Effectiveness as an outcome measure for treatment trials in psychiatry

There is at present some confusion about the relative value of clinical trials performed to investigate efficacy vs. those designed to investigate effectiveness. This is particularly challenging when studies performed as experiments for regulators by companies are used to shape and inform clinical practice, especially if studies conducted under more real life conditions fail to support predicted benefits. We review the field in relation to the new antipsychotics, in particular. Other indications, including mood disorders, which are also briefly touched upon, have so far received less definitive attention, but are likely to encounter the same difficulties. We conclude that, where the results of efficacy trials are positive and an effectiveness trial is negative, one should not necessarily prefer the effectiveness trial – it may simply have failed. Where efficacy trials and effectiveness trials point to similar conclusions, then the findings are mutually supportive.     

Are Phase 1 Trials Therapeutic? Risk,Ethics, and Division of Labor

Despite their crucial role in the translation of pre‐clinical research into new clinical applications, phase 1 trials involving patients continue to prompt ethical debate. At the heart of the controversy is the question of whether risks of administering experimental drugs are therapeutically justified. We suggest that prior attempts to address this question have been muddled, in part because it cannot be answered adequately without first attending to the way labor is divided in managing risk in clinical trials. In what follows, we approach the question of therapeutic justification for phase 1 trials from the viewpoint of five different stakeholders: the drug regulatory authority, the IRB, the clinical investigator, the referring physician, and the patient. Our analysis shows that the question of therapeutic justification actually raises multiple questions corresponding to the roles and responsibilities of the different stakeholders involved. By attending to these contextual differences, we provide more coherent guidance for the ethical negotiation of risk in phase 1 trials involving patients. We close by discussing the implications of our argument for various perennial controversies in phase 1 trial practice.     

A Critical Analysis and Discussion of Clinical Research Ethics in the Russian Federation and Their Implications for Western Sponsored Trials

Globalization, political upheavals, and Western economic struggles have caused a geographical reprioritization in the realm of drug development and human clinical research. Regulatory and cost hurdles as well as a saturation of research sites and subjects in Western countries have forced the pharmaceutical industry to place an unprecedented level of importance on emerging markets, injecting Western corporate initiatives into cultures historically and socially isolated from Western‐centric value systems. One of the greatest recipients of this onslaught of Western business and research practices is the Russian Federation. Namely, market forces are dictating a focused research initiative in the traditional emerging markets, but this focus may be at the expense of individual and societal dignity.     

The CLOCK Gene and Mood Disorders: A Case-Control Study and Meta-analysis

The clock gene (CLOCK) is considered to be a good candidate gene for the pathophysiology of mood disorders, including bipolar disorder (BP) and major depressive disorder (MDD). rs1801260 (T3111C) has been detected at position 3111 in the CLOCK mRNA 3' untranslated region, and was reported to be associated with a substantial delay in preferred timing for activity and sleep in a human study. As for function, rs1801260 has been speculated to affect mRNA. Therefore, the authors investigated the association between the three tagging single-nucleotide polymorphisms (SNPs) (rs3736544, rs1801260, and rs3749474) in CLOCK and risk of BP (n?=?867) and MDD (n?=?139) compared to controls (n?=?889) in the Japanese population. In addition, we also performed an updated meta-analysis of nine published, genetic association studies investigating the relationship between rs1801260 and mood disorder risk, comprising 3321 mood disorders cases and 3574 controls. We did not detect any associations between tagging SNPs in CLOCK and BP or MDD in the allele, genotype, or haplotype analysis (global p_BP?=?.605 and global p_MDD?=?.211). Moreover, rs1801260 was also not associated with BP, MDD, or any mood disorders in the meta-analysis. In conclusion, these data suggest that CLOCK does not play a major role in the pathophysiology of mood disorders. (Author correspondence: tarok@fujita-hu.ac.jp)     

混合家系中NOTCH4基因多态与精神分裂症、心境障碍关联研究

文章旨在探讨NOTCH4基因多态性与精神分裂症（SP）、心境障碍（MD）的关系,搜寻中国汉族人群SP与MD的共同易患基因。在中国汉族人群中收集61个SP与MD的混合家系,应用PCR-RFLP方法对NOTCH4基因多态性-1725T/G、-25T/C分型,进行传递不平衡检验（TDT）和基于单体型的单体型相对风险分析（HHRR）。结果显示-1725T/G 与SP或MD无明显关联（P>0.05）;-25T/C与SP无明显关联（P>0.05）,与女性或发病年龄≤25岁的MD相关联（P<0.05）;单体型-1725G/-25T与SP相关联（P<0.05）,与MD无明显关联（P>0.05）。本研究结果提示,在我们研究的家系中NOTCH4或邻近基因可能是精神分裂症与心境障碍的共同易患基因之一。     

Ethical Considerations in Clinical Trials: A Critique of the ICH‐GCP Guideline

This article examines issues relating to ethics decision‐making in clinical trials. The overriding concern is to ensure that the well being and the interests of human subjects are adequately safeguarded. In this respect, this article will embark on a critical analysis of the ICH‐GCP Guideline. The purpose of such an undertaking is to highlight areas of concern and the shortcomings of the existing ICH‐GCP Guideline. Particular emphasis is made on how ethics committees perform their duties and responsibilities in line with the principles outlined in the ICH‐GCP Guideline. This article will draw attention to the need for a new approach to addressing the weaknesses of the ICH‐GCP Guideline in its present form.     

The Use of Adaptive Blocks in the Design of Clinical Trials

This paper introduces a class of data-dependent allocation rules for use in sequential clinical trials designed to choose the better of two competing treatments, or to decide that they are of equal efficacy. These readily understood and easily implemented rules are shown to reduce, substantially the number of tests with the poorer treatment for a broad category of experimental situations. Allocation rules of this type are applied both to trials with an instantaneous binomial response and to delayed response trials where interest centers on exponentially distributed survival time. In each case, a comparison of this design with alternative designs given in the literature shows that the proposed design is superior with respect to ease of application and is comparable to the alternatives regarding inferior treatment number and average sample number. In addition, the proposed rules mitigate many of the difficulties generally associated with adaptive assignment rules, such as selection and systematic bias.     

Mood rhythmicity is associated with depressive symptoms and caffeinated drinks consumption in South American young adults

Among the factors that contribute to the onset and maintenance of depressive disorders, rhythmicity of symptoms and consumption of caffeine have recently gained attention. The current study aimed to examine the differential rhythmicity of relevant variables in a sample of young participants, considering the presence of depressive symptomatology and the frequency of caffeinated drinks consumption. A significant 24-hour differential rhythmicity of mood, cognitive and physiological variables was found indicating an evening peak pattern in the participants with depressive symptoms. Interestingly, caffeinated drinks consumption was differentially associated with self-perceived peaks, according to the presence of depressive symptomatology. Our findings are among the first reports about the potential association of the 24-hours rhythmicity of relevant mood-related variables, depressive symptoms, and caffeine intake. These results support the view that the identification of risk factors for depression, and the application of novel measurements and analysis methods in the development of new preventive strategies should be a public health priority.     

The Case For Randomized Clinical Trials on the Treatment of Obesity

Some say that randomized clinical trials on weight loss are unnecessary (“the benefits are ‘obvious’”) and others say that such trials are not feasible because too few participants will succeed in maintaining weight loss. Although the intermediate term benefits of weight loss are beyond dispute (lowering of blood pressure, lipids, blood sugar, etc), there is no proof that these benefits will translate into long term benefits, i.e., lower rates of cardiovascular disease and/or lower overall mortality. While this extrapolation may seem obvious, the clinical trials' literature is full of unexpected, adverse side effects of theoretically appealing therapies (e.g., higher mortality with clofibrate and higher cardiovascular disease rates with estrogen treatment in men). Although there is clearly a voluntary component to food ingestion, there are also powerful physiological forces at work which impact on energy balance. For example, individuals of similar height and weight may nevertheless have widely different daily energy expenditures and hence energy requirements. It has been shown in Pima Indians that those with low energy expenditure (i.e., those who are “fuel efficient”) are more prone to future weight gain than those with high energy expenditure. Also, reduced obese individuals have lower 24-hour energy expenditure than individuals who are spontaneously at the same lean weight It appears that this deficit in energy expenditure may last for several years, if not longer, implying that reduced obese individuals must exercise far greater vigilance over their caloric intake than their spontaneously lean peers. If they allow themselves to ingest the same number of calories as the latter, they are likely to regain weight, thereby exposing themselves to charges of overeating, even though their caloric intake does not exceed that of the spontaneously lean!. Epidemiologic data do not support a benefit of weight loss. Populations such as Mexican Americans, among whom obesity is more common than in the general population, do not have excess mortality past age 45. Life expectancy in the U.S. has improved steadily since the early 1970s, despite a rising prevalence of obesity. Lastly, prospective studies have suggested that people who lose weight die at a higher rate than those who maintain a stable weight. This effect persists even after controlling for latent, subclinical disease and cigarette smoking. Although none of the above considerations prove that voluntary weight loss is bad, they indicate that this treatment should lose its hitherto privileged status and be subjected to the rigors of clinical trials as have been treatments for hypercholesterolemia and hypertension.     

Metabolism and Excretion of Mood Stabilizers and New Anticonvulsants

1. The mood stabilizers lithium, carbamazepine (CBZ), and valproate (VPA), have differing pharmacokinetics, structures, mechanisms of action, efficacy spectra, and adverse effects. Lithium has a low therapeutic index and is renally excreted and hence has renally-mediated but not hepatically-mediated drug–drug interactions.2. CBZ has multiple problematic drug–drug interactions due to its low therapeutic index, metabolism primarily by a single isoform (CYP3A3/4), active epoxide metabolite, susceptibility to CYP3A3/4 or epoxide hydrolase inhibitors, and ability to induce drug metabolism (via both cytochrome P450 oxidation and conjugation). In contrast, VPA has less prominent neurotoxicity and three principal metabolic pathways, rendering it less susceptible to toxicity due to inhibition of its metabolism. However, VPA can increase plasma concentrations of some drugs by inhibiting metabolism and increase free fractions of certain medications by displacing them from plasma proteins.3. Older anticonvulsants such as phenobarbital and phenytoin induce hepatic metabolism, may produce toxicity due to inhibition of their metabolism, and have not gained general acceptance in the treatment of primary psychiatric disorders.4. The newer anticonvulsants felbamate, lamotrigine, topiramate, and tiagabine have different hepatically-mediated drug–drug interactions, while the renally excreted gabapentin lacks hepatic drug–drug interactions but may have reduced bioavailability at higher doses.5. Investigational anticonvulsants such as oxcarbazepine, vigabatrin, and zonisamide appear to have improved pharmacokinetic profiles compared to older agents.6. Thus, several of the newer anticonvulsants lack the problematic drug-drug interactions seen with older agents, and some may even (based on their mechanisms of action and preliminary preclinical and clinical data) ultimately prove to have novel psychotropic effects.     

The Social Value of Knowledge and International Clinical Research

In light of the growth in the conduct of international clinical research in developing populations, this paper seeks to explore what is owed to developing world communities who host international clinical research. Although existing paradigms for assigning and assessing benefits to host communities offer valuable insight, I criticize their failure to distinguish between those benefits which can justify the conduct of research in a developing world setting and those which cannot. I argue that the justification for human subjects research is fundamentally grounded in the social value of knowledge, and that this value is context‐dependent in a manner which should inform our ethical evaluation of the conduct of research in specific settings. I propose a new framework for the assessment of research benefits assigned to developing world host communities, a natural implication of which is to limit the types of research projects which may permissibly be conducted in developing world settings.     

临床试验进展：临床数据与实验室质量管理规范

将临床研究数据用于临床日常规范及健康相关决策的制定对于改善全球医疗保健至关重要。汤森路透Cortellis 临床试验情报对临床试验数据的应用价值及各国临床实验室质量管理规范的实施情况进行了介绍,提供描绘临床图景关键元素和当前趋势的专家分析,从而指导临床开发决策。     

Association of major depression and binge eating disorder with weight loss in a clinical setting

Objective: Obesity has been linked to both major depressive disorder (MDD) and binge eating disorder (BED) in clinical and epidemiological studies. The present study compared weight loss among patients with and without MDD and BED who participated in a hospital‐based weight loss program modeled after the Diabetes Prevention Program. Research Methods and Procedures: Of 131 obese patients who enrolled in treatment, 17% were diagnosed with MDD only, 13% were diagnosed with BED only, 17% were diagnosed with both MDD and BED, and 53% lacked either diagnosis in a pretreatment clinical interview. Results: After treatment, patients with MDD only attained 63% of the weight loss that non‐depressed patients attained. Patients with BED only attained 55% of the weight loss that non‐binge eaters attained. The effect of MDD on weight loss was not accounted for by the presence of BED or vice versa. Only 27% of patients with both MDD and BED achieved clinically significant weight loss compared with 67% of patients who had neither disorder. Results were not significantly altered when gender, age, and diabetes status were adjusted. Conclusion: Both MDD and BED were prevalent among this obese clinical population, and each disorder was independently associated with worse outcomes. Research is needed to investigate how to increase the efficacy of behavioral weight loss programs for individuals with MDD and/or BED.     

Clinical correlates of chronotypes in young persons with mental disorders

While important changes in circadian rhythms take place during adolescence and young adulthood, it is unclear how circadian profiles during this period relate to emerging mental disorders. This study aimed to: (i) characterise morningness–eveningness preference in young people with primary anxiety, depression, bipolar or psychotic disorders as compared to healthy controls, and (ii) to investigate associations between morningness–eveningness preference and the severity of psychiatric symptoms. Four hundred and ninety-six males and females aged between 12 and 30 years were divided into five groups according to primary diagnosis. The Hamilton Depression Rating Scale and the Brief Psychiatric Rating Scale were administered by a research psychologist and participants completed the Kessler Psychological Distress Scale and the Horne–Östberg Morningness–Eveningness Questionnaire (ME). ME scores were significantly lower (i.e. higher levels of “eveningness”) in all patient diagnosis subgroups compared to the control group. The psychosis group had higher ME scores than the depression and anxiety groups. Compared to the control group, the anxiety, depression and bipolar subgroups had a significantly higher proportion of “moderate evening” types, with a similar trend for the psychosis group. The proportion of “extreme evening” types was significantly higher in the anxiety and depression subgroups than in the control group. Lower ME scores correlated with worse psychological distress in males from the bipolar group. Lower ME scores correlated with higher depression severity in females with depression and in males with bipolar disorder. These results suggest that young persons with various mental disorders, especially those with affective disorders, present with a stronger “eveningness” preference and higher rates of evening chronotypes than healthy controls from the same age group. Later chronotypes were generally associated with worse psychological distress and symptoms severity. These associations were modulated by sex and primary diagnosis.     

药物基因组学在新药临床试验及个体化用药中的应用

药物安全性和有效性评价是药物临床试验和个体化用药的核心,也是药物基因组学研究的主要内容。药物基因组学研究贯穿于药物 研发、上市评价和临床应用整个过程, 根据药物代谢酶、转运体、受体相关基因多态性对用药者进行分层分析,评价与药物体内的处置过程、 安全性、有效性个体差异的相关性。综述药物基因组学在新药临床试验、个体化用药中的应用研究新进展。     

Off‐Shoring Clinical Research: Exploitation and the Reciprocity Constraint

The last 20 years have seen a staggering growth in the practice of off‐shoring clinical research to low‐and middle‐income countries (LICs and MICs), a growth that has been matched by the neoliberal policies adopted by host countries towards attracting trials to their shores. A recurring concern in this context is the charge of exploitation, linked to various aspects of off‐shoring. In this paper, I examine Alan Wertheimer's approach and offer an alternative view of understanding exploitation in this context. I will suggest that the justification for the enterprise of research is largely dependent on its integration within a health system from which participants regularly benefit and I argue that an attention to a principle of reciprocity will enable us to better recognize and address exploitation in international research.     

An Approximation to the Bayes Optimal Multi-Stage Design in the Colton Model for Clinical Trials

A simple and operationally convenient approximation is proposed for the Bayes optimal multistage design within the Colton decision-theoretic model for the comparison of two medical treatments. The two- and three-stage designs are developed in full; the latter is found to be superior to several existing designs including some involving sequential adaptive sampling.     

A Problem of Equivalence in Clinical Trials

Several methods exist for testing the bioequivalence in bioavailability trials. In this article we propose a method for testing the equivalence of two drugs in clinical trials when the response variable is assumed to have a normal distribution. The null and alternative hypotheses are formulated in a nonconventional manner. Computing aspects for the power and sample size are discussed.     

The future of psychopharmacology: a critical appraisal of ongoing phase 2/3 trials,and of some current trends aiming to de-risk trial programmes of novel agents

Despite considerable progress in pharmacotherapy over the past seven decades, many mental disorders remain insufficiently treated. This situation is in part due to the limited knowledge of the pathophysiology of these disorders and the lack of biological markers to stratify and individualize patient selection, but also to a still restricted number of mechanisms of action being targeted in monotherapy or combination/augmentation treatment, as well as to a variety of challenges threatening the successful development and testing of new drugs. In this paper, we first provide an overview of the most promising drugs with innovative mechanisms of action that are undergoing phase 2 or 3 testing for schizophrenia, bipolar disorder, major depressive disorder, anxiety and trauma-related disorders, substance use disorders, and dementia. Promising repurposing of established medications for new psychiatric indications, as well as variations in the modulation of dopamine, noradrenaline and serotonin receptor functioning, are also considered. We then critically discuss the clinical trial parameters that need to be considered in depth when developing and testing new pharmacological agents for the treatment of mental disorders. Hurdles and perils threatening success of new drug development and testing include inadequacy and imprecision of inclusion/exclusion criteria and ratings, sub-optimally suited clinical trial participants, multiple factors contributing to a large/increasing placebo effect, and problems with statistical analyses. This information should be considered in order to de-risk trial programmes of novel agents or known agents for novel psychiatric indications, increasing their chances of success.