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1.
Sullivan PF. Mortality in anorexia nervosa.  Am J Psychiatry. 1995;152:1073-1074PubMed
2.
Pike KM. Long-term course of anorexia nervosa: response, relapse, remission, and recovery.  Clin Psychol Rev. 1998;18:447-475PubMedArticle
3.
Jones LM, Halford WK, Dooley RT. Long term outcome of anorexia nervosa.  Behav Change. 1993;10:93-102
4.
Halmi KA, Eckert E, Marchi P, Sampugnaro V, Apple R, Cohen J. Comorbidity of psychiatric diagnoses in anorexia nervosa.  Arch Gen Psychiatry. 1991;48:712-718PubMedArticle
5.
Zhu AJ, Walsh BT. Pharmacologic treatment of eating disorders.  Can J Psychiatry. 2002;47:227-234PubMed
6.
Attia E, Haiman C, Walsh BT, Flater SR. Does fluoxetine augment the inpatient treatment of anorexia nervosa?  Am J Psychiatry. 1998;155:548-551PubMed
7.
Strober M, Freeman R, DeAntonio M, Lampert C, Diamond J. Does adjunctive fluoxetine influence the post-hospital course of anorexia nervosa? a 24-month prospective, longitudinal followup and comparison with historical controls.  Psychopharmacol Bull. 1997;33:425-431PubMed
8.
Kaye WH, Nagata T, Weltzin TE.  et al.  Double-blind placebo controlled administration of fluoxetine in restricting- and restricting-purging type anorexia nervosa.  Biol Psychiatry. 2001;49:644-652PubMedArticle
9.
Pike KM, Walsh BT, Vitousek K, Wilson GT, Bauer J. Cognitive behavior therapy in the posthospitalization treatment of anorexia nervosa.  Am J Psychiatry. 2003;160:2046-2049PubMedArticle
10.
Cachelin FM, Maher BA. Is amenorrhea a critical criterion for anorexia nervosa?  J Psychosom Res. 1998;44:435-440PubMedArticle
11.
Garfinkel PE, Lin E, Goering P.  et al.  Should amenorrhoea be necessary for the diagnosis of anorexia nervosa? evidence from a Canadian community sample.  Br J Psychiatry. 1996;168:500-506PubMedArticle
12.
Watson TL, Andersen AE. A critical examination of the amenorrhea and weight criteria for diagnosing anorexia nervosa.  Acta Psychiatr Scand. 2003;108:175-182PubMedArticle
13.
Garner DM, Olmsted MP. The Eating Disorder Inventory Manual. Odessa, Fla: Psychological Assessment Resources; 1984
14.
Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression.  Arch Gen Psychiatry. 1961;4:561-571PubMedArticle
15.
Beck AT, Epstein N, Brown G, Steer RA. An inventory for measuring clinical anxiety: psychometric properties.  J Consult Clin Psychol. 1988;56:893-897PubMedArticle
16.
Rosenberg M. Conceiving the Self. New York, NY: Basic Books; 1979
17.
Mazure CM, Halmi KA, Sunday SR, Romano SJ, Einhorn AM. The Yale-Brown-Cornell eating disorder scale: development, use, reliability and validity.  J Psychiatr Res. 1994;28:425-445PubMedArticle
18.
Endicott J, Nee J, Harrison W, Blumenthal R. Quality of life enjoyment and satisfaction questionnaire: a new measure.  Psychopharmacol Bull. 1993;29:321-326PubMed
19.
Eckert ED, Halmi KA, Marchi P, Grove W, Crosby R. Ten-year follow-up of anorexia nervosa: clinical course and outcome.  Psychol Med. 1995;25:143-156PubMedArticle
20.
Russell GFM, Szmukler GI, Dare C, Eisler I. An evaluation of family therapy in anorexia nervosa and bulimia nervosa.  Arch Gen Psychiatry. 1987;44:1047-1056PubMedArticle
21.
Koran LM, Cain JW, Dominguez RA, Rush AJ, Thiemann S. Are fluoxetine plasma levels related to outcome in obsessive-compulsive disorder?  Am J Psychiatry. 1996;153:1450-1454PubMed
22.
Holtkamp K, Konrad R, Kaiser N.  et al.  A retrospective study of SSRI treatment in adolescent anorexia nervosa: insufficient evidence for efficacy.  J Psychiatr Res. 2005;39:303-310PubMedArticle
23.
Lock J, le Grange D. Family-based treatment of eating disorders.  Int J Eat Disord. 2005;37:S64-S67PubMedArticle
24.
McIntosh VV, Jordan J, Carter FA.  et al.  Three psychotherapies for anorexia nervosa: a randomized, controlled trial.  Am J Psychiatry. 2005;162:741-747PubMedArticle
25.
Kaye WH, Weltzin TE, Hsu LK, Bulik CM. An open trial of fluoxetine in patients with anorexia nervosa.  J Clin Psychiatry. 1991;11:464-471PubMed
26.
Powers PS, Santana CA, Bannon YS. Olanzapine in the treatment of anorexia nervosa: an open label trial.  Int J Eat Disord. 2002;32:146-154PubMedArticle
27.
Lagakos SW. The challenge of subgroup analyses–reporting without distorting.  N Engl J Med. 2006;354:1667-1669PubMedArticle
28.
Ressler KJ, Rothbaum BO, Tannenbaum L.  et al.  Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear.  Arch Gen Psychiatry. 2004;61:1136-1144PubMedArticle
29.
Strober M. Pathologic fear conditioning and anorexia nervosa: on the search for novel paradigms.  Int J Eat Disord. 2004;35:504-508PubMedArticle
30.
Tchanturia K, Morris RG, Surguladze S, Treasure J. An examination of perceptual and cognitive set shifting tasks in acute anorexia nervosa and following recovery.  Eat Weight Disord. 2002;7:312-315PubMedArticle
31.
Steinglass JE, Walsh BT, Stern Y. Set shifting deficit in anorexia nervosa.  J Int Neuropsychol SocIn press
Original Contribution
June 14, 2006

Fluoxetine After Weight Restoration in Anorexia NervosaA Randomized Controlled Trial

Author Affiliations
 

Author Affiliations: New York State Psychiatric Institute/Columbia University Medical Center, New York, NY (Drs Walsh, Attia, Parides, Pike, and Devlin and Ms Roberto); and University of Toronto and Toronto General Hospital, Toronto, Ontario (Drs Kaplan, Olmsted, Carter, and Woodside and Ms Rockert).

JAMA. 2006;295(22):2605-2612. doi:10.1001/jama.295.22.2605
Context

Context Antidepressant medication is frequently prescribed for patients with anorexia nervosa.

Objective To determine whether fluoxetine can promote recovery and prolong time-to-relapse among patients with anorexia nervosa following weight restoration.

Design, Setting, and Participants Randomized, double-blind, placebo-controlled trial. From January 2000 until May 2005, 93 patients with anorexia nervosa received intensive inpatient or day-program treatment at the New York State Psychiatric Institute or Toronto General Hospital. Participants regained weight to a minimum body mass index (calculated as weight in kilograms divided by the square of height in meters) of 19.0 and were then eligible to participate in the randomized phase of the trial.

Interventions Participants were randomly assigned to receive fluoxetine or placebo and were treated for up to 1 year as outpatients in double-blind fashion. All patients also received individual cognitive behavioral therapy.

Main Outcome Measures The primary outcome measures were time-to-relapse and the proportion of patients successfully completing 1 year of treatment.

Results Forty-nine patients were assigned to fluoxetine and 44 to placebo. Similar percentages of patients assigned to fluoxetine and to placebo maintained a body mass index of at least 18.5 and remained in the study for 52 weeks (fluoxetine, 26.5%; placebo, 31.5%; P = .57). In a Cox proportional hazards analysis, with prerandomization body mass index, site, and diagnostic subtype as covariates, there was no significant difference between fluoxetine and placebo in time-to-relapse (hazard ratio, 1.12; 95% CI, 0.65-2.01; P = .64).

Conclusions This study failed to demonstrate any benefit from fluoxetine in the treatment of patients with anorexia nervosa following weight restoration. Future efforts should focus on developing new models to understand the persistence of this illness and on exploring new psychological and pharmacological treatment approaches.

Trial Registration clinicaltrials.gov Identifier: NCT00288574

Anorexia nervosa is a serious psychiatric illness with substantial morbidity and a lifetime mortality arguably as high as that associated with any psychiatric illness.1 A major contributor to the poor prognosis of this illness is the high rate of relapse following initial treatment. Despite successful weight restoration, 30% to 50% of patients require rehospitalization within 1 year of discharge.2,3 This discouraging experience has prompted interest in interventions aimed at preventing deterioration following weight restoration.

Patients with anorexia nervosa often exhibit symptoms of other psychiatric disorders,4 such as depression and obsessive-compulsive disorder, which are responsive to antidepressant medication, suggesting that pharmacological interventions might be of use. Surprisingly, virtually all of the controlled trials of medication (most of which have been conducted during the initial phase of treatment when patients are underweight) have shown no benefit of medication compared with placebo.5,6 Despite this lack of evidence of effectiveness, a substantial number of patients with anorexia nervosa receive antidepressant medications. In our sites, approximately 60% of patients with anorexia nervosa seeking treatment report having been treated with a selective serotonin reuptake inhibitor (SSRI). Since the ineffectiveness of medication at low weight might be attributable to the effects of starvation, researchers have more recently explored the utility of medication after initial treatment has reversed the acute effects of starvation, with differing results.

In a retrospective case-control analysis, Strober et al7 found no difference in the outcome of patients with anorexia nervosa taking fluoxetine following hospitalization compared with similar patients not taking fluoxetine. However, in a double-blind, placebo-controlled trial of 35 patients following significant weight restoration, Kaye et al8 found fluoxetine to be superior to placebo in preventing relapse.

The primary aim of the current study was to determine, in a large sample, whether fluoxetine, compared with placebo, reduced the rate of relapse and enhanced psychological and behavioral recovery following initial treatment for anorexia nervosa. After successfully completing a course of intensive treatment aimed at weight restoration, patients were randomly assigned to receive fluoxetine or placebo and treated for up to 1 year in double-blind fashion. In addition to medication or placebo, patients received individual cognitive behavioral therapy specifically designed to prevent relapse.9

METHODS
RESULTS
COMMENT
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Article Information

Corresponding Author: B. Timothy Walsh, MD, Department of Psychiatry, College of Physicians and Surgeons of Columbia University/New York State Psychiatric Institute, 1051 Riverside Dr, Unit 98, New York, NY 10032 (btw1@columbia.edu).

Author Contributions: Dr Walsh had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Walsh, Kaplan, Attia, Olmsted, Parides, Carter, Pike, Devlin, Woodside, Rockert.

Acquisition of data: Walsh, Kaplan, Attia, Olmsted, Carter, Pike, Devlin, Woodside, Roberto, Rockert.

Analysis and interpretation of data: Walsh, Kaplan, Attia, Olmsted, Parides, Roberto, Rockert.

Drafting of the manuscript: Walsh, Kaplan, Parides, Roberto.

Critical revision of the manuscript for important intellectual content: Attia, Olmsted, Carter, Pike, Devlin, Woodside, Rockert.

Statistical analysis: Walsh, Parides, Roberto.

Obtained funding: Walsh, Kaplan.

Administrative, technical, or material support: Walsh, Kaplan, Attia, Olmsted, Roberto, Rockert.

Study supervision: Walsh, Kaplan, Pike.

Financial Disclosures: Dr Walsh has reported receiving research support from Eli Lilly and Co, Abbott Laboratories, Ortho-McNeil Pharmaceuticals, and GlaxoSmithKline. Drs Kaplan and Woodside have reported receiving research support from Eli Lilly and Co. Dr Devlin has reported receiving research support from Ortho-McNeil Pharmaceuticals and Eli Lilly and Co. Dr Attia has reported receiving research support from Eli Lilly and Co and Pfizer Inc. No other authors reported disclosures.

Funding/Support: This study was supported in part by grants MH060271 and MH60336 from National Institutes of Health. Eli Lilly supplied fluoxetine and placebo.

Role of the Sponsor: The National Institutes of Health and Eli Lilly had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.

Previous Presentation: Preliminary results of this study were presented at the meeting of the Eating Disorders Research Society; September 29, 2005; Toronto, Ontario.

Acknowledgment: We thank the staffs of the General Clinical Research Unit at New York State Psychiatric Institute/Columbia University Medical Center, New York, NY and of Toronto General Hospital, Toronto, Ontario. The members of the data and safety monitoring board: Sidney Kennedy, MD, University of Toronto, Toronto, Ontario; Andrew Leon, PhD, Weill Medical College of Cornell University, New York, NY; Steven Roose, MD, New York State Psychiatric Institute/Columbia University Medical Center; Jane Pearson, PhD, program officer, National Institute of Mental Health, Bethesda, Md. The members of the Eating Disorders Research Unit at New York State Psychiatric Institute/Columbia University Medical Center: Lauren Escott, MA, and Dana Satir, BA, Boston University, Boston, Mass, for data collection; Juli Goldfein, PhD, Diane Klein, MD, Lisa Kotler, MD, Laurel Mayer, MD, Pamela Raizman, PhD, Joanna Steinglass, MD, and Sara Wolk, PhD, New York State Psychiatric Institute/Columbia University Medical Center, for clinical care of study participants; Katharine Loeb, PhD, Mt Sinai School of Medicine, New York, NY; Sally Woodring, RN, New York State Psychiatric Institute/Columbia University Medical Center, for medication supply management; Jonathan Cohen, MS, New York State Psychiatric Institute/Columbia University Medical Center, for database creation and support. The members of the Toronto General Hospital research team: Traci McFarlane, PhD, and Randy Staab, MD, FRCP(C), Toronto General Hospital/University of Toronto; Pavla Reznicek, PhD, private practice, Toronto, for clinical care of study participants; Anita Federici, MSc, York University, Toronto, for data collection; and Nancy Lipson, MSW, RSW, Concurrent Disorders Service, Center for Addiction and Mental Health, Toronto, for medication supply management.

The following individuals included in the acknowledgments reported having received compensation from the NIH grant for their involvement in the study: Jonathan Cohen, MS; Lauren Escott, MA; Anita Federici, MSc; Juli Goldfein, PhD; Lisa Kotler, MD; Nancy Lipson, MSW; Pamela Raizman, PhD; Pavla Reznicek, PhD; Randy Staab, MD, FRCP(C); Dana Satir, BA; and Sara Wolk, PhD.

REFERENCES
1.
Sullivan PF. Mortality in anorexia nervosa.  Am J Psychiatry. 1995;152:1073-1074PubMed
2.
Pike KM. Long-term course of anorexia nervosa: response, relapse, remission, and recovery.  Clin Psychol Rev. 1998;18:447-475PubMedArticle
3.
Jones LM, Halford WK, Dooley RT. Long term outcome of anorexia nervosa.  Behav Change. 1993;10:93-102
4.
Halmi KA, Eckert E, Marchi P, Sampugnaro V, Apple R, Cohen J. Comorbidity of psychiatric diagnoses in anorexia nervosa.  Arch Gen Psychiatry. 1991;48:712-718PubMedArticle
5.
Zhu AJ, Walsh BT. Pharmacologic treatment of eating disorders.  Can J Psychiatry. 2002;47:227-234PubMed
6.
Attia E, Haiman C, Walsh BT, Flater SR. Does fluoxetine augment the inpatient treatment of anorexia nervosa?  Am J Psychiatry. 1998;155:548-551PubMed
7.
Strober M, Freeman R, DeAntonio M, Lampert C, Diamond J. Does adjunctive fluoxetine influence the post-hospital course of anorexia nervosa? a 24-month prospective, longitudinal followup and comparison with historical controls.  Psychopharmacol Bull. 1997;33:425-431PubMed
8.
Kaye WH, Nagata T, Weltzin TE.  et al.  Double-blind placebo controlled administration of fluoxetine in restricting- and restricting-purging type anorexia nervosa.  Biol Psychiatry. 2001;49:644-652PubMedArticle
9.
Pike KM, Walsh BT, Vitousek K, Wilson GT, Bauer J. Cognitive behavior therapy in the posthospitalization treatment of anorexia nervosa.  Am J Psychiatry. 2003;160:2046-2049PubMedArticle
10.
Cachelin FM, Maher BA. Is amenorrhea a critical criterion for anorexia nervosa?  J Psychosom Res. 1998;44:435-440PubMedArticle
11.
Garfinkel PE, Lin E, Goering P.  et al.  Should amenorrhoea be necessary for the diagnosis of anorexia nervosa? evidence from a Canadian community sample.  Br J Psychiatry. 1996;168:500-506PubMedArticle
12.
Watson TL, Andersen AE. A critical examination of the amenorrhea and weight criteria for diagnosing anorexia nervosa.  Acta Psychiatr Scand. 2003;108:175-182PubMedArticle
13.
Garner DM, Olmsted MP. The Eating Disorder Inventory Manual. Odessa, Fla: Psychological Assessment Resources; 1984
14.
Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression.  Arch Gen Psychiatry. 1961;4:561-571PubMedArticle
15.
Beck AT, Epstein N, Brown G, Steer RA. An inventory for measuring clinical anxiety: psychometric properties.  J Consult Clin Psychol. 1988;56:893-897PubMedArticle
16.
Rosenberg M. Conceiving the Self. New York, NY: Basic Books; 1979
17.
Mazure CM, Halmi KA, Sunday SR, Romano SJ, Einhorn AM. The Yale-Brown-Cornell eating disorder scale: development, use, reliability and validity.  J Psychiatr Res. 1994;28:425-445PubMedArticle
18.
Endicott J, Nee J, Harrison W, Blumenthal R. Quality of life enjoyment and satisfaction questionnaire: a new measure.  Psychopharmacol Bull. 1993;29:321-326PubMed
19.
Eckert ED, Halmi KA, Marchi P, Grove W, Crosby R. Ten-year follow-up of anorexia nervosa: clinical course and outcome.  Psychol Med. 1995;25:143-156PubMedArticle
20.
Russell GFM, Szmukler GI, Dare C, Eisler I. An evaluation of family therapy in anorexia nervosa and bulimia nervosa.  Arch Gen Psychiatry. 1987;44:1047-1056PubMedArticle
21.
Koran LM, Cain JW, Dominguez RA, Rush AJ, Thiemann S. Are fluoxetine plasma levels related to outcome in obsessive-compulsive disorder?  Am J Psychiatry. 1996;153:1450-1454PubMed
22.
Holtkamp K, Konrad R, Kaiser N.  et al.  A retrospective study of SSRI treatment in adolescent anorexia nervosa: insufficient evidence for efficacy.  J Psychiatr Res. 2005;39:303-310PubMedArticle
23.
Lock J, le Grange D. Family-based treatment of eating disorders.  Int J Eat Disord. 2005;37:S64-S67PubMedArticle
24.
McIntosh VV, Jordan J, Carter FA.  et al.  Three psychotherapies for anorexia nervosa: a randomized, controlled trial.  Am J Psychiatry. 2005;162:741-747PubMedArticle
25.
Kaye WH, Weltzin TE, Hsu LK, Bulik CM. An open trial of fluoxetine in patients with anorexia nervosa.  J Clin Psychiatry. 1991;11:464-471PubMed
26.
Powers PS, Santana CA, Bannon YS. Olanzapine in the treatment of anorexia nervosa: an open label trial.  Int J Eat Disord. 2002;32:146-154PubMedArticle
27.
Lagakos SW. The challenge of subgroup analyses–reporting without distorting.  N Engl J Med. 2006;354:1667-1669PubMedArticle
28.
Ressler KJ, Rothbaum BO, Tannenbaum L.  et al.  Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear.  Arch Gen Psychiatry. 2004;61:1136-1144PubMedArticle
29.
Strober M. Pathologic fear conditioning and anorexia nervosa: on the search for novel paradigms.  Int J Eat Disord. 2004;35:504-508PubMedArticle
30.
Tchanturia K, Morris RG, Surguladze S, Treasure J. An examination of perceptual and cognitive set shifting tasks in acute anorexia nervosa and following recovery.  Eat Weight Disord. 2002;7:312-315PubMedArticle
31.
Steinglass JE, Walsh BT, Stern Y. Set shifting deficit in anorexia nervosa.  J Int Neuropsychol SocIn press
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