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Brexpiprazole is an oral antipsychotic agent indicated for use in patients with schizophrenia or as adjunctive treatment for major depressive disorder. As obesity (body mass index ≥35 kg/m2) has the potential to affect drug pharmacokinetics and is a common comorbidity of both schizophrenia and major depressive disorder, it is important to understand changes in brexpiprazole disposition in this population. This study uses a whole‐body physiologically based pharmacokinetic model to compare the pharmacokinetics of brexpiprazole in obese and normal‐weight (body mass index 18‐25 kg/m2) individuals known to be cytochrome P450 2D6 extensive metabolizers (EMs) and poor metabolizers (PMs). The physiologically based pharmacokinetic simulations demonstrated significant differences in the time to effective concentrations between obese and normal‐weight individuals within metabolizer groups according to the label‐recommended titration. Simulations using an alternative dosing strategy of 1 week of twice‐daily dosing in obese EMs or 2 weeks of twice‐daily dosing in obese poor metabolizers, followed by a return to once‐daily dosing, yielded more consistent plasma concentrations between normal‐weight and obese patients without exceeding the area under the plasma concentration–time curve observed in the normal‐weight EMs. These alternative dosing strategies reduce the time to effective concentrations in obese patients and may improve clinical response to brexpiprazole. [ABSTRACT FROM AUTHOR]

Accounting for subject nonadherence and eliminating inappropriate subjects in clinical trials are critical elements of a successful study. Nonadherence can increase variance, lower study power, and reduce the magnitude of treatment effects. Inappropriate subjects (including those who do not have the illness under study, fail to report exclusionary conditions, falsely report medication adherence, or participate in concurrent trials) confound safety and efficacy signals. This paper, a product of the International Society for CNS Clinical Trial Methodology (ISCTM) Working Group on Nonadherence in Clinical Trials, explores and models nonadherence in clinical trials and puts forth specific recommendations to identify and mitigate its negative effects. These include statistical analyses of nonadherence data, novel protocol design, and the use of biomarkers, subject registries, and/or medication adherence technologies. [ABSTRACT FROM AUTHOR]

The success rate in the development of psychopharmacological compounds is insufficient. Two main reasons for failure have been frequently identified: 1) treating the wrong patients and 2) using the wrong dose. This is potentially based on the known heterogeneity among patients, both on a syndromal and a biological level. A focus on personalized medicine through better characterization with biomarkers has been successful in other therapeutic areas. Nevertheless, obstacles toward this goal that exist are 1) the perception of a lack of validation, 2) the perception of an expensive and complicated enterprise, and 3) the perception of regulatory hurdles. The authors tackle these concerns and focus on the utilization of biomarkers as predictive markers for treatment outcome. The authors primarily cover examples from the areas of major depression and schizophrenia. Methodologies covered include salivary and plasma collection of neuroendocrine, metabolic, and inflammatory markers, which identified subgroups of patients in the Netherlands Study of Depression and Anxiety. A battery of vegetative markers, including sleep-electroencephalography parameters, heart rate variability, and bedside functional tests, can be utilized to characterize the activity of a functional system that is related to treatment refractoriness in depression (e.g., the renin-angiotensin-aldosterone system). Actigraphy and skin conductance can be utilized to classify patients with schizophrenia and provide objective readouts for vegetative activation as a functional marker of target engagement. Genetic markers, related to folate metabolism, or folate itself, has prognostic value for the treatment response in patients with schizophrenia. Already, several biomarkers are routinely collected in standard clinical trials (e.g., blood pressure and plasma electrolytes), and appear to be differentiating factors for treatment outcome. Given the availability of a wide variety of markers, the further development and integration of such markers into clinical research is both required and feasible in order to meet the benefit of personalized medicine. This article is based on proceedings from the "Taking Personalized Medicine Seriously--Biomarker Approaches in Phase IIb/III Studies in Major Depression and Schizophrenia" session, which was held during the 10th Annual Scientific Meeting of the International Society for Clinical Trials Meeting (ISCTM) in Washington, DC, February 18 to 20, 2014. [ABSTRACT FROM AUTHOR]

The article discusses aspects of the tendency of studies of innovative drugs for psychiatric disorders to fail in their third phase. It states that failures in third phase of the studies have consequences for both the industry and psychiatric patients. It notes that systematic collection of data on the efficacy of the approaches to the studies will be important so that pharmaceutical companies have some basis for deciding whether to add a particular approach to their research programs.

The article explores the review made by the U.S. Food and Drug Administration (FDA) on the drug interaction and pharmacogenomic studies on the development of new cytochrome P450 2D6 (CYP2D6) genotype-guided dosing recommendations for pimozide. It presents the results of a simulation of pimozide exposures in different CYP2D6 genotype groups. It concludes that the maximum dose of CYP2D6 poor metabolizers is four milligrams daily.

The article presents information on a study that explores the differences in efficacy data from randomized placebo-controlled trials submitted over a period of 18-years. The report was in support of new drug applications (NDAs) for the treatment of schizophrenia and the differences in results between trials that were conducted in North America and elsewhere. The study concluded a high and increasing placebo response and a declining treatment effect are of great concern in schizophrenia trials.

The article examines the decision of the U.S. Food and Drug Administration (FDA) to approve the drug vilazodone for major depressive disorder (MDD). Particular focus is given to the approach by FDA to its review of the clinical pharmacology and clinical efficacy and safety data for the drug. The pharmacokinetics and dose-response characterization of vilazodone are tackled. The similarity of the drug's adverse events with other selective serotonin reuptake inhibitors (SSRIs) is explained.

The article discusses exploratory analyses of differences in efficacy data from randomized, double-blind placebo-controlled major depressive disorder (MDD) clinical trials submitted in support of new drug applications (NDAs). It says that 81 clinical trials submitted to the U.S. Food and Drug Administration (FDA) were analyzed. The analyses found that treatment effect has declined over time in the trials. High failure rates were also observed in the trials during the entire period.

The article discusses changes in psychiatric drug development from the perspective of the U.S. Food and Drug Administration (FDA) in 2010. The role of the FDA in drug development regulation is explained. The FDA initiatives that have influenced drug development efforts are discussed. A discussion on the Critical Path Initiative (CPI) and the Safety Initiative of the FDA, and their likely influence on psychiatric drug development, is detailed.

The article comments on the hierarchical Bayesian reanalysis of the randomized clinical trials of antidepressant drugs in children that were summarized by the U.S. Food and Drug Administration for an advisory committee meeting. The sufficiency of the suicidability data from these trials to support the conclusion that the drugs increase the risk of suicidal impulses in pediatric patients has been questioned.

Focuses on regulatory issues in pediatric psychopharmacology. Encouragement from the Food and Drug Administration (FDA) for more informative labeling of drugs; Lack of valid research data as primary reason for inadequate labeling information.

A response by Ni A. Kin et al. to a letter to the editor about their article "Exploratory Analyses of Efficacy Data From Major Depressive Disorder Trials Submitted to the U.S. Food and Drug Administration in Support of New Drug Applications" published in 2011 is presented.

Objective: This article captures the proceedings of a meeting aimed at defining clinically meaningful effects for use in randomized controlled trials for psychopharmacological agents., Design: Experts from a variety of disciplines defined clinically meaningful effects from their perspectives along with viewpoints about how to design and interpret randomized controlled trials., Setting: The article offers relevant, practical, and sometimes anecdotal information about clinically meaningful effects and how to interpret them., Participants: The concept for this session was the work of co-chairs Richard Keefe and the late Andy Leon. Faculty included Richard Keefe, PhD; James McNulty, AbScB; Robert S. Epstein, MD, MS; Shelby D. Reed, PhD; Juan Sanchez, MD; Ginger Haynes, PhD; Andrew C. Leon, PhD; Helena Chmura Kraemer, PhD; Ellen Frank, PhD, and Kenneth L. Davis, MD., Results: The term clinically meaningful effect is an important aspect of designing and interpreting randomized controlled trials but can be particularly difficult in the setting of psychopharmacology where effect size may be modest, particularly over the short term, because of a strong response to placebo. Payers, regulators, patients, and clinicians have different concerns about clinically meaningful effects and may describe these terms differently. The use of moderators in success rate differences may help better delineate clinically meaningful effects., Conclusion: There is no clear consensus on a single definition for clinically meaningful differences in randomized controlled trials, and investigators must be sensitive to specific concerns of stakeholders in psychopharmacology in order to design and execute appropriate clinical trials.

Objective: To examine the risk of suicidal behaviour within clinical trials of antidepressants in adults., Design: Meta-analysis of 372 double blind randomised placebo controlled trials., Setting: Drug development programmes for any indication in adults., Participants: 99 231 adults assigned to antidepressants or placebo. Median age was 42 and 63.1% were women. Indications for treatment were major depression (45.6%), other depression (4.6%), other psychiatric disorders (27.6%), and non-psychiatric disorders (22.2%)., Main Outcome Measures: Suicidal behaviour (completed suicide, attempted suicide, or preparatory acts) and ideation., Results: For participants with non-psychiatric indications, suicidal behaviour and ideation were extremely rare. For those with psychiatric indications, risk was associated with age. For suicidal behaviour or ideation and for suicidal behaviour only, the respective odds ratios were 1.62 (95% confidence interval 0.97 to 2.71) and 2.30 (1.04 to 5.09) for participants aged <25, 0.79 (0.64 to 0.98) and 0.87 (0.58 to 1.29) for those aged 25-64, and 0.37 (0.18 to 0.76) and 0.06 (0.01 to 0.58) for those aged >or=65. When age was modelled as a continuous variable, the odds ratio for suicidal behaviour or ideation declined at a rate of 2.6% per year of age (-3.9% to -1.3%, P=0.0001) and the odds ratio for suicidal behaviour declined at a rate of 4.6% per year of age (-7.4% to -1.8%, P=0.001)., Conclusions: Risk of suicidality associated with use of antidepressants is strongly age dependent. Compared with placebo, the increased risk for suicidality and suicidal behaviour among adults under 25 approaches that seen in children and adolescents. The net effect seems to be neutral on suicidal behaviour but possibly protective for suicidal ideation in adults aged 25-64 and to reduce the risk of both suicidality and suicidal behaviour in those aged >or=65.

Concerns have been raised about the appropriateness of placebo controls in clinical trials for major depressive disorder (MDD), given that there are approved treatments for this illness. Critics have argued that patients with untreated depression would be exposed to an unnecessary risk of suicide. There is also a competing concern that antidepressant drug treatment itself may induce suicidal behavior and thinking (suicidality). To examine this question, we have evaluated the rate of suicide in placebo- and active drug-treated groups of patients with MDD and various anxiety disorders participating in short-term randomized controlled trials (RCTs). We examined data from all manufacturer-sponsored short-term RCTs of 9 commonly used antidepressants in patients with MDD and various anxiety disorders. All short-term RCTs of antidepressants in patients with MDD and various anxiety disorders were included. Individual patients' data were available for all trials. Data were available for the 207 trials conducted in patients with MDD, including a total of 40,028 patients. There were 21 cases of suicide in these patients. Forty-four trials were conducted in patients with various anxiety disorders, including a total of 10,972 patients. There were 2 cases of suicide in these patients. Overall, at least 1 case of suicide occurred in 21 of the 251 trials. Sixteen of the suicides in MDD trials occurred in trials that had only an active control comparison group, and most of these (14 cases) were observed in the non-North American trials. In the placebo-controlled MDD trials, the rate ratios of suicide in the combined drug groups compared with placebo were 1.07 (0.1-63.4) and 0.5 (0.0-36.7) for the non-North American and North American trials, respectively. In the anxiety disorder studies, the overall rate ratio of suicide for the selective serotonin reuptake inhibitors compared with placebo was 0.9 (0.0-71.4). Neither use of placebo nor of antidepressants in short-term RCTs was associated with an increased risk of completed suicide among patients with MDD or various anxiety disorders. Nonetheless, because of the small numbers of suicides in these trials and the subsequent lack of statistical power, an increased risk of completed suicide in association with either drug or placebo treatment cannot be definitively excluded.

Objective: The purpose of this review is to assess the relationship between mood disorders and development, course, and associated morbidity and mortality of selected medical illnesses, review evidence for treatment, and determine needs in clinical practice and research., Data Sources: Data were culled from the 2002 Depression and Bipolar Support Alliance Conference proceedings and a literature review addressing prevalence, risk factors, diagnosis, and treatment. This review also considered the experience of primary and specialty care providers, policy analysts, and patient advocates. The review and recommendations reflect the expert opinion of the authors., Study Selection/data Extraction: Reviews of epidemiology and mechanistic studies were included, as were open-label and randomized, controlled trials on treatment of depression in patients with medical comorbidities. Data on study design, population, and results were extracted for review of evidence that includes tables of prevalence and pharmacological treatment. The effect of depression and bipolar disorder on selected medical comorbidities was assessed, and recommendations for practice, research, and policy were developed., Conclusions: A growing body of evidence suggests that biological mechanisms underlie a bidirectional link between mood disorders and many medical illnesses. In addition, there is evidence to suggest that mood disorders affect the course of medical illnesses. Further prospective studies are warranted.

Objective: To achieve consensus among researchers, pharmaceutical industry representatives, federal regulatory agency staff, and family advocates on a template for clinical trials of acute mania/bipolar disorder in children and adolescents., Method: The American Academy of Child and Adolescent Psychiatry, in collaboration with Best Practice, convened a group of experts from the key stakeholder communities (including adult psychiatrists with expertise in bipolar disorder) and assigned them to workgroups to examine core methodological issues surrounding the design of clinical trials and, ultimately, to generate a consensus statement encompassing: (1) inclusion/exclusion criteria, (2) investigator training needs and site selection, (3) assessment and outcome measures, (4) protocol design and ethical issues unique to trials involving children/adolescents, and (5) regulatory agency perspectives on these deliberations., Results: Conference participants reached agreement on 18 broad methodological questions. Key points of consensus were to assign priority to placebo-controlled studies of acute manic episodes in children and adolescents aged 10-17 years, who may or may not be hospitalized, and who may or may not suffer from common comorbid psychiatric disorders; to require that specialist diagnostic "gatekeepers" screen youths' eligibility to participate in trials; to monitor interviewer and rater competency over the course of the trial using agreed upon standards; and to develop new tools for assessment, including scales to measure aggression/rage and cognitive function, while using the best available instruments (e.g., Young Mania Rating Scale) in the interim., Conclusions: Methodologically rigorous, large-scale clinical trials of treatment of acute mania are urgently needed to provide information regarding the safety and efficacy, in youth, of diverse agents with potential mood-stabilizing properties.