Clinical trials: Bridging the gap between efficacy and effectiveness

The need for clinical psychiatry research to provide practical information to clinicians, families, and consumers has led to the development of new approaches to clinical trials. Efficacy trials, the historical backbone of clinical research, have many shortcomings in delivering practical information to stakeholders. The ‘effectiveness’ or ‘public-health’ model of intervention research targets a diverse group of patients across multiple settings that are outside of academic medical centres, with study design and outcomes that are selected on the basis of their potential to produce clinically meaningful information. The National Institute of Mental Health has funded three such clinical trials in recent years, respectively targeting schizophrenia and Alzheimer's disease, depression, and bipolar disorder. Each of these studies has made a major impact, and provided new insights into the challenges of public health orientated trials in psychiatry. In this review, we describe the underlying principles and practical considerations in efficacy and effectiveness-orientated trials.     

Hippo signaling: bridging the gap between cancer and neurodegenerative disorders

During development, regulation of organ size requires a balance between cell proliferation, growth and cell death. Dysregulation of these fundamental processes can cause a variety of diseases. Excessive cell proliferation results in cancer whereas excessive cell death results in neurodegenerative disorders. Many signaling pathways known-to-date have a role in growth regulation. Among them, evolutionarily conserved Hippo signaling pathway is unique as it controls both cell proliferation and cell death by a variety of mechanisms during organ sculpture and development. Neurodegeneration, a complex process of progressive death of neuronal population, results in fatal disorders with no available cure to date. During normal development, cell death is required for sculpting of an organ. However, aberrant cell death in neuronal cell population can result in neurodegenerative disorders. Hippo pathway has gathered major attention for its role in growth regulation and cancer, however, other functions like its role in neurodegeneration are also emerging rapidly. This review highlights the role of Hippo signaling in cell death and neurodegenerative diseases and provide the information on the chemical inhibitors employed to block Hippo pathway. Understanding Hippo mediated cell death mechanisms will aid in development of reliable and effective therapeutic strategies in future.     

Functional MAPT haplotypes: bridging the gap between genotype and neuropathology

The microtubule-associated protein tau (MAPT) locus has long been associated with sporadic neurodegenerative disease, notably progressive supranuclear palsy and corticobasal degeneration, and more recently with Alzheimer's disease and Parkinson's disease. However, the functional biological mechanisms behind the genetic association have only now started to emerge. The genomic architecture in the region spanning MAPT is highly complex, and includes a approximately 1.8 Mb block of linkage disequilibrium (LD). The region is divided into two major haplotypes, H1 and H2, defined by numerous single nucleotide polymorphisms and a 900 kb inversion which suppresses recombination. Fine mapping of the MAPT region has identified sub-clades of the MAPT H1 haplotype which are specifically associated with neurodegenerative disease. Here we briefly review the role of MAPT in sporadic and familial neurodegenerative disease, and then discuss recent work which, for the first time, proposes functional mechanisms to link MAPT haplotypes with the neuropathology seen in patients.     

Molecular biology of medulloblastoma: bridging the gap between research and practice

Medulloblastoma, the most common primary pediatric malignant brain tumor, is a molecularly heterogeneous disease with different developmental origins, distinct phenotypes, diverse biological behavior and contrasting clinical outcomes. The current clinico-radiological risk classification fails to take account of this heterogeneity and resultant prognostic variability. It is widely accepted that dysregulation of normal developmental processes constitutes a key mechanism of tumorigenesis in at least a subset of medulloblastomas. Several attempts at biological classification have successfully identified distinct subgroups with subgroup-specific gene signatures, demographics, histologic subtypes and metastases; among these, tumors involving the wingless and sonic hedgehog signaling pathways have been the most reliably and consistently identified. However, such integrative genomic approaches have limited applicability in the clinic owing to the need for fresh frozen tissues and elaborate molecular biology tools. A novel four-antibody approach to subgroup medulloblastoma using immunohistochemistry on archival specimens as proposed by Northcott et al. appears extremely promising as it can be applied in any basic neuropathology laboratory across the globe. There is a compelling need to integrate assays of molecular biomarkers performed on archival specimens into stratification schemes for medulloblastoma alongside clinical and pathologic outcome indicators to refine risk stratification for individualizing therapy.     

Affect regulation and psychopathology: bridging the mind-body gap

A failure of affect regulation is put forward as central to the development of psychopathology. Giving affect regulation this pivotal role allows one to explain how the various theories of intervention (for example, dynamic, behavioural, medical) can all have relatively similar results. As well, it provides an explanation for the common findings of brain and language dysfunction in psychopathology, the co-occurrence of anxiety disorders in various other mental disorders and the responsiveness of individuals with severe pathology to the affect in their environments. A model is presented linking the reticular, limbic and frontal systems of the brain with the conceptual frameworks used by mental health workers in their efforts to intervene. To illustrate how the model may be used, it is applied to various disorders.     

Social cognition of schizophrenia: bridging gap between brain science and psychosocial intervention

The concept and assessment tools for social cognition of schizophrenia were reviewed in order to bridge the gap between brain cognitive science and psycho-social intervention. Social cognition as well as neuro-cognition strongly influences social functioning, and the impact of neuro-cognition is mediated by social cognition. Neuronal networks of personal identification, facial perception, emotional identification, eye contact, "theory of mind", mutual communication, and the decision-making process have been clarified recently. The results of face discrimination and emotion recognition tasks show impairment in persons with schizophrenia as compared with healthy controls, especially fear, dislike, and sad recognition tasks. It might be difficult for them to link ambiguous stimuli with specific emotions, and they have a tendency to recognize uncomfortable emotions easily. "Jumping to conclusions" tendency (JTC) was identified in previous research on delusion. JTC develops from information uptake bias and confidence bias, and they might be thought to be trait and state. Social problem-solving is the skill to use social cognition to comprehensively adjust to specific social situations, and processing skills of social problem-solving are related to divergent thinking. Rating scales and the results of previous studies on emotion recognition, social perception, attribution style, and "theory of mind" were summarized. Furthermore, psycho-social interventions to improve emotion recognition directly, JTC, and divergent thinking were reported. Interventions aiming at improving social cognition or meta-cognition directly have been recently developed, which might improve some components of social functioning that used to be difficult to improve. These concepts of social cognition and researches on brain science, assessment tools, and intervention methods would clarify the mechanisms of the effects of psycho-social interventions, improve their methodology, and help to develop new aspects of intervention.     

Pitfalls of multisite randomized clinical trials of efficacy and effectiveness

This article discusses common pitfalls of multisite randomized clinical trials of efficacy and effectiveness. Issues considered include (1) premature initiation, (2) ineffective study structure, (3) too much or too little communication among researchers, (4) neglect of site differences, (5) use of "naked" p values, (6) premature closure, and (7) overreliance on the interpretation and memory of individual researchers. If future researchers are aware of these common pitfalls, they may be able to avoid them.     

The 2 "Es" of research: efficacy and effectiveness trials.

Studies that investigate the usefulness of various therapies fall along a continuum that ranges from those looking at whether an intervention can work under ideal circumstances (efficacy trials) to those that focus on whether a treatment works when applied in the real world (effectiveness trials). Whether a study is closer to one end of the spectrum or the other affects almost every aspect of the trial. These aspects include which patients are eligible for enrollment, the degree of control over the way the intervention is delivered, which patients are or are not included in the analyses, how missing data are handled, and even which statistical tests may be used. The 2 types of trials may yield different results, but both provide useful information. This paper explores these issues, shows the decisions researchers must take at each phase of a trial, and discusses how clinicians should interpret the results.     

A model of working memory: bridging the gap between electrophysiology and human brain imaging.

Human neuroimaging methods such as positron emission tomography and functional magnetic resonance imaging have made possible the study of large-scale distributed networks in the behaving human brain. Although many imaging studies support and extend knowledge gained from other experimental modalities such as animal single-cell recordings, there have also been a substantial number of experiments that appear to contradict the animal studies. Part of the reason for this is that neuroimaging is an indirect measure of neuronal firing activity, and thus interpretation is difficult. Computational modeling can help to bridge the gap by providing a substrate for making explicit the assumptions and constraints provided from other sources such as anatomy, physiology and behavior. We describe a large-scale model of working memory that we have used to examine a number of issues relating to the interpretation of imaging data. The gating mechanism that regulates engagement and retention of short-term memory is revised to better reflect hypothesized underlying neuromodulatory mechanisms. It is shown that in addition to imparting better performance for the memory circuit, this mechanism also provides a better match to imaging data from working memory studies.     

The changing nature of consultation-liaison in primary care: bridging the gap between research and practice

Consultation-liaison (C-L) psychiatry is hypothesized to be a model of interface between primary care and specialist mental health services with significant advantages over other models of organizing mental health care. However, there are significant complexities in the definition and evaluation of this model. As well as discussing the definition of C-L in primary care, this paper highlights the gap between models of traditional C-L that are popular in practice and the increasingly complex models (based on chronic disease management) evaluated in research studies. It is hypothesized that traditional C-L approaches and newer models use different mechanisms of change to achieve their goals. The former focus on the relationships between primary care and specialist professionals, while the latter highlight the importance of the development of effective systems of delivering care. Although the latter may be crucial in enhancing the "efficacy" and "effectiveness" of these models in terms of clinician behavior change and patient outcome, the former may be crucial in terms of "dissemination" and "implementation" of these models from research contexts to routine care settings.