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Fluoxetine treatment of anorexia nervosa: important but disappointing results.

ANOREXIA NERVOSA IS A SEVERE,TREATMENT-RESISTANT illness primarily affecting women. It has one of the highest all-cause mortalities, and the highest suicide rate of any psychiatric illness. Restriction of food intake, refusal to maintain adequate body weight, and disturbed thinking about food, weight, and body image are hallmarks of this illness. A prominent associated feature is profoundambivalenceabout therapeuticefforts (whethernutritional, psychological, or pharmacological) aimed at weight restoration. In addition to the classic pattern of extreme food restriction, a subset of patients also report binge eating and purgingbehaviors (the“binge-purgesubtype”).Co-occurring psychopathologyiscommon,especiallydepression,obsessivecompulsive disorder, and other anxiety disorders. In severely malnourished patients with anorexia nervosa, nutritional rehabilitation with weight restoration is the cornerstone of treatment, and this intervention often requires hospitalization. Psychotherapy is also a regular part of treatment. Preliminary evidence supports use of a specific familybased psychotherapy in adolescents with anorexia nervosa who still reside at home; effective alternative psychotherapies for adolescents have not yet been determined. For adults with anorexia nervosa there is some evidence supporting the use of cognitive behavioral therapy, and other potential psychotherapies for adults are in development. Psychopharmacology is also a common treatment strategy, although the evidence base for psychopharmacologic approaches for anorexia nervosa is quite limited. The existing literature on pharmacotherapy for anorexia nervosa is modest in size and striking for the diversity of medications that have been studied. Agents as diverse as lithium, various antipsychotics, cyproheptadine, tricyclic antidepressants, and tetrahydrocannabinol have been examined with generally negative results in small trials. This wide diversity of agents is clearly an indication of the remarkable challenges inherent in treating individuals who have anorexia nervosa, and also reflects the generally negative results to date in pharmacotherapy trials for this illness. Recently, there has been much interest in the use of serotonin reuptake inhibitors for acute treatment and relapse prevention in anorexia nervosa. Trials of acute treatment (ie, while patients are still at low weight) with fluoxetine have failed to demonstrate clinical benefit. Modestsized studies of fluoxetine for anorexia nervosa relapse prevention (after an initial weight gain) have shown both positive (n=35) and negative (n=33) results. In this issue of JAMA, Walsh and colleagues report the results of a placebo-controlled trial of fluoxetine in the relapse prevention treatment of anorexia nervosa. Participants were 93 women aged 16 to 45 years who were completing multimodal inpatient or day hospital treatment and had weight restoration to a body mass index (calculated as weight in kilograms divided by the square of height in meters) of at least 19.0. The patients were randomly assigned to either placebo or fluoxetine, with a dosage goal of 60 mg/d (with decreases permitted for adverse effects and an increase to 80 mg/d permitted for clinical deterioration). A total of 12 months of treatment was provided, during which time all patients also received cognitive behavioral therapy. Relapse was defined as weight loss to a body mass index less than 16.5 or development of medical complications or imminent suicide risk or the onset of another severe psychiatric disorder. The results of the trial by Walsh et al did not support efficacy for fluoxetine in relapse prevention for anorexia nervosa. Response to fluoxetine was not different from placebo, whether measured in time-to-relapse, percentage of patients maintaining a body mass index of 18.5 or higher, or the percentage of patients meeting modified Morgan-Russell criteria for at least fair outcome (Morgan-Russell criteria provide a slightly broader assessment of anorexia nervosa treatment outcome, extending beyond simple weight restoration). Responsebysubtypeofanorexianervosa(restrictingvsbingepurge) was also examined. The authors note that since a previous fluoxetine trial with positive findings enrolled only participantswith therestrictingsubtypeofanorexianervosa, perhaps this subtype would respond to fluoxetine. In addition, given the efficacy of fluoxetine for purging in bulimia nervosa, patients with the purging subtype of anorexia nervosamighthavebeenexpected tohave faredbetterwith fluoxetine. However, analyses by subtype did not affect the results. Premature study termination, mainly due to treatment failures and patient-initiated withdrawals, was common, but the rate of premature termination did not differ between fluoxetineand placebo-treated patients. A variety of secondary outcomes were examined, including measures of eat-