Functioning in patients with major depression treated with duloxetine or a selective serotonin reuptake inhibitor in East Asia

PURPOSE: To assess and compare the levels of functioning in patients with major depressive disorder treated with either duloxetine with a daily dose of ≤60 mg or a selective serotonin reuptake inhibitor (SSRI) as monotherapy for up to 6 months in a naturalistic setting in East Asia. In addition, this study examined the impact of painful physical symptoms (PPS) on the effects of these treatments. PATIENTS AND METHODS: Data for this post hoc analysis were taken from a 6-month prospective observational study involving 1,549 patients with major depressive disorder without sexual dysfunction. The present analysis focused on a subgroup of patients from East Asia (n=587). Functioning was measured using the Sheehan Disability Scale (SDS). Depression severity was assessed using the 16-item Quick Inventory of Depressive Symptomatology-Self Report. PPS were rated using the modified Somatic Symptom Inventory. A mixed model with repeated measures was fitted to compare the levels of functioning between duloxetine-treated (n=227) and SSRI-treated (n=225) patients, adjusting for baseline patient characteristics. RESULTS: The mean SDS total score was similar between the two treatment cohorts (15.46 [standard deviation =6.11] in the duloxetine cohort and 16.36 [standard deviation =6.53] in the SSRI cohort, P=0.077) at baseline. Both descriptive and regression analyses confirmed improvement in functioning in both groups during follow-up, but duloxetine-treated patients achieved better functioning. At 24 weeks, the estimated mean SDS total score was 4.48 (standard error =0.80) in the duloxetine cohort, which was statistically significantly lower (ie, better functioning) than that of 6.76 (standard error =0.77) in the SSRI cohort (P<0.001). This treatment difference was more apparent in the subgroup of patients with PPS at baseline. Similar patterns were also observed for SDS subscores (work, social life, and family life). CONCLUSION: Depressed patients treated with duloxetine achieved better functioning compared to those treated with SSRIs. This treatment difference was mostly driven by patients with PPS at baseline

Effects of levomilnacipran extended-release on major depressive disorder patients with cognitive impairments

Performance-based cognitive data were collected using the Cognitive Drug Research System in a study of levomilnacipran extended-release (ER) 40-120 mg/day (NCT01034462) in adults with major depressive disorder. These data were analyzed post-hoc to explore the relationship between cognitive measures, depression symptoms (Montgomery-Asberg Depression Rating Scale, MADRS), and self-reported psychosocial functioning (Sheehan Disability Scale; SDS). Changes from baseline were analyzed in the intent-to-treat population and subgroups with impaired attention, as indicated by baseline Cognitive Drug Research System scores for Power of Attention and Continuity of Attention. Path analyses evaluated the direct and indirect effects of levomilnacipran ER on SDS total score change. Significantly greater improvements were observed for levomilnacipran ER versus placebo for Power of Attention, Continuity of Attention, MADRS, and SDS score changes; the mean differences were larger in the impaired subgroups than in the overall intent-to-treat population. Path analyses showed that the majority of SDS total score improvement (>=50%) was attributable to an indirect treatment effect through MADRS total score change; some direct effect of levomilnacipran ER on SDS total score improvement was also observed. In adults with major depressive disorder, levomilnacipran ER effectively improved measures of depression and cognition, which contributed toward reductions in self-reported functional impairment

New Antidepressant Medication: Benefits Versus Adverse Effects

Depression [major depressive disorder (MDD)] is a mood disturbance of multifactorial origin, associated with high rates of morbidity and mortality, lack of work productivity, adverse health behaviors, and increased healthcare expenses. MDD is a leading cause of suicide, and it affects the prognosis of chronic conditions (heart diseases, diabetes, and cancer, among others). Current pharmacological treatment for MDD covers different classes of drugs, including tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and atypical antidepressants. The aim of this chapter is to review the literature, highlight the side effects of newer antidepressants, and especially point out the most important aspects of the latest agents approved for the treatment of MDD in adults: desvenlafaxine, levomilnacipran, vilazodone, and vortioxetine. Desvenlafaxine is a SNRI and the primary active metabolite of venlafaxine; also a SNRI, levomilnacipran is an enantiomer of the racemate milnacipran. Vilazodone and vortioxetine are multimodal antidepressants, which combine SSRI activity with additional receptor activity. Although they have proven efficacy in treating MDD and are being investigated for other possible indications, further detailed clinical trials are needed to establish their pharmaco-toxicological profile, following prolonged administration in patients who may suffer from various comorbidities

Characterization of the Respiratory Syncytial Virus (RSV) Attachment Protein Mucin Domains

Respiratory Syncytial Virus (RSV) is currently a leading cause of acute lower respiratory infection (ALRI). Despite contributing to a significant mortality rate in young children and immunocompromised populations, it still lacks a vaccine. Live-attenuated vaccines are the preferred vaccination model for RSV, but achieving attenuation, immunogenicity, and stability can be difficult. Previous studies have indicated that deletion of the RSV G protein attenuates viral replication, but the role of the protein’s mucin domains has not been fully explored. We generate two new RSV strains here with varying G protein deletions: A2-line19F-G155 with deletion of the G-protein mucin domains, and A2- line19F-G155S with deletion of both the G-protein mucin domains and the transmembrane domain (thus only expressing a secreted G protein lacking mucin). In comparing these strains to a previously categorized strain with the same genetic background and a normal, complete G protein (A2-line19F), we categorize the phenotypes of these novel strains. Both G-protein viruses were more easily neutralized, more attenuated in Hep2 cells, and demonstrated less thermostability than A2-line19F. Therefore, with further testing these strains may have potential as future RSV vaccine candidates

Efficacy and safety of multiple doses of levomilnacipran extended-release for the treatment of major depressive disorder

OBJECTIVE: The aim of this meta-analysis was to evaluate the efficacy and safety of levomilnacipran extended-release (ER) in the treatment of major depressive disorder (MDD). METHODS: Randomized controlled trials were searched by electronic databases. Unpublished data were also searched by the relevant websites. Weighted mean difference (WMD) and risk ratio (RR) with 95% confidence interval (CI) were calculated and pooled using fixed-effects model or random-effects model. RESULTS: Five randomized placebo-controlled trials including 2,637 patients were analyzed. Compared with placebo, levomilnacipran ER had a greater reduction in the Montgomery–Åsberg Depression Rating Scale (MADRS) total score and Sheehan Disability Scale (SDS) total score (MADRS: WMD −3.49 [95% CI −4.28, −2.70; P<0.00001]; SDS: WMD −2.41 [95% CI −3.05, −1.77; P<0.00001]). Significantly more patients in levomilnacipran ER achieved MADRS response rate (RR 1.35 [95% CI 1.23, 1.47; P<0.00001]) and MADRS remission rate (RR 1.30 [95% CI 1.06, 1.59; P=0.01]). In terms of safety, more patients discontinued due to adverse events (AEs) in levomilnacipran ER compared with placebo (RR 3.15 [95% CI 2.26, 4.39; P<0.00001]), but it was generally well tolerated in each eligible trial. The most common AEs were nausea, delay in ejaculation, erectile dysfunction, tachycardia, headache and increase in heart rate. CONCLUSION: Levomilnacipran ER is a safe and effective short-term treatment for MDD (≤10 weeks). Long-term and head-to-head trials comparing levomilnacipran ER with other antidepressants are needed to confirm the conclusion

Pharmacokinetic and Pharmacodynamic Interactions between Antiepileptics and Antidepressants

INTRODUCTION: Antiepileptic-antidepressant combinations are frequently used by clinicians; their pharmacokinetic (PK) and pharmacodynamic (PD) drug interactions (DIs) have not been well studied but are frequently likely to be clinically relevant. AREAS COVERED: This article provides a comprehensive review of PK DIs between antiepileptics and antidepressants. In the absence of PD DI studies, PD information on pharmacological mechanisms and studies on efficacy and safety of individual drugs are reviewed. EXPERT OPINION: The clinical relevance of the inductive properties of carbamazepine, phenytoin, phenobarbital and primidone and the inhibitory properties of valproic acid and some antidepressants are well understood; correction factors are provided if appropriate DI studies have been completed. More PK studies are needed for: i) antiepileptics with potent inductive effects for all recently approved antidepressants; ii) high doses of mild CYP3A4 inducers, such as clobazam, eslicarbazepine, oxcarbazepine, rufinamide and topiramate for reboxetine and vilazodone; iii) valproate as a possible inhibitor, mild inducer or both a mild inducer and competitive inhibitor of some antidepressants; and iv) inhibitory effects of long-term fluoxetine use on clobazam, lacosamide, phenobarbital, primidone, carbamazepine, felbamate, tiagabine and zonisamide. Possible synergistic or additive beneficial PD DIs in generalized anxiety disorder, chronic pain, migraine prophylaxis, weight control and menopausal symptoms need study

Optimal doses of antidepressants in dependence on age: Combined covariate actions in Bayesian network meta-analysis

Background: The meta-analysis by Furukawa et al. (The Lancet Psychiatry 2019, 6(7)) reported optimal doses for antidepressants in adult major depressive disorder (MDD). The present reanalysis aimed to adjust optimal doses in dependence on age. Methods: Analysis was based on the same dataset by Cipriani et al. (The Lancet 2018, 391(10128)) comparing 21 antidepressants in MDD. Random-effects Bayesian network meta-analysis was implemented to estimate the combined covariate action using restricted cubic splines (RCS). Balanced treatment recommendations were derived for the outcomes efficacy (response), acceptability (dropouts for any reason), and tolerability (dropouts due to adverse events). Findings: The combined covariate action of dose and age suggested agomelatine and escitalopram as the best-balanced antidepressants in terms of efficacy and tolerability that may be escalated until 40 and 60 mg/day fluoxetine equivalents (mg/dayFE), respectively, for ages 30–65 years. Desvenlafaxine, duloxetine, fluoxetine, milnacipran, and vortioxetine may be escalated until 20–40 mg/dayFE, whereas bupropion, citalopram, mirtazapine, paroxetine, and venlafaxine may not be given in doses > 20 mg/dayFE. Amitriptyline, clomipramine, fluvoxamine, levomilnacipran, reboxetine, sertraline, and trazodone revealed no relevant balanced benefits and may therefore not be recommended for antidepressant treatment. None of the antidepressants was observed to provide balanced benefits in patients >70 years because of adverse events exceeding efficacy. Interpretation: Findings suggest that the combined covariate action of dose and age provides a better basis for judging antidepressant clinical benefits than considering dose or age separately, and may thus inform decision makers to accurately guide antidepressant dosing recommendations in MDD

Conditional power of antidepressant network meta-analysis

Background Conditional power of network meta-analysis (NMA) can support the planning of randomized controlled trials (RCTs) assessing medical interventions. Conditional power is the probability that updating existing inconclusive evidence in NMA with additional trial(s) will result in conclusive evidence, given assumptions regarding trial design, anticipated effect sizes, or event probabilities. Methods The present work aimed to estimate conditional power for potential future trials on antidepressant treatments. Existing evidence was based on a published network of 502 RCTs conducted between 1979-2018 assessing acute antidepressant treatment in major depressive disorder (MDD). Primary outcomes were efficacy in terms of the symptom change on the Hamilton Depression Scale (HAMD) and tolerability in terms of the dropout rate due to adverse events. The network compares 21 antidepressants consisting of 231 relative treatment comparisons, 164 (efficacy) and 127 (tolerability) of which are currently assumed to have inconclusive evidence. Results Required sample sizes to achieve new conclusive evidence with at least 80% conditional power were estimated to range between N = 894 - 4190 (efficacy) and N = 521 - 1246 (tolerability). Otherwise, sample sizes ranging between N = 49 - 485 (efficacy) and N = 40 - 320 (tolerability) may require stopping for futility based on a boundary at 20% conditional power. Optimizing trial designs by considering multiple trials that contribute both direct and indirect evidence, anticipating alternative effect sizes or alternative event probabilities, may increase conditional power but required sample sizes remain high. Antidepressants having the greatest conditional power associated with smallest required sample sizes were identified as those on which current evidence is low, i.e., clomipramine, levomilnacipran, milnacipran, nefazodone, and vilazodone, with respect to both outcomes. Conclusions The present results suggest that conditional power to achieve new conclusive evidence in ongoing or future trials on antidepressant treatments is low. Limiting the use of the presented conditional power analysis are primarily due to the estimated large sample sizes which would be required in future trials as well as due to the well-known small effect sizes in antidepressant treatments. These findings may inform researchers and decision-makers regarding the clinical relevance and justification of research in ongoing or future antidepressant RCTs in MDD