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Journal of Psychopharmacology (Oxford,... Mar 2020Major depressive disorder is characterized by the presence of at least five of nine specific symptoms that contribute to clinically significant functional impairment.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Major depressive disorder is characterized by the presence of at least five of nine specific symptoms that contribute to clinically significant functional impairment. This analysis examined the effect of desvenlafaxine (50 or 100 mg) versus placebo on symptom cluster scores and the association between early improvement in symptom clusters and symptomatic or functional remission at week 8.
METHODS
Using data from nine double-blind, placebo-controlled studies of desvenlafaxine for the treatment of major depressive disorder (=4317), the effect of desvenlafaxine 50 or 100 mg versus placebo on scores for symptom clusters based on 17-item Hamilton Rating Scale for Depression items was assessed using analysis of covariance. Association between early improvement in symptom clusters (⩾20% improvement from baseline at week 2) and symptomatic and functional remission (17-item Hamilton Rating Scale for Depression total score ⩽7; Sheehan Disability Scale score <7) at week 8 was analyzed using logistic regression. Symptom clusters based on Montgomery-Åsberg Depression Rating Scale were also examined.
RESULTS
Desvenlafaxine 50 or 100 mg was associated with significant improvement from baseline compared to placebo for all symptom clusters (<0.001), except a sleep cluster for desvenlafaxine 100 mg. For all symptom clusters, early improvement was significantly associated with achievement of symptomatic and functional remission at week 8 for all treatment groups (⩽0.0254).
CONCLUSION
Early improvement in symptom clusters significantly predicts symptomatic or functional remission at week 8 in patients with depression receiving desvenlafaxine (50 or 100 mg) or placebo. Importantly, patients without early improvement were less likely to remit.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antidepressive Agents; Depressive Disorder, Major; Desvenlafaxine Succinate; Female; Humans; Male; Middle Aged; Remission Induction; Young Adult
PubMed: 31913085
DOI: 10.1177/0269881119896066 -
Clinical Pharmacology and Therapeutics Jul 2020The US Food and Drug Administration (FDA) lists 22 medications as clinical inhibitors of cytochrome P450 2D6 isoenzyme, with classifications of strong, moderate, and... (Review)
Review
The US Food and Drug Administration (FDA) lists 22 medications as clinical inhibitors of cytochrome P450 2D6 isoenzyme, with classifications of strong, moderate, and weak. It is accepted that strong inhibitors result in nearly null enzymatic activity, but reduction caused by moderate and weak inhibitors is less well characterized. The objective was to identify if the classification of currently listed FDA moderate and weak inhibitors is supported by publicly available primary literature. We conducted a literature search and reviewed product labels for area under the plasma concentration-time curve (AUC) fold-changes caused by inhibitors in humans and identified 89 inhibitor-substrate pairs. Observed AUC fold-change of the substrate was used to create an observed inhibitor classification per FDA-defined AUC fold-change thresholds. We then compared the observed inhibitor classification with the classification listed in the FDA Table of Inhibitors. We found 62% of the inhibitors within the pairs matched the listed FDA classification. We explored reasons for discordance and suggest modifications to the FDA table of clinical inhibitors for cimetidine, desvenlafaxine, and fluvoxamine.
Topics: Area Under Curve; Cimetidine; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Desvenlafaxine Succinate; Fluvoxamine; Humans
PubMed: 31910286
DOI: 10.1002/cpt.1768 -
Australasian Psychiatry : Bulletin of... Jun 2020Domestic family violence (FV) is a serious problem with serious impacts on mental health of victims. One such impact is post-traumatic stress disorder (PTSD), and it can...
OBJECTIVE
Domestic family violence (FV) is a serious problem with serious impacts on mental health of victims. One such impact is post-traumatic stress disorder (PTSD), and it can be resistant to treatment (treatment-resistant or TR). This article offers novel treatment.
METHODS
Two treatment resistant case studies are described where adjunctive treatment with brexpiprazole was commenced. Possible theoretical considerations are presented to explain improvement.
RESULTS
Adjunctive treatment with brexpiprazole was associated with significant improvement in FV subjective and objective measures, with enhanced response to trauma therapy.
CONCLUSION
Brexpiprazole improved complex post traumatic stress disorder in FV victims and needs further evaluation.
Topics: Adult; Citalopram; Combined Modality Therapy; Desvenlafaxine Succinate; Domestic Violence; Drug Resistance; Drug Therapy, Combination; Female; Humans; Middle Aged; Psychotherapy; Quinolones; Stress Disorders, Post-Traumatic; Thiophenes
PubMed: 31896271
DOI: 10.1177/1039856219889303 -
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 -
Gastroenterologia Y Hepatologia Dec 2019
Topics: Abdominal Pain; Adult; Anti-Inflammatory Agents, Non-Steroidal; Depressive Disorder; Desvenlafaxine Succinate; Drug Synergism; Duloxetine Hydrochloride; Duodenal Ulcer; Gastrointestinal Hemorrhage; Gastroscopy; Humans; Male; Melena; Methimazole; Naproxen; Selective Serotonin Reuptake Inhibitors; Stomach Ulcer
PubMed: 31324464
DOI: 10.1016/j.gastrohep.2019.03.013 -
The Lancet. Psychiatry Aug 2019Antidepressant medications offer an effective treatment for depression, yet nearly 50% of patients either do not respond or have side-effects rendering them unable to...
BACKGROUND
Antidepressant medications offer an effective treatment for depression, yet nearly 50% of patients either do not respond or have side-effects rendering them unable to continue the course of treatment. Mechanistic studies might help advance the pharmacology of depression by identifying pathways through which treatments exert their effects. Toward this goal, we aimed to identify the effects of antidepressant treatment on neural connectivity, the relationship with symptom improvement, and to test whether these effects were reproducible across two studies.
METHODS
We completed two double-blind, placebo-controlled trials of SNRI antidepressant medications with MRI scans obtained before and after treatment. One was a 10-week trial of duloxetine (30-120 mg daily; mean 92·1 mg/day [SD 30·00]) and the other was a 12-week trial of desvenlafaxine (50-100 mg daily; 93·6 mg/day [16·47]). Participants consisted of adults with persistent depressive disorder. Adjusting for sex and age, we examined the effect of treatment on whole-brain functional connectivity. We also examined correlations between change in functional connectivity and improvement in symptoms of depression (24-item Hamilton Depression Rating Scale) and pain symptom severity (Symptom Checklist-90-Revised).
FINDINGS
Participants were enrolled between Jan 26, 2006, and Nov 22, 2011, for the duloxetine RCT and Aug 5, 2012, and Jan 28, 2016, for the desvenlafaxine RCT. Before and after treatment MRI scans were collected in 32 participants for the duloxetine RCT and 34 participants for the desvenlafaxine RCT. In both studies, antidepressants decreased functional connectivity compared with placebo (duloxetine study: β=-0·06; 95% CI -0·08 to -0·03; p<0·0001, η=0·44; desvenlafaxine study: -0·06, -0·09 to -0·03; p<0·0001, η=0·35) within a thalamo-cortico-periaqueductal network that has previously been associated with the experience of pain. Within the active drug groups, reductions in functional connectivity within this network correlated with improvements in depressive symptom severity in both studies (duloxetine study: r=0·38, 95% CI 0·01-0·65; p=0·0426; desvenlafaxine study: 0·44, 0·10-0·69; p=0·0138) and pain symptoms in the desvenlafaxine study (0·39, 0·04 to 0·65; p=0·0299).
INTERPRETATION
The findings suggest the thalamo-cortico-periaqueductal network associated with the experience of pain is a new and potentially important target for novel antidepressant therapeutics.
FUNDING
National Mental Health Institute, Eli Lilly and Company, Pfizer Pharmaceuticals, and the Edwin S Webster Foundation.
Topics: Adult; Antidepressive Agents; Brain; Connectome; Depressive Disorder; Desvenlafaxine Succinate; Double-Blind Method; Drug Administration Schedule; Duloxetine Hydrochloride; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Pain Measurement; Treatment Outcome
PubMed: 31248841
DOI: 10.1016/S2215-0366(19)30179-8 -
International Clinical... Sep 2019The aim of this study was to ensure patients' safety and to enhance treatment efficacy, knowledge about pharmacokinetic interactions even in complex clinical situations...
OBJECTIVE
The aim of this study was to ensure patients' safety and to enhance treatment efficacy, knowledge about pharmacokinetic interactions even in complex clinical situations of polypharmacy is invaluable. This study is to uncover the potential of pharmacokinetic interactions between venlafaxine and trimipramine in a naturalistic sample.
METHODS
Out of a therapeutic drug monitoring database with plasma concentrations of venlafaxine (VEN) and O-desmethylvenlafaxine (ODV), we considered two groups of patients receiving venlafaxine without known cytochrome P450 confounding medications, taking solely venlafaxine: V0 (n = 905), and a group of patients co-medicated with trimipramine, VTRIM (n = 33). For VEN, ODV and active moiety (sum of VEN + ODV) plasma concentrations and dose-adjusted concentrations as well as ODV/VEN ratios were compared between groups using the Mann-Whitney U test with a significance level of 0.05.
RESULTS
Patients co-medicated with trimipramine had higher plasma concentrations of VEN (183.0 vs. 72.0, +154%, P = 0.002) and AM (324.0 vs. 267.5, +21%, P = 0.005) and higher dose adjusted plasma concentrations than patients in the control group (P = 0.001 and P = 0.003). No differences were found for ODV and C/D ODV (P < 0.05 for both comparisons). The metabolite to parent ratio, ODV/VEN, was significantly lower in the VTRIM group (1.15 vs. 2.37, P = 0.012).
CONCLUSION
Findings suggest inhibitory effects of trimipramine on venlafaxine pharmacokinetics most likely via an inhibition of CYP 2D6 or by saturated enzyme capacity. The lack of in vitro data hampers the understanding of the exact mechanisms. Clinicians should be aware of drug-drug interactions when combining these agents. Therapeutic drug monitoring helps to ensure treatment efficacy and patients' safety.
Topics: Adult; Desvenlafaxine Succinate; Female; Humans; Male; Middle Aged; Trimipramine; Venlafaxine Hydrochloride
PubMed: 31094902
DOI: 10.1097/YIC.0000000000000268 -
CNS Spectrums Jun 2020The value of early functional improvement at week 2 for predicting subsequent functional outcomes at week 8 was assessed in a pooled analysis of patients with major... (Randomized Controlled Trial)
Randomized Controlled Trial
Predictors of functional response and remission with desvenlafaxine 50 mg and 100 mg: a pooled analysis of randomized, placebo-controlled studies in patients with major depressive disorder.
OBJECTIVE
The value of early functional improvement at week 2 for predicting subsequent functional outcomes at week 8 was assessed in a pooled analysis of patients with major depressive disorder (MDD) treated with desvenlafaxine (50 or 100 mg/d) or placebo.
METHODS
Data were pooled from eight double-blind, placebo-controlled studies of desvenlafaxine 50 mg/d or 100 mg/d for the treatment of MDD. Optimal week-2 improvement thresholds in Sheehan Disability Scale (SDS) score, which best predicted week-8 treatment success, were determined using receiver operating characteristic (ROC) analysis. Four definitions of treatment success were established: (1) functional response, (2) functional/depression response, (3) functional remission, and (4) functional/depression remission. Odds ratios (ORs) of early improvement for prediction (based on thresholds determined in the ROC analysis) of week-8 treatment success were computed using logistic regression models.
RESULTS
Functional early improvement thresholds of 17%-32% were predictive of week-8 treatment success across treatment groups and definitions of treatment success. Optimal thresholds were higher for more stringent definitions. Negative predictive value exceeded positive predictive value, indicating that failure to achieve early functional improvement was more informative about later treatment success than was the achievement of early functional improvement. Early change in SDS was a highly significant predictor of functional response/remission (ORs, 4.981-8.737; all p < 0.0001); the interaction between treatment and early functional improvement was not significant.
CONCLUSION
Early improvement in SDS total score was predictive of functional outcomes for patients treated with desvenlafaxine 50 mg, desvenlafaxine 100 mg, or placebo.
Topics: Adolescent; Adult; Aged; Antidepressive Agents; Depressive Disorder, Major; Desvenlafaxine Succinate; Female; Humans; Male; Middle Aged; Remission Induction; Treatment Outcome
PubMed: 31060632
DOI: 10.1017/S1092852919000828 -
European Journal of Clinical... Aug 2019To assess in a large naturalistic sample, whether clinical response to a treatment with venlafaxine is associated with different patterns of plasma concentrations of...
PURPOSE
To assess in a large naturalistic sample, whether clinical response to a treatment with venlafaxine is associated with different patterns of plasma concentrations of active moiety, AM (sum of venlafaxine (VEN) and its active metabolite O-desmethylvenlafaxine (ODVEN)).
METHODS
Applying a regression model, plasma concentrations and plasma concentrations corrected-by-dosage (C/D) for AM were included as independent variable with Clinical Global Impressions-Improvement (CGI-I) scale ratings as dependent variable. Moreover, AM, VEN, and ODVEN were compared between treatment responders and non-responders, defining response as much or very much improved on the CGI-I scale based on the non-parametric Mann-Whitney U (M-W-U) test with a significance level of 0.05.
RESULTS
No correlations were found between AM and C/D AM plasma concentrations and CGI-I ratings (regression coefficient 0.0, CI 0.000, 0.001, p = 0.492 for AM and 0.047, CI - 0.065, 0.159, p = 0.408 for C/D AM). Venlafaxine daily dosage did not differ between responders and non-responders (217.7 ± 76.9 vs. 222.0 ± 72.7 mg/day, p = 0.45 for M-W-U). Responders displayed lower ODVEN (p = 0.033) and AM (p = 0.031) plasma concentrations than non-responders (p = 0.033 and 0.031, respectively for M-W-U). No other differences were detected. Using a cut-off level of 400 ng/mL for AM concentrations, a higher percentage of responders was reported in the group of patients with AM < 400 ng/mL (13.04%) compared to patients with AM > 400 ng/mL (8%) (p = 0.038).
CONCLUSIONS
Higher ODVEN and AM concentrations in non-responders than in responders indicate that treatment escalation above upper thresholds of therapeutic reference ranges of venlafaxine is not promising. Hence, the therapeutic reference range for venlafaxine can help in improving outcomes in a measurement-based care model that takes advantage of therapeutic drug monitoring.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bipolar Disorder; Databases, Factual; Desvenlafaxine Succinate; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Retrospective Studies; Schizophrenia; Serotonin and Noradrenaline Reuptake Inhibitors; Treatment Outcome; Venlafaxine Hydrochloride; Young Adult
PubMed: 30968172
DOI: 10.1007/s00228-019-02675-4 -
European Archives of Psychiatry and... Oct 2019To address the potential correlation between plasma concentrations of venlafaxine (VEN), its active metabolite O-desmethylvenlafaxine (ODVEN) and the active moiety, AM,...
To address the potential correlation between plasma concentrations of venlafaxine (VEN), its active metabolite O-desmethylvenlafaxine (ODVEN) and the active moiety, AM, (ODVEN + VEN) and adverse drug reactions (ADR) in a large naturalistic sample of in- and outpatients. We compared plasma concentrations of VEN, ODVEN and AM and dose-adjusted (C/D) levels as well the ODVEN/VEN ratios between patients complaining ADRs, following the Udvalg for Kliniske Undersogelser side effect rating scales (UKU) (n = 114) and patients without ADRs (control group, n = 688) out of a naturalistic database. We also investigated potential pharmacokinetic correlates of the four UKU categories by comparing patients complaining ADRs with those who did not. Based on previous literature we applied different ODVEN/VEN ratio values as cut-offs to split our sample into two groups at a time and compare frequencies of ADRs between the groups. No differences for demographic and pharmacokinetic variables including plasma and C/D concentrations as well as ODVEN/VEN ratios were observed between study groups. Neither the comparisons between females and males nor between elderly and non-elderly patients revealed significant differences (p > 0.05 in all cases). No differences were also reported exploring the patients complaining ADRs from the 4 UKU categories separately. After applying various ODVEN/VEN cut-offs, groups did not display differences in frequencies of ADRs (p > 0.05 in all cases). Our findings do not demonstrate a direct link between venlafaxine metabolism measures and ADRs. Therefore, additional dimensions are needed to be considered in future trials aiming to disentangle the involved aspects of ADRs in patients receiving venlafaxine.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antidepressive Agents, Second-Generation; Databases, Factual; Desvenlafaxine Succinate; Drug-Related Side Effects and Adverse Reactions; Female; Germany; Humans; Male; Middle Aged; Mood Disorders; Venlafaxine Hydrochloride; Young Adult
PubMed: 30923938
DOI: 10.1007/s00406-019-01005-0