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Journal of Clinical Sleep Medicine :... Feb 2017To determine if patients with childhood onsets (CO) of both major depression and insomnia disorder show blunted depression and insomnia treatment responses to concurrent... (Randomized Controlled Trial)
Randomized Controlled Trial
STUDY OBJECTIVES
To determine if patients with childhood onsets (CO) of both major depression and insomnia disorder show blunted depression and insomnia treatment responses to concurrent interventions for both disorders compared to those with adult onsets (AO) of both conditions.
METHODS
This study was a secondary analysis of data obtained from a multisite randomized clinical trial designed to test the efficacy of combining a psychological/behavior insomnia therapy with antidepressant medication to enhance depression treatment outcomes in patients with comorbid major depression and insomnia. This study included 27 adults with CO of depression and insomnia and 77 adults with AO of both conditions. They underwent a 16-week treatment including: (1) a standardized two-step pharmacotherapy for depression algorithm, consisting of escitalopram, sertraline, and desvenlafaxine in a prescribed sequence; and (2) either cognitive behavioral insomnia therapy (CBT-I) or a quasi-desensitization control (CTRL) therapy. Main outcome measures were the 17-item Hamilton Rating Scale for Depression (HRSD-17) and the Insomnia Severity Index (ISI) completed pre-treatment and every 2 weeks thereafter.
RESULTS
The AO and CO groups did not differ significantly in regard to their pre-treatment HRSD-17 and ISI scores. Mixed model analyses that adjusted for the number of insomnia treatment sessions attended showed that the AO group achieved significantly lower, subclinical scores on the HRSD-17 and ISI than did the CO group by the time of study exit. Moreover, a significant group by treatment arm interaction suggested that HRSD-17 scores at study exit remained significantly higher in the CO group receiving the CTRL therapy than was the case for the participants in the CO group receiving CBT-I. Greater proportions of the AO group achieved a priori criteria for remission of insomnia (49.3% vs. 29.2%, p = 0.04) and depression (45.5% vs. 29.6%, p = 0.07) than did those in the CO group.
CONCLUSIONS
Patients with comorbid depression and insomnia who experienced the first onset of both disorders in childhood are less responsive to the treatments offered herein than are those with adult onsets of these comorbid disorders. Further research is needed to identify therapies that enhance the depression and insomnia treatment responses of those with childhood onsets of these two conditions.
Topics: Adult; Age of Onset; Antidepressive Agents; Citalopram; Cognitive Behavioral Therapy; Combined Modality Therapy; Depressive Disorder, Major; Desvenlafaxine Succinate; Humans; Middle Aged; Sertraline; Severity of Illness Index; Sleep Initiation and Maintenance Disorders; Treatment Outcome; United States
PubMed: 27784414
DOI: 10.5664/jcsm.6448 -
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 -
Canadian Family Physician Medecin de... Jun 2016
Topics: Adolescent; Amitriptyline; Antidepressive Agents, Tricyclic; Consciousness; Depression; Desvenlafaxine Succinate; Drug Overdose; Drug Therapy, Combination; Electrocardiography; Emergency Service, Hospital; Female; Glasgow Coma Scale; Humans; Hypotension; Long QT Syndrome; Seizures; Serotonin and Noradrenaline Reuptake Inhibitors
PubMed: 27303005
DOI: No ID Found -
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 -
Actas Espanolas de Psiquiatria 2016
Topics: Antidepressive Agents; Depressive Disorder, Major; Desvenlafaxine Succinate; Electroconvulsive Therapy; Humans; Treatment Outcome
PubMed: 27099215
DOI: No ID Found -
Journal of Pharmaceutical and... May 2016(±)-Venlafaxine, a bicyclic antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI) class, is prescribed for the treatment of depression and anxiety...
(±)-Venlafaxine, a bicyclic antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI) class, is prescribed for the treatment of depression and anxiety disorders. As is the case with other antidepressants, its precise mechanisms of action are still unknown. Pharmacometabonomic approaches allow for the detection of diverse metabolites, unlike classic methods for analysing drug interaction based on single metabolites and linear pathways. This provides a global view of the state of homeostasis during treatment and an insight into the mechanisms of action of a drug. Accordingly, the final outcome of treatment is characterised by the network of reactome pathways derived from the on-target and off-target effects of the drug. Regarding antidepressants, the drug network may be located in the gut-microbiome-brain-liver-kidney-immune-cardiovascular system axis (GMBLKICA), implying that neurotransmitters participate as signalling molecules in bidirectional communication. If their bioavailability is increased, this communication and the state of homeostasis may be disrupted. With a pharmacometabonomic approach using NMR in combination with different chemometric methods, a determination was made of subtle changes in the metabolic profile (metabotype) of urine and faeces in normal Wistar rats following a single administration of pharmacological doses of (±)-venlafaxine hydrochloride. Based on the drug-response metabotypes observed, (±)-venlafaxine had effects on gut microbial co-metabolites and osmolytes. Hence, it can be hypothesized that bidirectional communication in the multiorgan axis was perturbed by this drug, and very likely by its active metabolite, (±)-desvenlafaxine. This disrupted signalling could be related not only to therapeutic and adverse effects, but also to the lag period in treatment response.
Topics: Animals; Antidepressive Agents; Brain; Depression; Desvenlafaxine Succinate; Feces; Female; Magnetic Resonance Imaging; Metabolomics; Neurotransmitter Agents; Norepinephrine; Rats; Rats, Wistar; Selective Serotonin Reuptake Inhibitors; Urine; Venlafaxine Hydrochloride
PubMed: 26895493
DOI: 10.1016/j.jpba.2016.01.044 -
The Journal of Mental Health Policy and... Dec 2015Private health insurance plays a large role in the U.S. health system, including for many individuals with depression. Private insurers have been actively trying to...
BACKGROUND
Private health insurance plays a large role in the U.S. health system, including for many individuals with depression. Private insurers have been actively trying to influence pharmaceutical utilization and costs, particularly for newer and costlier medications. The approaches that insurers use may have important effects on patients' access to antidepressant medications.
AIMS OF THE STUDY
To report which approaches (e.g., tiered copayments, prior authorization, and step therapy) commercial health plans are employing to manage newer antidepressant medications, and how the use of these approaches has changed since 2003.
METHODS
Data are from a nationally representative survey of commercial health plans in 60 market areas regarding alcohol, drug abuse and mental health services in 2010. Responses were obtained from 389 plans (89% response rate), reporting on 925 insurance products. For each of six branded antidepressant medications, respondents were asked whether the plan covered the medication and if so, on what copayment tier, and whether it was subject to prior authorization or step therapy. Measures of management approach were constructed for each medication and for the group of medications. Bivariate and multivariate analyses were used to test for association of the management approach with various health plan characteristics.
RESULTS
Less than 1% of health plan products excluded any of the six antidepressants studied. Medications were more likely to be subjected to restrictions if they were newer, more expensive or were reformulations. 55% of products used placement on a high cost-sharing tier (3 or 4) as their only form of restriction for newer branded antidepressants. This proportion was lower than in 2003, when 71% of products took this approach. In addition, only 2% of products left all the newer branded medications unrestricted, down from 25% in 2003. Multivariate analysis indicated that preferred provider organizations were more likely than other product types to use tier 3 or 4 placement.
DISCUSSION
We find that U.S. health plans are using a variety of strategies to manage cost and utilization of newer branded antidepressant medications. Plans appear to be finding that approaches other than exclusion are adequate to meet their cost-management goals for newer branded antidepressants, although they have increased their use of administrative restrictions since 2003. Limitations include lack of information about how administrative restrictions were applied in practice, information on only six medications, and some potential for endogeneity bias in the regression analyses.
CONCLUSION
This study has documented substantial use of various restrictions on access to newer branded antidepressants in U.S. commercial health plans. Most of these medications had generic equivalents that offered at least some substitutability, reducing access concerns. At the same time, it is worth noting that high copayments and administrative requirements can nonetheless be burdensome for some patients.
IMPLICATIONS FOR HEALTH POLICY
Health plans' pharmacy management approaches may concern policymakers less than in the early 2000s, due to the lesser distinctiveness of today's branded medications. This may change depending on future drug introductions.
IMPLICATIONS FOR FURTHER RESEARCH
Future research should examine the impact of plans' pharmacy management approaches, using patient-level data.
Topics: Antidepressive Agents; Citalopram; Cost Control; Cost Sharing; Desvenlafaxine Succinate; Drug Costs; Drug Utilization; Duloxetine Hydrochloride; Fluvoxamine; For-Profit Insurance Plans; Health Care Surveys; Health Services Accessibility; Humans; Insurance Coverage; Insurance, Pharmaceutical Services; Preferred Provider Organizations; Private Sector; Selegiline; United States; Venlafaxine Hydrochloride
PubMed: 26729008
DOI: No ID Found -
Journal of Chromatography. A Nov 2015To-date, there has been no effective chiral capillary electrophoresis-mass spectrometry (CE-MS) method reported for the simultaneous enantioseparation of the...
Development of an enantioselective assay for simultaneous separation of venlafaxine and O-desmethylvenlafaxine by micellar electrokinetic chromatography-tandem mass spectrometry: Application to the analysis of drug-drug interaction.
To-date, there has been no effective chiral capillary electrophoresis-mass spectrometry (CE-MS) method reported for the simultaneous enantioseparation of the antidepressant drug, venlafaxine (VX) and its structurally-similar major metabolite, O-desmethylvenlafaxine (O-DVX). This is mainly due to the difficulty of identifying MS compatible chiral selector, which could provide both high enantioselectivity and sensitive MS detection. In this work, poly-sodium N-undecenoyl-L,L-leucylalaninate (poly-L,L-SULA) was employed as a chiral selector after screening several dipeptide polymeric chiral surfactants. Baseline separation of both O-DVX and VX enantiomers was achieved in 15 min after optimizing the buffer pH, poly-L,L-SULA concentration, nebulizer pressure and separation voltage. Calibration curves in spiked plasma (recoveries higher than 80%) were linear over the concentration range 150-5000 ng/mL for both VX and O-DVX. The limit of detection (LOD) was found to be as low as 30 ng/mL and 21 ng/mL for O-DVX and VX, respectively. This method was successfully applied to measure the plasma concentrations of human volunteers receiving VX or O-DVX orally when co-administered without and with indinivar therapy. The results suggest that micellar electrokinetic chromatography electrospray ionization-tandem mass spectrometry (MEKC-ESI-MS/MS) is an effective low cost alternative technique for the pharmacokinetics and pharmacodynamics studies of both O-DVX and VX enantiomers. The technique has potential to identify drug-drug interaction involving VX and O-DVX enantiomers while administering indinivar therapy.
Topics: Calibration; Chromatography, Micellar Electrokinetic Capillary; Desvenlafaxine Succinate; Drug Interactions; Electrophoresis, Capillary; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Limit of Detection; Polymers; Spectrometry, Mass, Electrospray Ionization; Stereoisomerism; Tandem Mass Spectrometry; Venlafaxine Hydrochloride
PubMed: 26460073
DOI: 10.1016/j.chroma.2015.09.088 -
Clinical Journal of the American... Oct 2015A safety signal regarding cases of AKI after exposure to serotonin-norepinephrine reuptake inhibitors (SNRIs) was identified by Health Canada. Therefore, this study... (Comparative Study)
Comparative Study Meta-Analysis
BACKGROUND AND OBJECTIVES
A safety signal regarding cases of AKI after exposure to serotonin-norepinephrine reuptake inhibitors (SNRIs) was identified by Health Canada. Therefore, this study assessed whether the use of SNRIs increases the risk of AKI compared with selective serotonin reuptake inhibitors (SSRIs) and examined the risk associated with each individual SNRI.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
Multiple retrospective population-based cohort studies were conducted within eight administrative databases from Canada, the United States, and the United Kingdom between January 1997 and March 2010. Within each cohort, a nested case-control analysis was performed to estimate incidence rate ratios (RRs) of AKI associated with SNRIs compared with SSRIs using conditional logistic regression, with adjustment for high-dimensional propensity scores. The overall effect across sites was estimated using meta-analytic methods.
RESULTS
There were 38,974 cases of AKI matched to 384,034 controls. Current use of SNRIs was not associated with a higher risk of AKI compared with SSRIs (fixed-effect RR, 0.97; 95% confidence interval [95% CI], 0.94 to 1.01). Current use of venlafaxine and desvenlafaxine considered together was not associated with a higher risk of AKI (RR, 0.96; 95% CI, 0.92 to 1.00). For current use of duloxetine, there was significant heterogeneity among site-specific estimates such that a random-effects meta-analysis was performed showing a 16% higher risk, although this risk was not statistically significant (RR, 1.16; 95% CI, 0.96 to 1.40). This result is compatible with residual confounding, because there was a substantial imbalance in the prevalence of diabetes between users of duloxetine and users of others SNRIs or SSRIs. After further adjustment by including diabetes as a covariate in the model along with propensity scores, the fixed-effect RR was 1.02 (95% CI, 0.95 to 1.10).
CONCLUSIONS
There is no evidence that use of SNRIs is associated with a higher risk of hospitalization for AKI compared with SSRIs.
Topics: Acute Kidney Injury; Adolescent; Adult; Aged; Canada; Case-Control Studies; Child; Databases, Factual; Desvenlafaxine Succinate; Duloxetine Hydrochloride; Female; Humans; Incidence; Male; Middle Aged; Risk Assessment; Selective Serotonin Reuptake Inhibitors; Serotonin and Noradrenaline Reuptake Inhibitors; United Kingdom; United States; Venlafaxine Hydrochloride; Young Adult
PubMed: 26231193
DOI: 10.2215/CJN.11271114 -
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