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.     

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.     

Pharmacogenetics of psychotropic drug response

OBJECTIVE: Molecular genetic approaches provide a novel method of dissecting the heterogeneity of psychotropic drug response. These pharmacogenetic strategies offer the prospect of identifying biological predictors of psychotropic drug response and could provide the means of determining the molecular substrates of drug efficacy and drug-induced adverse events. METHOD: The authors discuss methods issues in executing pharmacogenetic studies, review the first generation of pharmacogenetic studies of psychotropic drug response, and consider future directions for this rapidly evolving field. RESULTS: Pharmacogenetics has been most commonly used in studies of antipsychotic drug efficacy, antidepressant drug response, and drug-induced adverse effects. Data from antipsychotic drug studies indicate that polymorphisms within the serotonin 2A and dopamine receptor 2 genes may influence drug efficacy in schizophrenia. Moreover, a growing body of data suggests a relationship between the serotonin transporter gene and clinical effects of the selective serotonin reuptake inhibitors used to treat depression. A significant relationship between genetic variation in the cytochrome P450 system and drug-induced adverse effects may exist for certain medications. Finally, a number of independent studies point to a significant effect of a dopamine D(3) receptor polymorphism on susceptibility to tardive dyskinesia. CONCLUSIONS: Initial research into the pharmacogenetics of psychotropic drug response suggests that specific genes may influence phenotypes associated with psychotropic drug administration. These results remain preliminary and will require further replication and validation. New developments in molecular biology, human genomic information, statistical methods, and bioinformatics are ongoing and could pave the way for the next generation of pharmacogenetic studies in psychiatry.     

Pharmacogenetic approaches to cognitive enhancement in schizophrenia

Research in the area of pharmacogenetics in psychiatry is aimed at identifying clinically relevant genetic variations that can predict treatment response. Ultimately, the goal is to individualize treatment in order to optimize outcome in disorders in which incomplete treatment response is common. Positive symptoms in patients with schizophrenia appear to be the most amenable to the currently available agents; however, negative symptoms and cognitive deficits frequently persist even when frank psychosis is well controlled. Given the relationship between these persistent traits and functional disability in schizophrenia, efforts are under way to directly target cognitive impairment and negative symptoms pharmacologically in order to improve quality of life. To date, most pharmacogenetic studies of schizophrenia have been focused on predicting clinical efficacy and side effects. In this review, we discuss the potential use of cognition as a primary outcome measure of interest in future pharmacogenetic trials of schizophrenia.     

The case for practical clinical trials in psychiatry

OBJECTIVE: Clinical trials in psychiatry frequently fail to maximize clinical utility for practicing clinicians, or, stated differently, available evidence is not perceived by clinicians (and other decision makers) as sufficiently relevant to clinical practice, thereby diluting its impact. To attain maximum clinical relevance and acceptability, researchers must conduct clinical trials designed to meet the needs of clinicians and others who are making decisions about patients' care. The authors present the case for psychiatry's adoption of the practical clinical trials model, which is widely used in research in other areas of medicine. METHOD: The authors outline the characteristics and scope of practical clinical trials, give examples of practical clinical trials, and discuss the challenges of using the practical clinical trials model in psychiatry, including issues of funding. RESULTS: Practical clinical trials, which are intended to provide generalizable answers to important clinical questions without bias, are characterized by eight key features: a straightforward clinically relevant question, a representative sample of patients and practice settings, sufficient power to identify modest clinically relevant effects, randomization to protect against bias, clinical uncertainty regarding the outcome of treatment at the patient level, assessment and treatment protocols that enact best clinical practices, simple and clinically relevant outcomes, and limited subject and investigator burden. CONCLUSIONS: To implement the practical clinical trials model in psychiatry will require stable funding for network construction and maintenance plus methodological innovation in governance and trial selection, assessment, treatment, data management, site management, and data analytic procedures.     

Estudios farmacogenéticos en la enfermedad de Alzheimer

IntroductionAlzheimer disease (AD) is the most common cause of dementia and is considered one of the main causes of disability and dependence affecting quality of life in elderly people and their families. Current pharmacological treatment includes acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) and memantine; however, only one-third of patients respond to treatment. Genetic factors have been shown to play a role in this inter-individual variability in drug response.DevelopmentWe review pharmacogenetic reports of AD-modifying drugs, the pharmacogenetic biomarkers included, and the phenotypes evaluated. We also discuss relevant methodological considerations for the design of pharmacogenetic studies into AD. A total of 33 pharmacogenetic reports were found; the majority of these focused on the variability in response to and metabolism of donepezil. Most of the patients included were from Caucasian populations, although some studies also include Korean, Indian, and Brazilian patients. CYP2D6 and APOE are the most frequently studied biomarkers. The associations proposed are controversial.ConclusionsPotential pharmacogenetic biomarkers for AD have been identified; however, it is still necessary to conduct further research into other populations and to identify new biomarkers. This information could assist in predicting patient response to these drugs and contribute to better treatment decision-making in a context as complex as aging.     

Transcranial magnetic stimulation in the treatment of depression

OBJECTIVE: Transcranial magnetic stimulation (TMS) is a noninvasive and easily tolerated method of altering cortical physiology. The authors evaluate evidence from the last decade supporting a possible role for TMS in the treatment of depression and explore clinical and technical considerations that might bear on treatment success. METHOD: The authors review English-language controlled studies of nonconvulsive TMS therapy for depression that appeared in the MEDLINE database through early 2002, as well as one study that was in press in 2002 and was published in 2003. In addition, the authors discuss studies that have examined technical, methodological, and clinical treatment parameters of TMS. RESULTS: Most data support an antidepressant effect of high-frequency repetitive TMS administered to the left prefrontal cortex. The absence of psychosis, younger age, and certain brain physiologic markers might predict treatment success. Technical parameters possibly affecting treatment success include intensity and duration of treatment, but these suggestions require systematic testing. CONCLUSIONS: TMS shows promise as a novel antidepressant treatment. Systematic and large-scale studies are needed to identify patient populations most likely to benefit and treatment parameters most likely to produce success. In addition to its potential clinical role, TMS promises to provide insights into the pathophysiology of depression through research designs in which the ability of TMS to alter brain activity is coupled with functional neuroimaging.     

Mediators and moderators in early intervention research

Aim: The goal of this paper is to provide clarification with regard to the nature of mediator and moderator variables and the statistical methods used to test for the existence of these variables. Particular attention will be devoted to discussing the ways in which the identification of mediator and moderator variables may help to advance the field of early intervention in psychiatry. Methods: We completed a literature review of the methodological strategies used to test for mediator and moderator variables. Results: Although several tests for mediator variables are currently available, recent evaluations suggest that tests which directly evaluate the indirect effect are superior. With regard to moderator variables, two approaches (‘pick-a-point’ and regions of significance) are available, and we provide guidelines with regard to how researchers can determine which approach may be most appropriate to use for their specific study. Finally, we discuss how to evaluate the clinical importance of mediator and moderator relationships as well as the methodology to calculate statistical power for tests of mediation and moderation. Conclusion: Further exploration of mediator and moderator variables may provide valuable information with regard to interventions provided early in the course of a psychiatric illness.     

Reliability of psychiatric diagnosis. I. A methodological review.

This article reviews some methodological aspects of studies of diagnostic reliability in psychiatry. We define and discuss the concept of interrater reliability and review some of the ways in which the design of the reliability study can influence the results. Three basic methodological issues are raised, including: importance of structured interviews and objective diagnostic criteria, the importance of a test/retest vs an interviewer/observer design, and the calculation of reliability in a way that takes chance agreement into account.     

Functional neuroimaging of treatment effects in psychiatry: methodological challenges and recommendations

Functional magnetic resonance imaging (fMRI) has helped to elucidate the neurobiological bases of psychiatric and neurodevelopmental disorders by localizing etiologically-relevant aberrations in brain function. Functional MRI also has shown great promise to help understand potential mechanisms of action of effective treatments for a range of psychiatric and neurodevelopmental disorders, including mood and anxiety disorders, schizophrenia, and autism. However, the use of fMRI to probe intervention effects in psychiatry is associated with unique methodological considerations, including the psychometric properties of repeated fMRI scans, how to assess potential relations between the effects of an intervention on symptoms and on specific brain activation patterns, and how to best make causal inferences about intervention effects on brain function. Additionally, the study of treatment effects in neurodevelopmental disorders presents additional unique challenges related to brain maturation, analysis methods, and the potential for motion artifacts. We review these methodological considerations and provide recommendations for best practices for each of these topics.     

Biomarkers in psychiatry: methodological issues.

Particularly in psychiatry, biological measures are increasingly sought to detect exposure to toxic agents, to assist in early identification of illness, and to enhance diagnostic certainty, provide prognostic information, and permit the mapping of outcome in a variety of disorders. The authors explore the fundamental criteria necessary to designate a biological measure as a "biomarker" and discuss the potential applications, limitations, and hazards of such markers. Authors discuss methods for establishing the validity of a biomarker. Finally, they convey a word of caution about overinterpreting the clinical or scientific value of any biological measure.     

Perspectives on the Clinical Use of Pharmacogenetic Testing in Late-Life Mental Healthcare: A Survey of the American Association of Geriatric Psychiatry Membership

ObjectiveTo assess perspectives on pharmacogenetic (PGx) testing among members of the American Association of Geriatric Psychiatry (AAGP).DesignCross-sectional survey.ParticipantsMembers of the AAGP.MeasurementsAnonymous web-based survey consisting of 41 items covering experiences, indications, barriers, facilitators and ethical, legal and social implications for PGx testing.ResultsA total of 124 surveys were completed (response rate = 13%). Most respondents (60%) had used PGx testing but an equal proportion (58%) was uncertain about the clinical usefulness of PGx testing in late-life mental health. Despite self-reported confidence in the ability to order and interpret PGx testing, 60% of respondents felt there was not enough clinical evidence for them to use PGx testing in their practice. This was compounded by uncertainties related to their ethical obligation and legal liability when interpreting and using (or not using) PGx testing results. Respondents strongly affirmed that clinical and legal guidelines for PGx testing in older adults are needed and would be helpful.ConclusionThe findings suggest additional PGx research and physician education in late-life mental healthcare settings is required to reconcile uncertainties related to the clinical efficacy and ethico-legal aspects of PGx testing as well as address current knowledge barriers to testing uptake. These efforts would be further facilitated by the development of clinical practice guidelines to ensure equitable access to testing and standardized implementation of PGx-informed prescribing in older adults.     

Pharmacogenetic warfarin dose refinements remain significantly influenced by genetic factors after one week of therapy

By guiding initial warfarin dose, pharmacogenetic (PGx) algorithms may improve the safety of warfarin initiation. However, once international normalised ratio (INR) response is known, the contribution of PGx to dose refinements is uncertain. This study sought to develop and validate clinical and PGx dosing algorithms for warfarin dose refinement on days 6-11 after therapy initiation. An international sample of 2,022 patients at 13 medical centres on three continents provided clinical, INR, and genetic data at treatment days 6-11 to predict therapeutic warfarin dose. Independent derivation and retrospective validation samples were composed by randomly dividing the population (80%/20%). Prior warfarin doses were weighted by their expected effect on S-warfarin concentrations using an exponential-decay pharmacokinetic model. The INR divided by that "effective" dose constituted a treatment response index . Treatment response index, age, amiodarone, body surface area, warfarin indication, and target INR were associated with dose in the derivation sample. A clinical algorithm based on these factors was remarkably accurate: in the retrospective validation cohort its R(2) was 61.2% and median absolute error (MAE) was 5.0 mg/week. Accuracy and safety was confirmed in a prospective cohort (N=43). CYP2C9 variants and VKORC1-1639 G→A were significant dose predictors in both the derivation and validation samples. In the retrospective validation cohort, the PGx algorithm had: R(2)= 69.1% (p<0.05 vs. clinical algorithm), MAE= 4.7 mg/week. In conclusion, a pharmacogenetic warfarin dose-refinement algorithm based on clinical, INR, and genetic factors can explain at least 69.1% of therapeutic warfarin dose variability after about one week of therapy.     

Transcranial direct current stimulation in psychiatric disorders

The interest in non-invasive brain stimulation techniques is increasing in recent years. Among these techniques, transcranial direct current stimulation (tDCS) has been the subject of great interest among researchers because of its easiness to use, low cost, benign profile of side effects and encouraging results of research in the field. This interest has generated several studies and randomized clinical trials, particularly in psychiatry. In this review, we provide a summary of the development of the technique and its mechanism of action as well as a review of the methodological aspects of randomized clinical trials in psychiatry, including studies in affective disorders, schizophrenia, obsessive compulsive disorder, child psychiatry and substance use disorder. Finally, we provide an overview of tDCS use in cognitive enhancement as well as a discussion regarding its clinical use and regulatory and ethical issues. Although many promising results regarding tDCS efficacy were described, the total number of studies is still low, highlighting the need of further studies aiming to replicate these findings in larger samples as to provide a definite picture regarding tDCS efficacy in psychiatry.     

Allergic rhinitis: relationships with anxiety and mood syndromes

In this article, the authors examine the preponderance of publications pertaining to relationships between allergies and anxiety and mood syndromes. Through a review of the relevant articles in the PubMed and PsycINFO databases, the authors found that the majority of studies (9 of 11 studies on anxiety syndromes, 10 of 12 studies on depressive syndromes) indicate associations between allergies and anxiety/mood syndromes, despite a number of methodological variances. In addition, there appear to be a number of potential variables that mediate the relationship between allergies and these two psychiatric phenomena (e.g., allergies may heighten risk for these syndromes by triggering the immune system and cytokines; allergies may impair sleep through nasal obstruction and secondarily exacerbate psychiatric symptoms; and allergies may negatively affect cognitive functioning and contribute to psychiatric disturbance) as well as a possible shared genetic risk. The authors review and discuss these variables.     

Antidepressants and the risk of breast cancer.

BACKGROUND: A recent national newspaper article highlighted 2 published research papers that suggest an association between antidepressants and an increased risk of breast cancer. The authors of the 2 papers recommend switching or avoiding the antidepressants implicated in their studies. METHOD: We critically review these papers and, based on our review, consider what clinical practices, if any, should be modified as a result of their findings. RESULTS: Both articles are based upon case-control studies. In the first paper, the authors examine the relation between tricyclic antidepressants (TCAs) and an increased risk of breast cancer. The study upon which the paper is based has several design strengths, and the paper presents findings that have biological plausibility. However, the conclusions are weakened by the lack of accounting for potential confounding factors and multiple statistical comparisons. In the second paper, the authors combined survey and administrative data to examine the association between antidepressant use and breast cancer risk. The press article notwithstanding, the second paper does not find a significant association between specific antidepressants and an increased risk of breast cancer, after adjusting for potential confounders. There are significant methodological limitations to the research upon which the paper is based. CONCLUSIONS: The finding of an association between TCA use and increased risk of breast cancer merits further testing using stronger research designs. However, because of the methodological concerns described, the 2 papers we review provide insufficient evidence to guide practitioners to change clinical practice.     

Training general psychiatry residents in child and adolescent psychiatry

The authors describe the nature of current social and economic forces impacting on the education and future practice of general psychiatry residents in child and adolescent psychiatry. They review theoretical and practical reasons for training in child and adolescent psychiatry, analyze the form and content of what is currently taught based on a national survey of general training programs, and suggest guidelines for the training and postgraduate practice of general psychiatrists in evaluating and treating children and adolescents. The authors conclude that while social and economic changes necessitate general psychiatrists' clinical involvement with children and adolescents, insufficient general training may necessitate postgraduate education and supervision. They pose ethical and professional dilemmas for the field in meeting the national shortage of child and adolescent psychiatrists and propose strategies to enhance recruitment into child and adolescent residency training.     

Nursing staff development and facility design for medical-psychiatry units

Successful operation of a medical-psychiatry unit requires special considerations in nursing staff development and facility design. This article will discuss in detail issues related to the selection, training, and development of a medical-psychiatry unit nursing staff. Organizational details regarding establishing schedules and staffing patterns are examined in detail. Additional areas reviewed are special adaptations in the architectural and physical facility design as well as the medications, equipment, and supplies needed to provide optimal medical and nursing care to the medical-psychiatric patient population. The essential diagnostic and clinical services that should be available for patients on a medical psychiatry unit are also defined.     

The fate of integrated treatment: whatever happened to the biopsychosocial psychiatrist?

OBJECTIVE: The authors suggest that pharmacotherapy and psychotherapy, the major treatment modalities in psychiatry, have become fragmented from one another, creating an artificial separation of the psychosocial and biological domains in psychiatry. METHOD: After a brief discussion of the economic factors influencing this trend, the authors provide a selective overview of recent research. In the absence of systematic empirical data regarding which patients and which conditions might benefit from integrated treatment by one psychiatrist, the authors propose specific clinical situations that call for such integration and also discuss concerns about cost-effectiveness. RESULTS: Recent research suggests that combining psychotherapy and pharmacotherapy may have advantages over either treatment alone in certain clinical situations involving specific disorders. While few of the studies on combined treatment have tested whether a one-person or two-person model of treatment provision is more effective, there are a number of advantages to the one-person treatment model in which a psychiatrist conducts the psychotherapy and prescribes medication for the same patient. CONCLUSIONS: The authors suggest that further research is needed to clarify the optimal situations for the one-person model of integrated treatment and also propose systematic teaching of integrated treatment in all residency training programs.     

Magnetic resonance imaging in psychiatry

Magnetic resonance imaging (MRI) is a relatively new radiological technique that may be useful in the study of psychiatric illness. MRI gives detailed structural information about the brain and also allows quantification of functional change. Current areas of study relevant to psychiatry include: schizophrenia, dementia, epilepsy and, to a lesser extent, alcohol and affective disorders. The authors review the basic principles of MRI, discuss the recent application to psychiatry, indicate its potential advantages and comment on the current limitations of this imaging modality.