Old versus new: weighing the evidence between the first- and second-generation antipsychotics.

In our opinion the best guide to prescribing antipsychotics is the clinician's experience with his patients and in particular the patient being treated. If treatment works, stick with it. We feel it is also important for the clinician to consider the evidence from well-controlled double-blind random-assignment studies because in "evidence-based medicine," biases both known and unknown are controlled by blinding and randomization. The purpose of this paper is to summarize and discuss the evidence on efficacy. Choice of antipsychotic, in our opinion, is probably the most important decision that the clinician makes for the psychotic patient. This involves the choice of drug, its dose, balancing efficacy, side-effects and cost.     

Flexible treatment strategies in chronic disease: clinical and research implications.

Multiple treatments are available for nearly all the mood disorders. This range of treatment options adds a new dimension of choice to clinical decision making. In addition to prescribing the best initial treatment, clinicians should have an algorithm for deciding if and when to make subsequent changes in treatment to take advantage of second-line treatment options when necessary. This article aims to 1) show that a wide variety of clinical decisions can be framed as choices among adaptive (within-patient) threshold-based strategies or algorithms, illustrating the generality of the concept; 2) illustrate two ways to design randomized clinical trials to compare treatment strategies with each other to decide which strategy is best; and 3) discuss some of the advantages offered by these designs, in terms of both patient acceptability and adherence to experimental protocols.     

Unique design issues in clinical trials of patients with bipolar affective disorder

Two National Institute of Mental Health-sponsored meetings of experts on bipolar illness (in 1989 and 1994) noted a paucity of clinical psychopharmacological trials in this illness which has now extended over the past two decades. One of the reasons elucidated for this neglect was a lack of agreement in the field as to what constituted an optimal clinical trial design, consequently resulting in low-priority scores for funding of studies in bipolar illness. In this paper, we note some of the characteristics of bipolar illness that make it particularly difficult to study and find such agreed upon trial designs. Some of the assets and liabilities of the well-accepted traditional parallel group, placebo-controlled, randomized clinical trial (RCT) are reviewed, and a series of other potential design options, such as crossover, enrichment, off-on-off-on (B-A-B-A), and N-of-1 trials, are discussed that may help to better address some of the unique clinical characteristics of bipolar illness. Finally, a variety of statistical approaches to analyzing data in off-on-off-on trial designs, and in helping to predetermine necessary durations of clinical trials in individual patients with bipolar disorders, are suggested. Acceptance of a wider variety of clinical trial designs may help facilitate the funding and accelerate the acquisition of new data on treatment of bipolar illness.     

Offering patients choices: a pilot study of interactions in the seizure clinic

Using conversation analysis (CA), we studied conversations between one United Kingdom-based epilepsy specialist and 13 patients with seizures in whom there was uncertainty about the diagnosis and for whom different treatment and investigational options were being considered. In line with recent communication guidance, the specialist offered some form of choice to all patients: in eight cases, a course of action was proposed, to be accepted or rejected, and in the remaining five, a "menu" of options was offered. Even when presenting a menu, the specialist sometimes conveyed his own preferences in how he described the options, and in some cases the menu was used for reasons other than offering choice (e.g., to address patient resistance). Close linguistic and interactional analysis of clinical encounters can show why doctors may feel they are offering choices when patients report that the decision was clinician dominated.     

The statistical pitfalls of the partially randomized preference design in non-blinded trials of psychological interventions

In a partially randomized preference trial (PRPT) patients with no treatment preference are allocated to groups at random, but those who express a preference receive the treatment of their choice. It has been suggested that the design can improve the external and internal validity of trials. We used computer simulation to illustrate the impact that an unmeasured confounder could have on the results and conclusions drawn from a PRPT. We generated 4000 observations ("patients") that reflected the distribution of the Beck Depression Index (DBI) in trials of depression. Half were randomly assigned to a randomized controlled trial (RCT) design and half were assigned to a PRPT design. In the RCT, "patients" were evenly split between treatment and control groups; whereas in the preference arm, to reflect patient choice, 87.5% of patients were allocated to the experimental treatment and 12.5% to the control. Unadjusted analyses of the PRPT data consistently overestimated the treatment effect and its standard error. This lead to Type I errors when the true treatment effect was small and Type II errors when the confounder effect was large. The PRPT design is not recommended as a method of establishing an unbiased estimate of treatment effect due to the potential influence of unmeasured confounders.     

Single‐subject research designs in pediatric rehabilitation: a valuable step towards knowledge translation

Knowledge translation may be particularly challenging in pediatric rehabilitation, where study findings are often ambiguous owing to low statistical power or inconsistent responses to intervention. Disconnection between research protocols and clinical practicality, as well as variability of responsiveness in heterogeneous pediatric populations, may further impede integration of research findings into everyday practice. Use of single‐subject research designs (SSRDs) may bridge the gap between research and practice, with robust design options that better identify and preserve patterns of responsiveness to specific interventions and offer protocols that are more readily implemented in practice settings than can be done in traditional randomized controlled trials. This review defines SSRD, provides examples of research questions that can be answered using SSRD, details the experimental designs that can be used and the level of evidence of each design, and describes statistical analysis approaches and clinical application. This analysis will aid researchers, reviewers, clinicians, and others in better understanding SSRD methodology and its application in everyday practice.     

Research to improve the quality of care for depression: alternatives to the simple randomized clinical trial

Recognition of gaps between evidence gained from mental health research and clinical practice in the community together with changes in treatment patterns and patient/provider preferences for care have led to interest in enhancements in the designs and analyses of clinical and community trials of mental health interventions. Gaps between clinical trials and community care include differences in populations and treatment strategies. To bridge these gaps, we propose enhancing the simple randomized trial with several different designs with the immediate aims of improving patient recruitment and adherence in psychiatric intervention studies thus bringing study designs more in line with clinical practice. The goals are to estimate treatment efficacy and effectiveness so that both internal and external validity are optimized. In this discussion, we address design and analytic issues with respect to a number of enhancements of the randomized trial design, including partial patient-provider preference designs, randomized encouragement and consent designs, fixed adaptive design, and random between- and within-patient adaptive designs. Each has advantages and disadvantages depending on the effect under investigation. Some of these enhancements, such as the fixed adaptive design, have begun to be implemented in effectiveness trials in mental health services research, but all are worthy of more attention.     

Anti-epileptogenic Clinical Trial Designs in Epilepsy: Issues and Options

Although trials with anti-seizure drugs have not shown anti-epileptogenic or disease-modifying activity in humans, new compounds are on the horizon that may require novel trial designs. We briefly discuss the unique challenges and the available options to identify innovative clinical trial designs that differentiate novel anti-epileptogenic and disease-modifying compounds, preferably early in phase II, from current anti-seizure drugs. The most important challenges of clinical testing of agents for epilepsy prevention include having sufficient preclinical evidence for a suitable agent to proceed with a human trial of an anti-epileptogenic drug, and to demonstrate the feasibility of doing such a trial. Major challenges in trial design to assess agents for disease modification include the choice of suitable study parameters, the identification of a high-risk study population, the type of control, the time and duration of treatment, and a feasible follow-up period.     

Randomized controlled trials for schizophrenia: study designs targeted to distinct goals

Randomized controlled trials for antipsychotic drugs have a variety of design features suited to diverse purposes. Efficacy (or explanatory) trials seek to establish if a drug can reduce psychotic symptoms under ideal circumstances. To isolate drug effects, researchers enroll carefully selected patients. Specialized research personnel use rating scales of symptoms that are sensitive to drug effects as the study primary outcomes. Large simple trials (LSTs) are conducted at typical treatment settings with usual clinical personnel and enroll large numbers of participants so small but clinically important differences between treatment options can be detected. LSTs focus narrowly on clearly defined, patient-oriented outcomes. To some extent, practical trials can be conceptualized as hybrids of efficacy and large simple trials. Practical trials provide independent evidence to inform decision makers about the everyday effectiveness of clinically relevant alternative interventions. Practical trial researchers include a heterogeneous population of patients and collect data on a broad range of meaningful health outcomes at many types of practice settings intended to represent usual treatment. The designers of practical trials make trade-offs between internal validity, external validity, the breadth of issues addressed, and the ability to detect small differences. The different objectives of trials should be considered in the interpretation of the complete body of randomized evidence on antipsychotic drugs.     

Epilepsy treatment in adults and adolescents: Expert opinion, 2016

Introduction: There are over twenty anti-seizure medications and anti-seizure devices available commercially in the United States. The multitude of treatment options for seizures can present a challenge to clinicians, especially those who are not subspecialists in the epilepsy field. Many clinical questions are not adequately answered in double-blind randomized controlled studies. In the presence of a knowledge gap, many clinicians consult a respected colleague with acknowledged expertise in the field. Our survey was designed to provide expert opinions on the treatment of epilepsy in adults and adolescents.Method: We surveyed a group of 42 physicians across the United States who are considered experts based on publication record in the field of epilepsy, or a leadership role in a National Association of Epilepsy Centers comprehensive epilepsy program. The survey consisted of 43 multiple-part patient scenario questions and was administered online using Redcap software. The experts provided their opinion on 1126 treatment options based on a modified Rand 9-point scale. The patient scenarios focused on genetically-mediated generalized epilepsy and focal epilepsy. The scenarios first focused on overall treatment strategy and then on specific pharmacotherapies. Other questions focused on treatment of specific patient populations (pregnancy, the elderly, patients with brain tumors, and post organ transplant patients), epilepsy patients with comorbidities (renal and hepatic disease, depression), and how to combine medications after failure of monotherapy. Statistical analysis of data used the expert consensus method.Results: Valproate was considered a drug of choice in all genetically-mediated generalized epilepsies, except in the population of women of child-bearing age. Ethosuximide was a drug of choice in patient with absence seizures, and levetiracetam was a drug of choice in patients with genetic generalized tonic-clonic seizures and myoclonic seizures. Lamotrigine, levetiracetam and oxcarbazepine were considered drugs of choice for initial treatment of focal seizures. Lamotrigine and levetiracetam were the drugs of choice for women of child-bearing age with either genetic generalized epilepsy or focal epilepsy. Lamotrigine and levetiracetam were the drugs of choice in the elderly population. Lamotrigine was preferred in patients with co-morbid depression. Levetiracetam was the drug of choice in treating patients with hepatic failure, or who have undergone organ transplantation. Compared to the 2005 and 2001 surveys, there was increased preference for the use of levetiracetam and lamotrigine, and decreased preference for the use of phenytoin, gabapentin, phenobarbital and carbamazepine.Discussion: The study presented here provides a “snapshot” of the clinical practices of experts in the treatment of epilepsy. The experts were very often in agreement, and reached consensus in 81% of the possible responses. However, expert opinion does not replace the medical literature; instead, it acts to supplement existing information. Using the study results is similar to requesting an expert consultation. Our findings suggest options that the clinician should consider to achieve best practice.     

Randomized controlled trials in schizophrenia: a critical perspective on the literature

OBJECTIVE: The randomized trial provides an opportunity to minimize the inclusion of biases in the evaluation of interventions in psychiatry. Difficulties arise, however, when applying their results to 'real world' clinical practice and decision-making. We, therefore, examined the real world applicability of schizophrenia trials. METHOD: A narrative overview of the content and quality of the randomized trials relevant to the care of those with schizophrenia is provided. RESULTS: Complex, explanatory, under-powered randomized drug trials dominate evaluative research in schizophrenia. CONCLUSION: Explanatory designs are a necessary but insufficient step in establishing the true worth of interventions in schizophrenia. Research from other spheres of mental health and wider health care suggest that pragmatic trials are feasible. This design allows large scale trials to be conducted which include patients which we would recognize from routine practice and which record outcomes which are of genuine interest to decision-makers.     

Evaluation of psychiatric interventions in an observational study: issues in design and analysis

Characteristics of randomized controlled clinical trials (RCTs) and observational studies of psychiatric intervention effectiveness are contrasted. Randomization drives treatment assignment in an RCT, whereas clinician and patient selection determine treatment in an observational study. Strengths and weaknesses of randomized and observational designs are considered. The propensity adjustment, a statistical approach that allows for intervention evaluation in a nonrandomized observational study, is described here. The plausibility of propensity adjustment assumptions must be carefully evaluated. This data analytic strategy is illustrated with the longitudinal observational data from the National Institute of Mental Health Collaborative Depression Study. Evaluations presented here examine acute and maintenance antidepressant effectiveness and demonstrate effectiveness of the higher categorical doses.     

Selecting promising ALS therapies in clinical trials

Riluzole is the only approved medication that extends survival for patients with amyotrophic lateral sclerosis (ALS). While other potential neuroprotective agents have been evaluated in randomized clinical trials, none has shown unequivocal success and none has been approved by regulatory agencies. Few symptomatic therapies have been tested in ALS. Effectiveness for drugs with modest benefit can be established only through large phase III randomized clinical trials. With numerous potential agents but limited resources, priority should be given to agents that show promise in phase II trials before proceeding to evaluation in phase III trials. In this article, we review drug development in early phase ALS trials and introduce novel designs. First, to maximize the therapeutic potential of the test medication, we need to identify the highest dose that produces a tolerable level of side effects. Second, candidate treatments should be ranked by conducting randomized selection trials between competing new treatments. The selection paradigm adopts a statistical viewpoint different from the hypothesis testing framework in conventional trials. We exemplify this approach by describing a group-sequential selection design developed for a phase II, randomized, multicenter trial of two combination treatments in patients with ALS, and illustrate the sample size reduction from a conventional trial.     

Using treatment algorithms to bring patients to remission

Many patients treated with antidepressants fail to achieve full remission, and the costs, both social and economic, of response without remission as well as residual symptoms are high. Patients who experience incomplete remission to antidepressant treatment are candidates for a sequential treatment approach involving treatment options such as switching, augmentation, or combination of antidepressants. Recently, the number of alternatives for treatment has increased substantially. Algorithms and treatment guidelines that synthesize current data and research provide clinicians with a structure when changes in treatment strategy are necessary. Guidelines and algorithms are not designed to take away the clinician's autonomy but instead are intended to provide support for treatment decisions, and effective ones allow for a wide degree of flexibility. It can be easily argued that the use of algorithms with the associated decision support tools increases the role of the clinician in assessment of the clinical status and subsequent treatment choices.     

Lessons from Darwin: evolutionary biology's implications for Alzheimer's disease research and patient care

What are the aims appropriate for a science of clinical pharmacology and clinical trials: to test drugs for efficacy and safety in the clinic, to establish the optimal effectiveness and safety of drugs in patient care or both? Current designs of clinical trials test drugs for efficacy and safety in clinical settings-they do not address the clinician's problems adequately. Clinical trials better address the effectiveness of drugs in patient care with analyses to determine drug effects for each individual in the trial. We use current standards and designs for clinical trails supplemented to control random error effects for the individuals in the trials. Test-retest standard error of measurement can control random error effects for individuals. This allows individual clinical courses to be plotted with known precision and certainty. For individuals in a clinical trial the clinical course of surrogate outcome variables can be associated with long-term health outcomes in followup to develop clinical decision rules. Clinical courses on surrogate outcome variables during patient care can be interpreted using these clinical decision rules. In this Age of the Internet, Computers and Handhelds, electronic records and interpretations of clinical examinations and tests can be a part of decision making for every patient. We conclude that practical methods are available for making clinical trials more informative for clinical practice. This modification replaces "unsystematic clinical judgments" with statistically characterized data and interpretations for individuals available as care is delivered in the doctor's office. An AD demonstration can be viewed at www.healthpragmatics.com.     

Validity of clinical trials of antidepressants

OBJECTIVE: Recent reports have criticized the design of antidepressant studies and have questioned their validity. These critics have concluded that antidepressants are no better than placebo treatment and that their illusory superiority depends on methodologically flawed studies and biased clinical evaluations. It has been suggested that the blind in randomized trials is penetrable-since clinician's guesses exceed chance-and that only active placebo can appropriately camouflage the difference between drug and placebo response. Furthermore, evidence has been cited to suggest that psychotherapy is as effective as antidepressants in both the acute and maintenance treatment of depression. These positions are often accepted as valid and have been broadly discussed in both the lay press and scientific literature. The purpose of this review is to reassess the cited data that support these assertions. METHOD: The authors examined the specific studies that were cited in these reports, evaluated their methodology, and conducted aggregate analyses. RESULTS: Analyses of the original sources failed to substantiate 1) that standard antidepressants are no more effective than placebo, 2) that active placebo offers an advantage over inactive placebo, or 3) that substantial evidence of a medication bias is suggested by raters' treatment guesses exceeding chance. The authors also note that some researchers have suggested that the interpretation of psychotherapy trials can be complicated by "allegiance effects." CONCLUSIONS: The issue of bias or allegiance effects for both antidepressant and psychotherapy research is real. Investigators of all orientations must guard against potential bias. However, studies cited as supporting the questionable validity of antidepressant trials fail upon closer examination to support assertions that these trials are invalid.     

Remission rates with 3 consecutive antidepressant trials: effectiveness for depressed outpatients

OBJECTIVE: This effectiveness study assessed remission rates in patients who had the opportunity to receive up to 3 antidepressant trials if unresponsive. METHOD: One hundred seventy-one consecutive outpatients entered 1 of 3 studies for the treatment of major depressive disorder (DSM-IV criteria) from January 1999 through December 2001. This group primarily received fluoxetine as a first treatment in trials lasting 6 to 12 weeks (a small number received gepirone). If unimproved, patients received a second or third trial (primarily clinician's choice). A standard criterion to determine remission-a score of 7 or less on the 17-item Hamilton Rating Scale for Depression-was used. In order to contrast remission rates with first-generation antidepressants, patients' outcomes in a previously published study that compared placebo, phenelzine, and imipramine were also examined (N = 420). RESULTS: In an intent-to-treat analysis, 66% (113/171) of patients who were treated with second-generation antidepressants and 65% (275/420) of patients who were treated with first-generation antidepressants eventually achieved remission. CONCLUSIONS: Remission rates in the effectiveness study are approximately 20% higher than the rates usually cited, a result of our choice to examine outcome following 3 treatment trials. This choice is dictated by good clinical practice. The usual procedure when comparing treatment modalities is to assess outcome after a single anti-depressant trial. The cumulative high remission rates suggest antidepressants are effective and should encourage more patients to seek treatment and physicians to develop techniques to improve patient adherence.     

Randomized controlled trials in evidence-based mental health care: getting the right answer to the right question

The purpose of clinical research is to answer this question: Would a new treatment, when added to the existing range of treatment options available in practice, help patients? Randomized controlled trials (RCTs)--in particular, double-blind RCTs--have important methodological advantages over observational studies for addressing this question. These advantages, however, come at a price. RCTs compare treatments using a particular allocation rule for assigning patients to treatments (random assignment) that does not mimic real-world practice. "Favorable" results from an RCT indicating that a new treatment is superior to existing treatments are neither necessary nor sufficient for establishing a "yes" answer to the question posed above. Modeled on an experimental design, RCTs are expensive in time and money and must compare simple differences in treatments. Findings have a high internal validity but may not address the needs of the field, particularly where treatment is complex and rapidly evolving. Design of clinical research needs to take account of the way treatments are allocated in actual practice and include flexible designs to answer important questions most effectively.     

Time-to-event clinical trial designs: Existing evidence and remaining concerns

Well-designed placebo-controlled clinical trials are critical to the development of novel treatments for epilepsy, but their design has not changed for decades. Patients, clinicians, regulators, and innovators all have concerns that recruiting for trials is challenging, in part, due to the static design of maintaining participants for long periods on add-on placebo when there are an increasing number of options for therapy. A traditional trial maintains participants on blinded treatment for a static period (e.g., 12 weeks of maintenance), during which participants on placebo have an elevated risk of sudden unexpected death in epilepsy compared to patients on an active treatment. Time-to-event trials observe participants on blinded treatment until a key event occurs (e.g., post-randomization seizure count matches pre-randomization monthly seizure count). In this article, we review the evidence for these designs based on re-analysis of prior trials, one published trial that used a time-to-second seizure design, and experience from an ongoing blinded trial. We also discuss remaining concerns regarding time-to-event trials. We conclude that, despite potential limitations, time-to-event trials are a potential promising mechanism to make trials more patient friendly and reduce placebo exposure, which are urgent needs to improve safety and increase recruitment to trials.     

Clinical trials in Alzheimer''s disease. A report from the Medical Research Council Alzheimer''s Disease Clinical Trials Committee.

Recent advances in Alzheimer's disease imply a need for adequate clinical trials of new treatments which require careful design. The disorder is progressive and shows clinical heterogeneity. While large-scale trials of elderly subjects are appropriate in relation to assessment of drugs or other treatments designed to prevent progression of the disorder, the outcome measurements in such biological treatment trials require careful planning. Studies of individual patients are relevant for answering certain specific questions. Relatively short cross-over trial designs may be appropriate to some pharmacological studies. The choice of neuropsychological instruments for measuring change is critically important, particularly in excluding test/retest artefact and in avoiding floor and ceiling effects. Test scales designed for assessment of specific neuropsychological deficits, or forming part of standard IQ assessments are unlikely to prove robust. Tests can be selected and developed for individual patients, but generalisation of the results of such experiments to the disease as a whole is not inevitable. There is a need to develop psychological instruments for measuring change that are robust and relevant to the clinical problem of progressive dementia.