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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]

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]

Background: Clinical trials are an important source of adverse effects data, including analyses in systematic reviews and recommendations in therapy guidelines. Trial publication bias may have profound effects on safety perceptions. This MiniReview presents and discusses biases in reporting of safety data in clinical trials and the implications for systematic reviews and guidelines. Objectives: The objectives of this work are to analyse risk of gastrointestinal bleeding in systemic corticosteroid trials and to assess adverse effects reporting in a fluoxetine trial in depression (Treatment for Adolescents With Depression Study [TADS]) and descriptions of adverse effects in adolescent depression therapy guidelines. Methods: We performed literature reviews and descriptive analyse of clinical trials with corticosteroids, and publications from the TADS trial. Risk of gastrointestinal bleeding from corticosteroids was analysed by meta‐analysis. Findings: Gastrointestinal bleeding definitions varied considerably between trials. The incidence was significantly increased in hospitalized, but not in ambulant, patients compared to placebo. We identified several biases concerning TADS safety reporting, including severity thresholds and nonpublication of most adverse effects data beyond the initial 12 weeks. Therapy guidelines on adolescent depression mentioned suicidality risk, but many failed to mention other adverse effects. Conclusions: We identified several pitfalls in adverse effects reporting in clinical trials. These include heterogeneous disease definitions, reporting thresholds, and incomplete reporting. Trial bias may have great impact on risk assessments in systematic reviews and meta‐analyses. [ABSTRACT FROM AUTHOR]

Depression like many diseases is pleiotropic but unlike cancer and Alzheimer's disease for example, is still largely stigmatized and falls into the dark shadows of human illness. The failure of depression to be in the spotlight for successful treatment options is inherent in the complexity of the disease(s), flawed clinical diagnosis, overgeneralization of the illness, inadequate and biased clinical trial design, restrictive and biased inclusion/exclusion criteria, lack of approved/robust biomarkers, expensive imaging technology along with few advances in neurobiological hypotheses in decades. Clinical trial studies summitted to the regulatory agencies (FDA/EMA) for approval, have continually failed to show significant differences between active and placebo. For decades, we have acknowledged this failure, despite vigorous debated by all stakeholders to provide adequate answers to this escalating problem, with only a few new antidepressants approved in the last 20 years with equivocal efficacy, little improvement in side effects or onset of efficacy. It is also clear that funding and initiatives for mental illness lags far behind other life-treating diseases. Thus, it is no surprise we have not achieved much success in the last 50 years in treating depression, but we are accountable for the many failures and suboptimal treatment. This review will therefore critically address where we have failed and how future advances in medical science offers a glimmer of light for the patient and aid our future understanding of the neurobiology and pathophysiology of the disease, enabling transformative therapies for the treatment of depressive disorders. [ABSTRACT FROM AUTHOR]

Network meta-analysis enables comprehensive synthesis of evidence concerning multiple treatments and their simultaneous comparisons based on both direct and indirect evidence. A fundamental pre-requisite of network meta-analysis is the consistency of evidence that is obtained from different sources, particularly whether direct and indirect evidence are in accordance with each other or not, and how they may influence the overall estimates. We have developed an efficient method to quantify indirect evidence, as well as a testing procedure to evaluate their inconsistency using Lindsay's composite likelihood method. We also show that this estimator has complete information for the indirect evidence. Using this method, we can assess the degree of consistency between direct and indirect evidence and their contribution rates to the overall estimate. Sensitivity analyses can be also conducted with this method to assess the influences of potentially inconsistent treatment contrasts on the overall results. These methods can provide useful information for overall comparative results that might be biased from specific inconsistent treatment contrasts. We also provide some fundamental requirements for valid inference on these methods concerning consistency restrictions on multi-arm trials. In addition, the efficiency of the developed method is demonstrated based on simulation studies. Applications to a network meta-analysis of 12 new-generation antidepressants are presented. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: To investigate baseline demographics and disease characteristics as predictors of the analgesic effect of duloxetine and pregabalin on diabetic peripheral neuropathic pain (DPNP).Methods: Based on data from the COMBO-DN study, a multinational clinical trial in DPNP, the potential impact of baseline characteristics on pain relief after 8-week monotherapy with 60 mg/day duloxetine or 300 mg/day pregabalin was assessed using analyses of covariance. Subgroups of interest were characterized regarding their baseline characteristics and efficacy outcomes.Results: A total of 804 patients were evaluated at baseline. A significant interaction with treatment was observed in the mood symptom subgroups with a larger pain reduction in duloxetine-treated patients having no mood symptoms [Hospital Anxiety and Depression Scale (HADS) depression or anxiety subscale score <11; -2.33 (duloxetine); -1.52 (pregabalin); p = 0.024]. There were no significant interactions between treatment for subgroups by age (<65 or ≥65 years), gender, baseline pain severity [Brief Pain Inventory Modified Short Form (BPI-MSF) average pain <6 or ≥6], diabetic neuropathy duration (≤2 or >2 years), baseline haemoglobin A1c (HbA1c) (<8% or ≥8%), presence of comorbidities and concomitant medication use.Conclusions: Our analyses suggest that the efficacy of duloxetine and pregabalin for initial 8-week treatment in DPNP was consistent across examined subgroups based on demographics and disease characteristics at baseline except for the presence of mood symptoms. Duloxetine treatment appeared to be particularly beneficial in DPNP patients having no mood symptoms. [ABSTRACT FROM AUTHOR]

Objective Paroxetine is commonly used to treat depression in the elderly; however, titration issues have been raised. Rapid titration may lead to increased anxiety and early dropout. The aim of this cost-utility analysis was to compare the potential benefit of standard (10 mg the first day) versus slow titration (2.5 mg gradually increased). Methods Clinical analysis was based on a naturalistic trial integrated with a decision-analytic model representing second treatments for those who initially did not respond and for dropout cases. Treatment setting was a public outpatient center for mental disorders in Italy. Service use data were estimated from best practice guidelines, whereas costs (Euros; 2012) were retrieved from Italian official sources. Results Slow titration approach produced 0.031 more quality-adjusted life years (remission rate: 57% vs 44% in standard titration group) at an incremental cost of €5.53 (generic paroxetine) and €54.54 (brand paroxetine syrup). Incremental cost-effectiveness ratio (ICER) values were €159 and €1768, respectively, in favor of slow titration approach. Cost-effectiveness threshold, defined as ICER < 1 GDP per capita according to World Health Organization criteria, is about €25 000 in Italy. Conclusions Our results are consistent with a superiority of slow titration of paroxetine in older depressed patients. However, these findings, in part based on simulated data, need to be replicated in clinical trials. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background Saffron, a spice derived from the flower of Crocus sativus, has now undergone several trials examining its antidepressant effects and, in a recent meta-analysis, was confirmed to be effective for the treatment of major depression. Objective To provide an expanded systematic analysis of the completed clinical studies on saffron and depression, detailing dosages, extract sources, standardisations, safety profile and treatment duration; and, through a narrative review, to examine its potential antidepressant mechanisms of action. Design In the systematic review of clinical trials, electronic databases were searched for high-quality, randomised, double-blind studies, with placebo or antidepressant controls. A narrative review of in vivo and in vitro studies was conducted to examine its potential antidepressant mechanisms of action. Results In the systematic review, six studies were identified. In the placebo-comparison trials, saffron had large treatment effects and, when compared with antidepressant medications, had similar antidepressant efficacy. Saffron's antidepressant effects potentially are due to its serotonergic, antioxidant, anti-inflammatory, neuro-endocrine and neuroprotective effects. Conclusions Research conducted so far provides initial support for the use of saffron for the treatment of mild-to-moderate depression. Further research is required to expand our understanding of the role and actions of saffron in major depression. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the impact of controllable design factors on the power of antidepressants trials. Methods: Using clinical trial simulation (CTS), we analyzed the combined impact on the power of trials of controllable design factors (sample size, outcome metrics, and disease severity at inclusion) and uncontrollable parameters (heterogeneity of diseases labeled "depression" in the source population and selective effects of drugs on items of the Hamilton Depression Rating Scale [HDRS], the most used outcome measurement tool). We elaborated 3,840 scenarios calibrated with real data, particularly the publication bias‐corrected effect size. Results: For an effect size of 0.26, simulations revealed that in trials with ≤650 participants, power was less than 80%. Among the tested outcome metrics, the "remission" outcome provided more robustness for sample heterogeneity, whereas the continuous outcome "HDRS changes" provided more robustness when investigating drugs with a selective effect on the HDRS items. For the "remission" outcome, the power of trials increased with increasing HDRS threshold at inclusion but decreased with the outcomes "response" and "HDRS changes. Drugs with a selective effect on the HDRS items could not reach the same power as for the reference drug. Conclusion: Our study allows for drawing recommendations to avoid underpowered trials of antidepressants. [ABSTRACT FROM AUTHOR]

Objectives: Site‐independent ratings surveillance assessed ratings reliability in a clinical trial. Methods: Inter‐rater reliability was assessed at the screen visit in a 6‐week, double‐blind, placebo‐controlled study of lurasidone for the treatment of major depressive disorder (MDD) with subthreshold hypomanic ("mixed") symptoms (clinicaltrials.gov NCT01421134). Site‐based Montgomery‐Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) interviews were paired with 184 site‐independent ratings derived from audio‐digital recordings. Results: The paired MADRS and YMRS scores were highly correlated (r = 0.708 and 0.885, respectively) and generated minimal scoring discordance. The surveillance program identified 14 MADRS scores (7.6% of this sample) that were below the study entry criterion (MADRS ≥26) and resulted in screen failure. When present, paired scoring discordance was associated with symptom severity, interview length, interview quality, and the level of patient cooperation. Higher severity scores (MADRS ≥40 and YMRS ≥15) were associated with greater paired scoring discordance. Further, MADRS scores <30 and short MADRS interviews conducted in ≤12 min revealed significantly more pairs of discordant outliers (p = 0.04 and 0.009, respectively). Conclusions: The findings suggest that MDD patients with mixed features can be reliably assessed, that paired site‐based and site‐independent assessments were generally concordant, and that ratings surveillance may reinforce ratings precision. [ABSTRACT FROM AUTHOR]