The dilemma of the control condition in experience-based cognitive and behavioural treatment research

Rehabilitation using cognitive and behavioural treatment methods (i.e., experience-based interventions) faces particular challenges in improving its evidence base through rigorous studies such as randomised controlled trials (RCTs). Experience-based treatments are often complex, with multiple "active ingredients" that may be difficult to characterise. In addition to the difficulty in specifying treatment ingredients, experience-based rehabilitation researchers face challenges in designing or selecting appropriate control or comparison conditions to test the efficacy of complex treatments. Based on lessons learned in designing a cognitive-behavioural intervention for anger self-management for people with traumatic brain injury (TBI) for the National Institutes of Health (NIH)-funded TBI Clinical Trials Network, we review the advantages, disadvantages and applications of a variety of control conditions for experience-based interventions. We discuss controls in which active treatments are withheld (no-treatment controls, waitlist controls, and placebo-analogue designs); controls that involve comparison to naturally occurring or devised usual care treatments; and conditions that compare active treatments (dismantling designs, dose controls, and equivalence trials). Recommendations for selecting and developing control groups that maximise both equipoise and participant enrolment/retention are discussed.     

Principles of a new treatment algorithm in multiple sclerosis

We are entering a new era in the management of patients with multiple sclerosis (MS). The first oral treatment (fingolimod) has now gained US FDA approval, addressing an unmet need for patients with MS who wish to avoid parenteral administration. A second agent (cladribine) is currently being considered for approval. With the arrival of these oral agents, a key question is where they may fit into the existing MS treatment algorithm. This article aims to help answer this question by analyzing the trial data for the new oral therapies, as well as for existing MS treatments, by applying practical clinical experience, and through consideration of our increased understanding of how to define treatment success in MS. This article also provides a speculative look at what the treatment algorithm may look like in 5 years, with the availability of new data, greater experience and, potentially, other novel agents.     

Limitations in randomised controlled trials evaluating drug effects in mania

Considering the increasing number of drugs evaluated for mania in randomised controlled trials (RCTs) and the potential discrepancies between recommendations based on RCTs and the antimanic treatment given in clinical practice, this paper addresses some issues related to RCTs on drug effects in mania. One major question raised in the paper is to what extent selection prior to the point of randomisation in RCTs in mania may limit the applicability of study results to patients seen in ordinary clinical practice. Although such limitations in generalisability can be difficult to investigate empirically, it is emphasised that they should be openly discussed in the reports of RCTs. Another major focus is the issue of evaluation and interpretation of outcome, including a discussion of various response criteria based on mania rating scale scores. It is pointed out that essential criteria of dimensionality have only been sufficiently evaluated for the Bech-Rafaelsen Mania Rating Scale, although the fulfilment of such criteria are prerequisites for adding up the item scores to a total score reflecting the severity of mania. It is suggested that response defined as a decline in mania score below a certain limit may have some advantages over the commonly used 50% reduction criterion. The issues arising from the unusual high drop-out rates of around 50% are also addressed. Despite the fact that we need rigorous placebo-controlled trials to establish antimanic efficacy of new compounds, we also need large scale pragmatic studies using broad inclusion criteria, comparing the various treatments, alone or in combination, to investigate how they work in clinical practice. These studies maybe randomised but open and use simple but relevant outcome measures.     

Strengthening clinical effectiveness trials: equipoise-stratified randomization.

As psychiatric practice patterns evolve to take advantage of the growing list of treatments with proven efficacy, research studies with broader aims will become increasingly important. Randomized trials may need to accommodate multiple treatment options. In completely randomized designs, patients are assigned at random to one of the options, requiring that patients and clinicians find each of the options acceptable. In "clinician's choice" designs, patients are randomized to a small number of broad strategies and the choice of specific option within the broad strategy is left up to the clinician. The clinician's choice design permits some scope to patient and clinician preferences, but sacrifices the ability to make randomization-based comparisons of specific options. We describe a new approach, which we call the "equipoise stratified" design, that merges the advantages and avoids the disadvantages of the other two designs for clinical trials. The three designs are contrasted, using the National Institute of Mental Health Sequenced Treatment Alternatives to Relieve Depression trial as an example.     

Opportunities and challenges presented by the new generation antipsychotics

The widespread availability of the new generation of atypical antipsychotics offers the clinician valuable new opportunities to prescribe effective and well-tolerated drug treatments for schizophrenia. As a group, the atypical antipsychotics are distinguished from the conventional agents by their lower propensity to induce extrapyramidal symptoms (EPS). In addition, some of these agents seem to be less likely to cause hyperprolactinaemia; this may contribute to a lower incidence of sexual and hormonal side-effects than with standard treatment regimens. EPS and sexual difficulties cause considerable distress to patients; there are grounds for predicting that better tolerability will lead to better compliance with treatment and thereby better long-term outcome. There is accumulating evidence that the atypical antipsychotics are more efficacious than the standard treatments; this may reflect greater tolerability and enhanced compliance with treatment, in addition to intrinsic efficacy. But, at the same time, the new treatments pose fresh challenges to the clinician. These agents differ from one another and the traditional antipsychotics in their pharmacology, side-effects and dosing requirements; clinicians are thus required to develop new treatment strategies, if these drugs are to be deployed to best effect. In particular, it is important that the new treatments are given rationally. Polypharmacy should be avoided, as this is unlikely to be more effective, and may lead to the tolerability benefits of the new agents being lost. Although clozapine is, rightly, reserved for treatment-resistant patients, on grounds of haematological safety, the practice of reserving other atypical antipsychotics for specific groups of patients, such as those with severe illness or established EPS, is misguided and results in the advantages of the atypical agents being denied to many patients who might otherwise have benefited greatly. These newer agents are best used within the setting of a strong therapeutic alliance between clinician and patient, in which an ongoing dialogue regarding symptoms, side-effects and treatment expectations is an important element. Used rationally, they offer new opportunities for clinicians and renewed hope to many patients.     

Algorithms for optimizing the treatment of depression: making the right decision at the right time

Medication algorithms for the treatment of depression are designed to optimize both treatment implementation and the appropriateness of treatment strategies. Thus, they are essential tools for treating and avoiding refractory depression. Treatment algorithms are explicit treatment protocols that provide specific therapeutic pathways and decision-making tools at critical decision points throughout the treatment process. The present article provides an overview of major projects of algorithm research in the field of antidepressant therapy. The Berlin Algorithm Project and the Texas Medication Algorithm Project (TMAP) compare algorithm-guided treatments with treatment as usual. The Sequenced Treatment Alternatives to Relieve Depression Project (STAR*D) compares different treatment strategies in treatment-resistant patients.     

Randomized controlled trials in psychiatry. Part II: their relationship to clinical practice

OBJECTIVE: To discuss the extent to which the results of randomized controlled trials (RCTs) in psychiatry can be generalized to clinical practice. METHOD: Threats to internal and external validity in psychiatric RCTs are reviewed. RESULTS: Threats to internal validity increase the possibility of bias. Psychiatric RCTs have problems with small samples, arbitrary definitions of caseness, disparate definitions of outcome and high spontaneous recovery rates. Particular issues arise in psychotherapy RCTs. Threats to external validity reduce the extent to which the results of a RCT produce a correct basis for generalization to other circumstances. These include high rates of comorbidity and sub syndromal pathology in normal clinical practice, manual-based treatment protocols and varying definitions of successful treatment. CONCLUSIONS: Randomized controlled trials remain the most robust design to investigate the effectiveness of treatments. They should be applied to important clinical questions; and carried out, as far as possible, with typical patients in the clinical conditions in which the treatment is likely to be used.     

Challenges to evidence-based medicine:

BACKGROUND: The practice of evidence-based medicine depends on the availability of clinically relevant research, yet questions have been raised about the generalizability of findings from randomized controlled trials (RCTs). OBJECTIVES: The aim of this study was to quantify differences between RCT patients and treatments and those in day-to-day clinical practice. RESEARCH DESIGN: Data from published reports of two key RCTs underlying recent treatment advances in psychiatry were compared with data on routine psychiatric practice collected through a Practice Research Network (PRN). SETTING: Hospital inpatient units (RCT) and the full range of psychiatric practice settings in the United States (PRN). SUBJECTS: Adults with bipolar I disorder and adults with schizophrenia. MEASURES: Demographic (age, gender, race), clinical (principal diagnoses, comorbid conditions, psychosocial functioning, and histories of hospitalization), and treatment (medication name and dosage) characteristics. RESULTS: PRN patients had more comorbid conditions and were more likely to be white, female, and older than RCT patients. In all, 38% of PRN patients with schizophrenia and 55% of PRN patients with bipolar I disorder would have been ineligible for the corresponding RCT. Most PRN patients receiving an RCT study medication were also receiving other medications not allowed by the RCT protocol. CONCLUSIONS: Findings support the assertion that RCT patients and treatments are not typical of those in clinical practice, and most patients in clinical practice are receiving treatments that do not have direct empirical support. Research is needed to determine the extent to which RCT findings should be used to guide routine clinical decisions.     

Best interests in the 'vegetative state'

Treatment decisions for patients in the vegetative state often have to be based on the patient's best interests, if the patient's will is not known. Physicians are, however, highly uncertain what kind of treatment is in such a difficult situation the patient's best interests. This article presents new insights from neuroscience and shows how treatment decision making should proceed to reach an ethically justified decision. Pivotal elements are a careful diagnosis using validated behavioural scales, an informed judgment about the existence of awareness and sentience, and an early prognostic assessment. As new imaging techniques and treatment options are not yet clinical standard due to low evidence, the best interests have to be judged in the context of uncertainty. The leading question should be whether the preferred treatment goal can be achieved with a realistic probability and a justifiable benefit-harm-ratio. This has to be judged for the individual patient, considering his personality and communicating with the family members. There cannot be a general answer to the question of best interests in the vegetative state, but only an individual answer in shared responsibility and based on the particular features of a special case.     

Treatment of cocaine dependence and depression.

In common with all other classes of substance use disorders, cocaine dependence has been shown to be strongly associated with depression by community and clinical surveys. Diagnosing depression in cocaine abusers can be challenging because it is difficult to distinguish transient symptoms caused by cocaine from enduring depression syndromes. Nonetheless, both "substance-induced" and "independent" depression syndromes require clinical attention, especially when symptoms have been persistent and severe before entering treatment. Use of antidepressant medications for combined cocaine dependence and depression is supported by a preponderance of evidence from 4 randomized clinical trials (RCTs) that prospectively targeted both depression and cocaine dependence and 7 RCTs in which a post hoc analyses demonstrated efficacy in the subgroup of cocaine abusers with comorbid depression. Notably, most negative studies have evaluated SSRIs while positive studies have used agents such as desipramine or buproprion. A substantial clinical trials literature supports the efficacy of behavioral treatments for general populations of cocaine abusers and of patients with depression but few studies have addressed patients with both disorders. Treatment development and research are needed on models of care that truly integrate strategies for addressing both cocaine use and depression. Recent advances have paved the way for a new generation of research. These include validation of efficacious cocaine treatments, improved diagnostic methods, organization of the Clinical Trials Network and development of guidelines for managing methodological challenges posed by high rates of current medication use and polysubstance abuse in treatment entering cocaine abusers.     

Randomized controlled versus naturalistic studies: a new research agenda

The present article addresses the question of what kind of evidence is required to demonstrate that a method of psychotherapy works. Referring to recent conceptualizations of the logical structure of scientific theories, that is, the structuralistic view of theories, the author shows that randomized controlled studies (RCTs) and naturalistic studies (effectiveness studies) refer to different domains of intended applications (laboratory vs. field). This view has several important implications: (1) RCTs and naturalistic studies do not differ concerning their internal and external validity; (2) naturalistic studies do not necessarily provide lower-level evidence than RCTs; (3) evidence from RCTs cannot be transferred to psychotherapeutic practice in the field; (4) naturalistic studies are required to demonstrate that a form of therapy works in the field; (5) The proposed catalogues for levels of evidence focus on RCTs; thus, they cannot be applied to the question if a therapy works in the field; (6) It is necessary to define separate criteria for levels of evidence of naturalistic studies; and (7) a new research agenda for naturalistic studies can be derived, which is analogous to that of efficacy studies. In this article, a proposal is made to define levels of evidence of naturalistic studies. A gold standard for naturalistic studies is proposed.     

Past and present progress in the pharmacologic treatment of schizophrenia

Despite treatment advances over the past decades, schizophrenia remains one of the most severe psychiatric disorders that is associated with a chronic relapsing course and marked functional impairment in a substantial proportion of patients. In this article, a historical overview of the pharmacologic advances in the treatment of schizophrenia over the past 50 years is presented. This is followed by a review of the current developments in optimizing the treatment and outcomes in patients with schizophrenia. Methodological challenges, potential solutions, and areas of particular need for further research are highlighted. Although treatment goals of response, remission, and recovery have been defined more uniformly, a good "effectiveness" measure mapping onto functional outcomes is still lacking. Moreover, the field must advance in transferring measurement-based approaches from research to clinical practice. There is an ongoing debate regarding whether and which first- or second-generation antipsychotics should be used. However, especially when considering individual adverse effect profiles, the differentiation into first- and second-generation antipsychotics as unified classes cannot be upheld, and a more differentiated view and treatment selection are required. The desired, individualized treatment approach needs to consider current symptoms, comorbid conditions, past therapeutic response, and adverse effects, as well as patient choice and expectations. Acute and long-term goals and effects of medication treatment should be balanced. To date, clozapine is the only evidence-based treatment for refractory patients, and the role of antipsychotic polypharmacy and other augmentation strategies remains unclear, at best. To discover novel treatments with enhanced/broader efficacy and improved tolerability, and to enable personalized treatment, the mechanisms underlying illness development and progression, symptomatic improvement, and side effect development need to be elucidated.     

Treating nerves: a call to arms

Abstract   The process of proving that new treatments for peripheral nerve diseases work has often been slow and inefficient. The lack of adequate evidence for some existing treatments has been highlighted by Cochrane systematic reviews. This article uses four different conditions to illustrate the need for more research. Both corticosteroid injections and surgical decompression of the median nerve are efficacious in carpal tunnel syndrome, but whether corticosteroid injections avoid the need for operation needs to be discovered. Corticosteroids are efficacious for Bell's palsy, but the role of antiviral agents needs clarification, which should come from ongoing trials. Intravenous immunoglobulin (IVIg) and plasma exchange are both efficacious in Guillain-Barré syndrome, but corticosteroids are not. More trials are needed to discover the best dose of IVIg in severe cases and whether mild cases need treatment. In chronic inflammatory demyelinating polyradiculoneuropathy, corticosteroids, IVIg and plasma exchange are all efficacious, at least in the short term, but trials are needed to discover whether and which other immunosuppressive agents help. The Peripheral Nerve Society has formed a standing committee, the Inflammatory Neuropathy Consortium ( http://pns.ucsd.edu/INC.htm ), to facilitate the trials needed to answer the remaining questions in the inflammatory neuropathies.     

Conducting clinical research in community mental health settings: Opportunities and challenges

Tremendous progress has been made in the past decade surrounding the underlying mechanisms and treatment of neuropsychiatric disease. Technological advancements and a broadened research paradigm have contributed to the understanding of the neurochemistry, brain function and brain circuitry involved in neuropsychiatric disorders. The predominant area of unmet medical need in the United States is major psychiatric disorders, and major depressive disorder is the leading cause of disability for ages 15-44. Total spending on research and development by the pharmaceutical industry has grown exponentially during the past decade, but fewer new molecular entities (NME) for the treatment of major psychiatric disorders have received regulatory approvals compared to other therapeutic areas. Though significant expansion has occurred during the “decade of the brain”, the translation of clinical trials outcomes into the community mental health setting is deficient. Randomized controlled trials (RCTs) have been the standard approach to clinical evaluation of the safety and efficacy of NMEs for the past 60 years; however, there are significant barriers and skepticism in the implementation of evidence-based outcomes into clinical practice. Recruitment of patients, shortages of experienced clinical researchers, regulatory requirements and later translation of outcomes into clinical practice are ever growing problems faced by investigators. The community mental health setting presents particular barriers in the replication of therapeutic outcomes from RCTs. The diagnostic complexity of major psychiatric diseases and the highly selective patient populations involved in clinical trials lend to the gap in translation from the “bench to the bedside”. The community mental health setting lends to a diverse patient population with numerous co-morbidities and environmental factors that are unaccounted in the average RCT. While we acknowledge the enormous complexity in developing novel and innovative treatments for major psychiatric disorders, we must continue to improve the translatability of clinical trials to real world settings. Progress has been rather slow but as the gap in treatment effectiveness is reduced, so will costs and barriers in community mental health.     

Psychotherapy for personality disorders

Personality disorders are widely prevalent among those seeking mental health services, resulting in substantial distress and a heavy burden on public assistance and health resources. We conducted a qualitative review of randomized controlled trials (RCTs) of psychosocial interventions for personality disorders. Articles were identified through searches of electronic databases and classified based on the focus of the psychological intervention. Data regarding treatment, participants and outcomes were identified. We identified 33 RCTs that evaluated the efficacy of various psychosocial treatments. Of these studies, 19 focused on treatment of borderline personality disorder, and suggested that there are several efficacious treatments and one well-established treatment for this disorder. In contrast, only five RCTs examined the efficacy of treatments for Cluster C personality disorders, and no RCTs tested the efficacy of treatments for Cluster A personality disorders. Although other personality disorders, especially Cluster A, place heavy demands on public assistance, and in spite of recommendations that psychosocial interventions should be the first line of treatment for these disorders, our review underscored the dearth of treatment research for many of these personality disorders. We highlight some obstacles to such research and suggest directions for future research.     

Are co-therapies indicated in schizophrenia?]

The "cotherapies" which are often indicated for neurotic patients, see to be more difficult to be used for psychotic patients. What are the advantages of such treatments for schizophrenic patients? Using case stories we are going to try to know the good prognosis factors for the success of these cotherapeutical treatment. Our situation is particular: one of us is a full-time, the other is psychoanalyst and a consultant-psychiatrist in the same hospital.     

Pharmacotherapy of Alzheimer disease.

OBJECTIVE: To systematically review published clinical trials of the pharmacotherapy of Alzheimer disease (AD). METHOD: We searched MEDLINE for published English-language medical literature, using Alzheimer disease and treatment as key words. No other search engine was used. Our review focused on randomized clinical trials (RCTs) and corresponding metaanalyses. RESULTS: Although there are many RCTs for the treatment of mild cognitive impairment (MCI), none have been successful in their primary analysis. The cholinesterase inhibitors donepezil, rivastigmine, and galantamine have demonstrated efficacy in 3- to 12-month placebo-controlled RCTs assessing cognitive, functional, behavioural, and global outcomes in patients with mildly to moderately severe AD. Recent data from patients with severe stages of AD demonstrate the efficacy of donepezil on cognitive and functional measures but not on behaviour. The N-methyl-D-aspartate receptor antagonist memantine has been demonstrated to be effective in 6-month, placebo-controlled RCTs of 6 months duration assessing cognitive, functional, and global outcomes of inpatients with moderate-to-severe AD (defined as a Mini Mental State Examination score below 20). Post hoc analyses have demonstrated a benefit in regard to agitation and (or) aggression, but this needs to be confirmed in a prospective RCT across Canada. Disease-modifying treatments are being tested in mild stages of AD in 18-month RCTs with cognitive and global outcomes as primary efficacy outcomes, primarily with drugs reducing amyloid synthesis or aggregation. Successful treatment in mild stages of AD could lead to RCTs in MCI and, possibly, in genetically high-risk asymptomatic individuals. CONCLUSION: The significant advances in the symptomatic pharmacotherapy of AD may be followed by disease-modification treatments.     

Generating evidence to inform policy and practice: the example of the second generation "atypical" antipsychotics

The introduction of the second generation "atypical" antipsychotics has been heralded as a major advance in the treatment of schizophrenia and other psychotic disorders. Systematic reviews have revealed only modest advantages over conventional antipsychotics and uncertainty about long-term efficacy and safety, yet the second generation antipsychotic drugs have been widely accepted into clinical practice. Although the existing evidence of the benefits and harms of atypical antipsychotics can facilitate decision making about individual patients, the randomized evidence remains inadequate to make valid and fully evidence-based policy statements such as clinical practice guidelines that are designed to apply to groups of patients. Further large randomized trials are needed, but these require patients and clinicians to be in equipoise, or substantially uncertain, about alternative therapies. Premature clinical practice guidelines or expert opinion can lead to changes in clinical practice that make it difficult or impossible to conduct the required trials and are therefore a disservice to patients.     

Updates and future horizons on the understanding, diagnosis, and treatment of Sturge-Weber syndrome brain involvement

Aim To review recent developments in the understanding, diagnosis, and treatment of Sturge–Weber syndrome (SWS). Method Members of the Brain Vascular Malformation Consortium Sturge–Weber Syndrome National Workgroup contributed their expertise to review the literature and present promising directions for research. Results The increasing number of reports dealing with SWS over the last decade reflects progress in the diagnosis and understanding of the neurological involvement. The proliferation of centers and advocacy groups to care for patients with SWS and to stimulate research has aided the development of new insights into the clinical manifestations and the pathophysiology of neurological progression, and the development of novel hypotheses to direct future research. Many key questions remain, but the tools and networks to answer them are being developed. Interpretation This review summarizes important new knowledge and presents new research directions that are likely to provide further insights, earlier diagnosis, improved treatments, and possibly, prevention of this syndrome.     

Psychotherapy for personality disorders

Abstract

Personality disorders are widely prevalent among those seeking mental health services, resulting in substantial distress and a heavy burden on public assistance and health resources. We conducted a qualitative review of randomized controlled trials (RCTs) of psychosocial interventions for personality disorders. Articles were identified through searches of electronic databases and classified based on the focus of the psychological intervention. Data regarding treatment, participants and outcomes were identified. We identified 33 RCTs that evaluated the efficacy of various psychosocial treatments. Of these studies, 19 focused on treatment of borderline personality disorder, and suggested that there are several efficacious treatments and one well-established treatment for this disorder. In contrast, only five RCTs examined the efficacy of treatments for Cluster C personality disorders, and no RCTs tested the efficacy of treatments for Cluster A personality disorders. Although other personality disorders, especially Cluster A, place heavy demands on public assistance, and in spite of recommendations that psychosocial interventions should be the first line of treatment for these disorders, our review underscored the dearth of treatment research for many of these personality disorders. We highlight some obstacles to such research and suggest directions for future research.