all groups through week 4. The incidence of any TPAE was lower for taper versus abrupt discontinuation at week 1 (P < .001), similar at week 2, and lower for taper versus abrupt discontinuation at weeks 3 and 4 (P ≤ .034). The most common TPAEs (incidence ≥ 3%) in the taper group were nausea and headache (3% each) at week 1 and dizziness (5%) and headache (4%) at week 2. The most common TPAEs in the abrupt discontinuation group were dizziness (8%), headache (8%), nausea (4%), irritability (3%), and diarrhea (3%) at week 1 and headache (3%) at weeks 2 and 3. The most common TPAE in the no discontinuation group was nausea (6%) at week 2.
CONCLUSION
The overall incidence of any TPAE was lower in the taper versus abrupt discontinuation groups.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT01056289.
PubMed: 26137358
DOI: 10.4088/PCC.14m01715 -
Canadian Journal of Psychiatry. Revue... Jan 2022Major depressive disorder (MDD) is a common and burdensome condition that has low rates of treatment success for each individual treatment. This means that many patients...
BACKGROUND
Major depressive disorder (MDD) is a common and burdensome condition that has low rates of treatment success for each individual treatment. This means that many patients require several medication switches to achieve remission; selecting an effective antidepressant is typically a sequential trial-and-error process. Machine learning techniques may be able to learn models that can predict whether a specific patient will respond to a given treatment, before it is administered. This study uses baseline clinical data to create a machine-learned model that accurately predicts remission status for a patient after desvenlafaxine (DVS) treatment.
METHODS
We applied machine learning algorithms to data from 3,399 MDD patients (90% of the 3,776 subjects in 11 phase-III/IV clinical trials, each described using 92 features), to produce a model that uses 26 of these features to predict symptom remission, defined as an 8-week Hamilton Depression Rating Scale score of 7 or below. We evaluated that learned model on the remaining held-out 10% of the data ( = 377).
RESULTS
Our resulting classifier, a trained linear support vector machine, had a holdout set accuracy of 69.0%, significantly greater than the probability of classifying a patient correctly by chance. We demonstrate that this learning process is stable by repeatedly sampling part of the training dataset and running the learner on this sample, then evaluating the learned model on the held-out instances of the training set; these runs had an average accuracy of 67.0% ± 1.8%.
CONCLUSIONS
Our model, based on 26 clinical features, proved sufficient to predict DVS remission significantly better than chance. This may allow more accurate use of DVS without waiting 8 weeks to determine treatment outcome, and may serve as a first step toward changing psychiatric care by incorporating clinical assistive technologies using machine-learned models.
Topics: Antidepressive Agents; Depressive Disorder, Major; Desvenlafaxine Succinate; Humans; Machine Learning; Treatment Outcome
PubMed: 34379019
DOI: 10.1177/07067437211037141 -
British Journal of Clinical Pharmacology May 1998To characterise the transfer of venlafaxine (V) and its O-desmethyl metabolite (ODV) into human milk by measuring milk/plasma (M/P) ratio, and to estimate the likely... (Clinical Trial)
Clinical Trial
AIMS
To characterise the transfer of venlafaxine (V) and its O-desmethyl metabolite (ODV) into human milk by measuring milk/plasma (M/P) ratio, and to estimate the likely dose received by a breast-fed infant.
METHODS
Milk and plasma samples were collected from three lactating women who were taking venlafaxine for depression, and were at steady-state. In two of the patients, venous blood and milk samples were collected 0, 1, 2, 3, 4, 6, 8 and 12 h post dose, while in the third patient a single pair of blood and milk samples was obtained 0.83 h post dose. A plasma sample was obtained from each of their infants. V and ODV were measured in plasma and milk by high performance liquid chromatography. M/P was calculated and infant dose estimated as drug concentration in milk x a milk intake of 0.15 l kg(-1) day(-1), relative to the weight-adjusted maternal dose.
RESULTS
Mean M/P for V was 4.1 (range 2.8-4.8) and 3.1 for ODV (range 2.8-3.8). The mean total infant dose (as V equivalents) was 7.6% (range 4.7-9.2%) of the maternal weight-adjusted dose, with approximately equal amounts of V (3.5%) and ODV (4.1%) in the dose. ODV (median 100 microg I(-1)) was detected in the plasma of all three infants. The infants were healthy and showed no acute adverse effects.
CONCLUSIONS
These preliminary data show that the total dose of V and ODV ingested by breast-fed infants can be as high as 9.2% of maternal intake. Moreover there were measurable concentrations of ODV in the infants' plasma. We recommend that exposed infants should be observed closely.
Topics: Adult; Antidepressive Agents; Area Under Curve; Breast Feeding; Chromatography, High Pressure Liquid; Cyclohexanols; Desvenlafaxine Succinate; Female; Humans; Infant; Infant, Newborn; Milk, Human; Tissue Distribution; Venlafaxine Hydrochloride
PubMed: 9643618
DOI: 10.1046/j.1365-2125.1998.00710.x -
Pharmacogenetics and Genomics Jan 2017Pharmacogenetic-based dosing support tools have been developed to personalize antidepressant-prescribing practice. However, the clinical validity of these tools has not...
BACKGROUND
Pharmacogenetic-based dosing support tools have been developed to personalize antidepressant-prescribing practice. However, the clinical validity of these tools has not been adequately tested, particularly for specific antidepressants.
OBJECTIVE
To examine the concordance between the actual dose and a polygene pharmacogenetic predicted dose of desvenlafaxine needed to achieve symptom remission.
MATERIALS AND METHODS
A 10-week, open-label, prospective trial of desvenlafaxine among Caucasian adults with major depressive disorder (n=119) was conducted. Dose was clinically adjusted and at the completion of the trial, the clinical dose needed to achieve remission was compared with the predicted dose needed to achieve remission.
RESULTS
Among remitters (n=95), there was a strong concordance (Kendall's τ-b=0.84, P=0.0001; Cohen's κ=0.82, P=0.0001) between the actual and the predicted dose need to achieve symptom remission, showing high sensitivity (≥85%), specificity (≥86%), and accuracy (≥89%) of the tool.
CONCLUSION
Findings provide initial evidence for the clinical validity of a polygene pharmacogenetic-based tool for desvenlafaxine dosing.
Topics: ATP Binding Cassette Transporter, Subfamily B; Adult; Antidepressive Agents; Depressive Disorder, Major; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Double-Blind Method; Female; Glucuronosyltransferase; Humans; Male; Middle Aged; Multidrug Resistance-Associated Proteins; Pharmacogenomic Variants; Prospective Studies; Psychiatric Status Rating Scales; Treatment Outcome; White People
PubMed: 27779571
DOI: 10.1097/FPC.0000000000000253 -
British Journal of Clinical Pharmacology Jan 2002To characterize milk/plasma (M/P) ratio and infant dose, for venlafaxine (V) and its O-desmethyl metabolite (ODV), in breastfeeding women taking venlafaxine for the...
AIMS
To characterize milk/plasma (M/P) ratio and infant dose, for venlafaxine (V) and its O-desmethyl metabolite (ODV), in breastfeeding women taking venlafaxine for the treatment of depression, and to determine the plasma concentration and effects of these drugs in their infants.
METHODS
Six women (mean age 34.5 years, mean weight 84.3 kg) taking venlafaxine (median dose 244 mg day(-1), range 225-300 mg day(-1)) and their seven infants (mean age 7.0 months, mean weight 7.3 kg) were studied. V and ODV in plasma and milk were measured by high-performance liquid chromatography over a 12 h dose interval at steady-state. Infant exposure was estimated as the product of estimated milk production rate (0.15 l kg(-1)day(-1)) and average drug concentration in milk, normalized to body weight and expressed as a percentage of the weight-adjusted maternal dose.
RESULTS
Mean M/PAUC values of 2.5 (range 2.0-3.2) and 2.7 (range 2.3-3.2) were calculated for V and ODV, respectively. The mean maximum concentrations (95% CI) of V and ODV in milk were 1161 (95% CI, 588, 1734) microg l(-1) and 796 (362, 1230) microg l(-1). Mean infant exposure was 3.2% (1.7, 4.7%) for V and 3.2% (1.9, 4.9%) for ODV (as V equivalents). V was detected in the plasma of one out of seven infants studied (5 microg l(-1)), while ODV was detected in four of the infants, at concentrations ranging from 3 to 38 microg l(-1). All of the infants in the study were healthy, as reported by their mothers and/or by clinical examination on the study day.
CONCLUSIONS
The concentrations of V and ODV in breast milk were 2.5 and 2.7 times those in maternal plasma. The mean total drug exposure (as venlafaxine equivalents) of the breastfed infants was 6.4% (5.5-7.3%), which is below the 10% notional level of concern. There were no adverse effects in any of the infants. The data support the use of V in breastfeeding. Nevertheless, since low concentrations of ODV were detected in the plasma of four out of the seven infants studied, we recommend breastfed infants should be monitored closely. Each decision to breast feed should be made as an individual risk:benefit analysis.
Topics: Adult; Antidepressive Agents; Area Under Curve; Breast Feeding; Confidence Intervals; Cyclohexanols; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Female; Humans; Infant; Lactation; Male; Milk, Human; Selective Serotonin Reuptake Inhibitors; Venlafaxine Hydrochloride
PubMed: 11849190
DOI: 10.1046/j.0306-5251.2001.01518.x -
PloS One 2014Adult hippocampal neurogenesis has been linked to the effects of anti-depressant drugs on behavior in rodent models of depression. To explore this link further, we...
Adult hippocampal neurogenesis has been linked to the effects of anti-depressant drugs on behavior in rodent models of depression. To explore this link further, we tested whether the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine impacted adult hippocampal neurogenesis differently than its primary active SNRI metabolite desvenlafaxine. Adult male Long Evans rats (n = 5-6 per group) were fed vehicle, venlafaxine (0.5 or 5 mg) or desvenlafaxine (0.5 or 5 mg) twice daily for 16 days. Beginning the third day of drug treatment, the rats were given a daily bromodeoxyuridine (BrdU; 50 mg/kg) injection for 5 days to label dividing cells and then perfused 2 weeks after the first BrdU injection to confirm total new hippocampal cell numbers and their phenotypes. The high desvenlafaxine dose increased total new BrdU+ cell number and appeared to accelerate neuronal maturation because fewer BrdU+ cells expressed maturing neuronal phenotypes and more expressed mature neuronal phenotypes in the dentate gyri of these versus vehicle-treated rats. While net neurogenesis was not increased in the dentate gyri of rats treated with the high desvenlafaxine dose, significantly more mature neurons were detected. Our data expand the body of literature showing that antidepressants impact adult neurogenesis by stimulating NPC proliferation and perhaps the survival of neuronal progeny and by showing that a high dose of the SNRI antidepressant desvenlafaxine, but neither a high nor low venlafaxine dose, may also accelerate neuronal maturation in the adult rat hippocampus. These data support the hypothesis that hippocampal neurogenesis may indeed serve as a biomarker of depression and the effects of antidepressant treatment, and may be informative for developing novel fast-acting antidepressant strategies.
Topics: Animals; Antidepressive Agents; Biomarkers; Body Weight; Cell Count; Cell Differentiation; Cyclohexanols; Dentate Gyrus; Desvenlafaxine Succinate; Male; Neurogenesis; Pyramidal Cells; Rats
PubMed: 24896246
DOI: 10.1371/journal.pone.0098530 -
The International Journal of... Aug 2017Major depressive disorder is a debilitating illness, which is most commonly treated with antidepressant drugs. As the majority of patients do not respond on their first... (Clinical Trial)
Clinical Trial
BACKGROUND
Major depressive disorder is a debilitating illness, which is most commonly treated with antidepressant drugs. As the majority of patients do not respond on their first trial, there is great interest in identifying biological factors that indicate the most appropriate treatment for each patient. Studies suggest that microRNA represent excellent biomarkers to predict antidepressant response.
METHODS
We investigated the expression of miR-1202, miR-135a, and miR-16 in peripheral blood from 2 cohorts of depressed patients who received 8 weeks of antidepressant therapy. Expression was quantified at baseline and after treatment, and its relationship to treatment response and depressive symptoms was assessed.
RESULTS
In both cohorts, responders displayed lower baseline miR-1202 levels compared with nonresponders, which increased following treatment.
CONCLUSIONS
Ultimately, our results support the involvement of microRNA in antidepressant response and suggest that quantification of their levels in peripheral samples represents a valid approach to informing treatment decisions.
Topics: Antidepressive Agents; Biomarkers; Citalopram; Clinical Decision-Making; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Desvenlafaxine Succinate; Duloxetine Hydrochloride; Humans; MicroRNAs; Psychiatric Status Rating Scales; ROC Curve; Treatment Outcome
PubMed: 28520926
DOI: 10.1093/ijnp/pyx034