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.     

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.     

Advances in treatment for postpartum major depressive disorder

ABSTRACT

Introduction: Postpartum depressive disorder (PPD) is a burdensome medical condition. To date, only one treatment (Brexanolone) has undergone registrational trials and is approved in the United States with an indication for the treatment of PPD. However, other treatments are prescribed and have been tested for this condition. Herein, the authors review the available scientific evidence pertaining to the somatic treatments of PPD.

Areas covered: The authors evaluate the published open-label and randomized controlled trials (RCTs), examine the biological mechanisms of PPD treatments, and evaluate how the available data translates into information that may be useful for clinical practice.

Expert opinion: Antidepressants have long been the mainstay of PPD treatment, despite the limited evidence from randomized clinical trials that supports this practice. Brexanolone improves treatment options for women with PPD. However, the relatively burdensome administration and monitoring protocol, along with the high cost of the medication, limit the possibility for an extensive use of this medication. Large, randomized, controlled trials of hormonal treatments in patients with PPD are warranted. Also, treatment with mood stabilizers and/or antipsychotics in women with major depressive disorder, who meet the DSM-5 mixed features specifiers in the post-partum period, should be tested in controlled clinical trials.     

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.     

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.     

Pharmacodynamic and pharmacokinetic evaluation of buprenorphine + samidorphan for the treatment of major depressive disorder

Introduction: Treatment resistant depression (TRD) represents approximately 20% of all individuals receiving care for major depressive disorder. The opioidergic system is identified as a novel target which hitherto has not been sufficiently investigated in adults with TRD. The combination product buprenorphine + samidorphan is an opioid modulatory agent which has demonstrated replicated evidence of efficacy in TRD without abuse liability.

Areas covered: Databases Pubmed, Google Scholar and clinicaltrials.gov were searched from inception through December 2017 for clinical trial information, pharmacokinetics, and pharmacodynamics of buprenorphine + samidorphan. Herein we provide a summary of the available information. Eight clinical trials were identified for inclusion, of the eight trials, five trials had available results and are included in detail in our review.

Expert opinion: Buprenorphine + samidorphan has demonstrated efficacy in TRD. Extant evidence surrounding the safety and tolerability profile of buprenorphine + samidorphan does not identify any significant safety concerns. Additional studies are needed in order to assess the long-term safety and efficacy of this product.     

Brexpiprazole for treatment-resistant major depressive disorder

ABSTRACT

Introduction:Treatment-resistant depression (TRD), seldom interchangeably referred to as ‘depression inadequately responding to the standard antidepressant drug,’ carries a significant burden. The atypical antipsychotics represent a popular augmentation strategy for antidepressant-resistant depression, although their efficacy/safety profiles vary across different agents and presentations of depression.

Areas covered: This review appraises the evidence supporting the use of brexpiprazole augmentation for major depressive disorder (MDD) adults showing an inadequate response to standard antidepressants, covering the related regulatory affairs, and essential pharmacology.

Expert opinion: Brexpiprazole is a ‘third-generation’ antipsychotic featuring dopaminergic D₂ and serotonergic 5-HT_1A partial agonism approved by the U.S. Food and Drug Administration for the treatment of MDD, besides schizophrenia in adults. The clinical trials leading to the extended approval of brexpiprazole rely on the definition of ‘inadequate response’ to antidepressants, which seems to poorly represent the most severe cases of TRD seen in clinical practice. TRD definitions appraised in the literature are likewise inconsistent and questionable from a clinical-standpoint. Compared to aripiprazole, brexpiprazole has lower D₂ intrinsic activity, although the latter features a more potent serotonergic 5-HT_2A antagonism. The actual propensity of brexpiprazole to induce akathisia and tardive dyskinesia warrants assessment by ad-hoc designed long-term, controlled trials.     

盐酸度洛西汀肠溶胶囊治疗抑郁症的疗效和安全性

目的 评价盐酸度洛西汀肠溶胶囊(抗抑郁药)治疗抑郁症的疗效和安全性.方法 采用随机双盲双模拟多中心活性药平行对照临床研究,共入组抑郁症患者246例,试验组(n=123)口服度洛西汀60 mg·d-1;对照组(n=123)口服氟西汀20 mg·d-1,疗程均6周;以17项汉密尔顿抑郁量表(HAMD17)和临床总体印象量表(CGI)进行疗效评价;以不良事件、实验室检查和心电图检查等评价安全性.结果 度洛西汀组与氟西汀组有效率分别为85.47%和85.12%,痊愈率分别为64.10%和61.98%,2组差异无统计学意义(P>0.05);汉密尔顿焦虑量表(HAMA)和CGI的评分,在治疗结束时2组比较差异均无统计学意义.2组药物不良反应发生率分别为35.00%、24.79%,差异无统计学意义(P>0.05).结论 度洛西汀治疗抑郁症安全有效.     

Paroxetine treatment of major depressive disorder

Major depression is recognized as a common, often chronic and recurrent illness that is associated with significant disability and comorbidity. The treatment of patients with major depressive disorder has advanced tremendously in the past decade as a result of the availability of effective and well-tolerated antidepressants. Paroxetine is a widely studied selective serotonin reuptake inhibitor (SSRI) with evidence for efficacy and safety that is supported by a large body of published literature. Evidence for the efficacy and tolerability of anew controlled-release formulation of paroxetine also has been published. Findings from paroxetine clinical studies have added considerably to our knowledge and understanding of the treatment of major depressive disorder, particularly with regard to duration of treatment, the need for treating to full remission and with full doses, and treatment of patients with concurrent symptoms of anxiety.     

米氮平与氟西汀治疗抑郁症的多中心对照研究

目的 :评价米氮平与氟西汀治疗抑郁症的有效性和安全性。方法 :采用DSM Ⅳ抑郁症的诊断标准 ,为期 6wk的观察。结果 :经 6wk治疗 ,米氮平组有效率和治愈率分别为 78%和 64% ,氟西汀组为 90 %和 55% (P >0 .0 5)。治疗 1wk后 ,米氮平组的有效率高于氟西汀组。 2组HAMD和MADRS总分治疗前后比较差异有显著意义 ,2组间差异无显著意义。治疗 1wk后 ,米氮平组HAMD总分和睡眠紊乱因子分的减分较氟西汀组明显。米氮平组主要不良反应是眩晕或 (和 )头昏等 ,与氟西汀组相比 ,米氮平组嗜睡发生率高 (P <0 .0 5)。结论 :米氮平是一种安全、有效的新型抗抑郁药物。起效较快 ,且有改善焦虑及睡眠作用     

Desvenlafaxine in the treatment of major depressive disorder

Desvenlafaxine (DESV) is a newer antidepressant, which inhibits serotonin-norepinephrine reuptake neurotransmission, similarly to venlafaxine, milnacipran and duloxetine. It was approved in February 2008 by the FDA for the treatment of major depressive disorder (MDD), based on well-controlled and adequately powered, large clinical trials demonstrating efficacy and safety for patients with MDD. Currently available data show that DESV has proven efficacy, acceptable safety and tolerability profiles, convenient once-daily dosing and minimal impact on the cytochrome P450 enzyme system in patients with MDD. This mini-review summarizes the clinical data and practical use of DESV under this approved indication.     

Desvenlafaxine in the treatment of major depressive disorder

Desvenlafaxine (DESV) is a newer antidepressant, which inhibits serotonin-norepinephrine reuptake neurotransmission, similarly to venlafaxine, milnacipran and duloxetine. It was approved in February 2008 by the FDA for the treatment of major depressive disorder (MDD), based on well-controlled and adequately powered, large clinical trials demonstrating efficacy and safety for patients with MDD. Currently available data show that DESV has proven efficacy, acceptable safety and tolerability profiles, convenient once-daily dosing and minimal impact on the cytochrome P450 enzyme system in patients with MDD. This mini-review summarizes the clinical data and practical use of DESV under this approved indication.     

Investigational drugs for treating major depressive disorder

Introduction: Treatment of patients suffering from major depression could be highly challenging for psychiatrists. Intractability as well as relapse is commonly seen among these patients, leading to functional impairment and poor quality of life. The present review discusses some of the novel investigational drugs that are under pre-clinical or clinical phases in the treatment of major depression.

Areas covered: Molecules belonging to different classes such as triple reuptake inhibitors, opioid receptors, ionotropic and metabotropic glutamate receptors, and neurotrophin in the treatment of major depression are covered in this article.

Expert opinion: Although the historical discovery of earlier antidepressant molecules (iproniazid and imipramine) is through serendipitous discovery, the present research focuses on discovering novel molecules based on our current pathophysiological knowledge of the disease condition. The fast-acting antidepressant property of N-methyl-d-aspartate (NMDA) receptor molecules, including ketamine is an exciting area of research. Other drug molecules such as amitifadine (triple reuptake inhibitor), ALKS-5461 (kappa receptor antagonist and mu opioidergic receptor agonist), rapastinel (NMDA glutamatergic receptor modulator) are under Phase-III clinical trials and could be approved in the near future for the treatment of major depression.     

Direct and indirect costs of employees with treatment-resistant and non-treatment-resistant major depressive disorder

Abstract

Objective:

Treatment-resistant depression (TRD) imposes substantial cost from the perspective of employers. The objective of this study was to assess direct healthcare costs and indirect (disability and medical-related absenteeism) costs associated with TRD compared with non-treatment-resistant major depressive disorder (MDD).     

Leukocyte telomere length is reduced in patients with major depressive disorder

Major depressive disorder (MDD) is a chronic, severe psychiatric illness with an incidence of 3% worldwide. MDD patients have a significantly impaired quality of life and reduced life expectancy compared to unaffected individuals, the latter being largely accounted for by an increased incidence of suicide and cardiovascular disorders. The premature mortality observed in MDD has been considered a signature of accelerated aging, a hypothesis supported by data showing altered functioning and morphology of several brain regions that are typically present in the aging population. Telomere shortening is a hallmark of cellular aging, and as such several studies explored the involvement of disrupted telomere dynamics in MDD, reporting contrasting findings. In the current study, we measured leukocyte telomere length (LTL) in a sample of 54 MDD patients and 47 non-psychiatric controls characterized for response to antidepressant treatment. After correcting for age, sex, and body mass index, we showed significantly reduced LTL in affected individuals compared to controls (beta = −.22, p = .02). There was no difference in LTL between treatment resistant or responsive MDD patients. Moreover, we observed no correlation between lifetime exposure to antidepressants and LTL. Our study showed that MDD patients have shorter telomeres compared to controls, supporting the hypothesis of accelerated aging in this disorder. However, LTL seemed not to be influenced by antidepressant treatment or to correlate with clinical response to these antidepressants. Further investigations in larger samples and possibly with longitudinal design are warranted to elucidate the role of altered telomere dynamics in MDD.     

Rapastinel - an investigational NMDA-R modulator for major depressive disorder: evidence to date

Introduction: Major depressive disorder (MDD) is a debilitating disorder with increasing prevalence globally. Despite the development of novel treatments for MDD, many patients present with treatment resistant depression (TRD), identified by treatment non-response following one or more adequate trials of an antidepressant. Rapastinel may prove to be a viable treatment for TRD; it has the potential to produce a rapid antidepressant response without serious adverse events and improve functional symptoms.

Areas covered: We review the efficacy of rapastinel via completed and on-going clinical trials. The online databases Pubmed, clinicaltrials.gov and clinicaltrialsregister.eu were searched for rapastinel (GLYX-13) treatment in subjects with MDD. Nine clinical trials were identified.

Expert opinion: Rapastinel is a novel and potentially transformative treatment for individuals with TRD. There is a limited number of clinical studies so far, but this compound has the potential to provide rapid, reliable and robust antidepressant effects without psychotomimetic and other unwanted side effects. Alternative formulations such as the oral formulation, provide the opportunity for rapastinel to be administered less frequently, i.e. once weekly. Furthermore, the beneficial effects on measures of cognition and suicidality so far, represent a tremendous advantage.     

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.