Expanding Clinical Knowledge of Eating Disorders Through Clinical Trials

Yvonne S. Bannon, BSN, MSHS

Ms. Bannon is an assistant in research in the Department of Psychiatry and Behavioral Medicine at the University of South Florida in Tampa.

Disclosure: Ms. Bannon reports no affiliation with or financial interest in any commercial organization that might pose a conflict of interest.

Please direct all correspondence to: Yvonne S. Bannon, BSN, MSHS, Department of Psychiatry and Behavioral Medicine, University of South Florida, 3515 E Fletcher Ave, Tampa, FL 33613; Tel: 813-974-2832; E-mail: [email protected].

Abstract

Adapting research into clinical practice routinely takes 10–20 years. The translation of research into immediate improvements in clinical practice is of particular importance in improving the quality of health care. Translating eating disorder research into clinical practice is challenging due to the dearth of randomized clinical trials in the field. This article will review the benefits of early implementation of research findings and practices, identify common barriers to translating research into practice, define key clinical research terminology, present a brief overview of evidence-based treatments for anorexia nervosa and bulimia nervosa, and provide recommendations from current research procedures to expand clinical knowledge and improve the quality of care of patients with eating disorders.

Introduction

Anorexia nervosa (AN) has a reported mortality rate of at least 10% after 10–20 years of illness.¹ The onset of AN frequently occurs in adolescence,² resulting in a high mortality rate in individuals who are 20–40 years of age.^3,4 The mean annual cost for treatment (when treatment is available) is reported to be $6,045.00,⁵ which makes AN one of the most costly of the mental illnesses to treat. The cost of treatment does not reflect the medical costs associated with frequent hospitalizations and medical care required to treat the many physical consequences of eating disorders, such as electrolyte imbalances, osteoporosis, gastrointestinal dysfunction, and cardiac complications. The true cost of treating AN is difficult to determine because the physical complications of AN are frequently billed under various codes in the International Statistical Classification of Diseases and Related Health Problems, 10th Revision,⁶ and are therefore not captured in the cost analysis. Determining the costs of other eating disorders is equally difficult.

The mean annual cost for treatment of bulimia nervosa is reported to be $2,962.00.⁵ Again, the cost of treatment does not reflect the associated medical costs to treat the many physical complications of bulimia nervosa, such as gastrointestinal dysfunction associated with long-term laxative abuse or damage to the esophagus from frequent purging. The annualized mortality rate of bulimia nervosa is estimated at 0.2%⁵; however, the diagnosis of bulimia nervosa frequently is not considered in clinical practice because the primary symptoms, binge eating and purging, may not be disclosed by the patient to the diagnosing clinician.

Even less is known about the costs of treating binge-eating disorder (BED). The comorbidity of BED is assumed to be similar to obesity²; however, this has yet to be determined.

Evidence-based research provides society with scientifically sound options for effective treatments.⁷ Evidence-based treatments may reduce the actual costs of care, provide support for treatment guidelines, reduce recidivism, and reduce the economic and social burdens of illness, such as AN, bulimia nervosa, and BED. Research also provides a basis for resource distribution and allocation, educational and prevention efforts, outcome expectations, and standardized performance measures.^8-10 All of these factors can decrease the morbidity and mortality of eating disorders.

Benefits of Early Implementation of Research Findings and Practices

Clinicians are expected to provide quality health care in a system riddled with dwindling resources and higher outcome expectations and within an ever-increasing complex delivery system. They face an increased demand for accountability in health care, which includes the reporting of clinical performance using standardized quality measures and the incorporation of objective criteria into treatment decisions. However, although federal and pharmaceutical industry research expenditures increase annually, it reportedly takes 10–20 years for original research to become part of routine clinical practice.¹¹ This is particularly true in pharmaceutical research and development, where it may take a new drug 1–2 decades to move through the preclinical phases of development to approval¹² and into clinical practice.

Research findings focused on identifying at-risk groups, prevention strategies, pharmacologic treatments, behavioral interventions, patient and family education strategies, quality-of-life factors, and health outcomes predictors may not be available in time to aid in renovating and restructuring the current healthcare system. Simply put, decisions made today are based on outdated data. A 1998 review of published studies¹³ on the quality of care received by Americans demonstrated this fact when it found only 60% of patients with chronic conditions received the recommended medical care.

A need to move evidence-based research findings into clinical practice quickly and thoroughly is not a new concept, but it is a concept that has recently been rejuvenated by several government agencies, including the National Institutes for Health (NIH) and the Agency for Healthcare Research and Quality (AHRQ). The NIH and AHRQ, as well as other government-funded agencies, have increased their support of initiatives to identify strategies to translate research findings into clinical practice. Despite the efforts of these governmental agencies, the direct impact of this initiative on healthcare providers and patients has been limited.¹⁴

Common Barriers to Translating Research into Practice

The difficulty of translating research into practice is well documented in the literature. Potential barriers include ineffective use of information technology,¹¹ limitations of clinician time, competing priorities, poor access to current best-evidence and treatment guidelines, organizational constraints, ineffective continuing medical education, disinterest, lack of motivation, difficulties with change,¹⁵ and lack of confidence in critical appraisal skills.¹⁶

The successful translation of research into practice is dependent not only on the clinician’s, policy maker’s, and administrator’s acceptance and ability to integrate new strategies and findings into the practice setting, but also on the researcher’s ability to design trials that are sustainable, reproducible, and generalizable.¹⁴ The researcher must also communicate findings in a way that is clear, concise, and understandable.

An example of data that can be easily misinterpreted is the tendency of researchers to report subgroup analysis. In and of itself, exploration of subgroup data is not bad and can lead to promising future research; however, overemphasis of the conclusions drawn from this type of analysis can be misleading due to dilution of the sample size and power of the study.¹⁷ Another problematic area is the inherent differences between research and clinical practice.

Clinical trials follow a protocol designed to objectively measure scientific questions with minimal outside influences. Study entrance criteria typically eliminate patients with secondary diagnoses, medical conditions except those that are stable and actively treated, and concomitant medication use. The instruments and scales utilized in psychiatric clinical trials are usually not familiar to most clinicians and are not routinely used in clinical practice. Individuals who volunteer in trials may have increased insight into their illness, often have families involved in their care, and may have an increased readiness for change compared to patients in a clinical setting.^9,18 These differences represent yet another barrier to the translation of research to clinical practice.

A solution to the inherent differences between research and clinical practice in psychiatry may be the implementation of translational evidence-based research centers or practice based research networks within psychiatry. In these centers, research could be designed and/or replicated in actual clinical settings; pharmacologic or therapeutic treatments could also be implemented and utilized by practicing clinicians using the same measurements, scales, or instruments as the original research but without the constraints and rigidity of the original research protocol. The goal of this type of evidence-based research center would be to determine if the treatment is effective in the general patient population and is practical in a clinical setting. In addition, health outcomes and measures of improvements in quality of life for individual patients with a specific treatment could be determined.

Eating disorder research is particularly challenging because of the scarcity of randomized controlled trials and the lack of long-term outcome data.¹⁹ Eating disorder research is in its infancy: the majority of research in the eating disorder field has occurred only within the last 20–30 years. Some research in the eating disorder field is difficult to translate into a primary psychiatric setting because much of it is psychotherapy based. For example, cognitive-behavioral therapy (CBT) has been found to be an effective approach in treating bulimia nervosa patients. However, researchers in this field have typically been experienced clinicians and skilled in therapy with this patient population. This highlights the point that even though a treatment is effective, it may not be generalizable in and of itself without the benefit of special training or even something as simple as a manual. Researchers should make these tools available if they want others to incorporate their findings into the clinical setting. Fortunately, there are CBT manuals, books, and guides available which have stemmed from the research in bulimia nervosa and CBT. Additionally, scales and instruments utilized in research should be made available at no or relatively low cost to clinicians. Information technology has made such instruments more accessible to practicing clinicians via the Internet.

Another promising change toward translating research into practice is in medical and healthcare education. There is increased funding from government agencies to support research education and fellowships within the healthcare professions. An increased expectation of educational programs to incorporate research into didactic instruction and practica will improve the confidence and ability of healthcare providers to integrate research findings into clinical practice. Other efforts include continuing medical education focused not only on research topics but also on research procedures, practices, concepts, and terminology.

Over the past 15 years, the pharmaceutical industry has widened its pool of investigators from academicians to independent community-based practitioners. In 2000, 44% of industry-sponsored clinical trials were conducted by academic medical center and/or major medical centers, while 56% were conducted by independent community-based practitioners.²⁰ In the same survey, 68% of principal investigators reported the primary reason they became involved in clinical trials was to “get closer” to advances in science.²⁰ With this trend of moving industry-sponsored clinical trials out of the large academic and medical centers to community-based practitioners, there is a greater emphasis on educating or re-educating practitioners in research basics.

Review of Select Clinical Research Terminology

Reviewing and considering the implications of research requires critical appraisal skills and a solid knowledge base of the research process and terminology. Although the majority of clinicians possess critical thinking skills in their area of practice, many lack confidence with statistical terminology and research concepts.¹⁶ This is not surprising with the constraints of medical and other healthcare education programs; many programs in the recent past placed little emphasis on the review and critique of current research and even less on research methodology. Fortunately, this is in the midst of change.

Research education is now emphasized in many medical- and healthcare-related graduate level and professional programs. New degree programs and fellowships in clinical research have been developed in many of the nation’s top universities. Duke University, Harvard University, the University of South Carolina, the University of North Carolina, and George Washington University, to name a few, all offer graduate programs in clinical research though their colleges of medicine or nursing. The NIH has made funding available for schools to develop research fellowships for physicians. Two of the leading associations for clinical research professionals, the Association of Clinical Research Professionals and the Drug Information Association, have been at the forefront of initiating certification programs for clinical research professionals, particularly those participating in industry-sponsored trials. This is of particular importance since an increasing number of community-based physicians are assuming the role of principal investigator in pharmaceutical-industry–sponsored trials.

Within the field of eating disorders, there has been a recent increase in both federally funded research opportunities and industry-sponsored studies. Clinical drug development is divided into four phases: Phase I, Phase II, Phase III, and Phase IV. Phase I, or the healthy volunteers phase, is usually of short duration and focuses on safety in human subjects and dose range. Phase II trials focus on safety and drug tolerability in a targeted patient population. Phase III continues to collect safety data, but the prime emphasis is on the drug’s efficacy. Phase IV trials are initiated after the drug has received marketing approval from the Food and Drug Administration; they focus on postmarketing data, such as comparison trials, as well as safety data. Table 1 outlines the subject population, focus, duration, and percentage of success of the four phases of clinical drug development.¹² It is important to note that approximately one out of five new drugs in development will be approved for marketing by the FDA.¹²

Clinicians in the field of eating disorders have an increased opportunity to become involved in multicenter clinical trials, particularly Phase II and Phase III trials. To participate meaningfully, specialists and primary care providers will need to increase their general knowledge of research concepts and terminology. For the purpose of this article, select regulatory terminology (Table 2),^21,22 research design terminology (Table 3),²¹ and clinical trial terminology (Table 4),^12,21,23 are defined.

In addition to understanding regulatory and trial terminology and trial design, it is also important for clinicians to have a basic understanding of statistical terminology to critically review research findings. A review of some common statistical terminology in randomized controlled trials is provided in Table 5.^21,22,24 Clinicians do not need to be statisticians to critically assess and apply research findings into their practice; however, they do need to recognize the limitations of clinical trial results.

Evidence-Based Treatments for Eating Disorders

Although many anecdotal case studies, pilot studies, and some 6–12 week randomized controlled trials can be found in the literature regarding the short-term treatment of eating disorders,²⁵ very little is known of the long-term effectiveness of eating disorder treatments.²⁶ Conservative reviews of evidenced-based treatments identify very few efficacious eating disorder treatments²⁷; however, the experts in the field of eating disorders have agreed upon guidelines for treatment for clinicians.²⁵ With this said, it is critically important to review the data that exists to ensure that not only the theory and design of the research is sound, but also to understand the impressions of the researcher for future research needs and how to apply the findings to clinical practice.

Misuse or misinterpretation of research leads to ineffective treatment regimens. For example, the use of selective serotonin reuptake inhibitors (SSRIs) in underweight women with AN (who are often amenorreahic) is widespread, although serotonin can inhibit food intake and gonadotropin secretion.²⁸ Another example stems from the pilot study of Powers and colleagues²⁹ on the effectiveness of an antipsychotic in the treatment of AN. This was an open-label, 10-week, pilot study of the safety and efficacy of olanzapine in 20 patients with AN. Data had suggested that olanzapine was effective and safe in the short-term treatment of AN; however, the effectiveness, safety, and long-term outcomes needed to be determined through double-blind randomized clinical trials. Powers and colleagues have received many new patients in their practice who had been maintained for long periods of time on olanzapine even after they had reached their ideal body weight. Many of these patients were adolescents. In the olanzapine study, 6 of the 20 subjects enrolled were adolescents 14–17 years of age. Even though this subgroup did well in the study, the statistical power was insufficient to detect what effects olanzapine truly had on adolescents. In all participants, the long-term effect of olanzapine was beyond the scope of the research and long-term use was not investigated.

The American Psychiatric Association’s (APA) “Practice Guideline for the Treatment of Patients with Eating Disorders”²⁵ and Clinical Evidence^27,30 have provided summaries of current clinical practice from the experts in the field and a review of the evidence-based information available. In a field where few randomized controlled trials are found, it is especially important to integrate expert opinion and evidence-based information. Weight restoration in AN and treatment of physical complications in both AN and bulimia nervosa is the first objective in treatment and frequently can be done simultaneously while treating the underlying symptoms of the disorders, such as obsessive-compulsive behaviors, anxiety, depressed mood, and body image distortion.

Nutritional rehabilitation, in the form of refeeding in AN and correcting patterns of binge eating and purging in bulimia nervosa, are the primary foci of treatment.²⁵ The APA practice guideline does not provide guidance for treating the many other eating disorders, such as BED or night-eating syndrome.²⁵ This is primarily due to the lack of information about these disorders and their treatments. However, many promising pilot studies have recently been completed and randomized controlled trials are currently underway.

A brief summary of the primary evidence-based pharmacologic and therapy data for AN and bulimia nervosa follows.

Anorexia Nervosa

Pharmacology

There are only a few controlled trials available on pharmacologic treatments for AN¹⁹ and there are no FDA-approved medications for AN. With this said, this summary includes data from pilot studies and open-label trials.

Antidepressants, including SSRIs and tricyclics, have not been found to be helpful in treating underweight anorexics,²⁷ although there may be some modest benefit of symptom relief in weight-restored anorexics.¹⁹ Cyproheptadine demonstrated weight gain and improvement in other symptoms in one of only three controlled trials studying that drug.¹⁹

Atypical antipsychotic treatment in AN has been associated with weight gain and improvement in depressive symptoms, anxiety, obsessive-compulsive thoughts, and body image distortions. Unfortunately, the majority of the evidence is from small open trials of relatively short duration. Further research is needed to determine the safety and efficacy of atypical antipsychotic treatment in AN.

Therapy

Again, there is insufficient evidence in the way of randomized controlled trials to clearly state the effectiveness of psychotherapy in treating AN.²⁷ However, expert opinion states that nutritional rehabilitation, psychosocial efforts, and psychoeducational efforts focused on nutritional and physical rehabilitation, dysfunctional attitudes related to the eating disorder, improving interpersonal and social functioning, and interventions that address comorbid psychopathology and psychological conflicts that reinforce or maintain disordered eating, combined with psychotherapy, are effective.²⁵

Bulimia Nervosa

Pharmacology

Fluoxetine is currently the only FDA-approved medication for the treatment of bulimia nervosa in the US.^19,25 There are a few pilot studies and randomized clinical trials which indicate other SSRIs may be as effective as fluoxetine.¹⁹

Therapy

CBT has been widely studied and has demonstrated the most evidence of efficacy in bulimia nervosa.²⁵ The focus of CBT is on the eating disorder symptoms and underlying cognitions in the patient with bulimia nervosa.²⁵ Other types of therapy, such as nutritional counseling, group psychotherapy, and individual psychotherapy, although less well studied, have also been shown to be effective.²⁵

Recommendations from Current Research to Improve Clinical Practice

There is a wealth of diagnostic tools, symptom rating scales, and instruments available in psychiatry. Diagnostic tools can aid in the initial evaluation of patients and are particularly helpful in identifying co-occurring primary and secondary diagnoses. The Structured Clinical Interview for Diagnosis³¹ and the Multi International Neurodiagnostic Instrument³² are two that provide easy algorithms correlated to current diagnostic criteria (Table 6). Although neither should replace the clinical interview or psychiatric evaluation, both are helpful in forming a diagnostic impression.

The adoption of objective scales and instruments into routine clinical practice as adjunctive measures has three distinct benefits. First, it provides the clinician with an objective measure of symptoms which can then be compared to previous ratings to determine effectiveness of treatments and overall well being. Secondly, many scales may pick up symptoms that are not typically assessed during standard clinical evaluations. An example of this is the obsessive-compulsive component of eating disorders which can be measured through instruments, such as the Yale-Brown-Cornell Eating Disorder Scale.³³ Lastly, instruments and scales provide an objective measurement that can aid in justifying hospitalizations to third party payers.

Many scales specific to eating disorders exist. Other more general scales that measure symptoms common to many psychiatric illnesses may also be helpful. When assessing and treating patients with eating disorders, scales and instruments are helpful in identifying symptoms that may be missed in a standard evaluation, such as preoccupations and rituals, body image distortions, anxiety, depressed mood, delusions, paranoia, and hallucinations. Table 6^31-40 provides a review of the instruments commonly reported in the research literature which could easily be utilized in a clinical setting.

Conclusion

There is a great need for evidence-based effective treatments for eating disorders to reduce morbidity and mortality and improve the quality of life of individuals with these illnesses. In addition to research, it is imperative that eating disorder research findings be translated into clinical practice. Evidence-based research centers within psychiatry may determine if new treatments are effective in clinical settings. Community-based clinicians have an increased opportunity to become involved in clinical research and its implementation into practice. Clinical research education is an essential component of the research translation process. PP

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