Six-month compliance with antidepressant medication in the treatment of major depressive disorder

The investigation of compliance in patients with major depressive disorder (in drop-outs versus completers and in first episode versus recurrent episode patients). A total of 85 outpatients with major depressive disorder were followed for 6 months. Different dimensions of compliance were investigated: drop-outs versus completers and their medication adherence (with electronic monitoring). General linear mixed models were applied to examine the time courses of adherence. Drop-out rates were higher in younger patients and in patients with a lower initial depression severity. The adherence during 6 months of treatment with selective serotonin reuptake inhibitors was above 80 in 70% of the patients. The adherence decreased by 2.5% per month and decreased more than three times more rapidly in drop-outs (from baseline to time of drop-out). A medical visit resulted in a temporary increase in pill intake. General linear mixed model analysis showed that the predicted outcome was worse in drop-outs than in completers and worse in recurrent episode patients than in first episode patients (the former showing a higher adherence). Adherence decreases with time during 6 months of treatment with antidepressants and is influenced by demographic and clinical variables. Completers show a higher adherence than drop-outs. The outcome was worse in recurrent episode patients than first episode patients although they had a higher adherence.     

Vortioxetine: a novel antidepressant for the treatment of major depressive disorder

Introduction: Vortioxetine is a novel antidepressant drug approved for the treatment of major depressive disorder (MDD) in adults. It is formulated into tablets and has a dose range of 5–20 mg. The recommended starting dose is 10 mg administered orally once daily without the need for food.

Areas covered: This review focuses on the preclinical and clinical discovery of vortioxetine. It analyzes the pharmacological, neurochemical, and behavioral mechanisms of the medication and how these contribute to its potential therapeutic advantages as described in published preclinical and clinical studies and product labels.

Expert opinion: Vortioxetine displays high affinity for serotonin transporter (SERT), and serotonin 5-HT₃, 5HT_1A, 5HT₇ receptors. Functional studies show that vortioxetine acts as a SERT blocker, a 5-HT₃, 5-HT₇ receptor antagonist, and a 5-HT_1A receptor agonist. The drug is active in animal models predictive of antipsychotic and antidepressant activities and demonstrates procognitive effects in several animal models that assessed memory, cognition, and executive functions. Short- and long-term clinical trials demonstrated the clinical efficacy of vortioxetine in treating depressive symptoms and cognitive deficits in MDD patients. It also displays fairly benign safety and tolerability profiles. Vortioxetine’s unique psychopharmacological properties might contribute to an improved clinical outcome in MDD patient populations.     

TPH1 is associated with major depressive disorder but not with SSRI/SNRI response in Taiwanese patients

Rationale  

Tryptophan hydroxylase 1 (TPH1), which encodes the rate-limiting enzyme tryptophan hydroxylase in the biosynthesis of serotonin, is a candidate gene in the development and treatment response of major depressive disorder (MDD); however, its actual role is uncertain.     

Agomelatine for the treatment of major depressive disorder

INTRODUCTION: This article discusses agomelatine (Valdoxan(?)/Thymanax(?); Servier/Novartis), which is a melatonin (MT1/MT2) agonist and serotonin (5-HT2c) receptor antagonist. Agomelatine has been approved for the treatment of adults with major depression by several regulatory agencies and is now on the market in 41 countries. AREAS COVERED: Literature related to agomelatine was reviewed on PubMed using the search terms 'agomelatine OR S-20098' and 204 articles were found. Twelve published, randomized, double-blind studies were included in this review. EXPERT OPINION: Agomelatine produces strong effects on circadian sleep phase disturbances, improving time to sleep onset and quality of sleep. It has been shown to be superior to placebo and similar to existing antidepressants, as demonstrated by short-term clinical trials and one relapse prevention trial. However, 0 - 0.6% and 3 - 4.5% of patients treated with 25 and 50 mg, respectively, showed elevated transaminases. Although none of these reactions so far seem to have been serious, the adverse effects in the liver may present a regulatory and marketing challenge. Given equivalence or modest superiority to existing, generic alternatives, the acceptability in a third-party reimbursement environment is questionable. Future clinical trials are needed to establish an appropriate market niche.     

Desvenlafaxine for the treatment of major depressive disorder

Introduction: Major depressive disorder (MDD) is a chronic and debilitating condition often characterized by inadequate treatment. Notwithstanding the availability of more than a dozen first-line agents across disparate classes (e.g., selective serotonin reuptake inhibitors), the majority of individuals with MDD do not achieve and sustain a recovered state. A substantial percentage of MDD patients require a treatment change due to poor efficacy or tolerability.

Areas covered: This review focuses on recent (≤ 5 years) literature describing the pharmacokinetics, efficacy, and tolerability of desvenlafaxine, one of the more recently approved antidepressant drugs. Published papers identified via PubMed search and congress presentations were included. Results from short-term, placebo-controlled, MDD trials and randomized withdrawal trials, as well as post hoc analyses in patient subgroups, are reviewed.

Expert opinion: Desvenlafaxine has been shown to be an effective antidepressant with a favorable safety and tolerability profile in the general MDD population and in important patient subgroups. It has several notable differences from other serotonin-norepinephrine reuptake inhibitors, and those differences suggest populations in which it may have the most clinical benefit.     

Vortioxetine for the treatment of major depressive disorder

Vortioxetine (Brintellix^®, 1-[2-(2,4-dimethylphenyl-sulfanyl)-phenyl]-piperazine) is a multimodal antidepressant targeting the 5-HT_1A, 5-HT_1B, 5-HT_1D, 5-HT₃, 5-HT₇ receptors and the serotonin (5-HT) transporter (5-HTT). Vortioxetine administration induces antidepressant- and anxiolytic-like effects, and can enhance cognitive performance in rodents. Several clinical trials have reported the efficiency and a satisfactory tolerability of vortioxetine treatment in depressed patients. Remarkably, vortioxetine has a specific positive impact on cognitive symptoms in depressed patients. Overall, vortioxetine is an efficacious antidepressant drug for the treatment of patients with a major depressive episode and has a unique mechanism of action offering a new therapeutic option.     

Duloxetine for the treatment of major depressive disorder

>55% were observed in two of the studies, while in a third study the probability of remission with duloxetine treatment was nearly three times that observed with placebo (44% versus 16%). Duloxetine also produced significant improvement in painful physical symptoms compared with placebo, in many cases after only 2 weeks of treatment. The discontinuation rate due to adverse events (14.6%) was similar to those observed with selective serotonin reuptake inhibitors. The most frequently reported adverse events were nausea, dry mouth, fatigue, and insomnia. Conclusion. Duloxetine was demonstrated to be safe and effective in the treatment of MDD. The starting dose with the best balance of efficacy and tolerability is 60 mg QD.     

Agomelatine for the treatment of major depressive disorder

Introduction: This article discusses agomelatine (Valdoxan^?/Thymanax^?; Servier/Novartis), which is a melatonin (MT1/MT2) agonist and serotonin (5-HT2c) receptor antagonist. Agomelatine has been approved for the treatment of adults with major depression by several regulatory agencies and is now on the market in 41 countries.

Areas covered: Literature related to agomelatine was reviewed on PubMed using the search terms ‘agomelatine OR S-20098’ and 204 articles were found. Twelve published, randomized, double-blind studies were included in this review.

Expert opinion: Agomelatine produces strong effects on circadian sleep phase disturbances, improving time to sleep onset and quality of sleep. It has been shown to be superior to placebo and similar to existing antidepressants, as demonstrated by short-term clinical trials and one relapse prevention trial. However, 0 – 0.6% and 3 – 4.5% of patients treated with 25 and 50 mg, respectively, showed elevated transaminases. Although none of these reactions so far seem to have been serious, the adverse effects in the liver may present a regulatory and marketing challenge. Given equivalence or modest superiority to existing, generic alternatives, the acceptability in a third-party reimbursement environment is questionable. Future clinical trials are needed to establish an appropriate market niche.     

Cardiovascular effects of high dose venlafaxine XL in patients with major depressive disorder

OBJECTIVE: To assess cardiovascular safety profile of high dose Venlafaxine XL in patients with major depression. METHOD: Effects of high dose venlafaxine (mean 346.15 mg;) on the cardiovascular system in 37 patients with major depressive disorder were evaluated: BP, ECG (PR, QT, QRSD and QTc intervals) and heart rate. RESULTS: 12.5% of patients developed hypertension after starting treatment with venlafaxine. There was an association between heart rate and the dose of venlafaxine although not statistically significant. There was no association between dose of venlafaxine and PR, QT, QRSD and QTc intervals. One patient on 300 mg who was hypertensive and on other medications that may prolong QTc, had mildly prolonged QTc. However this was not clinically significant. CONCLUSION: This study of subjects on high dose venlafaxine (mean 346.15 mg; range 225-525 mg) did not demonstrate any clinical or statistically significant effects on electrocardiogram (ECG) parameters including PR, QT, QRSD and QTc interval.     

Variations in circulating cytokine levels during 52 week course of treatment with SSRI for major depressive disorder

Major depressive disorder (MDD) is a psychiatric condition characterized by hypercortisolism and variations in circulatory cytokines. Previously it has been reported that administration of selective serotonin reuptake inhibitors (SSRI) in MDD patients modify cortisol and cytokine levels but these studies only evaluated changes over a short time period. This work reports the long-term effects of administration of SSRI on the cortisol levels and pro-/anti-inflammatory cytokine profile in a group of MDD patients treated for 52 weeks. A total of 31 patients diagnosed with MDD received anti depressant treatment with SSRI. HDRS and BDI were administered over a year, and levels of interleukin IL-1β, IL-10, IL-2, IFN-γ, IL-4, IL-13, and 24-h urine cortisol were determined at weeks (W) 0, 5, 20, 36 and 52 of treatment. Before treatment we found high levels of cortisol, IL-4, IL-13 (Th2) and IL-10 in MDD patients when compared with healthy volunteers. At W20 psychiatric scales indicated a remission of the depressive episode concomitantly with increments in IL-2 and IL-1β but without changes in cortisol. Towards the end of the treatment (W52) we observed a significant reduction (p < 0.01) in cortisol levels, with an increment in IL-1β and IFN-γ and a decrease in Th2 cytokines. Our results suggest that depressed patients only reach a partial reestablishment of HPA axis function after the long-term administration of SSRI.     

Efficacy and tolerability of switching therapy to vortioxetine versus other antidepressants in patients with major depressive disorder

Objectives:

To assess the relative efficacy and tolerability of vortioxetine against different antidepressant monotherapies in patients with major depressive disorder (MDD) with inadequate response to selective serotonin reuptake inhibitor (SSRI) or serotonin–norepinephrine reuptake inhibitor (SNRI) therapy.

Methods:

A systematic search was conducted for monotherapy studies in patients with MDD with inadequate response to first-line therapy. Treatments included SSRIs, SNRIs, and other antidepressants. Identified studies underwent a three-stage screening/data extraction process and critical appraisal. Adjusted indirect treatment comparisons (ITCs) on systematic literature review outputs were made using Bucher’s method, comparing remission rates and withdrawal rates due to adverse events (AEs).

Results:

Of 27 studies meeting the inclusion criteria, a few studies were of high quality according to the National Institute of Health and Care Excellence checklist. Three studies contributed to an evidence network for quantitative assessment comparing vortioxetine with agomelatine, sertraline, venlafaxine XR, and bupropion SR. Vortioxetine had a statistically significantly higher remission rate than agomelatine (risk difference [RD]: ?11.0% [95% CI: ?19.4; ?2.6]), and numerically higher remission rates than sertraline (RD: ?14.4% [95% CI: ?29.9; 1.1]), venlafaxine (RD: ?7.20% [95% CI: ?24.3; 9.9]), and bupropion (RD: ?10.70% [95% CI: ?27.8; 6.4]). Withdrawal rates due to AEs were statistically significantly lower for vortioxetine than sertraline (RD: 12.1% [95% CI: 3.1; 21.1]), venlafaxine XR (RD: 12.3% [95% CI: 0.8; 23.8]), and bupropion SR (RD: 18.3% [95% CI: 6.4; 30.1]).

Conclusions:

The current systematic literature review found a few high quality switch studies assessing monotherapies in patients with MDD with inadequate response to SSRI/SNRIs. ITCs indicated that switching to vortioxetine leads to numerically higher remission rates compared with other antidepressants. Vortioxetine is a well tolerated treatment, showing statistically lower withdrawal rates due to AEs compared with other antidepressants. Vortioxetine is a relevant therapeutic alternative in patients experiencing inadequate response to prior SSRI or SNRI therapy.     

Adjunctive brexpiprazole for the treatment of major depressive disorder

Introduction: The lifetime prevalence of major depressive episodes in the United States is nearly 17%. Clinical trials and clinical effectiveness studies have demonstrated that many patients will fail to achieve remission using traditional monotherapy, contributing to significant morbidity and suffering. Because of this, augmentation strategies have been proposed to improve both treatment response and remission.

Areas covered: Brexpiprazole is a second generation antipsychotic (SGA) approved by the US FDA in 2015 as an add-on treatment to an antidepressant medication for the treatment of adults with MDD, based on the results of two large-scale, randomized, placebo-controlled trials. It is thought to exert its antidepressant effect by a partial agonism of both the dopamine D2 and serotonin 5HT1A receptors. In addition, it also has potent antagonistic activity at 5HT2A, α1B and α2 C receptors, which may also contribute to monoamine transmission regulation.

Expert Opinion: Overall, the tolerability of brexpiprazole is promising with relatively low rates of side effects and discontinuation rates, thus establishing it as a new option for the treatment of depression.     

Cost-effectiveness analysis of escitalopram: a new SSRI in the first-line treatment of major depressive disorder in Austria

SUMMARY

Objectives: To compare the cost-effectiveness of escitalopram, a new selective serotonin reuptake inhibitor (SSRI), with (generic) citalopram in the first-line treatment of major depressive disorder (MDD) in Austria.

Methods: A two-path decision analytic model with a 6-month horizon was adapted to the Austrian setting using Austrian clinical guidelines. All patients (aged ≥ 18?years) started at the primary care path and were referred to specialist care in the secondary care path in case of insufficient response. Model inputs included drug-specific probabilities from head-to-head trial data, literature and expert opinion. The main outcome measure was success (i.e., remission defined as Montgomery–Åsberg Depression Rating Scale (MADRS) score ≤ 12) and costs of treatment (i.e., drug costs and medical care). The analysis was performed from the Austrian societal and Social Healthcare Insurance System (SHIS) perspectives. The Human Capital approach was used to estimate the societal costs of lost productivity.

Results: Treatment with escitalopram yielded lower expected cost and greater effectiveness compared with citalopram. The expected success rate was higher for escitalopram (64.5%) compared to citalopram (59.1%). From the SHIS perspective, the total expected cost per successfully treated patient was lower (€115) for escitalopram (€608) compared with citalopram (€723). From the societal perspective, these expected costs were €3034 and €3269 respectively. Sensitivity analyses on unit costs and probabilities demonstrated the robustness of the results. From the societal perspective, escitalopram remained the dominant treatment option, even at a cost of €0 for (generic) citalopram.

Conclusion: Escitalopram is a cost-effective alternative compared to (generic) citalopram in the first-line treatment of MDD in Austria.     

Desvenlafaxine succinate for the treatment of major depressive disorder

Major depressive disorder (MDD) remains one of the most common psychiatric disorders with high morbidity and mortality. Effective treatment is limited and response/remission to antidepressant pharmacotherapy remains poor and unpredictable. The development of new antidepressants is thus of great importance to the field. Desvenlafaxine succinate (DVS) is the active metabolite of the serotonin and noradrenaline re-uptake inhibitor venlafaxine and was recently FDA approved for the treatment of MDD. DVS showed efficacy in clinical trials in MDD with doses ranging from 50 – 400 mg. Advantages compared to other antidepressants include once daily dosing at effective doses, no CYP450 metabolism and low drug–drug interactions. Concerns include side effect profile and moderate efficacy. DVS might be a useful addition to the arsenal of antidepressants available to the clinician. Additional studies, in particular head-to-head comparison to other antidepressants and long-term treatment studies, will be necessary to comprehensively evaluate DVS safety and efficacy for clinical practice.     

Desvenlafaxine succinate for the treatment of major depressive disorder

Major depressive disorder (MDD) remains one of the most common psychiatric disorders with high morbidity and mortality. Effective treatment is limited and response/remission to antidepressant pharmacotherapy remains poor and unpredictable. The development of new antidepressants is thus of great importance to the field. Desvenlafaxine succinate (DVS) is the active metabolite of the serotonin and noradrenaline re-uptake inhibitor venlafaxine and was recently FDA approved for the treatment of MDD. DVS showed efficacy in clinical trials in MDD with doses ranging from 50 - 400 mg. Advantages compared to other antidepressants include once daily dosing at effective doses, no CYP450 metabolism and low drug-drug interactions. Concerns include side effect profile and moderate efficacy. DVS might be a useful addition to the arsenal of antidepressants available to the clinician. Additional studies, in particular head-to-head comparison to other antidepressants and long-term treatment studies, will be necessary to comprehensively evaluate DVS safety and efficacy for clinical practice.