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Research on eating disorders: current status and future prospects
REVIEWS Research on Eating Disorders: Current Status and Future Prospects Benedetto Vitiello and Israel Lederhendler This report summarizes the main themes addressed at a workshop on research on eating disorders (EDs), which was hosted by the National Institute of Mental Health in December 1998. Both basic behavioral neuroscientists and clinical investigators met in an effort to integrate areas of research and foster collaborations. Considerable advances have been made in understanding the neuroendocrinological mechanisms that regulate appetite and food intake. These achievements are in sharp contrast with the limited progress in elucidating the pathogenesis of EDs and developing effective treatment and preventive interventions. Anorexia nervosa remains a highly morbid condition with the highest mortality of any other psychiatric disorder. Besides acute refeeding techniques, no specific interventions have been proven effective in changing the long-term course of anorexia nervosa. Efficacious treatments exist for bulimia nervosa, but their underutilization calls for research on translating experimental findings into clinical practice. Closer interface between neuroscientists and clinical researchers is required for advancing our understanding of ED pathogenesis and developing effective treatments. Recent studies are suggestive of a substantial genetic contribution to EDs that deserves further investigation. Finally, there is an urgent need to examine risk and protective factors for EDs, on which safe and effective prevention can be built. Biol Psychiatry 2000;47:777–786 Key Words: Anorexia, bulimia, eating disorders, research
Background
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esearch on the pathogenesis, treatment, and prevention of eating disorders (EDs) is an important component of the mission of the National Institute of Mental Health (NIMH). The NIMH is now supporting research in this area for a total of about $7 million per year. Among recent NIMH efforts to advance research on EDs, there have been the workshop, Development of Research Priorities in Eating Disorders (Grilo et al 1997) and the program announcement, Mental Health Research in Eating Disorders (National Institutes of
From the National Institute of Mental Health, Bethesda, Maryland. Address reprint requests to Benedetto Vitiello, M.D., NIMH, Child & Adolescent Treatment & Preventive Interventions Research Branch, Room 7149, 6001 Executive Boulevard, MSC 9633, Bethesda MD 20892-9633. Received June 15, 1999; revised November 18, 1999; accepted December 17, 1999.
Published 2000 by Elsevier Science Inc.
Health 1996). Still, given the public health importance of these disorders and the inadequacies of the present treatments, there is awareness that the current research activities must be further expanded. This is particularly the case for anorexia nervosa (AN), a disorder that affects about 0.5% of women during their life (Gotestam et al 1995; Walters and Kendler 1995), has a protracted course, high morbidity, low rate of full recovery (Herzog et al 1999), and the highest mortality (up to 6% per decade of illness) of any psychiatric disorder (Eckert et al 1995; Harris and Barraclough 1998; Herzog et al 1993; Sullivan 1995). Refeeding strategies in the acute phase of AN are effective, but interventions aimed at reaching and maintaining full recovery still need validation and improvement (Walsh and Devlin 1998). The urgent need for effective treatments, on one hand, and the rapid advance of neuroscience, on the other, demand a debate on how to identify new research strategies and opportunities. Recent findings concerning the regulation of feeding and appetite, such as the discovery of leptin (Friedman and Halaas 1998), together with other neuropeptides, their receptors, and their actions in specified brain circuits (e.g., Hagan et al 1999; Leibowitz et al 1998), may contribute to understanding the pathogenesis of EDs and developing novel treatments (Campfield et al 1998; Woods et al 1998). In parallel, the elucidation of brain circuits underlying reward mechanisms (Berridge 1996; Matsumoto et al 1999; Schultz 1998) and their connection to the neurobiological regulation of fear and anxiety (Davis et al 1994) are potentially relevant to the psychological disturbances that sustain the clinical manifestations of EDs. In December 1998, NIMH hosted a workshop with the purpose of discussing research needs and opportunities in the area of EDs. The present report is intended to be a summary of the major aspects addressed at this meeting. The focus of the workshop was on knowledge gaps and possible approaches to integrating recent neuroscience findings. Likewise, in this report, emphasis has been placed on future research perspectives, rather than on a comprehensive examination of published studies. Readers interested in comprehensive reviews of research findings in EDs are referred to other publications (Becker et al 1999; Kaye et al 1999b; Yager 1996). 0006-3223/00/$20.00
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Current Status Pathogenesis FAMILIAL RISK FOR EDS. A high degree of familial aggregation of EDs has been reported (Lilenfeld et al 1998). A recent case-control study examined the prevalence of EDs among first-degree relatives of about 300 patients with AN or bulimia nervosa (BN) (Strober et al, in press). In this study, no cases of AN or BN were found among the male relatives of these patients. Among the female relatives of AN patients, the life-time rate of AN was about 3.5% and that of BN was 3.8%. In comparison, the rate of AN was 0.3% among the relatives of never-ill control subjects. Among the female relatives of BN patients, the rate of AN was 3.7% and that of BN 4%. Thus, there was a total rate of EDs of about 8% among the first-degree relatives of ED patients, and there was familial co-transmission of AN and BN. Based on these data, the familial relative risk of AN (that is the ratio between the rate of AN in first-degree relatives and rate of AN in the general population) is about 10. If confirmed, this can be considered a substantial increase in risk. As a comparison, the relative risk of insulin-dependent diabetes mellitus is 15. It is noteworthy that not only ED seems to run in families, but also attitudes toward shape and weight may as well. Relatives of patients with EDs are more likely to be preoccupied with weight and overconcerned about food and eating (Rutherford et al 1993). GENETIC RISK FOR AN. A few twin studies have been conducted to estimate the genetic contribution to AN. The results are not all consistent in suggesting high heritability (Fairburn et al 1999). One twin study showed a concordance rate for AN of 56% among 25 monozygotic twin pairs (MZ) versus 5% among 20 dizygotic twin pairs (DZ) (Holland et al 1988). Based on the Holzinger’s index, a conservative estimate of genetic heritability, about half of the relative risk for AN is due to genetic factors. Results of a previous twin community study did not support a genetic contribution to the familial aggregation of this disorder, probably due to the rarity of cases on AN in this sample (Walters and Kendler 1995). In studying the possible genetic risk for AN, a multilocus model should be considered. Several approaches are possible. A general search for susceptibility genes for AN across the whole human genome is hampered by the difficulty to find extended families with 20 or more affected individuals. Another approach is the affected sibling pair method that aims at identifying genomic regions that are shared with a frequency significantly greater than 50%. This increase in genomic sharing between affected siblings may indicate the presence of susceptibility genes. Seven sites across the United States (P.I.: W. Kaye, Co-P.I.s: W. Berrettini, K. Halmi, A. Kaplan, M. Strober, and B. Woodside) and
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Europe (J. Treasure and M. Fichter) have started such a study, which is supported by the Price Foundation. Thus far, almost 200 families with 2 affected siblings (or in some cases an affected half-sibling or aunt or cousin) have been identified and DNA obtained. It is estimated that with a sample size of 200, there will be a 90% power to detect a single locus that increases the risk for AN by three fold or greater. Another possible approach is the association study design, involving affected probands and their parents. But this method requires the previous identification of susceptibility genes and their exact sequence. A proposed susceptibility locus is a variant of the 5HT2A receptor gene. Some studies investigating this locus have found an association with AN (Collier et al 1997, as corrected by Collier 1999; Enoch et al 1998; Sorbi et al 1998), but others have been unable to replicate (Campbell et al 1998; Hinney et al 1997). The A/A genotype frequency was similar in all the studies aside from Hinney et al, who did not have controls and did not report the A/A genotype. GENETIC RISK FOR BN. As for AN, also for BN results of twin studies are not all consistent in indicating high heritability (Fairburn et al 1999). One recent report that controlled for error of measurement estimated that about 80% of the heritability of BN is due to genetic factors, whereas shared environment does not seem to be a significant contributor (Bulik et al 1998). A previous study from the same twin registry had reported a heritability of 55% based on a single assessment (Kendler et al 1991). Genes that contribute to bingeing and vomiting overlap considerably (Sullivan et al 1998). The genetic contribution to the development of EDs seems to become more evident with puberty (Klump et al, in press). BN was found to share genetic risk with phobia and panic disorder (Kendler et al 1995), thus raising the possibility that a general susceptibility to anxiety-related psychopathology is genetically transmitted. AN AND OBSESSIVE–COMPULSIVE SYMPTOMS. An association between obsessive– compulsive tendencies and AN was first reported more than 50 years ago. Certain personality traits, such as conformity, inflexible thinking, emotional restraint, and high harm avoidance, and obsessions about perfectionism, exactness, and symmetry are associated with AN (Matsunaga et al 1999). These features can be found also among patients with BN, who, in addition, often display impulsiveness and novelty seeking tendencies, as measured on self-administered scales like the Tridimensional Personality Questionnaire (Bulik et al 1995). These symptoms persist after the patient has reached remission. Familial aggregation of obsessive– compulsive disorder (OCD) seems to be independent of that of AN or BN, whereas the risk for AN (but not for BN) is co-transmitted with the risk for obsessive– compulsive personality (Lilenfeld et al 1998). The conceptualiza-
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tion of AN as akin to OCD has clear appeal, but also limitations, most notably the apparent lack of insight of these patients and the “ego syntonic” nature of the disorder. This characteristic makes AN closer to a monosymptomatic delusion, a specific “food and weight phobia,” or an “overvalued idea” with loss of insight. Contrary to OCD, AN can be seen as an overriding of normal subcortical functions by the cortex. Also, the persistent and self-injurious drive for thinness of AN patients resembles addictive behavior (Davis and Claridge 1998). The risk for AN, however, appears to be transmitted independently of the risk for substance abuse. NEUROBIOLOGY. Altered serotonin levels are associated with changes in a wide range of behaviors in animals and humans, including behaviors relevant to homeostasis like ingestion and sleep, as well as those related to affect regulation. In both AN and BN, abnormalities of the serotonin system have been reported, such as increased cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid in ED patients who have recovered from the acute phase of the illness (Kaye et al 1991, 1998). Preliminary data of positron emission tomography with altaserin, a serotonergic ligand that binds to 5-HT2A receptors, in 9 women who had recovered from BN versus 12 normal controls have shown reduced 5-HT2A binding in the medial orbital cortex, an area involved in regulating emotional and impulse control (Frank et al 1998). However strong the link between EDs and serotonin seems to be, it is unlikely that a specific dysfunction of one neurotransmitter system can fully explain the pathogenesis of AN and BN. The involvement of other systems, such as the dopaminergic system, should be further considered and studied (Kaye et al 1999a). Further insight into the pathogenesis of EDs may come from neuroendocrine studies. The role of gonadal steroids, for example, in EDs is suggested by the clear gender effect in the risk for these disorders, their emergence at puberty or soon after, and the increased risk for EDs of girls who had an early menarche. BASIC NEUROSCIENCE OF FEEDING BEHAVIOR. In recent years, important advances have been made in elucidating the molecular bases of obesity and calorie intake control. The recognition of the role of the ventromedial hypothalamus in controlling food intake goes back 60 years. The modern understanding that this brain region participates in complex circuitry regulating ingestion promises more applicable advances. A major finding has been the identification of two monogenic mouse models of obesity: the obese ob/ob and the diabetic db/db mice. It was shown that the locus of the ob mutation encodes a protein, called leptin, whose synthesis is expressed by the white adipose tissue (Maffei et al 1995; Zhang et al 1994).
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Leptin acts in the ventro-medial hypothalamus that is dense in leptin receptors and leads to reduced caloric intake (Elmquist et al 1998). It was also discovered that the genetic locus db encodes for the leptin receptor (Chua et al 1996). This receptor belongs to the cytokine receptor family and is similar to the IL6 receptor. Leptin accelerates puberty in animals, by enhancing the release of hypothalamic hormones. As expected, underweight AN patients have low serum (Grinspoon et al 1996), plasma and CSF concentrations of leptin (Mantzoros et al 1997). One study suggests that leptin levels increase with weight restoration but normalize before full weight recovery is achieved, thus possibly explaining why it is so difficult for patients with anorexia to reach complete recovery (Mantzoros et al 1997). The SOCS-3 molecule (or suppressor of cytokine signaling) is an intracellular inhibitor of leptin signaling (Bjorbaek et al 1998). A neuropeptide that seems to require leptin for its expression is CART (or cocaineand amphetamine-regulated transcript), which is widely present in the mammalian brain (Kristensen et al 1998). Another substance expressed in the lateral hypothalamic area is the melanin concentrating hormone (MCH) that increases food intake in mice and appears to be downregulated by leptin. MCH is upregulated in ob/ob mice that lack leptin, and also in starving rats whose leptin levels fall. In fact, knocking-out the MCH gene results in a lean body phenotype even if leptin levels are low (Shimada et al 1998). The latest players to be identified are the orexins, peptides that are found exclusively in the lateral hypothalamus (Griffond et al 1999; Risold et al 1999) and whose concentration rises with starvation and with decreasing levels of leptin (Sakurai et al 1998). Injection of orexins into animal brain increases food intake. There is now evidence for a circuit that from leptin-activated cells in the medio-basal hypothalamus goes to the lateral hypothalamus that in turn projects diffusely to the cortex. REGULATION OF ENERGY HOMEOSTASIS. In mammals, capacity to reproduce is dependent on access to a positive energy expenditure. In order to activate the reproductive function, the message that there is a positive energy balance is needed. Leptin seems to be such a messenger. It increases fatty acid oxidation, glucose activation, and thermogenesis. The administration of leptin reverses the infertility of the ob/ob mice and of starved animals. It has been proposed that the evolutionary meaning of leptin is to signal that starvation is not occurring and that reproductive endocrine function can be resumed (Flier 1998). Regulation of food intake and of fertility is intertwined. The caudal brain stem is implicated in the metabolic control of both reproduction and food intake. Of possible relevance to EDs, the repeated exposure to hypoglycemic stress results in attenuated glucoregulatory
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responses in animals, thus suggesting that the metabolic regulatory system stops responding if it is repeatedly stressed (Jill Schneider, oral communication). DYNAMIC BRAIN CIRCUITRY. There is active research in identifying the neuroanatomical circuits underlying sexual and social behavior in mammals, which can serve as an illustration of the kind of integration required to understand motivated behavior in general. It is the activity of the circuit as a whole, rather than individual brain areas in isolation, that produces a certain pattern of behavior. By focusing on common themes that various behaviors may share in terms of activated neuroanatomical areas, a unitary social behavior network may be postulated. According to how this network is activated, different behaviors can result. Thus, social behaviors that are quite different in terms of motivation, physiological prerequisites, and neuroanatomical substrates, can emerge from a single neuroanatomical network (Newman 1999). Brain imaging techniques may be helpful in studying the neuroanatomic abnormalities of EDs. These techniques allow the identification in vivo of areas that display a specific activation during certain behaviors, but they also have important limitations. Causality cannot be inferred from brainimaging data alone: the dynamic circuitry relating a brain area to function is necessary to provide an adequate context, and it is also necessary to study how the system operates in the absence of that brain area (for instance, through brain lesion models in animals and studies of brain damaged patients). Furthermore, it is difficult to compare imaging data across subjects, given that brains are as differently shaped as individual faces are. Nevertheless, functional magnetic resonance studies are an important opportunity to look at novel hypotheses related to cognitive processing in EDs (Wojciulik et al 1998), and the development of new ligands has the potential of elucidating differences and similarities in receptor systems among EDs and OCD, anxiety, substance dependence, and mood disorders.
Treatment: Anorexia Nervosa CLINICAL COURSE OF AN. The course of AN is very protracted, even for those patients with the best ultimate prognosis. A 10- to 15-year follow-up of patients with AN found that 14% had not recovered, 10% had a partial recovery, and 75% a complete recovery (Strober et al 1997). Median time to partial recovery was 60 months and to full recovery 80 months. Full recovery was rare before 70 months. Once full recovery is achieved, however, relapse is rare. Few predictors of long-term course and outcome were identified in this study. A recently reported 7.5- year follow-up study of women with AN found that 33% reached full recovery, but 40% of them relapsed after full recovery
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(Herzog et al 1999). Low minimum weight at time of presentation and duration of episode have been found to be associated with more negative long-term outcome for AN patients (Hebebrand et al 1997; Herzog et al 1999). Poor relationship with family has also been shown to predict poor outcome in adolescents (Bryant-Waugh et al 1988; North et al 1997). TREATMENT OF AN: ACUTE PHASE. AN is a specific, relatively homogeneous illness that calls for a specific treatment program, thus supporting the concept of “ED programs.” There are three main treatment phases: 1) restoring severe weight loss; 2) treating cognitive distortions and relationship disturbances (i.e., distortion of body image, low self-esteem, and family conflict); and 3) achieving long-term remission and rehabilitation (i.e., full recovery). We are currently fairly successful at the first phase of treatment, that is the acute management of the severe weight loss of AN patients, usually in inpatient settings. Some success can also be claimed at addressing low-self esteem and family conflict; however, these treatments are time consuming and expensive. It is estimated that the average cost of a hospitalization for AN is about $18,000, versus $11,000 for schizophrenia, $10,000 for bulimia, and $8,700 for depression (StriegelMoore, oral communication). Concern has been expressed that financially dictated limitations on the duration of inpatient treatment may compromise the ability to restore severe weight loss in severe AN. Beyond the acute phase of the illness, there is a clear need to develop effective interventions for achieving long-term remission and sustained nutritional rehabilitation. There is no “anti-anorexia nervosa” drug or psychotherapy, and no treatment seems to counteract the drive for thinness of AN patients. Virtually all the known pharmacological and psychological interventions have been suggested as a treatment of AN. Only limited empirical support exists for some of these interventions. Among the medications tried, there are typical antipsychotics, first- and second-generation antidepressants, cyproheptadine, lithium, tetrahydrocannabilol, and cisapride. Studies of atypical antipsychotics are in progress. The sample size of most controlled clinical trials is small, but the results have not been encouraging. It must be taken into account that these drugs have not been compared to a no-treatment control group; rather, medications were added to a psychosocial intervention that all patients in both experimental and control group received. Thus, what was tested was whether medication plus standard psychosocial management was more effective than psychosocial management alone. Based on current data, the benefit of adding pharmacotherapy to psychosocial treatment seems to be negligible (Attia et al 1998). TREATMENT OF AN: RELAPSE PREVENTION. Prevention of relapse is a critical aspect of treating AN. As already
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noted, about 40 –50% of the weight-restored AN patients relapse after achieving full recovery (Eckert et al 1995; Herzog et al 1999). Factors that seem to influence the risk for relapse are patient’s motivation for treatment, degree of insight, and severity of AN symptoms (Eckert et al 1995), but others have found no predictors of relapse (Herzog et al 1999). A longer and more intense treatment of the acute phase of AN may translate into a lower relapse rate. Patients who were discharged in more stable physical and psychological conditions were found to be less likely to relapse (Baran et al 1995). Therapeutic strategies that target these factors need to be developed and tested. The managed care environment has reduced the length of inpatient stay for treatment of AN, but it not known if a time cohort effect on relapse rate since the introduction of managed care exists. The administration of fluoxetine after weight restoration has been associated with decreased relapse rate in one reported study (Kaye et al 1997). The application of techniques that can enhance patient motivation may be worth considering. Several studies are in progress to test treatments aimed at preventing relapse. Among these, the McKnight Foundation is supporting a four-site (Cornell University, University of Minnesota, University of North Dakota, and Stanford University) clinical trial to compare the efficacy of cognitive– behavioral therapy (CBT), medication management, combined CBT plus medication management in the prevention of relapse in AN. LEVELS OF CARE FOR AN PATIENTS. Levels of care for patients with AN include inpatient, residential, dayhospital, and outpatient treatment. Empirically validated criteria for determining the appropriate level of care for individual patients based on disease severity would be useful to clinicians and health resources administrators. Developed from consensus among experts, a draft of such criteria has been prepared and waits validation (Kaye et al, unpublished). FOCUS ON ADOLESCENTS. Adolescents are the age group at highest risk for developing AN and BN. They may also offer the greatest opportunity for effective treatment and recovery. Early identification and treatment of AN can result in a better outcome (Russell et al 1987). Family systems psychotherapy was found to be better than individual psychotherapy for adolescents with AN (Eisler et al 1997; Robin et al 1994). Adolescence offers a “window of opportunity” for treatment of AN that should be fully exploited.
Treatment of Bulimia Nervosa Only 15 years ago, no effective treatments were available for BN. Controlled clinical trials have made great strides in discovering effective treatments for this common and
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debilitating condition (for reviews see Agras 1997; Wilfley and Cohen 1997). The principal findings of such studies are as follows: 1. Both antidepressant medications and specific psychotherapy modality, such as CBT and interpersonal therapy (IPT) are effective in the treatment of BN (Fairburn et al 1993; Walsh et al 1997). CBT is more effective than the use of a single antidepressant, and both the dropout and relapse rates from medication are higher (Mitchell et al 1990). A 12-week course of CBT results in recovery rates of about 50%. If a second antidepressant is administered to patients who did not respond to the first medication, then the efficacy of pharmacotherapy seems to be comparable to that on CBT (Mitchell et al 1989). 2. Interpersonal psychotherapy (IPT) is less effective than CBT at the end of the treatment, but it seems to catch up with CBT during a 6- to 8-month follow-up (Fairburn et al 1993), suggesting a delay effect for IPT. Because it takes longer for IPT to work, CBT may be preferred as initial choice of therapy. 3. The addition of an antidepressant medication to CBT appears to be marginally more effective than CBT alone on the short term. Combined CBT and pharmacotherapy seems to offer advantages over single treatment on the long term (Agras et al 1992, 1994). 4. For patients who did not respond to CBT, either antidepressant medication or IPT can be considered, but the efficacy of this second-step treatment is limited to about 20% of the patients (Wilson 1996). 5. Self-help versions of CBT with brief therapist supervision seem to be somewhat helpful, with recovery rates of about 25% (Treasure et al 1996). 6. Despite the empirical support for the efficacy of CBT, this treatment is largely underutilized in common clinical practice (Crow et al 1999). This dissemination failure is not specific for BN, as it involved psychological treatments in general, but it is indeed a serious obstacle to delivering effective treatment to patients with BN. 7. Little is known about moderators and mediators of treatment change in BN. Still the importance of research on these factors is clear. If more were known about moderators, we could individualize treatment and match it to patient characteristics. If more were known about mediators, we could try to modify treatments and to make them more effective. In the case of BN, we can identify likely candidates for mediators of treatment, such as reduction of dietary restraint, increase self-efficacy for coping with triggers of binge eating, and modification of the overevaluation of shape and weight.
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Prevention Preventive interventions have been comprehensively conceptualized on a continuum from primary prevention through screening and early identification of subjects at particular risk, to minimal intervention, to gold standard treatment, to relapse prevention and rehabilitation (National Institutes of Health 1998; Striegel-Moore and SteinerAdair 1998). Five domains of risk factors have been reported to be associated with the development of EDs: culture, family (e.g., high socioeconomic status, parental psychopathology, family conflict, parental dieting), personality and behavior, genetics, and traumatic events like physical and sexual abuse (Fairburn et al 1997; StriegelMoore et al 1986). These risk domains are not independent. For instance, it is expected that genetically transmitted characteristics are likely to elicit predictable environmental responses. Risks for childhood disturbances of weight regulation, both genetic and environmental, are clearly relevant to EDs, and should be the object of research. One study has found that childhood obesity is a risk factor for BN (Fairburn et al 1997). Ethnicity does not seem to contribute a significant risk in itself (Striegel-Moore and Smolak 1996). The prevalence of BN and binge eating disorder has been found to be similar in African Americans as in Caucasians (Striegel-Moore et al, 2000a, 2000b). No data are available for AN, however. Moreover, the clinical manifestations of EDs do not appear to differ in ethnic minorities as compared to Caucasian samples (le Grange et al 1997). In considering risk factors as possible targets of prevention, several aspects must be taken into account, including the attributable risk. Because preventive interventions can be aimed at many levels of risk or disease process, and encompass a variety of levels (e.g., individual, families, sororities, inpatient service settings), careful thought is needed to consider the appropriate targets and likely effects. Thus far, research in prevention of EDs has been on interventions that have not clarified either the population (some have combined both asymptomatic and symptomatic participants in interventions) or the malleable components of risk that the intervention targets (Striegel-Moore and Steiner-Adair 1998). As a result, the outcomes have been disappointing, and even disturbing where symptoms after intervention have actually increased (Mann et al 1997).
Future Research Prospects In addition to identifying specific areas of opportunity, the workshop pursued a strategic issue: Can the clinical evidence provide a framework for basic neurobiological studies, and how can advances in the neuroendocrinology of ingestion and appetite translate into new approaches to
the etiology and pathogenesis of EDs? These were the main conclusions at the end of the workshop:
Pathogenesis BASIC NEUROSCIENCE. The explosion of basic neuroscience research has brought new insight into the regulation of metabolic homeostasis, appetite, and food intake. It has also started to identify the neuroanatomical circuits underlying emotions and behavior, and the connections between cognition and motivation. To advance our understanding on the pathogenesis of eating disorders, it is essential to integrate these new findings into novel conceptualizations of EDs where the focus is not simply on ingestion. Attention to basic neuroscience and a closer dialogue between neuroscientists and clinical researchers are critical. GENETICS. There seems to be sufficient data from family and twin studies suggesting a high heritability of AN and BN. According to the latest studies, the heritability seems to be comparable to that of other psychiatric disorders, such as schizophrenia, bipolar, and unipolar disorders. This can provide justification for DNA linkage and candidate gene studies. The affected sibling pair method can be adopted and expanded by including other relatives, such as the parents and one unaffected sibling per family. It was recommended that NIMH consider issuing a program announcement, request for applications, or other similar mechanisms, to start a multicenter DNA based linkage and candidate gene study similar to that created for schizophrenia and bipolar disorder. The large DNA database that would be obtained from such a study could be used by multiple researchers to investigate candidate genes. This seems especially important now that new neuropeptides relevant to food intake regulation are being identified and their function studied. In parallel, twin studies may be still worth considering to answer certain questions. For instance, a longitudinal twin study can inform on the relative contribution of genes and environment as they may change over time and across developmental periods. NEUROIMAGING. There are specific ligands for serotonin, and dopamine sites can be now utilized in positron emission studies to clarify the involvement of these neurotransmitter systems in EDs. Functional MRI can offer an opportunity to look at differences and similarities between EDs and other disorders, such as OCD and depression, and to study reward mechanisms that are related to food intake. Imaging brain responses to stimuli that relate to eating, perception of body shape and selfimage are feasible and needed. NEUROBIOLOGY. A human brain bank would be a critical resource to facilitate identification of brain changes.
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Knock-out gene approaches to studying the role of recently identified neuropeptides that regulate appetite and ingestion should be considered. Animal models of AN would clearly be helpful in comparative studies of brain circuitry. Brain banks would also facilitate comparative studies of the neuronal circuitry of eating behavior and its interaction with other affective systems and cognition. It is also critically important to pursue the developmental changes of hypothalamic neuropeptides, especially as they change during puberty.
Treatment INFRASTRUCTURE FOR CLINICAL TRIALS IN AN.
These studies present multiple challenges, most notably difficulties in patient recruitment and retention into research protocols and need for specialized research staff trained in the treatment and management of patients with AN. To obviate the limitations and inconclusiveness of the existing small-sized studies, multisite clinical trials are needed. There is a need to support the infrastructure that can sustain these studies at a time when the financial return from clinical services is being eroded at most research institutions. Collaborations with managed care organizations to access patients and test models of treatment in these settings are needed. RESEARCH TRAINING. There are only a few researchers active in studying treatments for AN patients. Efforts to enlarge this limited research basis by recruiting new investigators into this area and training young researchers are needed. INTENSITY OF TREATMENT OF ACUTE AN. There is an urgent need to test whether more intensive treatment programs, such as inpatient and day-hospital care, that are known for achieving a greater degree of weight restoration, are in the long term more effective and cost-effective than less intensive and less costly interventions. These data are essential for clinicians, patients, policy makers, and health administrators. RELAPSE PREVENTION IN AN. This a critical step on the way to treat AN. Treatment of AN should aim at full recovery. We should not accept chronicity of AN as a fact. Current efforts to develop effective interventions to prevent relapse after successful initial treatment of AN need to be continued and intensified. It is important to develop therapies that can increase patients’ motivation to adhere to treatment.
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TREATMENT OF CHRONIC AN. Efforts should be undertaken to develop and test effective interventions for individuals with long-standing anorexia nervosa. This is a relatively small, but morbidly affected, group of patients who are chronically ill, require recurrent hospitalizations, and for whom no treatments have been effective. EARLY INTERVENTIONS IN ADOLESCENTS. Adolescence offers a “window of opportunity” for successful treatment of AN soon after its onset and before it has become chronic. Psychosocial interventions focused on family systems seem to be among the most promising approaches worth pursuing.
EFFECTIVENESS AND TRANSLATIONAL RESEARCH
The underutilization of treatment modalities, such as CBT and IPT, whose efficacy is supported by controlled studies, is troublesome. Research is needed to see if efficacious treatment do and can generalize to different clinical situations. Because CBT and IPT are not widely available in the community, research should examine the comparative effectiveness of sequential treatments, beginning with the least complex and costly interventions.
IN BN.
IMPROVING TREATMENT OF BN. The response rate on CBT is about 50%. This treatment can be improved. The current manualized CBT does not adequately address emotional regulation, especially of negative affect, that is a major trigger of binge eating and purging. Also, CBT manuals could be enriched by incorporating interpersonal and family issues, and by addressing abnormal concerns about body shape and weight. Because emotional dysregulation seems to lead to binge eating, therapeutic efforts that specifically aim at regulating emotional state are worth considering. The study of moderators and mediators of treatment can provide useful elements to make treatment more targeted and effective. Likewise, improvements of the current forms of IPT are to be considered. The possible role for combined use of psychotherapy and pharmacotherapy in treating the most severe patients needs to be studied.
DEVELOPMENT OF TREATMENT ALGORITHMS FOR
TREATMENT FOR BINGE EATING DISORDER. There is convincing evidence that binge eating disorder and other disorders of eating behavior that result in obesity are associated with substantial morbidity, share risk factors with BN, and respond to interventions of known utility in BN, such as CBT and antidepressant pharmacotherapy. Research focused on prevention, early identification, and treatment of these disorders should be encouraged.
The effectiveness of a multistep treatment approach to AN needs to be studied, where different treatments are tested in a consistent sequential approach.
NEED FOR TREATMENT INNOVATION. Small, innovative studies to explore new psychosocial approaches to
AN.
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EDs should be encouraged, in parallel to large multisite trials to test specific hypotheses in a definitive way. EXPERTISE AT GRANT REVIEW. The peer review process of grant applications must involve reviewers who are aware of the critical questions in ED research and are familiar with the state-of-the-art of treatment interventions for these disorders.
Prevention: Redefining Methods and Strategies The current state of prevention research in EDs calls for a specific research workshop on prevention of EDs. Among the main purposes of such a meeting, there would be the identification of risk factors to target for prevention, promising strategies for prevention, and appropriate methods for testing proposed interventions. In addition to experts in EDs, experts in prevention research in general and patient representatives should be involved in this effort.
Proceedings of a National Institute of Mental Health research workshop held on December 7– 8, 1998 in Bethesda, Maryland. Speakers: Stewart Agras (Stanford University), Wade Berrettini (University of Pennsylvania), Jennifer Bieley (Eating Disorder Awareness and Prevention), Cynthia Bulik (Virginia Commonwealth University), Joel Elmquist (Harvard Medical School), Laura Lee Hall (National Association for the Mentally Ill), Katherine Halmi (Cornell University), David Jimerson (Harvard Medical School), Nancy Kanwisher (Massachusetts Institute of Technology), Allan Kaplan (University of Toronto), Walter Kaye (University of Pittsburgh), James Lock (Stanford University), Sarah Newman (Cornell University), Jill Schneider (Lehigh University), Ruth StriegelMoore (Wesleyan University), Michael Strober (University of California Los Angeles), Timothy Walsh (Columbia University), and Terence Wilson (Rudgers University). The opinions and assertions contained in this article are the private views of the authors and are not to be construed as official or as reflecting the views of the National Institute of Mental Health or the Department of Health and Human Services.
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Background
R
esearch on the pathogenesis, treatment, and prevention of eating disorders (EDs) is an important component of the mission of the National Institute of Mental Health (NIMH). The NIMH is now supporting research in this area for a total of about $7 million per year. Among recent NIMH efforts to advance research on EDs, there have been the workshop, Development of Research Priorities in Eating Disorders (Grilo et al 1997) and the program announcement, Mental Health Research in Eating Disorders (National Institutes of
From the National Institute of Mental Health, Bethesda, Maryland. Address reprint requests to Benedetto Vitiello, M.D., NIMH, Child & Adolescent Treatment & Preventive Interventions Research Branch, Room 7149, 6001 Executive Boulevard, MSC 9633, Bethesda MD 20892-9633. Received June 15, 1999; revised November 18, 1999; accepted December 17, 1999.
Published 2000 by Elsevier Science Inc.
Health 1996). Still, given the public health importance of these disorders and the inadequacies of the present treatments, there is awareness that the current research activities must be further expanded. This is particularly the case for anorexia nervosa (AN), a disorder that affects about 0.5% of women during their life (Gotestam et al 1995; Walters and Kendler 1995), has a protracted course, high morbidity, low rate of full recovery (Herzog et al 1999), and the highest mortality (up to 6% per decade of illness) of any psychiatric disorder (Eckert et al 1995; Harris and Barraclough 1998; Herzog et al 1993; Sullivan 1995). Refeeding strategies in the acute phase of AN are effective, but interventions aimed at reaching and maintaining full recovery still need validation and improvement (Walsh and Devlin 1998). The urgent need for effective treatments, on one hand, and the rapid advance of neuroscience, on the other, demand a debate on how to identify new research strategies and opportunities. Recent findings concerning the regulation of feeding and appetite, such as the discovery of leptin (Friedman and Halaas 1998), together with other neuropeptides, their receptors, and their actions in specified brain circuits (e.g., Hagan et al 1999; Leibowitz et al 1998), may contribute to understanding the pathogenesis of EDs and developing novel treatments (Campfield et al 1998; Woods et al 1998). In parallel, the elucidation of brain circuits underlying reward mechanisms (Berridge 1996; Matsumoto et al 1999; Schultz 1998) and their connection to the neurobiological regulation of fear and anxiety (Davis et al 1994) are potentially relevant to the psychological disturbances that sustain the clinical manifestations of EDs. In December 1998, NIMH hosted a workshop with the purpose of discussing research needs and opportunities in the area of EDs. The present report is intended to be a summary of the major aspects addressed at this meeting. The focus of the workshop was on knowledge gaps and possible approaches to integrating recent neuroscience findings. Likewise, in this report, emphasis has been placed on future research perspectives, rather than on a comprehensive examination of published studies. Readers interested in comprehensive reviews of research findings in EDs are referred to other publications (Becker et al 1999; Kaye et al 1999b; Yager 1996). 0006-3223/00/$20.00
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Current Status Pathogenesis FAMILIAL RISK FOR EDS. A high degree of familial aggregation of EDs has been reported (Lilenfeld et al 1998). A recent case-control study examined the prevalence of EDs among first-degree relatives of about 300 patients with AN or bulimia nervosa (BN) (Strober et al, in press). In this study, no cases of AN or BN were found among the male relatives of these patients. Among the female relatives of AN patients, the life-time rate of AN was about 3.5% and that of BN was 3.8%. In comparison, the rate of AN was 0.3% among the relatives of never-ill control subjects. Among the female relatives of BN patients, the rate of AN was 3.7% and that of BN 4%. Thus, there was a total rate of EDs of about 8% among the first-degree relatives of ED patients, and there was familial co-transmission of AN and BN. Based on these data, the familial relative risk of AN (that is the ratio between the rate of AN in first-degree relatives and rate of AN in the general population) is about 10. If confirmed, this can be considered a substantial increase in risk. As a comparison, the relative risk of insulin-dependent diabetes mellitus is 15. It is noteworthy that not only ED seems to run in families, but also attitudes toward shape and weight may as well. Relatives of patients with EDs are more likely to be preoccupied with weight and overconcerned about food and eating (Rutherford et al 1993). GENETIC RISK FOR AN. A few twin studies have been conducted to estimate the genetic contribution to AN. The results are not all consistent in suggesting high heritability (Fairburn et al 1999). One twin study showed a concordance rate for AN of 56% among 25 monozygotic twin pairs (MZ) versus 5% among 20 dizygotic twin pairs (DZ) (Holland et al 1988). Based on the Holzinger’s index, a conservative estimate of genetic heritability, about half of the relative risk for AN is due to genetic factors. Results of a previous twin community study did not support a genetic contribution to the familial aggregation of this disorder, probably due to the rarity of cases on AN in this sample (Walters and Kendler 1995). In studying the possible genetic risk for AN, a multilocus model should be considered. Several approaches are possible. A general search for susceptibility genes for AN across the whole human genome is hampered by the difficulty to find extended families with 20 or more affected individuals. Another approach is the affected sibling pair method that aims at identifying genomic regions that are shared with a frequency significantly greater than 50%. This increase in genomic sharing between affected siblings may indicate the presence of susceptibility genes. Seven sites across the United States (P.I.: W. Kaye, Co-P.I.s: W. Berrettini, K. Halmi, A. Kaplan, M. Strober, and B. Woodside) and
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Europe (J. Treasure and M. Fichter) have started such a study, which is supported by the Price Foundation. Thus far, almost 200 families with 2 affected siblings (or in some cases an affected half-sibling or aunt or cousin) have been identified and DNA obtained. It is estimated that with a sample size of 200, there will be a 90% power to detect a single locus that increases the risk for AN by three fold or greater. Another possible approach is the association study design, involving affected probands and their parents. But this method requires the previous identification of susceptibility genes and their exact sequence. A proposed susceptibility locus is a variant of the 5HT2A receptor gene. Some studies investigating this locus have found an association with AN (Collier et al 1997, as corrected by Collier 1999; Enoch et al 1998; Sorbi et al 1998), but others have been unable to replicate (Campbell et al 1998; Hinney et al 1997). The A/A genotype frequency was similar in all the studies aside from Hinney et al, who did not have controls and did not report the A/A genotype. GENETIC RISK FOR BN. As for AN, also for BN results of twin studies are not all consistent in indicating high heritability (Fairburn et al 1999). One recent report that controlled for error of measurement estimated that about 80% of the heritability of BN is due to genetic factors, whereas shared environment does not seem to be a significant contributor (Bulik et al 1998). A previous study from the same twin registry had reported a heritability of 55% based on a single assessment (Kendler et al 1991). Genes that contribute to bingeing and vomiting overlap considerably (Sullivan et al 1998). The genetic contribution to the development of EDs seems to become more evident with puberty (Klump et al, in press). BN was found to share genetic risk with phobia and panic disorder (Kendler et al 1995), thus raising the possibility that a general susceptibility to anxiety-related psychopathology is genetically transmitted. AN AND OBSESSIVE–COMPULSIVE SYMPTOMS. An association between obsessive– compulsive tendencies and AN was first reported more than 50 years ago. Certain personality traits, such as conformity, inflexible thinking, emotional restraint, and high harm avoidance, and obsessions about perfectionism, exactness, and symmetry are associated with AN (Matsunaga et al 1999). These features can be found also among patients with BN, who, in addition, often display impulsiveness and novelty seeking tendencies, as measured on self-administered scales like the Tridimensional Personality Questionnaire (Bulik et al 1995). These symptoms persist after the patient has reached remission. Familial aggregation of obsessive– compulsive disorder (OCD) seems to be independent of that of AN or BN, whereas the risk for AN (but not for BN) is co-transmitted with the risk for obsessive– compulsive personality (Lilenfeld et al 1998). The conceptualiza-
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tion of AN as akin to OCD has clear appeal, but also limitations, most notably the apparent lack of insight of these patients and the “ego syntonic” nature of the disorder. This characteristic makes AN closer to a monosymptomatic delusion, a specific “food and weight phobia,” or an “overvalued idea” with loss of insight. Contrary to OCD, AN can be seen as an overriding of normal subcortical functions by the cortex. Also, the persistent and self-injurious drive for thinness of AN patients resembles addictive behavior (Davis and Claridge 1998). The risk for AN, however, appears to be transmitted independently of the risk for substance abuse. NEUROBIOLOGY. Altered serotonin levels are associated with changes in a wide range of behaviors in animals and humans, including behaviors relevant to homeostasis like ingestion and sleep, as well as those related to affect regulation. In both AN and BN, abnormalities of the serotonin system have been reported, such as increased cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid in ED patients who have recovered from the acute phase of the illness (Kaye et al 1991, 1998). Preliminary data of positron emission tomography with altaserin, a serotonergic ligand that binds to 5-HT2A receptors, in 9 women who had recovered from BN versus 12 normal controls have shown reduced 5-HT2A binding in the medial orbital cortex, an area involved in regulating emotional and impulse control (Frank et al 1998). However strong the link between EDs and serotonin seems to be, it is unlikely that a specific dysfunction of one neurotransmitter system can fully explain the pathogenesis of AN and BN. The involvement of other systems, such as the dopaminergic system, should be further considered and studied (Kaye et al 1999a). Further insight into the pathogenesis of EDs may come from neuroendocrine studies. The role of gonadal steroids, for example, in EDs is suggested by the clear gender effect in the risk for these disorders, their emergence at puberty or soon after, and the increased risk for EDs of girls who had an early menarche. BASIC NEUROSCIENCE OF FEEDING BEHAVIOR. In recent years, important advances have been made in elucidating the molecular bases of obesity and calorie intake control. The recognition of the role of the ventromedial hypothalamus in controlling food intake goes back 60 years. The modern understanding that this brain region participates in complex circuitry regulating ingestion promises more applicable advances. A major finding has been the identification of two monogenic mouse models of obesity: the obese ob/ob and the diabetic db/db mice. It was shown that the locus of the ob mutation encodes a protein, called leptin, whose synthesis is expressed by the white adipose tissue (Maffei et al 1995; Zhang et al 1994).
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Leptin acts in the ventro-medial hypothalamus that is dense in leptin receptors and leads to reduced caloric intake (Elmquist et al 1998). It was also discovered that the genetic locus db encodes for the leptin receptor (Chua et al 1996). This receptor belongs to the cytokine receptor family and is similar to the IL6 receptor. Leptin accelerates puberty in animals, by enhancing the release of hypothalamic hormones. As expected, underweight AN patients have low serum (Grinspoon et al 1996), plasma and CSF concentrations of leptin (Mantzoros et al 1997). One study suggests that leptin levels increase with weight restoration but normalize before full weight recovery is achieved, thus possibly explaining why it is so difficult for patients with anorexia to reach complete recovery (Mantzoros et al 1997). The SOCS-3 molecule (or suppressor of cytokine signaling) is an intracellular inhibitor of leptin signaling (Bjorbaek et al 1998). A neuropeptide that seems to require leptin for its expression is CART (or cocaineand amphetamine-regulated transcript), which is widely present in the mammalian brain (Kristensen et al 1998). Another substance expressed in the lateral hypothalamic area is the melanin concentrating hormone (MCH) that increases food intake in mice and appears to be downregulated by leptin. MCH is upregulated in ob/ob mice that lack leptin, and also in starving rats whose leptin levels fall. In fact, knocking-out the MCH gene results in a lean body phenotype even if leptin levels are low (Shimada et al 1998). The latest players to be identified are the orexins, peptides that are found exclusively in the lateral hypothalamus (Griffond et al 1999; Risold et al 1999) and whose concentration rises with starvation and with decreasing levels of leptin (Sakurai et al 1998). Injection of orexins into animal brain increases food intake. There is now evidence for a circuit that from leptin-activated cells in the medio-basal hypothalamus goes to the lateral hypothalamus that in turn projects diffusely to the cortex. REGULATION OF ENERGY HOMEOSTASIS. In mammals, capacity to reproduce is dependent on access to a positive energy expenditure. In order to activate the reproductive function, the message that there is a positive energy balance is needed. Leptin seems to be such a messenger. It increases fatty acid oxidation, glucose activation, and thermogenesis. The administration of leptin reverses the infertility of the ob/ob mice and of starved animals. It has been proposed that the evolutionary meaning of leptin is to signal that starvation is not occurring and that reproductive endocrine function can be resumed (Flier 1998). Regulation of food intake and of fertility is intertwined. The caudal brain stem is implicated in the metabolic control of both reproduction and food intake. Of possible relevance to EDs, the repeated exposure to hypoglycemic stress results in attenuated glucoregulatory
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responses in animals, thus suggesting that the metabolic regulatory system stops responding if it is repeatedly stressed (Jill Schneider, oral communication). DYNAMIC BRAIN CIRCUITRY. There is active research in identifying the neuroanatomical circuits underlying sexual and social behavior in mammals, which can serve as an illustration of the kind of integration required to understand motivated behavior in general. It is the activity of the circuit as a whole, rather than individual brain areas in isolation, that produces a certain pattern of behavior. By focusing on common themes that various behaviors may share in terms of activated neuroanatomical areas, a unitary social behavior network may be postulated. According to how this network is activated, different behaviors can result. Thus, social behaviors that are quite different in terms of motivation, physiological prerequisites, and neuroanatomical substrates, can emerge from a single neuroanatomical network (Newman 1999). Brain imaging techniques may be helpful in studying the neuroanatomic abnormalities of EDs. These techniques allow the identification in vivo of areas that display a specific activation during certain behaviors, but they also have important limitations. Causality cannot be inferred from brainimaging data alone: the dynamic circuitry relating a brain area to function is necessary to provide an adequate context, and it is also necessary to study how the system operates in the absence of that brain area (for instance, through brain lesion models in animals and studies of brain damaged patients). Furthermore, it is difficult to compare imaging data across subjects, given that brains are as differently shaped as individual faces are. Nevertheless, functional magnetic resonance studies are an important opportunity to look at novel hypotheses related to cognitive processing in EDs (Wojciulik et al 1998), and the development of new ligands has the potential of elucidating differences and similarities in receptor systems among EDs and OCD, anxiety, substance dependence, and mood disorders.
Treatment: Anorexia Nervosa CLINICAL COURSE OF AN. The course of AN is very protracted, even for those patients with the best ultimate prognosis. A 10- to 15-year follow-up of patients with AN found that 14% had not recovered, 10% had a partial recovery, and 75% a complete recovery (Strober et al 1997). Median time to partial recovery was 60 months and to full recovery 80 months. Full recovery was rare before 70 months. Once full recovery is achieved, however, relapse is rare. Few predictors of long-term course and outcome were identified in this study. A recently reported 7.5- year follow-up study of women with AN found that 33% reached full recovery, but 40% of them relapsed after full recovery
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(Herzog et al 1999). Low minimum weight at time of presentation and duration of episode have been found to be associated with more negative long-term outcome for AN patients (Hebebrand et al 1997; Herzog et al 1999). Poor relationship with family has also been shown to predict poor outcome in adolescents (Bryant-Waugh et al 1988; North et al 1997). TREATMENT OF AN: ACUTE PHASE. AN is a specific, relatively homogeneous illness that calls for a specific treatment program, thus supporting the concept of “ED programs.” There are three main treatment phases: 1) restoring severe weight loss; 2) treating cognitive distortions and relationship disturbances (i.e., distortion of body image, low self-esteem, and family conflict); and 3) achieving long-term remission and rehabilitation (i.e., full recovery). We are currently fairly successful at the first phase of treatment, that is the acute management of the severe weight loss of AN patients, usually in inpatient settings. Some success can also be claimed at addressing low-self esteem and family conflict; however, these treatments are time consuming and expensive. It is estimated that the average cost of a hospitalization for AN is about $18,000, versus $11,000 for schizophrenia, $10,000 for bulimia, and $8,700 for depression (StriegelMoore, oral communication). Concern has been expressed that financially dictated limitations on the duration of inpatient treatment may compromise the ability to restore severe weight loss in severe AN. Beyond the acute phase of the illness, there is a clear need to develop effective interventions for achieving long-term remission and sustained nutritional rehabilitation. There is no “anti-anorexia nervosa” drug or psychotherapy, and no treatment seems to counteract the drive for thinness of AN patients. Virtually all the known pharmacological and psychological interventions have been suggested as a treatment of AN. Only limited empirical support exists for some of these interventions. Among the medications tried, there are typical antipsychotics, first- and second-generation antidepressants, cyproheptadine, lithium, tetrahydrocannabilol, and cisapride. Studies of atypical antipsychotics are in progress. The sample size of most controlled clinical trials is small, but the results have not been encouraging. It must be taken into account that these drugs have not been compared to a no-treatment control group; rather, medications were added to a psychosocial intervention that all patients in both experimental and control group received. Thus, what was tested was whether medication plus standard psychosocial management was more effective than psychosocial management alone. Based on current data, the benefit of adding pharmacotherapy to psychosocial treatment seems to be negligible (Attia et al 1998). TREATMENT OF AN: RELAPSE PREVENTION. Prevention of relapse is a critical aspect of treating AN. As already
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noted, about 40 –50% of the weight-restored AN patients relapse after achieving full recovery (Eckert et al 1995; Herzog et al 1999). Factors that seem to influence the risk for relapse are patient’s motivation for treatment, degree of insight, and severity of AN symptoms (Eckert et al 1995), but others have found no predictors of relapse (Herzog et al 1999). A longer and more intense treatment of the acute phase of AN may translate into a lower relapse rate. Patients who were discharged in more stable physical and psychological conditions were found to be less likely to relapse (Baran et al 1995). Therapeutic strategies that target these factors need to be developed and tested. The managed care environment has reduced the length of inpatient stay for treatment of AN, but it not known if a time cohort effect on relapse rate since the introduction of managed care exists. The administration of fluoxetine after weight restoration has been associated with decreased relapse rate in one reported study (Kaye et al 1997). The application of techniques that can enhance patient motivation may be worth considering. Several studies are in progress to test treatments aimed at preventing relapse. Among these, the McKnight Foundation is supporting a four-site (Cornell University, University of Minnesota, University of North Dakota, and Stanford University) clinical trial to compare the efficacy of cognitive– behavioral therapy (CBT), medication management, combined CBT plus medication management in the prevention of relapse in AN. LEVELS OF CARE FOR AN PATIENTS. Levels of care for patients with AN include inpatient, residential, dayhospital, and outpatient treatment. Empirically validated criteria for determining the appropriate level of care for individual patients based on disease severity would be useful to clinicians and health resources administrators. Developed from consensus among experts, a draft of such criteria has been prepared and waits validation (Kaye et al, unpublished). FOCUS ON ADOLESCENTS. Adolescents are the age group at highest risk for developing AN and BN. They may also offer the greatest opportunity for effective treatment and recovery. Early identification and treatment of AN can result in a better outcome (Russell et al 1987). Family systems psychotherapy was found to be better than individual psychotherapy for adolescents with AN (Eisler et al 1997; Robin et al 1994). Adolescence offers a “window of opportunity” for treatment of AN that should be fully exploited.
Treatment of Bulimia Nervosa Only 15 years ago, no effective treatments were available for BN. Controlled clinical trials have made great strides in discovering effective treatments for this common and
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debilitating condition (for reviews see Agras 1997; Wilfley and Cohen 1997). The principal findings of such studies are as follows: 1. Both antidepressant medications and specific psychotherapy modality, such as CBT and interpersonal therapy (IPT) are effective in the treatment of BN (Fairburn et al 1993; Walsh et al 1997). CBT is more effective than the use of a single antidepressant, and both the dropout and relapse rates from medication are higher (Mitchell et al 1990). A 12-week course of CBT results in recovery rates of about 50%. If a second antidepressant is administered to patients who did not respond to the first medication, then the efficacy of pharmacotherapy seems to be comparable to that on CBT (Mitchell et al 1989). 2. Interpersonal psychotherapy (IPT) is less effective than CBT at the end of the treatment, but it seems to catch up with CBT during a 6- to 8-month follow-up (Fairburn et al 1993), suggesting a delay effect for IPT. Because it takes longer for IPT to work, CBT may be preferred as initial choice of therapy. 3. The addition of an antidepressant medication to CBT appears to be marginally more effective than CBT alone on the short term. Combined CBT and pharmacotherapy seems to offer advantages over single treatment on the long term (Agras et al 1992, 1994). 4. For patients who did not respond to CBT, either antidepressant medication or IPT can be considered, but the efficacy of this second-step treatment is limited to about 20% of the patients (Wilson 1996). 5. Self-help versions of CBT with brief therapist supervision seem to be somewhat helpful, with recovery rates of about 25% (Treasure et al 1996). 6. Despite the empirical support for the efficacy of CBT, this treatment is largely underutilized in common clinical practice (Crow et al 1999). This dissemination failure is not specific for BN, as it involved psychological treatments in general, but it is indeed a serious obstacle to delivering effective treatment to patients with BN. 7. Little is known about moderators and mediators of treatment change in BN. Still the importance of research on these factors is clear. If more were known about moderators, we could individualize treatment and match it to patient characteristics. If more were known about mediators, we could try to modify treatments and to make them more effective. In the case of BN, we can identify likely candidates for mediators of treatment, such as reduction of dietary restraint, increase self-efficacy for coping with triggers of binge eating, and modification of the overevaluation of shape and weight.
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Prevention Preventive interventions have been comprehensively conceptualized on a continuum from primary prevention through screening and early identification of subjects at particular risk, to minimal intervention, to gold standard treatment, to relapse prevention and rehabilitation (National Institutes of Health 1998; Striegel-Moore and SteinerAdair 1998). Five domains of risk factors have been reported to be associated with the development of EDs: culture, family (e.g., high socioeconomic status, parental psychopathology, family conflict, parental dieting), personality and behavior, genetics, and traumatic events like physical and sexual abuse (Fairburn et al 1997; StriegelMoore et al 1986). These risk domains are not independent. For instance, it is expected that genetically transmitted characteristics are likely to elicit predictable environmental responses. Risks for childhood disturbances of weight regulation, both genetic and environmental, are clearly relevant to EDs, and should be the object of research. One study has found that childhood obesity is a risk factor for BN (Fairburn et al 1997). Ethnicity does not seem to contribute a significant risk in itself (Striegel-Moore and Smolak 1996). The prevalence of BN and binge eating disorder has been found to be similar in African Americans as in Caucasians (Striegel-Moore et al, 2000a, 2000b). No data are available for AN, however. Moreover, the clinical manifestations of EDs do not appear to differ in ethnic minorities as compared to Caucasian samples (le Grange et al 1997). In considering risk factors as possible targets of prevention, several aspects must be taken into account, including the attributable risk. Because preventive interventions can be aimed at many levels of risk or disease process, and encompass a variety of levels (e.g., individual, families, sororities, inpatient service settings), careful thought is needed to consider the appropriate targets and likely effects. Thus far, research in prevention of EDs has been on interventions that have not clarified either the population (some have combined both asymptomatic and symptomatic participants in interventions) or the malleable components of risk that the intervention targets (Striegel-Moore and Steiner-Adair 1998). As a result, the outcomes have been disappointing, and even disturbing where symptoms after intervention have actually increased (Mann et al 1997).
Future Research Prospects In addition to identifying specific areas of opportunity, the workshop pursued a strategic issue: Can the clinical evidence provide a framework for basic neurobiological studies, and how can advances in the neuroendocrinology of ingestion and appetite translate into new approaches to
the etiology and pathogenesis of EDs? These were the main conclusions at the end of the workshop:
Pathogenesis BASIC NEUROSCIENCE. The explosion of basic neuroscience research has brought new insight into the regulation of metabolic homeostasis, appetite, and food intake. It has also started to identify the neuroanatomical circuits underlying emotions and behavior, and the connections between cognition and motivation. To advance our understanding on the pathogenesis of eating disorders, it is essential to integrate these new findings into novel conceptualizations of EDs where the focus is not simply on ingestion. Attention to basic neuroscience and a closer dialogue between neuroscientists and clinical researchers are critical. GENETICS. There seems to be sufficient data from family and twin studies suggesting a high heritability of AN and BN. According to the latest studies, the heritability seems to be comparable to that of other psychiatric disorders, such as schizophrenia, bipolar, and unipolar disorders. This can provide justification for DNA linkage and candidate gene studies. The affected sibling pair method can be adopted and expanded by including other relatives, such as the parents and one unaffected sibling per family. It was recommended that NIMH consider issuing a program announcement, request for applications, or other similar mechanisms, to start a multicenter DNA based linkage and candidate gene study similar to that created for schizophrenia and bipolar disorder. The large DNA database that would be obtained from such a study could be used by multiple researchers to investigate candidate genes. This seems especially important now that new neuropeptides relevant to food intake regulation are being identified and their function studied. In parallel, twin studies may be still worth considering to answer certain questions. For instance, a longitudinal twin study can inform on the relative contribution of genes and environment as they may change over time and across developmental periods. NEUROIMAGING. There are specific ligands for serotonin, and dopamine sites can be now utilized in positron emission studies to clarify the involvement of these neurotransmitter systems in EDs. Functional MRI can offer an opportunity to look at differences and similarities between EDs and other disorders, such as OCD and depression, and to study reward mechanisms that are related to food intake. Imaging brain responses to stimuli that relate to eating, perception of body shape and selfimage are feasible and needed. NEUROBIOLOGY. A human brain bank would be a critical resource to facilitate identification of brain changes.
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Knock-out gene approaches to studying the role of recently identified neuropeptides that regulate appetite and ingestion should be considered. Animal models of AN would clearly be helpful in comparative studies of brain circuitry. Brain banks would also facilitate comparative studies of the neuronal circuitry of eating behavior and its interaction with other affective systems and cognition. It is also critically important to pursue the developmental changes of hypothalamic neuropeptides, especially as they change during puberty.
Treatment INFRASTRUCTURE FOR CLINICAL TRIALS IN AN.
These studies present multiple challenges, most notably difficulties in patient recruitment and retention into research protocols and need for specialized research staff trained in the treatment and management of patients with AN. To obviate the limitations and inconclusiveness of the existing small-sized studies, multisite clinical trials are needed. There is a need to support the infrastructure that can sustain these studies at a time when the financial return from clinical services is being eroded at most research institutions. Collaborations with managed care organizations to access patients and test models of treatment in these settings are needed. RESEARCH TRAINING. There are only a few researchers active in studying treatments for AN patients. Efforts to enlarge this limited research basis by recruiting new investigators into this area and training young researchers are needed. INTENSITY OF TREATMENT OF ACUTE AN. There is an urgent need to test whether more intensive treatment programs, such as inpatient and day-hospital care, that are known for achieving a greater degree of weight restoration, are in the long term more effective and cost-effective than less intensive and less costly interventions. These data are essential for clinicians, patients, policy makers, and health administrators. RELAPSE PREVENTION IN AN. This a critical step on the way to treat AN. Treatment of AN should aim at full recovery. We should not accept chronicity of AN as a fact. Current efforts to develop effective interventions to prevent relapse after successful initial treatment of AN need to be continued and intensified. It is important to develop therapies that can increase patients’ motivation to adhere to treatment.
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TREATMENT OF CHRONIC AN. Efforts should be undertaken to develop and test effective interventions for individuals with long-standing anorexia nervosa. This is a relatively small, but morbidly affected, group of patients who are chronically ill, require recurrent hospitalizations, and for whom no treatments have been effective. EARLY INTERVENTIONS IN ADOLESCENTS. Adolescence offers a “window of opportunity” for successful treatment of AN soon after its onset and before it has become chronic. Psychosocial interventions focused on family systems seem to be among the most promising approaches worth pursuing.
EFFECTIVENESS AND TRANSLATIONAL RESEARCH
The underutilization of treatment modalities, such as CBT and IPT, whose efficacy is supported by controlled studies, is troublesome. Research is needed to see if efficacious treatment do and can generalize to different clinical situations. Because CBT and IPT are not widely available in the community, research should examine the comparative effectiveness of sequential treatments, beginning with the least complex and costly interventions.
IN BN.
IMPROVING TREATMENT OF BN. The response rate on CBT is about 50%. This treatment can be improved. The current manualized CBT does not adequately address emotional regulation, especially of negative affect, that is a major trigger of binge eating and purging. Also, CBT manuals could be enriched by incorporating interpersonal and family issues, and by addressing abnormal concerns about body shape and weight. Because emotional dysregulation seems to lead to binge eating, therapeutic efforts that specifically aim at regulating emotional state are worth considering. The study of moderators and mediators of treatment can provide useful elements to make treatment more targeted and effective. Likewise, improvements of the current forms of IPT are to be considered. The possible role for combined use of psychotherapy and pharmacotherapy in treating the most severe patients needs to be studied.
DEVELOPMENT OF TREATMENT ALGORITHMS FOR
TREATMENT FOR BINGE EATING DISORDER. There is convincing evidence that binge eating disorder and other disorders of eating behavior that result in obesity are associated with substantial morbidity, share risk factors with BN, and respond to interventions of known utility in BN, such as CBT and antidepressant pharmacotherapy. Research focused on prevention, early identification, and treatment of these disorders should be encouraged.
The effectiveness of a multistep treatment approach to AN needs to be studied, where different treatments are tested in a consistent sequential approach.
NEED FOR TREATMENT INNOVATION. Small, innovative studies to explore new psychosocial approaches to
AN.
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EDs should be encouraged, in parallel to large multisite trials to test specific hypotheses in a definitive way. EXPERTISE AT GRANT REVIEW. The peer review process of grant applications must involve reviewers who are aware of the critical questions in ED research and are familiar with the state-of-the-art of treatment interventions for these disorders.
Prevention: Redefining Methods and Strategies The current state of prevention research in EDs calls for a specific research workshop on prevention of EDs. Among the main purposes of such a meeting, there would be the identification of risk factors to target for prevention, promising strategies for prevention, and appropriate methods for testing proposed interventions. In addition to experts in EDs, experts in prevention research in general and patient representatives should be involved in this effort.
Proceedings of a National Institute of Mental Health research workshop held on December 7– 8, 1998 in Bethesda, Maryland. Speakers: Stewart Agras (Stanford University), Wade Berrettini (University of Pennsylvania), Jennifer Bieley (Eating Disorder Awareness and Prevention), Cynthia Bulik (Virginia Commonwealth University), Joel Elmquist (Harvard Medical School), Laura Lee Hall (National Association for the Mentally Ill), Katherine Halmi (Cornell University), David Jimerson (Harvard Medical School), Nancy Kanwisher (Massachusetts Institute of Technology), Allan Kaplan (University of Toronto), Walter Kaye (University of Pittsburgh), James Lock (Stanford University), Sarah Newman (Cornell University), Jill Schneider (Lehigh University), Ruth StriegelMoore (Wesleyan University), Michael Strober (University of California Los Angeles), Timothy Walsh (Columbia University), and Terence Wilson (Rudgers University). The opinions and assertions contained in this article are the private views of the authors and are not to be construed as official or as reflecting the views of the National Institute of Mental Health or the Department of Health and Human Services.
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