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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]

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]

Prevention of depressive disorders is one of the most important challenges for health care in coming decades. Depressive disorders in all age groups have a high disease burden and are associated with huge economic costs, and current treatments are only capable of taking away one-third of the (nonfatal) disease burden of depression under optimal conditions. Prevention may be one alternative strategy that may help in further reducing the disease burden of depression. Because of the worldwide increase in the number of older adults, the number of depressed older adults will also increase considerably in the next few decades, making prevention of depression an important priority for research. Identifying the high-risk target groups for preventive interventions is complicated because most risk indicators have a low specificity, indicating that most people from these groups will not develop the disorder despite increased risk levels. We describe one promising method to identify the best target groups, based on the principle that the high-risk group should be as small as possible, should be responsible for as many new cases of depression as possible, and that intervention be as effective as possible. The number of trials examining the possibility to prevent the onset of depressive disorders in those who do not (yet) meet diagnostic criteria for depression is increasing rapidly. A recent meta-analysis identified more than 30 randomized trials and these studies showed that the incidence of depressive disorders was 21% lower in the prevention groups compared with the control groups who did not receive the preventive intervention. Most of these trials are aimed at adolescents and younger adults. Only six trials were specifically aimed at older adults. The development of evidence-based preventive interventions for major depression and other mental disorders should be an important scientific and public health objective for the 21st century. [ABSTRACT FROM AUTHOR]

A randomized clinical trial was undertaken to investigate the relative efficacy of rational-emotive behavior therapy (REBT), cognitive therapy (CT), and pharmacotherapy in the treatment of 170 outpatients with nonpsychotic major depressive disorder. The patients were randomly assigned to one of the following: 14 weeks of REBT, 14 weeks of CT, or 14 weeks of pharmacotherapy (fluoxetine). The outcome measures used were the Hamilton Rating Scale for Depression and the Beck Depression Inventory. No differences among treatment conditions at posttest were observed. A larger effect of REBT (significant) and CT (nonsignificant) over pharmacotherapy at 6 months follow-up was noted on the Hamilton Rating Scale for Depression only. © 2008 Wiley Periodicals, Inc. J Clin Psychol 64:728-746, 2008. [ABSTRACT FROM AUTHOR]

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]