Virtual reality treatment and assessments for post-stroke unilateral spatial neglect: A systematic literature review

Unilateral spatial neglect (USN) is a highly prevalent post-stroke deficit. Currently, there is no gold standard USN assessment which encompasses the heterogeneity of this disorder and that is sensitive to detect mild deficits. Similarly, there is a limited number of high quality studies suggesting that conventional USN treatments are effective in improving functional outcomes and reducing disability. Virtual reality (VR) provides enhanced methods for USN assessment and treatment. To establish best-practice recommendations with respect to its use, it is necessary to appraise the existing evidence. This systematic review aimed to identify and appraise existing VR-based USN assessments; and to determine whether VR is more effective than conventional therapy. Assessment tools were critically appraised using standard criteria. The methodological quality of the treatment trials was rated by two authors. The level of evidence according to stage of recovery was determined. Findings were compiled into a VR-based USN Assessment and Treatment Toolkit (VR-ATT). Twenty-three studies were identified. The proposed VR tools augmented the conventional assessment strategies. However, most studies lacked analysis of psychometric properties. There is limited evidence that VR is more effective than conventional therapy in improving USN symptoms in patients with stroke. It was concluded that VR-ATT could facilitate identification and decision-making as to the appropriateness of VR-based USN assessments and treatments across the continuum of stroke care, but more evidence is required on treatment effectiveness.     

Do effectiveness (“real world”) studies on antipsychotics tell us the real truth?

In recent years, so-called "effectiveness studies" have gained increasing importance in the context of evidence-based medicine. These studies supposedly follow less restrictive methodological standards than phase III studies in terms of patient selection, co-medication and other design issues, and their results should therefore be better generalisable than those of phase III studies. Effectiveness studies, like other types of phase IV studies, can therefore contribute to the knowledge about antipsychotics or other psychopharmaceuticals and supply relevant information in addition to that gained from phase III trials. However, the less restrictive design and inherent methodological problems of phase IV studies mean that their results cannot falsify the results of phase III studies. The greater complexity of phase IV studies, for example the greater variance caused by the different kinds of confounders, means that their results have to be interpreted with great care and especially with a high degree of awareness of problematic design issues, such as insensitive primary outcome criteria, biased randomisation, unblinded treatment conditions, inclusion of chronic refractory patients, etc. Some recently published effectiveness studies on antipsychotic treatment of schizophrenia will be discussed under these methodological aspects. The main conclusions of these trials will be questioned on the basis of their severe methodological pitfalls.     

First-onset tics in patients with attention-deficit-hyperactivity disorder: impact of stimulants

First-onset tics during stimulant treatment of attention-deficit-hyperactivity disorder (ADHD) are clinically relevant and remain a matter of scientific debate. Because there are limited clinical trials analyzing the risk of first-onset tics in stimulant-treated ADHD, a comprehensive evaluation is required for evidence-based clinical recommendations. An analysis of studies with high methodological quality (i.e. double-blind placebo-controlled) on first-onset tics during stimulant treatment of ADHD revealed that there seems to be no elevated risk of first-onset tics in children undergoing this treatment. Although a close temporal relationship might be seen in a few patients, the role of treatment duration, dose of stimulant, genetic vulnerability, and developmental aspects need to be further explored to clarify possible pathophysiological mechanisms of tic emergence under stimulant treatment. The results of high quality studies, in addition to specialized studies with methodological limitations, suggest that stimulants are the criterion standard for the safe and successful treatment of ADHD.     

Pharmacoeconomic evaluation of medical treatment of epilepsy: where do we stand?

Qualitative and quantitative improvements of pharmaco-economic evaluation of antiepileptic drugs have been realized during the last decade. Assessment of medical treatments is mainly performed through cost-minimization studies, owing to similar effectiveness of AED. Studies recently published generally consider hypothetical cohorts of patients and assess resource utilization and medical effects on the basis of clinical trials and expert panels, limiting evaluation to direct costs. But they differ in numerous ways due to: the type of patients and treatment considered, the time span of evaluation, and cost measurement. Comparison between studies is therefore tricky but it seems that, when considering monotherapy treatments, carbamazepine and phenytoin are somewhat cheaper than valproate while lamotrigine is much more expensive but no more effective. However, these and other antiepileptic agents appear as close substitutes when prescribed as adjunctive treatments. Refined tools have been developed to take into account slight differences exhibited on certain outcomes. One direction currently under evaluation relates to quality of life, and this will probably leads to an increasing number of cost-utility studies. Some advances, regarding information on medical resources consumed and outcomes associated with alternative drugs, as well as methodological options, are still needed to fully develop pharmacoeconomic evaluation of antiepileptic treatments.     

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.     

Lessons from large trials: the MTA study as a model for evaluating the treatment of childhood psychiatric disorder.

OBJECTIVE: To review the methodology of the Multimodal Treatment Study of Children With Attention-Deficit Hyperactivity Disorder (ADHD), the MTA study, and its implications for the design of future child mental health treatment studies. METHOD: The characteristics of large-scale studies envisioned by trialists engaged in cardiovascular and cancer research provide the framework for reviewing key elements of the MTA study--objectives, research questions, measurement, sampling, and exposure to treatment--and discussing important methodological decisions the MTA investigators had to make. RESULTS: The MTA study is a complex, standardized, carefully implemented, randomized control trial. Review of the MTA study indicated that future studies should be aligned clearly with either effectiveness or efficacy objectives but not both. Questions selected for study should be simple, clear, and important. Measurement, sampling, and data collection must adhere to the principle of simplicity to ensure maximum participation. All methodological decisions should be geared to attaining the research objectives: in effectiveness trials, this means evaluating treatments that have a high potential for dissemination if proven successful and recruiting only new referrals from child mental health settings. CONCLUSIONS: The MTA study has raised the standard for technical excellence in child treatment research and will draw attention to some fundamental issues in large-scale child treatment studies, including articulating objectives and questions, setting priorities for measurement and sampling, and identifying treatments for evaluation that have a high probability of dissemination if found effective.     

Clinical trials in multiple sclerosis: methodological issues

PURPOSE OF REVIEW: The availability of partially effective immunomodulatory and immunosuppressive treatments for relapsing multiple sclerosis (MS) opens important ethical, methodological and practical issues in the design and conduct of new clinical trials in these patients. RECENT FINDINGS: The recommendation of the National Health Authorities to prioritize phase III clinical trials using placebo arm raises ethical questions. In addition, patients are reluctant to be involved in such trials. Alternative clinical trial designs will be discussed. Relapses and active lesions are accepted measures of disease activity; new/enlarging T2 lesions and/or enhancing lesions are accepted surrogate markers of disease activity in phase II clinical trials. On the contrary, there are no accepted magnetic resonance imaging (MRI) surrogate markers of disease progression and also the clinical measures to monitor the degenerative aspects of the disease are not without important limitations. New scales of impairment, disability and quality of life will be reviewed extensively. We will also focus on the value of modern and quantitative MRI techniques, which hold substantial promise as tools to estimate the extent of MS-related irreversible tissue loss. SUMMARY: The use of an active comparator in a superior clinical-trial design is becoming an attractive option for testing the efficacy of new drugs in relapsing MS. At present there are no fully reliable and sensitive clinical markers of the accumulation of irreversible tissue damage in MS. Although additional extensive application in longitudinal studies is needed, modern MRI techniques are promising tools to monitor the neurodegenerative aspects of MS.     

Clinical trial design in schizophrenia: implications for clinical decisions

PURPOSE OF REVIEW: Results from clinical trials do not necessarily provide information for decisions in clinical practice. This review aims to present strengths and limitations of different methodological types of clinical trials and to offer an overview of how knowledge from clinical trails can be distilled for clinical practice. Selected key questions in the treatment of schizophrenia are presented, with a focus on the possibilities and restrictions of translating trial results into real-world practice. RECENT FINDINGS: Randomized controlled trials are the gold standard for proving efficacy of a diagnostic or therapeutic procedure. They have a high degree of internal validity and a clear-cut message when conducted to good-quality standards but suffer from a lack of generalizability (external validity). Effectiveness studies evaluate effects of treatments under conditions approximating usual care. They may include patient-centred outcomes or health economic evaluations. According to the type of trial, specific problems arise in the interpretation of results. Typical examples are given for the treatment of acute exacerbations of schizophrenia, for relapse prevention and for the treatment of cognitive impairment. SUMMARY: Clinical decisions have to be made upon the best knowledge. Therefore, well conducted studies addressing all major issues from all relevant perspectives are needed. The assessment of a treatment regimen for clinical utility requires both efficacy and effectiveness studies. An understanding of the design, analysis and conventions of both study types is essential for the interpretation of results and their translation to the clinical decision-making process.     

Development of an Instrument to Characterize Methodological and Collaborative Factors that May Influence Community-Based Clinician Post-Trial Adoption of Clinical Research Interventions

Participation in clinical research trials has been hypothesized to facilitate the adoption of evidence-based practices by community-based substance abuse treatment providers. However, little empirical information is available regarding the methodological and collaborative characteristics of research trials that may affect the chances of adoption. The current paper describes the development of the Survey of Practiced Research Efforts to Aid Dissemination (SPREAD), a standardized instrument designed to measure characteristics of clinical trials that may facilitate adoption. The survey was administered to a sample of 33 community-based research trials from the top four impact factor journals of 2007. Overall, methodological quality was high and levels of collaboration were low, with little involvement of community-based clinic staff in most study related activities. Future research to determine the predictive validity of the SPREAD instrument on post-trial adoption of studies interventions in clinical research is encouraged.     

Technology insight: neuroengineering and epilepsy-designing devices for seizure control

Despite substantial innovations in antiepileptic drug therapy over the past 15 years, the proportion of patients with uncontrolled epilepsy has not changed, highlighting the need for new treatment strategies. New implantable antiepileptic devices, which are currently under development and in pivotal clinical trials, hold great promise for improving the quality of life of millions of people with epileptic seizures worldwide. A broad range of strategies to stop seizures is currently being investigated, with various modes of control and intervention. The success of novel antiepileptic devices rests upon collaboration between neuroengineers, physicians and industry to adapt new technologies for clinical use. The initial results with these technologies are exciting, but considerable development and controlled clinical trials will be required before these treatments earn a place in our standard of clinical care.     

Interventions for treating the posterior interosseus nerve syndrome: a systematic review of observational studies

For the posterior interosseus nerve syndrome (PINS), no randomised controlled trials or controlled clinical trials about the effectiveness of interventions are available; only case series can be found. Although the validity of case series is inferior to controlled trials, they may provide valuable data about the efficacy of treatment options. Therefore, we systematically reviewed all available observational studies on treatment of PINS. A literature search and additional reference checking was done. On the basis of previous checklists, we constructed a quality assessment and rating system to analyse the included case series. Studies with less than 50% of the maximum points on the methodological quality assessment were excluded from the analysis. The results are summarised according to a rating system for the strength of the scientific evidence. Six eligible case series for this review were found. After the data extraction and methodological quality assessment, two higher quality studies that evaluated the effectiveness of surgical decompression of the PIN were included in the final analysis. There is a tendency for the effectiveness of surgical decompression of the PIN in patients with PINS. The effectiveness of a conservative treatment for PINS is unknown because no higher quality studies are available. Additional high-quality controlled studies are needed to assess the level of 'conclusive evidence' for surgical treatment. There is also a need for high-quality controlled trials into the effectiveness of conservative treatments for PINS.     

Clinical trials in Europe and the development of new psychotropics as viewed by European manufacturers

A number of external and internal (industry-specific) difficulties and problems related to clinical trials and the development of new psychotropics in Europe, are reviewed. These can be classified into 3 interdependent categories of problems: 1. strategy-related; 2. implementation-related; 3. time-related. Apart from ethical and methodological issues, the external problems are: a) diversity of country-specific regulations and requirements for registration and drug approval; b) differences in culture, traditions, education and training background of investigators and patients; c) high competition for good trial centers; d) increasing pressure and negative attitude from public media with respect to clinical testing of drugs. In the strategic planning of the development of a new drug, resources and heavy/costly logistic commitments for each individual study have to be taken into consideration. For the manufacturers it is therefore imperative to fix the plans and the kind of the studies to be performed sometimes several years in advance. Conflict often arises with respect to the developmental changes, both in environmental conditions and in the state of the art. Implementation of the clinical, particularly multicenter/multinational trials poses problems of multilingual documentation, heavy logistics of drug supply, quality control and monitoring of the studies. Inherent to these European problems is a unproportional high time expenditure which has important consequences for scientific progress and economy. Possible solutions for these problems are discussed. The initial steps in this direction will be the establishment of European standards for clinical trials, and uniform requirements for drug registration and approval.     

The effectiveness of physiotherapy for cervical dystonia: a systematic literature review

Cervical dystonia is a form of adult-onset, focal dystonia characterized by involuntary contractions of the neck muscles, leading to a disabling, abnormal head posture. CD has a great impact on the activities of daily living (ADL) and quality of life. Currently, the most widely used and recommended first line treatment is botulinum toxin type A (BoNT/A) injections. Physiotherapy is a potentially useful adjuvant, but little is known about its effectiveness. Consequently, our objective was to investigate the effectiveness of physiotherapy alone or as an adjuvant treatment to BoNT/A injections in cervical dystonia (CD) by means of a systematic literature review. Two online databases, PubMed and Web of Science, were searched for articles describing the effectiveness of physiotherapy treatment for CD. After screening, based on predefined in- and exclusion criteria, 16 studies were retained. Their methodological quality was assessed according to Cochrane guidelines. The methodological quality of most studies was low. Examples of shortcomings are small sample sizes, lack of randomization or blinding, and diversity in therapeutic techniques and outcome measures. Only seven studies were clinical trials; the remaining were either case reports or case series. The reported physiotherapy treatments included EMG biofeedback training, muscular elongation, postural exercises and electrotherapy. Improvements in head position, pain, cervical range of motion, quality of life and ADL have been reported, which is promising. Cautious interpretation on the effectiveness of physiotherapy as an adjuvant therapy is required. Before firm conclusions can be drawn, additional high quality trials are needed.     

The effect of waiting: A meta-analysis of wait-list control groups in trials for tinnitus distress

Objective

The response rates and effects of being placed on a wait-list control condition are well documented in psychiatric populations. Despite the usefulness of such estimates and the frequent use of no-treatment controls in clinical trials for tinnitus, the effect of waiting in a tinnitus trial has not been investigated systematically. The aim of the present study was to quantify the overall effect of wait-list control groups on tinnitus distress.

Methods

Studies were retrieved via a systematic review of randomised controlled trials of cognitive behaviour therapy for tinnitus distress. Outcomes of psychometrically robust tinnitus-specific measures (Tinnitus Handicap Inventory, Tinnitus Questionnaire, Tinnitus Reaction Questionnaire) from wait-list control groups were quantified using meta-analytic techniques. Percentage of change and standard mean difference effect sizes were calculated using the pre and post wait period.

Results

Eleven studies involving 314 wait-list subjects with tinnitus were located. The analysis for a waiting period of 6 to 12 weeks revealed a mean decrease in scores on tinnitus-specific measures of 3% to 8%. Across studies, a statically significant small mean within-group effect size was obtained (Hedges' g=.17). The effects were moderated by methodological quality of the trial, sample characteristics (i.e., age, tinnitus duration), time of the wait-list and how diagnosis was established.

Conclusion

Subjects in a tinnitus trial improve in tinnitus distress over a short waiting phase. The effects of waiting are highly variable and depend on the characteristics of the sample and of the trial.     

Lessons learned from failed and discontinued clinical trials for the treatment of Alzheimer's disease: future directions

While advances have been made in understanding the neurobiological processes underlying Alzheimer's disease (AD), few treatment options currently exist. Numerous potential therapeutic and/or preventive agents have been tested in clinical trials, yet most have failed to show a clear therapeutic benefit. The lack of effective medical therapies coupled with the incipient projected dramatic increase in the number of persons with AD in the coming decades has put medical research in a crisis to urgently find effective treatment and prevention strategies. Researchers and funding agencies have been rethinking investigative approaches in order to accelerate scientific discovery in AD therapeutics, including methodological issues in the design and implementation of clinical trials. This review discusses lessons learned from discontinued and failed clinical trials for the treatment and prevention of AD with an emphasis on future directions of AD clinical trials. In particular, attention is given to choice of study outcome measures, participant selection and retention, and clinical trial design. While there are few treatments available for AD currently, the potential for discovery over the next decade is promising.     

Valerian for insomnia: a systematic review of randomized clinical trials

Objective: To systematically review the evidence for the effects of the herb valerian (Valeriana officinalis) on insomnia, based on randomized, placebo-controlled, double-blind trials.Background: Valerian has long been advocated and used for promoting sleep but until quite recently evidence was solely anecdotal. However, during the last two decades a number of clinical trials have been conducted.Materials and methods: Systematic literature searches were performed to locate randomized, placebo-controlled, double-blind trials measuring the effect of valerian monopreparations on sleep in human participants. Data were extracted in a standardized manner and methodological quality was assessed by the Jadad score.Results: Nine trials were located meeting the selection criteria. The findings of the studies were contradictory and there was great inconsistency between trials in terms of patients, experimental design and procedures and methodological quality.Conclusion: The evidence for valerian as a treatment for insomnia is inconclusive. There is a need for rigorous trials to determine its efficacy.     

Studies of cognitive change in patients with schizophrenia following novel antipsychotic treatment

OBJECTIVE: Novel antipsychotic medications have been reported to have beneficial effects on cognitive functioning in patients with schizophrenia. However, these effects have been assessed in studies with considerable variation in methodology. A large number of investigator-initiated and industry-sponsored clinical trials are currently underway to determine the effect of various novel antipsychotics on cognitive deficits in patients with schizophrenia. The ability to discriminate between high- and low-quality studies will be required to understand the true implications of these studies and their relevance to clinical practice. METHOD: This article addresses several aspects of research on cognitive enhancement in schizophrenia, emphasizing how the assessment of cognitive function in clinical trials requires certain standards of study design to lead to interpretable results. RESULTS: Novel antipsychotic medications appear to have preliminary promise for the enhancement of cognitive functioning. However, the methodology for assessing the treatment of cognitive deficits is still being developed. CONCLUSIONS: Researchers and clinicians alike need to approach publications in this area with a watchful eye toward methodological weaknesses that limit the interpretability of findings.     

General and comparative efficacy and effectiveness of antidepressants in the acute treatment of depressive disorders: a report by the WPA section of pharmacopsychiatry

Current gold standard approaches to the treatment of depression include pharmacotherapeutic and psychotherapeutic interventions with social support. Due to current controversies concerning the efficacy of antidepressants in randomized controlled trials, the generalizability of study findings to wider clinical practice and the increasing importance of socioeconomic considerations, it seems timely to address the uncertainty of concerned patients and relatives, and their treating psychiatrists and general practitioners. We therefore discuss both the efficacy and clinical effectiveness of antidepressants in the treatment of depressive disorders. We explain and clarify useful measures for assessing clinically meaningful antidepressant treatment effects and the types of studies that are useful for addressing uncertainties. This includes considerations of methodological issues in randomized controlled studies, meta-analyses, and effectiveness studies. Furthermore, we summarize the differential efficacy and effectiveness of antidepressants with distinct pharmacodynamic properties, and differences between studies using antidepressants and/or psychotherapy. We also address the differential effectiveness of antidepressant drugs with differing modes of action and in varying subtypes of depressive disorder. After highlighting the clinical usefulness of treatment algorithms and the divergent biological, psychological, and clinical efforts to predict the effectiveness of antidepressant treatments, we conclude that the spectrum of different antidepressant treatments has broadened over the last few decades. The efficacy and clinical effectiveness of antidepressants is statistically significant, clinically relevant, and proven repeatedly. Further optimization of treatment can be helped by clearly structured treatment algorithms and the implementation of psychotherapeutic interventions. Modern individualized antidepressant treatment is in most cases a well-tolerated and efficacious approach to minimize the negative impact of otherwise potentially devastating and life-threatening outcomes in depressive disorders.

     

Cognitive impairment in multiple sclerosis

BACKGROUNd: Cognitive impairment is increasingly being recognized as a common and disabling symptom of multiple sclerosis (MS) that contributes to poor quality of life in affected patients. Despite the high prevalence of cognitive impairment in MS, cognitive function is not assessed routinely in clinical practice or in clinical trials. The perception that cognitive assessments are costly, time-consuming, complicated, and difficult to administer and interpret has contributed, at least in part, to the failure to incorporate cognitive testing into standard clinical evaluation of patients with MS. Detailed studies of cognitive impairment in MS are rare and guidelines for the assessment of cognitive function in MS are lacking.TREATMENT: How to manage cognitive decline in MS also requires further study. Licensed disease-modifying drug (DMD) treatments for MS reduce brain lesion development, and associations between brain lesions and cognitive performance have been reported, providing a rationale for DMD treatment of MS-associated cognitive impairment. There is some evidence for cognitive benefits of DMDs, but as few pivotal DMD trials included cognitive assessments, the effects of these agents on cognition are not fully understood and more studies are needed.CONCLUSIONS: It is only through further studies that it will be possible to identify patients with, or at risk of, cognitive impairment and to provide appropriate therapy to limit the effects of this potentially devastating symptom.