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.     

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.     

Assertive community treatment in the Netherlands: a randomized controlled trial

OBJECTIVE: Assertive community treatment is rapidly implemented by many European mental health services, but recently the evidence base has been questioned. Positive results of randomized trials in the USA were not replicated in the UK. The question is whether the UK findings are representative for other European countries with modern mental health services. METHOD: Open randomized controlled trial of long-term severely mentally ill patients [Health of the Nation Outcome Scales (HoNOS) total score >or=15], assigned to assertive community treatment (n = 59) or to standard community mental health care (n = 59). Primary outcome: sustained contact; housing stability and admission days. This trial is registered as an International Standard Randomized Clinical Trial, number ISRCTN 11281756. RESULTS: Assertive community treatment was significantly better in sustaining contact with patients, but not in reducing admission days. No differences in housing stability, psychopathology, social functioning or quality of life were found. CONCLUSION: The results are in agreement with UK studies. However, the sustained contact potential of assertive community treatment is important, as too many patients are lost in standard care.     

Compulsory Community and Involuntary Outpatient Treatment for People With Severe Mental Disorders

There is controversy as to whether compulsory community treatment (CCT) for people with severe mental illness (SMI) reduces health service use or improves clinical outcome and social functioning. To examine the effectiveness of CCT for people with SMI. We searched the Cochrane Schizophrenia Group’s Trials Register and Science Citation Index (2003, 2008, 2012, and 2013). We obtained all references of identified studies and contacted authors where necessary. All relevant randomized controlled clinical trials (RCTs) of CCT compared with standard care for people with SMI (mainly schizophrenia and schizophrenia-like disorders, bipolar disorder, or depression with psychotic features). Standard care could be voluntary treatment in the community or another preexisting form of compulsory community treatment such as supervised discharge. We found 3 trials with a total of 752 people. Two trials compared a form of CCT called ‘Outpatient Commitment’ (OPC) versus standard voluntary care, whereas the third compared Community Treatment Orders with intermittent supervised discharge. CCT was no more likely to result in better service use, social functioning, mental state, or quality of life compared with either standard voluntary or supervised care. However, people receiving CCT were less likely to be victims of crime than those on voluntary care. Further research is indicated into the effects of different types of CCT as these results are based on 3 relatively small trials.Key words: community treatment orders, outpatient commitment, mental health law, hospitalization/CTO     

An examination of leading mental health journals for evidence to inform evidence-based practice

OBJECTIVE: This study examined whether data needed to inform evidence-based practice can be found in leading mental health journals. METHODS: Research studies described in articles that were published in 12 leading mental health journals in 1999 were examined to determine whether they evaluated clinical interventions, used rigorous designs, were conducted in routine practice settings, and included well-defined diagnostic groups and heterogeneous samples. RESULTS: Twenty-seven percent (N=295) of the 1,076 articles that were reviewed described research that evaluated interventions. Of these 295 articles, 64 percent evaluated pharmacologic interventions and 33 percent evaluated psychosocial or psychotherapeutic interventions. Of the articles that evaluated interventions, 60 percent described randomized designs, but samples were modest; 25 percent of the studies reported 31 or fewer participants. Of the 295 articles, 84 percent described studies conducted in specialty mental health settings; very few (4 percent) described studies conducted in public mental health or managed care environments, which are common practice settings. Most samples were diagnostically well defined, but evidence of treatments for diagnoses other than schizophrenia and mood disorders was limited. CONCLUSIONS: This systematic review suggested that data needed to inform and advance evidence-based practice does not have the prominent place it deserves in leading journals. Only a quarter of the research studies that were examined evaluated clinical interventions, and articles that described pharmacologic interventions were published twice as often as articles that described psychosocial or psychotherapeutic interventions. Rigorous research designs predominated, but sample sizes were modest. Evidence was scarce on treatment effectiveness in routine practice settings.     

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.     

Bayesian adaptive non-inferiority with safety assessment: retrospective case study to highlight potential benefits and limitations of the approach

Adaptive trial design applied to randomized clinical trials of psychiatric medicines offers the potential to make clinical trials more efficient. In the current analysis, we retrospectively applied Bayesian adaptive allocation methods to a case study in agitated patients with schizophrenia and related diseases. The original study used a randomized, double-blind, parallel design. The objective of this analysis was to demonstrate the potential benefits of Bayesian adaptive designs by shortening the study duration and therefore limiting patient exposure to ineffective placebo or an active comparator with a known side effect. Bayesian methods allowed us to fully leverage historical data along with data observed as the study was ongoing to calculate predictive probabilities of patient response to treatment without experiencing a specified side effect. Using the Bayesian adaptive approach would have required less than half the number of patients as the original study to draw the same conclusion. Sample size was reduced from 311 to 156 patients, thereby decreasing the number of patients exposed to placebo from 54 to 30 and the number exposed to the active control with a known side effect from 126 to 60.     

What is the effectiveness of acute hospital treatment of older people with mental disorders?

AIM: To appraise the effectiveness of acute hospital service delivery in old age psychiatry. METHOD: A systematic literature search of the Medline, PsycINFO, CINAHL, EMBASE and Cochrane Collaboration databases was undertaken to obtain articles published in English from 1966 to May 2004 about old age psychiatry services. Articles were excluded if they did not focus on subjects over 60 years of age, did not include quantitative data on outcomes, or if the intervention was purely pharmacological or a specific non-pharmacological technique. The two authors independently assessed data quality. The overall quality of the evidence for the effectiveness of old age mental health service delivery was rated on an evidence hierarchy that has four levels of evidence. RESULTS: Forty-six studies were identified that met our criteria. The only randomized controlled trials (RCTs) were of consultation/liaison service provision and delirium prevention and hence the best quality evidence is for interventions to prevent delirium, reduce costs and length of stay (LOS) in medical wards (level II). There is lower quality (level III/IV), albeit consistently positive, evidence that acute hospital treatment by old age psychiatry services is effective. By contrast, there is no evidence (level I) that non-psychiatric hospital medical services improve mental health outcomes. CONCLUSION: There are gaps in our knowledge regarding the effectiveness of acute hospital treatment of mental disorders in old age. Multicenter studies involving comparisons of day hospitals, multidisciplinary community teams and acute hospital settings (old age mental health and adult mental health, with and without post-discharge community care) are required.     

Improving adherence to antidepressants: a systematic review of interventions

BACKGROUND: Effectiveness of antidepressant medication is reduced by patients' nonadherence. Several interventions to improve adherence in patients diagnosed with unipolar depression have been tested. OBJECTIVE: To systematically review the effectiveness of interventions that aimed to improve adherence to antidepressant medication in patients with unipolar depression. METHOD: Systematic review of English-language articles of randomized controlled trials obtained by a computerized literature search of MEDLINE (1966-January 2002) using the terms patient compliance, patient dropout, treatment refusal, patient education, adherence, clinical trial, randomized controlled trial, controlled trial, depressive disorder, and depression; PSYCINFO (1984-January 2002) using the terms random, clinical, control, trial, adherence, compliance, noncompliance, dropouts, patient education, depression, major depression, affective disorders, and dysthymic disorder; EMBASE (1980-January 2002) using the terms patient compliance, patient dropouts, illness behavior, treatment refusal, patient education, clinical trial, controlled study, randomized controlled trial, and depression; and the Cochrane Controlled Trials Register (no restrictions) using the terms random*, complian*, adheren*, pharmacotherapy, regimen*, educat*, medicat*, depression, and depressive disorder. RESULTS: Educational interventions to enhance adherence failed to demonstrate a clear benefit on adherence and depression outcome. However, collaborative care interventions tested in primary care demonstrated significant improvements in adherence during the acute and continuation phase of treatment and were associated with clinical benefit, especially in patients suffering from major depression who were prescribed adequate dosages of antidepressant medication. CONCLUSION: We found evidence to support the introduction of interventions to enhance adherence with antidepressant medication in primary care, not only because of better adherence but also because of better treatment results. Because collaborative care interventions require additional resources, a better understanding of the mode of action of different programs is needed to reduce avoidable costs. The effectiveness of educational interventions needs more evidence.     

Integrated care for co-occurring disorders: psychiatric symptoms, social functioning, and service costs at 18 months

OBJECTIVE: Persons with severe mental illness have high rates of comorbid substance use disorders. These co-occurring disorders present a significant challenge to community mental health services, and few clinical trials are available to guide the development of effective services for this population. The study aimed to evaluate the effectiveness of a program for case managers that trained them to manage substance use disorders among persons with severe mental illness. METHODS: A cluster-randomized controlled trial design was used in South London to allocate case managers either to training or to a waiting list control condition. Outcomes and service costs (health care and criminal justice) over 18 months of 127 patients treated by 40 case managers who received training were compared with those of 105 patients treated by 39 case managers in the control condition. RESULTS: Brief Psychiatric Rating Scale scores for the intervention group indicated significant improvements in psychotic and general psychopathology symptoms. Participants in the intervention group also reported fewer needs for care at follow-up. No significant differences were found between the two groups in levels of substance use at 18 months. At follow-up both groups reported increased satisfaction with care. Service costs were also similar for the two groups. CONCLUSIONS: Compared with standard care, integrated treatment for co-occurring disorders provided by nonspecialist mental health staff produced significant improvements in symptoms and level of met needs, but not in substance use or quality of life, at no additional cost.     

Lithium in mental handicap: A review

SUMMARY. Most mentally handicapped people live in the community where, like other people, their mental illnesses need treatment with a view to continued community care and health. Three aspects of mental ill health in people of average intelligence are known to be aided by lithium: cyclothymia (manic depression), depression, and overt aggression. This article reviews lithium literature in respect of mentally handicapped people, and goes on to illustrate its use with case studies of three successfully treated patients, and to discuss the clinical cues for mental health professionals. The information is based on community practice and two randomised controlled trials detailed elsewhere.     

Bridging the Gap Between Inpatient and Outpatient Providers Using Organizational Elements of Assertive Community Treatment

Even among comprehensive local public mental health systems, there remain large gaps in continuity of care following discharge from inpatient settings. The authors describe a modification of the assertive community treatment (ACT) program model that links inpatients to ongoing community-based care, and provide preliminary evidence of its effectiveness as a component in a rationally organized comprehensive system of care. Given the recent trend toward managed Medicaid arrangements, there will be increased pressure to reduce clients' length of stay in ACT programs. State mental health authorities are cautioned to resist allowing managed care contractors to radically change the conditions under which ACT programs operate until there is greater evidence of the effectiveness of alternative approaches.     

The Risperidone Outcomes Study of Effectiveness (ROSE): a model for evaluating treatment strategies in typical psychiatric practice

We describe the design of a multicenter, randomized clinical trial to compare clinical, quality-of-life, and economic outcomes in patients with schizophrenia or schizoaffective disorder who were treated with risperidone or any of 13 conventional antipsychotic drugs approved for use in the United States. This 1-year trial was designed to approximate conditions of typical clinical practice: protocol-mandated care was minimized, and all health services (including medication) were provided according to usual community practices. Measures of interest included changes in psychiatric symptoms, medication side effects, health-related quality of life, satisfaction with drug therapy, therapy switching, rehospitalization for the management of relapse, the use of psychiatric services of all types, and the cost of psychiatric care. We review the rationale for this type of trial and discuss the potential value of such trials in setting policy and in clinical practice.     

Teambasierte Gemeindepsychiatrie

The German Society for Psychiatry, Psychotherapy and Neurology (DGPPN) guidelines on psychosocial interventions for people with severe mental illness appraise the transferability of results of trials evaluating community-based mental health services to the German situation. This assessment has to draw on research results on factors determining effectiveness. This must be seen against the background of a lack of high-quality trials in Germany. The article discusses system, context and setting factors related to the transfer of evidence on community-based service models from other countries. These issues are discussed on the basis of evidence concerning the models of case management, assertive community treatment and community mental health teams. International differences in study findings are highlighted and the importance of treatment-as-usual in influencing study results is emphasized. The more control services including elements of community-based care there are and the less the pressure to reduce inpatient treatment (threshold to inpatient care admission), the smaller the relative effect sizes of innovative care models will be.In the absence of direct evidence, careful examination of transferability is required before introducing health care models. Research has revealed solid evidence for several factors influencing the effects of innovative community mental health care. Among key factors in the care of people with severe mental illness, home visits and joint team responsibility for both psychiatric and social care were identified. This evidence can facilitate the adaptation of successful mental health care models in Germany.     

Are Randomized Control Trials the Best Method to Assess the Effectiveness of Community Treatment Orders?

Many jurisdictions have enacted community treatment order (CTO) legislation that requires a person, who suffers from a severe mental disorder, to follow a treatment plan when living in the community. CTOs have been a source of debate because of controversies on whether evidence of effectiveness should only be considered from randomized controlled trials (RCTs). RCTs are considered the “gold standard” method to evaluate effectiveness of simple therapeutic interventions such as medication, but they are problematic for evaluation of complex interventions because valid attribution of causation in complex interventions is not guaranteed with RCTs. CTOs are complex interventions that require the interaction of many individuals and organizations to achieve their effects and effectiveness research must measure these complexities of delivery and outcomes. This paper examines conceptual, methodological and analytical challenges of CTO research within the context of RCTs and other research designs. It also discusses the current state of knowledge on effectiveness of CTOs. Finally, we suggest a way forward by presenting alternative causal inference approaches and potential models for evaluation complex interventions, such as CTOs. We propose that these approaches should be used alongside other research designs in a nuanced approach that may involve using findings from initial studies to refine the intervention and/or its implementation.     

FACT: Integrating Family Psychoeducation and Assertive Community Treatment

Family Psychoeducation and Assertive Community Treatment are both state-of-the-art service systems with rich empirical foundations, demonstrating unusual effectiveness in randomized clinical trials. Recent research suggests a possible additive effect on selected outcomes when the two approaches are integrated. This paper reviews the role of family support and intervention in the care of persons with serious mental illnesses, presents the research literature on psychoeducation, and highlights benefits of merging the multiple-family version of this approach into the work of assertive community treatment programs.     

Design and implementation of a randomized trial evaluating systematic care for bipolar disorder

Objectives: Everyday care of bipolar disorder typically falls short of evidence‐based practice. This report describes the design and implementation of a randomized trial evaluating a systematic program to improve quality and continuity of care for bipolar disorder. Methods: Computerized records of a large health plan were used to identify all patients treated for bipolar disorder. Following a baseline diagnostic assessment, eligible and consenting patients were randomly assigned to either continued usual care or a multifaceted intervention program including: development of a collaborative treatment plan, monthly telephone monitoring by a dedicated nurse care manager, feedback of monitoring results and algorithm‐based medication recommendations to treating mental health providers, as‐needed outreach and care coordination, and a structured psychoeducational group program (the Life Goals Program by Bauer and McBride) delivered by the nurse care manager. Blinded assessments of clinical outcomes, functional outcomes, and treatment process were conducted every 3 months for 24 months. Results: A total of 441 patients (64% of those eligible) consented to participate and 43% of enrolled patients met criteria for current major depressive episode, manic episode, or hypomanic episode. An additional 39% reported significant subthreshold symptoms, and 18% reported minimal or no current mood symptoms. Of patients assigned to the intervention program, 94% participated in telephone monitoring and 70% attended at least one group session. Conclusions: In a population‐based sample of patients treated for bipolar disorder, approximately two‐thirds agreed to participate in a randomized trial comparing alternative treatment strategies. Nearly all patients accepted regular telephone monitoring and over two‐thirds joined a structured group program. Future reports will describe clinical effectiveness and cost‐effectiveness of the intervention program compared with usual care.     

Mental health first aid training: review of evaluation studies

OBJECTIVE: To review studies evaluating mental health first aid (MHFA) training. METHOD: Review of three published trials: one uncontrolled with members of the public in a city, one randomized controlled efficacy trial in a workplace setting and one cluster randomized effectiveness trial with the public in a rural area. RESULTS: Most mental health first aiders tend to be middle-aged women whose work involves people contact. All trials found the following statistically significant benefits 5-6 months post-training: improved concordance with health professionals about treatments, improved helping behaviour, greater confidence in providing help to others and decreased social distance from people with mental disorders. Only one trial evaluated the mental health benefits to participants and this found positive effects. CONCLUSIONS: Although MHFA training has been found to change knowledge, attitudes and helping behaviours, and even benefit the mental health of participants, there has not yet been an evaluation of the effects on those who are the recipients of the first aid.