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Despite advances in clinical trial design, failure rates near 80% in phase 2 and 50% in phase 3 have recently been reported. The challenges to successful drug development are particularly acute in central nervous system trials such as for pain, schizophrenia, mania, and depression because high‐placebo response rates lessen assay sensitivity, diminish estimated treatment effect sizes, and thereby decrease statistical power. This paper addresses the importance of rigorous patient selection in major depressive disorder trials through an enhanced enrichment paradigm. This approach led to a redefinition of an ongoing, blinded phase 3 trial algorithm for patient inclusion (1) to eliminate further randomization of transient placebo responders and (2) to exclude previously randomized transient responders from the primary analysis of the double blind phase of the trial. It is illustrated for a case study for the comparison between brexpiprazole + antidepressant therapy and placebo + antidepressant therapy. Analysis of the primary endpoint showed that efficacy of brexpiprazole versus placebo could not be established statistically if the original algorithm for identification of placebo responders was used, but the enhanced enrichment approach did statistically demonstrate efficacy. Additionally, the enhanced enrichment approach identified a target population with a clinically meaningful treatment effect. Through its successful identification of a target population, the innovative enhanced enrichment approach enabled the demonstration of a positive treatment effect in a very challenging area of depression research. [ABSTRACT FROM AUTHOR]

Background: For many years, placebo has been defined by its inert content and use in clinical trials. In recent years, several studies have demonstrated its effect in the treatment of major depression. The aim of this paper is to present the conclusions of recent meta-analyses of the placebo effect in major depression, to explain the mechanism by which placebo exerts its effect, and to discuss whether placebo can be used in the treatment of patients with major depression in clinical practice. Recent meta-analyses have demonstrated that the placebo effect is estimated to account for 67% of the treatment effect in patients receiving antidepressants, and furthermore that placebo is as effective as antidepressants in patients with mild to moderate major depression (reporting a Hamilton Depression Rating Scale score lower than 25), whereas placebo is less effective than antidepressants in severely depressed patients. However, several limitations make the translation of these conclusions into clinical practice impracticable. Clinicians should learn from the "placebo lesson" to maximize the nonspecific effects of treatment when they prescribe an antidepressant, particularly in less severely depressed patients, who show a higher placebo response in randomized controlled trials. This strategy can increase the antidepressant effect and may reduce nonadherence with treatment [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is one of the most disabling diseases worldwide and is becoming a significant public health threat. Current treatments forMDDprimarily consist of monoamine-targeting agents and have limited efficacy. However, the glutamate neurotransmitter system has recently come into focus as a promising alternative for novel antidepressant treatments. We review the current data on the glutamate NMDA receptor antagonist ketamine, which has been shown in clinical trials to act as a rapid antidepressant inMDD.We also examine ketamine efficacy on dimensions of psychopathology, including anhedonia, cognition, and suicidality, consistent with theNIMH Research Domain Criteria initiative. Other aspects of ketamine reviewed in this paper include safety and efficacy, different administration methods, and the risks of misuse of ketamine outside of medical settings. Finally, we conclude with a discussion of glutamatergic agents other than ketamine currently being tested as novel antidepressants. [ABSTRACT FROM AUTHOR]

Levomilnacipran is a novel serotonin and norepinephrine reuptake inhibitor (SNRI) for the treatment of major depressive disorder. This paper reviews up-to-date data on the pharmacology, short- and long-term efficacy, safety and tolerability of levomilnacipran. The drug differs from previously available SNRIs in having twice the potency for norepinephrine versus serotonin reuptake inhibition. In four of the six short-term clinical trials, levomilnacipran was statistically significantly more efficacious than placebo. The only available relapse prevention study did not show reduction in time to relapse, perhaps because relapse rates were low. The commonest adverse events occurring twice as often as on placebo were nausea, hyperhidrosis, constipation, tachycardia, vomiting, erectile dysfunction, palpitations, and ejaculation disorder. In a few patients, hypertension or orthostatic hypotension may occur. Levomilnacipran has been shown to be effective in the short-term treatment of major depressive disorder and may represent an incremental advance. However, further research about its efficacy in subgroups of patients and comparing it to other antidepressants is needed. [ABSTRACT FROM AUTHOR]

Previous comparative reviews of add-on therapies for patients with major depressive disorder (MDD) with an inadequate response to antidepressants have not used meta-analytic techniques to compare different drug classes and have included non-licensed therapies. This meta-analysis reviewed all published peer-reviewed evidence for the efficacy of EU-licensed therapies in patients with MDD and an inadequate response to antidepressant monotherapy. Papers concerning randomized clinical trials (RCTs) were identified using criteria from the Cochrane Handbook for Systematic Reviews of Interventions. Add-on therapies reviewed were antidepressants, quetiapine XR, lithium, and S-adenosyl-l-methionine (SAMe). Seven RCTs that reported response and remission in a way that allowed quantitative analysis were included in this meta-analysis. Comparison of the different drug classes indicated that most interventions had similar efficacy. The likelihood of response was significantly greater with SAMe versus placebo and lithium and with quetiapine XR versus placebo. Most add-on interventions demonstrated comparable efficacy in patients with MDD and an inadequate response to initial antidepressants. However, there is currently a paucity of high-quality data regarding the use of add-on treatments in patients with MDD who are inadequate responders to antidepressants, with quetiapine XR presenting the most comprehensive evidence base to date. [ABSTRACT FROM PUBLISHER]

ABSTRACT Nefazodone, an antidepressant agent with a phenylpiperazine structure, has a pharmacological profile that is distinct from other antidepressant drugs. Like many other antidepressants, nefazodone inhibits the reuptake of norepinephrine and serotonin from the synaptic cleft. Unlike other antidepressants, nefazodone is also a potent antagonist of 5-HT2 serotonergic receptors. In addition, nefazodone is a weak antagonist of α1-adrenergic receptors, but has little or no affinity for cholinergic, histaminergic, or dopaminergic receptors. In placebo-controlled clinical trials, nefazodone has been found to be an effective antidepressant drug with minimal cardiovascular action and significantly fewer side effects than imipramine. Since nefazodone is an effective antidepressant with a low incidence of serious adverse effects, it may be particularly useful in major depressive disorder patients who are intolerant of the anticholinergic or serotonergic side effects of other antidepressants, or who do not respond to treatment with other antidepressant agents. In this paper, we review the mechanisms of action, the pharmacokinetics, and the antidepressant efficacy of nefazodone. [ABSTRACT FROM AUTHOR]

Background: Sleep disturbances are frequently reported in patients with major depressive disorder. We aimed to investigate the effects of vortioxetine on sleep quality and association between changes in sleep and treatment response.Methods: This study is a post-hoc analysis of a clinical trial that sought to evaluate the sensitivity to cognitive change of THINC-integrated tool in patients with major depressive disorder. In total, 92 patients (aged 18 to 65) meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for moderate or severe major depressive disorder and 54 healthy controls were included. All patients received open-label vortioxetine (10-20 mg/day, flexibly dosed) for 8 weeks. Herein, the primary outcomes of interest were changes in sleep, as measured by the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and Insomnia Severity Index, between weeks 0, 2, and 8. The association between changes in sleep and depressive symptom severity was secondarily assessed.Results: We observed that sleep, as indicated by scores of Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and Insomnia Severity Index, was significantly poorer in patients with major depressive disorder compared to healthy controls at weeks 0, 2, and 8 (p < 0.05). Among patients with major depressive disorder, we observed significant improvements on the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and Insomnia Severity Index between weeks 0 and 8 (p < 0.05). We observed a significant association between improvements on the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, and Insomnia Severity Index and improvement of depressive symptoms.Conclusion: Improvement of depressive symptoms in major depressive disorder patients treated with vortioxetine was associated with significant improvements in sleep. Furthermore, improvements in sleep were predictive of antidepressant response and were linearly correlated with improvement in overall depressive symptom severity. [ABSTRACT FROM AUTHOR]

Background: Some individuals with major depressive disorder do not experience a remission even after one or more adequate treatment trials. In some others who experience remission, it happens at variable times. This study sought to estimate the prevalence of nonremission in a large sample of patient participating in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial and to identify correlates of nonremission and time to remission among remitters.Methods: Using data from 3,606 participants of STAR*D, the study used cure regression modeling to estimate nonremission and jointly model correlates of nonremission and time to remission among the remitters.Results: Overall, 14.7% of the STAR*D participants were estimated to be nonremitters. Among remitters, the rate of remission declined over time. Greater severity, poorer physical health, and poor adherence with treatments were associated with both nonremission and a longer time to remission among the remitters in multivariable analyses, whereas unemployment, not having higher education, and longer duration of current episode were uniquely associated with nonremission; whereas, treatment in specialty mental health settings, poorer mental health functioning, and greater impairment in role functioning with a longer time to remission among remitters.Conclusion: Poor treatment adherence and poor physical health appear to be common risk factors for both nonremission and longer time to remission, highlighting the importance of integrated care models that address both medical and mental healthcare needs and interventions aimed at improving treatment adherence. [ABSTRACT FROM AUTHOR]

In the present study, we aimed to confirm the previous finding of an association between GRIK4 and GNB3 variants (rs195478 and rs5443) and remission and treatment resistance in major depression, using a multicenter sample of 223 patients. We did not find any supporting evidence for such associations. These conflicting data may result from difficulties in the replication of candidate gene association studies. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Fluvoxamine, one of the oldest selective serotonin reuptaking inhibitors, is commonly prescribed to patients with major depression. Several studies have reviewed the efficacy and tolerability of fluvoxamine for the treatment of major depression. However, these reviews are outdated, have not been systematic and/or suffered from several methodological weaknesses. We conducted a systematic review to synthesize the best available evidence on the efficacy of fluvoxamine for adult patients suffering from major depression in comparison with other active antidepressive agents. Relevant randomized controlled trials were identified through a comprehensive search. The primary outcome was a relative risk of response, and the secondary outcome was a relative risk of remission. Tolerability and side-effect profile were also examined. Fifty-three trials were included. There were no large differences between fluvoxamine and any other antidepressants in terms of efficacy and tolerability. There is evidence of differing side effect profiles, especially when comparing gastrointestinal side effects between fluvoxamine and tricyclics. Clinicians should focus on practically or clinically relevant differences including those in side-effect profiles. [ABSTRACT FROM AUTHOR]

Objective: To test the hypothesis that in patients with major depressive disorder (MDD), the response for specific Hamilton Depression Rating Scale items will differ for duloxetine compared with selective serotonin reuptake inhibitors (SSRIs) and that patterns of response will differ based on symptom severity at baseline. Method: Data were pooled from all Lilly-sponsored clinical trials where duloxetine was compared with placebo and an SSRI in patients with MDD: 7 randomized, double-blind, fixed-dose, 8-week studies of duloxetine (n = 1,133) versus SSRI (n = 689) versus placebo (n = 641). Duloxetine doses were 40, 60, 80 and 120 mg/day. SSRI doses were 10 mg/day (escitalopram) and 20 mg/day (fluoxetine and paroxetine). Results: Compared to SSRI-treated patients, duloxetine-treated patients had a significantly greater (p ≤ 0.05) reduction in the 17-item Hamilton Depression Rating Scale (HAMD17) total score and HAMD17 items of work and activities, psychomotor retardation, genital symptoms and hypochondriasis. Differences favoring the SSRIs approached significance for middle insomnia (p = 0.057) and late insomnia (p = 0.06), with effect sizes at least twice the magnitude of the corresponding effect sizes for duloxetine. Similarly, the advantage for duloxetine versus the SSRIs approached significance for general somatic symptoms (p = 0.056), with an effect size twice that observed for the SSRIs. The HAMD17 total score difference was driven mostly by patients with lower baseline MDD severity (HAMD17 total score ≤19), where the HAMD17 effect size advantage for duloxetine over combined SSRIs was statistically significant (p = 0.031). Conclusion: Potentially important differences in symptom response patterns were found between duloxetine and the combined SSRIs depending on symptom severity, and different HAMD17 items responded differently to duloxetine compared with SSRIs. Understanding these differences may be useful in tailoring antidepressant therapy for individual patients. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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Rolipram improves signal transmission in central noradrenergic neurones with a novel mechanism of action: enhanced noradrenaline (first messenger) synthesis and release, and inhibition of cAMP (second messenger) breakdown. Several comparative trials to prove antidepressant activity are under way. Results of a multicentre double-blind trial with three different dosages of rolipram involving 98 patients will be presented. Response rates in all dosages were similar and comparable to those reported in the literature on tricyclic antidepressants. In addition rolipram was tolerated well. A significant relationship between dosages and effects, however, could not be established. [ABSTRACT FROM AUTHOR]