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A randomized controlled trial of fluoxetine and cognitive behavioral therapy for bulimia nervosa: Short-term outcome
Pergamon
Behav. Res. Ther. Vol. 35, No. 9, pp. 803-811, 1997 i 1997 Elsevier Science Ltd. All rights reserved Printed in Great Britain PII: S 0 0 0 5 - 7 9 6 7 ( 9 7 ) 0 0 0 4 1 - 7 0005-7967/97 $17.00 + 0.00
A RANDOMIZED CONTROLLED TRIAL OF FLUOXETINE AND COGNITIVE BEHAVIORAL THERAPY FOR BULIMIA NERVOSA: SHORT-TERM OUTCOME DAVID S. GOLDBLOOM,* MARION OLMSTED, RON DAVIS, JANET CLEWES, MARGUS HEINMAA, WENDI ROCKERT and BRIAN SHAW Clarke Institute of Psychiatry; Departments of Psychiatry and Psychology, The Toronto Hospital, and University of Toronto, Toronto, Ontario, Canada (Received II April 1997) S u m m a r y - - T h i s study compared and combined fluoxetine and individual cognitive behavioral therapy in the treatment of bulimia nervosa. Participants were 76 women who sought treatment at the Eating Disorders Program of the Toronto Hospital and who met DSM-III-R criteria for bulimia nervosa. Subjects were randomly assigned to receive fluoxetine alone, cognitive behavior therapy alone, or the two in combination and were treated over 16 weeks. Short-term outcome revealed that all three treatment conditions were associated with clinical improvement across a wide range of parameters. The combination of pharmacotherapy and psychotherapy was superior to pharmacotherapy alone on specific parameters and there was no statistically significant advantage to the combination over psychotherapy alone. Limitations to the study include the absence of a placebo pill group and a waiting list control group as well as a substantial dropout rate across all three treatment conditions. © 1997 Elsevier Science Ltd
INTRODUCTION
The treatment of bulimia nervosa (BN) has been the focus of numerous treatment studies since the disorder was described clinically in 1979 (Russell, 1979) and codified in DSM-III in 1980 (American Psychiatric Association, 1980); indeed, therapeutic research on BN has been far more prolific than that conducted on the related and long-recognized disorder anorexia nervosa. The principal domains of treatment have been individual and group psychotherapy and antidepressant pharmacotherapy (Garfinkel & Goldbloom, 1994; Kennedy & Goldbloom, 1995). Within the former, a variety of approaches has been studied, including psychodynamic, interpersonal, behavioral, and cognitive-behavioral modalities. Where waiting list controls have been employed, these active treatments have demonstrated superiority; when active forms of psychotherapy have been compared, short-term outcomes seldom differ, although long-term differences have been documented (Garfinkel & Goldbloom, 1994; Fairburn et al., 1995). Similarly, the vast majority of placebo-controlled trials of antidepressants have confirmed the antibulimic efficacy of the active medications, with benefits documented not only for behavioral symptomatology (Walsh & Devlin, 1995) but also for characteristic attitudinal patterns (Goldbloom & Olmsted, 1993). More recently, studies have compared and combined disparate forms of treatment for BN; these include trials of imipramine and intensive outpatient cognitive behavioral group therapy (Mitchell et al., 1990), fluoxetine and intensive inpatient eclectic behavioral therapy (Fichter et al., 1991), two trials of desipramine and outpatient individual cognitive-behavioral therapy (CBT) (Agras et al., 1992; Leitenberg et al., 1994), fluoxetine and nutritional counselling (Beumont et al., 1996), and a comparison of CBT and psychodynamically oriented supportive therapy with and without active pharmacotherapy using desipramine or, if it was ineffective or intolerable, fluoxetine (Walsh et al., 1997). In general, these studies have demonstrated a superiority of active drug over placebo and a superiority of individual CBT alone over drug alone. *Author for correspondence at: Clarke Institute of Psychiatry, 250 College Street, Toronto, Ontario, Canada M5T 1R8. 803
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The combination of psychotherapy and medication has not conferred major additional benefit over psychotherapy alone but this finding is most pronounced in studies where the psychotherapy is intensive and thus very costly to reproduce. Further, one of the leading exponents of CBT for BN has recently stated with regard to its effectiveness that "no more than roughly 50o of patients cease binge eating and purging. Of the remainder, some show partial improvement, whereas a small number derive no benefit at all. Current CBT for bulimia nervosa has significant limitations. Attention must now be focused on devising treatment strategies for those patients for whom CBT is ineffective or insufficiently helpful" (Wilson, 1996). Indeed, a recent effort to examine cost-effectiveness of different treatment options for BN-issues of availability of specific treatments notwithstanding--speaks to the economic benefits of drug therapy over psychotherapy or a combination (Koran et al., 1995); however, methodological limitations prevent more definitive interpretation of the data. To date, outpatient individual CBT is the most studied and effective form of psychotherapy for BN (Wilson, 1996). At the same time, it has not demonstrated unequivocal superiority to other forms of psychotherapy--notably, interpersonal therapy (Fairburn et al., 1995). Of the various antidepressants studied, fluoxetine has received the greatest scrutiny in placebo-controlled and fixed-dose comparison studies (Fluoxetine Bulimia Nervosa Collaborative Study Group, 1992; Goldstein, Wilson, Thompson, Potvin, Rampey & the Fluoxetine Bulimia Nervosa Research Group, 1995); it has been given an official indication for the treatment of BN by the health authorities of a number of countries. However, these two dominant forms of treatment have yet to be compared directly or combined in a published randomized clinical trial. The purpose of the present study was to compare fluoxetine therapy alone, individual CBT alone, and the two in combination in female outpatients with BN. Because of the previously well established efficacy of these treatments compared to pill placebo or waiting list controls in BN Ss, we elected not to include a placebo or waiting list condition in the randomization options; a similar decision has been taken in earlier randomized treatment trials in BN (Garner et aL, 1993). Based on review of existing clinical trials in BN, it was deemed important that this study maintain or improve the standard by including the following features: comparison of disparate active treatments; use of clearly specified diagnostic criteria; patient recruitment through clinical referral; identification of clinical subgroups in terms of psychiatric comorbidity; use of manualbased treatments for both pharmacotherapy and psychotherapy; audiotaping and review of all treatments to insure protocol adherence; use of experienced therapists; documentation of attrition rates; assessment and outcome data collection by evaluators independent of therapy delivery; multimodal and multidimensional assessment of outcome; assessment of beliefs about illness and expectations of treatment prior to randomization; and absence of a 'Mecca effect' with regard to a particular form of treatment (the Eating Disorders Program at the Toronto Hospital is recognized clinically and academically for its trials of both pharmacotherapy and psychotherapy as well as other interventions for BN).
METHOD Subjects
The Ss in the study were 76 females who were referred by health professionals for consultation and treatment to the Eating Disorders Program of the Toronto Hospital. This is a tertiary care program that offers evaluation as well as outpatient, day hospital, and inpatient treatment for people with eating disorders. It has also been the setting of numerous research studies into the etiology, clinical course, and treatment of eating disorders. Over 300 new referrals are seen annually in clinical consultation, and Ss in the current study were drawn from that pool. After a semi-structured clinical evaluation, potential participants were informed of the availability of this research trial in addition to standard clinical care options at the Toronto Hospital--which, in the Canadian health care system, are available to all citizens free of charge. Thus, there was no financial incentive to take part in the study.
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Female Ss who expressed an interest in the study and who met the following inclusion criteria were invited to participate: ages 18-45 yr, 85-125% matched population mean weight, DSMIII-R (American Psychiatric Association, 1987) diagnosis of BN on structured interview; binge and vomit frequency of at least twice per week as defined by the Eating Disorder Examination; minimum 6-month duration of illness; ability and willingness to provide informed consent. Exclusion criteria included: ongoing pharmacotherapy or psychotherapy or use of MAO inhibitots within 2 weeks prior to the onset of the study treatment; immediate suicide risk or psychosis; medical contraindications to drug treatment; and previous exposure to the research treatments. Procedure
Eligible Ss were referred to the study by the clinicians who conducted the initial consultation. The study coordinator explained the protocol, verified their eligibility, and obtained informed consent. Baseline structured diagnostic interviews and self-report measures were completed and then Ss were randomized to one of three treatment arms: Fluoxetine alone (FL), CBT alone (CBT), or the two in combination (FL-CBT), stratified for high (> 30 episodes per month) or low (< 30 episodes per month) frequency of vomiting and for presence or absence of a history of anorexia nervosa. Selected interviewer-based and self-report measures were repeated after 6weeks of treatment, at the end of treatment, and 4weeks after treatment had concluded. Additionally, Ss kept weekly symptom diaries documenting episodes of binge eating and purging. Treatments FL. Four psychiatrists (including the first author) with expertise in eating disorders met with Ss individually once a week for 4 weeks then biweekly for 12 weeks for a total of 10 sessions. The initial meeting allowed for a full clinical assessment by the psychiatrist but subsequent meetings were typically l0 min or less and focused on medication issues--both clinical response and side effects. Sessions were based on a format described in the Clinical Management--Fluoxetine Manual, a pharmacotherapy manual written expressly for this study and modeled on the Clinical Management--Imipramine Manual for the National Institute of Mental Health Collaborative Study on the Treatment of Depression (Fawcett, Epstein, Fiester, Elkin & Autry, 1987). It allows for the establishment of a generally supportive therapeutic relationship but proscribes specific psychotherapeutic techniques. Additionally, supervision of the pharmacotherapists was provided by the principal investigator (D.S.G.), who had previous experience in clinical trials with fluoxetine for BN. Subjects were prescribed 60 mg per day of fluoxetine based on previous fixed-dose comparison research which indicated the efficacy of this dose (Fluoxetine Bulimia Nervosa Collaborative Study Group, 1992); pharmacotherapists were able to adjust the dose if side effects emerged. Monthly plasma levels of fluoxetine were drawn to monitor compliance and all sessions were tape-audited to monitor for therapist adherence to the treatment manual. CBT. Subjects assigned to this condition met weekly with one of two psychologists for 16 weeks in a format previously described by Fairburn and others (Fairburn, 1985). Sessions were 1 hr in length and were based on a previously written manual specific to CBT in BN (Fairburn, Marcus & Wilson, 1993). The therapists met for weekly supervision by a senior clinicianresearcher experienced in the clinical and research applications of CBT for BN (R.D.) and all therapy sessions were tape-audited to monitor therapist adherence to the treatment protocol. FL-CBT. Subjects assigned to this condition met separately with pharmacotherapists and psychotherapists in a manner identical to the above two conditions but clearly involving a greater frequency of professional contacts than either of the non-combined treatments. Consideration of this time inequity in striking a balance between clinical reality and research equipoise has been discussed in previous psychotherapy-pharmacotherapy comparative trials (Elkin, Parloff, Hadley & Autry, 1985). Measures
Baseline measures were administered by an independent assessor prior to randomization. The Eating Disorder Examination (EDE) (Cooper & Fairburn, 1987) provided baseline data on a
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variety of bulimic behaviours and was repeated 4 weeks post-treatment; it captures the preceding 4 weeks of eating behaviour and was the principal measure of behavioral change. The Structured Clinical Interview for DSM-III-R (SCID) (Spitzer, Williams, Gibbon & First, 1992; Williams et al., 1992) was administered at baseline to determine a range of Axis I and Axis II psychiatric disorders. Secondary measures also repeated 4 weeks post-treatment included the Eating Disorder Inventory (EDI) (Garner, Olmsted & Polivy, 1983); the Hamilton Rating Scale for Depression (HRSD) (Hamilton, 1960); and the Beck Depression Inventory (BDI) (Beck, Ward, Mendelson, Mock & Erbaugh, 1961). Self-esteem was measured by the Rosenberg SelfEsteem Scale (RSE) (Rosenberg, 1979) and social adjustment by the Social Adjustment ScaleSelf-report (SAS-SR) (Weissman, Prusoff, Thompson, Harding & Myers, 1978).
Data analysis The principal analyses used only those Ss who were considered treatment completers (defined for these purposes as completion of 14 or more weeks of the 16-week protocol). Intent-to-treat analyses were also conducted for all 76 Ss enrolled. To ensure the initial comparability of Ss within the three treatment groups, univariate and multivariate analyses of variance were first conducted on baseline scores of the 76 enrolled Ss for all measures of eating disorder symptomatology, current psychological status, personality measures, psychosocial adjustment, and relevant demographic and clinical features. These analyses were repeated on Ss who completed treatment to ensure maintenance of comparability. Non-parametric chi square analyses were used to compare remaining sociodemographic features. The assessment measures were subjected to an analysis of covariance for the three treatment conditions 4 weeks post-treatment by using pre-treatment symptom frequencies as the covariates. A series of repeated-measures multivariate analyses of variance (MANOVA) was conducted on measures of psychological functioning to determine whether the three treatment groups evidenced changes over time on primary and secondary outcome measures. For this purpose, results are reported only for time effects observed. Significant omnibus time effects were followed by subsequent analyses of simple effects. RESULTS Seventy-six women with BN were enrolled in the study subsequent to their initial clinical consultation. It is impossible to determine factors which may have selectively influenced recruitment because of the large number of clinical consultants involved in the Eating Disorders Program, the clinical availability of fluoxetine and CBT to which potential Ss might have already been exposed (which were exclusionary criteria for entry into the study) as well as the presence of other ongoing research treatment protocols. Subjects were recruited over a 2 yr period, and the number of patients who participated in the study represents approximately 13% of all of the initial consultations for eating disorders conducted during the same period. Of the 76 enrolled Ss (FL = 23; CBT = 24; FL-CBT = 29), 43 (57%) completed at least 14 weeks of treatment. There were no group differences in the number of treatment completers in the FL group (n = 14; 60.9%), the CBT group (n = 16; 66.7%), and the FL-CBT group (n = 13; 43.8%). The number of patients who did not complete treatment is high in this study, and the reasons for treatment dropouts are as follows: almost all of the patients who discontinued FL (n = 9) did so because of either medication side effects (n = 4) or early termination of the course of treatment (n = 4). Although these two factors together also accounted for the majority of dropouts from FL-CBT (n = 16), most of these patients were not compliant with the attendance requirements of the combined treatment protocol (n = 10) and a relatively smaller number discontinued treatment because of medication side effects (n = 2). Of the 10 patients who did not comply with the FL-CBT protocol, 2 completed 16 weeks of FL but terminated early from CBT, 5 stopped taking their medication before 16 weeks had elapsed and were dropped from the study (CBT was continued on compassionate grounds but their data were not included beyond the point of drug discontinuation), and 3 discontinued both FL and CBT prior to the end of the protocol. Reasons for termination from CBT alone amongst the remaining 8 dropouts from the overall study were equally distributed amongst a variety of factors. Treatment completers and dropouts were compared on comorbid psychopathology to determine
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if these patient characteristics were related to dropout rates. They did not differ significantly with regard to pre-treatment levels of depression or the presence of Axis I or Axis II disorders. Of the patients who completed 14 weeks of treatment, one patient from FL-CBT and two each from FL and CBT did not attend their assessments 4 weeks post-treatment. Thus, the principal outcome analyses reported here are for the remaining 38 treatment completers for whom post-treatment symptom data were available (FL = 12; CBT = 14; FL-CBT = 12). An additional 3 patients in FL and 2 patients in FL-CBT did not complete questionnaires at the end of treatment, although their symptom status is available. The mean + SD age of the 38 Ss was 25.8 + 5.5 yr. 72.2% were single, 25.0% were married or in a common-law relationship, and 2.8% were separated or divorced. The majority (77.1%) were employed either full or part-time at entry into the study and 30.6% were attending school. 36.1% had attended some college or university, and 27.8% had completed high school or less. The sample had a mean __+SD body mass index (BMI; kg/m 2) of 23.0 + 2.5, a past highest BMI of 25.8 + 3.6, and a past lowest BMI of 19.8 + 2.2. Six Ss (15.8%) had met DSM-III-R criteria for anorexia nervosa in the past. In terms of other DSM-III-R psychiatric comorbidity, SCID interviews conducted pre-treatment showed that 13.2% had concurrent mood disorders, 10.5% had concurrent anxiety disorders, and 5.3% had concurrent substance use disorders. 18.4% of the sample met threshold criteria for at least one personality disorder diagnosis. None of the CBT patients met DSM-III-R criteria on the SCID for a current mood disorder, compared to 2 of FL and 3 of FL-CBT patients. Moreover, the groups did not differ in BDI mean levels of depression pre-treatment. Eight CBT patients, 8 FL patients, and 6 FL-CBT patients did, however, meet criteria for a lifetime mood disorder. Three CBT patients, 1 FL patient, and 2 FL-CBT patients had met DSM-III-R criteria for anorexia nervosa in the past. There were low rates of DSM-III-R Axis II disorders among the treatment completers and there were no group differences in rates of individual personality disorder diagnoses. Only one patient in FL met criteria for a Cluster A diagnosis, with none in the two other treatment groups. One patient in each of the three treatment groups met criteria for a Cluster B diagnosis. Three FL patients and 2 FL-CBT patients but no CBT patients received a Cluster C diagnosis. There were no significant between-group differences at baseline on any of the demographic or clinical variables, symptom frequencies, primary measures of eating disturbance, psychological distress, or personality functioning--with the sole exception of the Drive for Thinness subscale of the EDI. On this scale, CBT patients had significantly lower scores than did either the FL or FL-CBT patients 0r = 4.89, df = 2,35, P < 0.013). Pre-treatment and 4 weeks post-treatment frequencies of objective binge episodes, subjective binge episodes, vomit episodes and dietary restraint (as measured by the EDE) are provided in Table 1. An analysis of covariance (ANCOVA) was performed on each post-treatment symptom using pre-treatment levels as the covariate. Significant group differences were found for subjective binges, and differences approaching significance were identified for objective binges and vomit episodes. In the month following treatment, patients in the FL group reported a higher number of both objective binge and vomit episodes than did patients in the FL-CBT group, and there was a trend for FL patients to report a greater number of vomit episodes than CBT patients. Subjective binge episodes were significantly higher in FL patients than in CBT patients and a similar difference approached significance in comparison between FL and FL-CBT. Interestingly, the number of subjective binge episodes attenuated over the course of treatment in both CBT and FL-CBT, but actually increased in FL. Levels of dietary restraint reported at 4 weeks post-treatment were equivalent in the three treatment conditions and decreased equally across groups over the course of treatment. All three treatment groups evidenced similarly high reductions in objective binges following completion of treatment, with mean percentage reductions in binge frequency of 70% for FL, 80% for CBT, and 87% for FL-CBT. FL, however, had a lower percentage reduction in vomit episodes (37.4%) than CBT (79.2%) and FL-CBT (82.4%) ( f = 3.36, df = 2,30, P < 0.05). With regard to issues of abstinence and residual symptomatology separate from consideration of percentage symptom reduction, the distribution of patients within each treatment group in the following categories was: abstinent (no binges or vomit episodes in the 4 weeks posttreatment)--CBT 43%, FL 17%, and FL-CBT 25%; subthreshold (less than two binge or vomit
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Table I. A n a l y s i s o f c o v a r i a n c e on e a t i n g s y m p t o m s at 1 m o n t h p o s t - t r e a t m e n t
Objective binges Subjective binges Vomit episodes Dietary restraint
Pre Post Pre Post Pre Post Pre Post
CBT (n = 14)
FL (n = 12)
33.6 (29.5) 7.4 (16.6) 3.2 (5.5) 1.9 (3.8) 41.8 (34.4) 9.0 (16.8) 3.1 (1.5) 1.6 (1.6)
21.0 (12.2) 10.0 (15.9) 6.3 (9.6) 10.7 (13.3) 24.6 (20.4) 17.3 (27.2) 3.8 (1.0) 2.3 (1.5)
FL-CBT (n = 12) 29.6 (16.5) 1.8 (3.3) 9.7 (14.3) 4.7 (6.2) 30.9 (29.7) 3.3 (4.5) 3.7 (1.5) 1.6 (1.8)
f
df
P
3.03
2
0.061 a
3.37
2
0.046 c'a
2.92
2
0.068 b'a
0.58
2
NS
~FL > FL-CBT P < 0.03. bFL > CBT P < 0.07. CFL > CBT P < 0.02. dFL > FL-CBT P < 0.07.
episodes per week in the 4weeks post-treatment)--CBT 21% FL 25%, FL-CBT 50%; and threshold (two or more binge or vomit episodes per week in the 4 weeks post-treatment)--CBT 36%, FL 58%, FL-CBT 25%. The treatment groups did not differ statistically across these three outcome categories. Although patients did not deviate significantly from each other in terms of the magnitude of body weight change over the course of treatment, it is notable that in terms of mean + SD weight changes, FL patients lost 2.0 + 10.0 pounds, while CBT patients gained 5.0 + 7.7 pounds and FL-CBT patients gained 3.2 + 7.3 pounds. In terms of indices of psychological functioning, repeated-measures analysis of variance on the eight subscales of the EDI yielded a significant omnibus time effect [Hotelling's Tz = 86.11, F (8,22) = 8.17, P < 0.000]. Multivariate analyses of simple effects indicated that there were time effects for CBT [Hotelling's T2 = 37.92, F(8,22) = 3.60, P < 0.008], for FL [Hotelling's T2 = 49.41, F(8,22) = 4.69, P < 0.002], and for FL-CBT [Hotelling's T2 = 46.91, F(8,22) = 4.45, P < 0.003]. Univariate analyses indicated that in both CBT and FL-CBT all subscales decreased over treatment except Maturity Fears and also Ineffectiveness in FL-CBT. In FL, only Drive for Thinness and Bulimia declined significantly. ANCOVAs on each of the eight EDI subscales yielded only one significant group comparison at 4 weeks post-treatment, with FL patients reporting a higher degree of perfectionism than those in the other groups. On the EDE (Table 2), there was a significant omnibus time effect for the Shape Concerns subscale [Hotelling's T2 = 24.00, F(1,35) = 19.53, P < 0.0001] with FL and FL-CBT but not CBT demonstrating a significant reduction. Similarly, there was a significant time effect for the Weight Concerns subscale [Hotelling's T2 = 28.79, F(1,35) = 21.92, P < 0.0000], with significant univariate ANOVAs for FL and FL-CBT, and a trend for CBT to decline over treatment. ANCOVAs indicated that the groups did not differ at post-treatment on either of these scales. Secondary outcome measures examined more general psychological functioning in areas of depression, self-esteem, and social adjustment which are affected by BN. There were no significant outcome differences between groups on measures of depression (BDI, HRSD) (Table 2), selfesteem (RSE) or social adjustment (SAS-SR). There was no significant time effect on the H R S D and only a marginally significant omnibus time effect on the BDI [Hotelling's T2 = 374.76, F(1,29) = 3.50, P < 0.072]. Subsequent univariate ANOVAs revealed that self-reported levels of T a b l e 2. Analysis of c o v a r i a n c e on psychological functioning at 1 m o n t h p o s t - t r e a t m e n t
EDE Shape Concern EDE Weight Concern Beck Depression
CBT
FL
FL-CBT
f
df
P
n Pre Post
14 3.0 (1.8) 2.3 (2.0)
12 4.1 (l.0) 2.8 (1.8)
12 3.7 (1.7) 2.3 (1.9)
0.36
2
NS
n Pre Post
14 2.6 0.9) 1.8 (2.2)
12 3.4 (1.4) 2.1 (1.4)
12 3.3 (1.8) 1.8 (1.7)
0.35
2
NS
n Pre Post
13 18.4 (11.5) 13.8 (14.2)
9 16.3 (9.4) 13.6 (15.3)
10 14.8 (13.0) 7.5 (9.0)
0.58
2
NS
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depression on the BDI did not significantly decrease in any of the three treatment conditions. There was a significant time effect on the RSE [Hotelling's T2 = 374.64, F(1,29)= 28.31, P < 0.000] with all three treatment groups reporting significant improvements in self-esteem over the course of treatment. Finally, in addition to the above analyses, the data were analyzed using an intent-to-treat approach involving all 76 Ss initially enrolled in the protocol. Baseline and last-visit levels of symptoms and measures of psychological distress were used in place of 4 weeks post-treatment data for patients who did not complete at least 14 weeks of treatment. ANCOVAs failed to identify any significant differences between FL, CBT, and FL-CBT on any of the measures.
DISCUSSION The aim of this study was to compare two well-established but theoretically and therapeutically disparate treatments for BN alone and in combination. The results indicate that all three treatments are associated with improvements in objective binge eating, vomiting, dietary restraint and other disturbed eating attitudes, and a variety of measures of mood, social adjustment and self-esteem. While the absence of control groups limits interpretation of the statistical significance of the change, inspection of the data reveals the degree of change to be clinically meaningful for all three treatments. There is limited support for the superiority of the FL-CBT condition over FL and no statistically significant evidence that the combination of pharmacotherapy and psychotherapy is superior to psychotherapy alone. The results are compatible with those of Agras et al. (1992), who found evidence of superiority of combined psychopharmacological-psychotherapeutic treatment over its isolated components across a number of outcome parameters. An interesting finding is the apparent worsening of subjective binge eating in the context of FL treatment. It occurred against a backdrop of both a decrease in objective binge eating in this group and the absence of therapist-led relabelling of eating behaviour; in CBT, eating a small amount of food with a sense of loss of control would be therapeutically redefined as not being a binge. As the actual quantity of food consumed in binges may have decreased with FL treatment, the attitudinal and affective residua may have remained in the absence of psychotherapy, leading to an increase in the number of patient-defined qualitative binge eating episodes. The precise nature of the therapeutic effect of fluoxetine in BN awaits elucidation; its effectiveness is not related to the presence or absence of comorbid depression (Fluoxetine Bulimia Nervosa Collaborative Study Group, 1992) and its effects may be mediated through changes in brain serotonin activity, abnormalities of which have been documented in BN (Goldbloom & Garfinkel, 1990; Goldbloom, Garfinkel, Brown & Katz, 1996). Previously, Craighead and Agras (1991) have argued that tricyclic antidepressants appear to enhance dietary restraint in BN as reflected by measures in a trial of desipramine in non-purging BN Ss; because CBT seeks to decrease dietary restraint, they argued for the incompatibility of these treatments in combination. However, the data from the current study do not support an increase in dietary restraint as measured by the EDE in the context of FL treatment. At the same time, however, it is striking that the FL patients had a modest mean weight loss while CBT and FL-CBT patients experienced modest mean weight gain. We have previously demonstrated that FL alone in the context of a placebo-controlled multicentre study was associated with clinically significant attitudinal change as measured on the EDI (Goldbloom & Olmsted, 1993). In the current study, there were no significant post-treatment between-group differences in virtually all EDI subscale scores and all three forms of treatment were associated with a move toward healthier attitudes at the end of treatment. The issue of depression and response to the study treatments bears further consideration. As can be seen in Table 2, there was significant variability in levels of depression within each treatment condition. At pre-treatment, BDI scores ranged from 1 to 34 in CBT, and from 4 to 34 in both FL and FL-CBT. It is perhaps not surprising that we failed to find group differences in depression following treatment given this variability. Using a cutoff score of 17 on the BDI to examine the effect of treatment on pre-treatment depression, 7 CBT patients, 3 FL patients, and
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4 FL-CBT patients were classified as depressed pre-treatment. Of these, 3 CBT patients, 1 FL patient, and 3 FL-CBT patients fell below the cutoff for depression at the end of treatment. Patients were then categorized as 'improved' if they evidenced at least a 50% decrease in BDI scores over treatment, 'worse' if their BDI scores increased by 50% over treatment, or 'no change' if their BDI scores changed less than 50% in either direction. One CBT patient and 2 FL-CBT patients who had a pre-treatment BDI score of 1 and a post-treatment score of 0-3 were also considered to be in the 'no change' group. Three CBT patients, 4 FL patients, and 5 FL-CBT patients were categorized as 'improved'. Nine CBT patients, 4 FL patients, and 5 CBT patients were categorized as 'no change'. One patient from each of the three treatment groups was categorized as 'worse'; the patients in the 'worse' category had very low pre-treatment BDI scores and post-treatment scores above 17. There were no significant group differences in the percentage of patients whose presenting level of depression had improved, stayed the same, or worsened over the course of treatment. A number of limitations are evident to this study. First, at the design level we opted not to include a pill placebo or waiting list control. Second, the treatments were unequally weighted in terms of global amount of therapist contact. We felt there were ethical constraints on the basis of existing literature against randomization to inactive treatment versus treatments of established efficacy; we also felt that clinical verisimilitude was a more important component for this clinical treatment study than careful balancing of contact time. We realize this leaves the data vulnerable to the interpretation that better outcomes may reflect simply more time spent with a professional dealing with a problem. Another serious issue was the high dropout rate, which was higher than many pharmacological and psychotherapy studies for BN. The protocol was, in retrospect, demanding with regard to hours of assessment and follow-up and many patients found the repeat measures draining. Scheduling appointments, particularly for FL-CBT Ss, proved to be overly complex, especially when Ss found either one of the two components more helpful than the other and voiced reluctance to continue with combined treatment. This high dropout rate may well have significantly compromised the power of the data to detect significant differences. We are conducting a separate analysis of the dropouts with regard not only to their clinical outcomes but also their pre-randomization expectations of benefit and wishes for particular treatment. We are also examining the long-term effects of these short-term interventions through follow-up evaluations.
Acknowledgements--This study was supported by an operating grant from Eli Lilly Canada Inc. The authors gratefully acknowledge the efforts of Adrienne Bonello BA in the coordination and execution of the study. They also thank the therapists in the study: Joel Katz PhD, Venera Bruto PhD, Janet de Groot MD, Robert Levitan MD, and Mark Katz MD.
REFERENCES Agras, W. S., Rossiter, E. M., Arnow, B., Schneider, J. A., Telch, C. F., Raeburn, S. D., Bruce, B., Perl, M., & Koran, L. M. (1992). Pharmacologic and cognitive-behavioral treatment for bulimia nervosa: A controlled comparison. American Journal of Psychiatry, 149, 82 87. American Psychiatric Association (1980). Diagnostic and statistical manual of mental disorders (3rd ed.). Washington, DC: American Psychiatric Press. American Psychiatric Association (1987). Diagnostic and statistical manual of mental disorders (3rd ed., revised). Washington, DC: American Psychiatric Press. Beck, A. T., Ward, C. H., Mendelson, M., Mock, J., & Erbaugh, J. (1961). An inventory for measuring depression. Archives of General Psychiatry, 4, 561-571. Beumont, P. J. V., Russell, J. D., Touyz, S. W., Buckley, C., Lowinger, K., Talbot, P., & Johnson, G. F.S. (1996). Intensive nutritional counselling in bulimia nervosa: A role for supplementation with fluoxetine? Submitted for publication. Cooper, Z., & Fairburn, C. J. (1987). The eating disorder examination: A semistructured interview for the assessment of the specific psychopathology of eating disorders. International Journal of Eating Disorders, 6, 1-8. Craighead, L. W., & Agras, W. S. (1991). Mechanisms of action in cognitive-behavioral and pharmacological interventions for obesity and bulimia nervosa. Journal of Consulting and Clinical Psychology, 59, 115-125. Elkin, I., Parloff, M. B., Hadley, S. W., & Autry, J. H. (1985). NIMH treatment of depression collaborative research program: Background and research plan. Archives of General Psychiatry, 42, 305-316. Fairburn, C. G. (1985). Cognitive-behavioral treatment for bulimia. In D. M. Garner & P. E. Garfinkel (Eds.), Handbook of psychotherapy for anorexia nervosa and bulimia. New York: Guilford Press.
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Fairburn, C. G., Marcus, M. D., & Wilson, G. T. (1993). Cognitive behaviour therapy for binge eating and bulimia nervosa: a comprehensive treatment manual, in C. J. Fairburn & G. T. Wilson (Eds). Binge eating: Nature. assessment and treatment. New York: Guilford Press. Fairburn, C. G., Norman, P. A., Welch, S. L., O'Connor, M. E., Doll, H. A., & Peveler, R. C. (1995). A prospective study of outcome in bulimia nervosa and the long-term effects of three psychological treatments. Archives of General Psychiato,, 52. 304-312. Fawcett, J., Epstein, P., Fiester, S. J., Elkin, 1., & Autry, J. H. (1987). Clinical management--imipramine/placebo administration manual. Psvchopharmacology Bulletin, 23, 309 324. Fichter, M. M., Leibl, K., Rief, W., Brunner, E., Schmidt-Auberger, S., & Engel, R. R. (1991). Fluoxetine versus placebo: A double-blind study with bulimic inpatients undergoing intensive psychotherapy. Pharmacops)'chiatry, 24, 1-7. Fluoxetine Bulimia Nervosa Collaborative Study Group (1992). Fluoxetine in the treatment of bulimia nervosa: A multicenter, placebo-controlled, double-blind trial. Archives of General Psychiatry, 49, 139 147. Garfinkel, P. E., & Goldbloom, D. S. (1994). Bulimia nervosa: A review of therapy research. Journal of Psychotherapy Practice and Research, 2, 38-50. Garner, D. M., Olmsted, M. P., & Polivy, J. (1983). Development and validation of a multidimensional eating disorder inventory for anorexia nervosa and bulimia. International Journal of Eating Disorders, 2, 15 34. Garner, D. M., Rockert, W., Davis, R., Garner, M. V., Olmsted, M. P., & Eagle, M. (1993). Comparison between cognitive-behavioral and supportive-expressive therapy for bulimia nervosa. American Journal of Psychiatry, 150, 37-46. Goldbloom, D. S., & Garfinkel, P. E. (1990). The serotonin hypothesis of bulimia nervosa: Theory and evidence. Canadian Journal of Psychiatry, 35, 741-744. Goldbloom, D. S., Garfinkel, P. E., Brown, G., & Katz, R. (1996). The hormonal response to 5-hydroxytryptophan in bulimia nervosa. Journal of Psychosomatic Research, 40, 289-297. Goldbloom, D. S., & Olmsted, M, P. (1993). Pharmacotherapy of bulimia nervosa and its associated attitudinal disturbances: The clinical significance of change. American Journal of Psychiatry, 150, 770-774. Goldstein, D. J., Wilson, M. G., Thompson, V. L., Potvin, J. H., Rampey, A. H., & the Fluoxetine Bulimia Nervosa Research Group (1995). Long-term fluoxetine treatment of bulimia nervosa. British Journal of Psychiatry, 166. 660666. Hamilton, M. (1960). A rating scale for depression, Journal of Neurology, Neurosurgery and Psychiatry, 23, 56-65. Kennedy, S. H., & Goldbloom, D, S. (1995). Psychopharmacologic treatments for anorexia nervosa and bulimia nervosa. In G. O. Gabbard (Ed.), Treatments of psychiatric disorders." The DSM-IV edition. Washington, DC: American Psychiatric Press. Koran, L. M., Agras, W, S., Rossiter, E. M., Arnow, B., Schneider, J. A., Telch, C. F., Raeburn, S., Bruce, B., PerL M., & Kraemer, H. C. (1995). Comparing the cost-effectiveness of psychiatric treatments: Bulimia nervosa. Psychiatric Research, 58, 13-21. Leitenberg, H., Rosen, J. C., Wolf, J., Vara, L. S., Detzer, M. J.. & Srebnik, D. (1994). Comparison of cognitivebehavior therapy and desipramine in the treatment of bulimia nervosa. Behavior Research and Therapy. 32, 37 46. Mitchell, J. E., Pyle, R. L., Eckert, E. D., Hatsukami, D., Pomeroy, C., & Zimmerman, R. (1990). A comparison study of antidepressants and structured intensive group psychotherapy in the treatment of bulimia nervosa. Archives of General Psychiatry, 47, 149-157. Rosenberg, M. (1979). Conceiving the self. New York: Basic Books. Russell, G. F. M, (1979). Bulimia nervosa: An ominous variant of anorexia nervosa. Psychological Medicine, 9, 429 448. Spitzer, R. L., Williams, J. B. W., Gibbon, M., & First, M. B. (1992). The structured clinical interview for DSM-III-R (SCID). I. History, rationale, and description. Archives of General Psvchiato'. 49, 624-629. Walsh, B. T., & Devlin, M. J. (1995). Psychopharmacology of anorexia nervosa, bulimia nervosa, and binge eating. In F. E. Bloom & D. J. Kupfer (Eds), Psychopharmacology: The fourth generation of progress. New York: Raven Press. Walsh, B. T., Wilson, G. T., Loeb, K. L., Devlin, M. J., Pike, K. M., Roose, S. P., Fleiss, J., & Waternaux, C. (1997). Medication and psychotherapy in the treatment of bulimia nervosa. American Journal of Psvchiato,, 154, 523-531. Weissman. M. M., Prusoff, B. A., Thompson, W. D., Harding, P. S., & Myers, J. K. (1978). Social adjustment by selfreport in a community sample and in psychiatric outpatients. Journal of Nervous and Mental Disease, 166, 317 326. Williams, J. B. W., Gibbon, M., First, M. B., Spitzer, R. L., Davis, M., Borus, J., Howes, M. J., Kane, J., Pope, H. G., Rounsaville, B., & Wittchen, H. U. (1992). The structured clinical interview for DSM-III-R (SCID). If. Multisite test-retest reliability. Archives of General Psychiatry. 49, 630-635. Wilson, G. T. (1996). Treatment of bulimia nervosa: When CBT fails. Behavior Research and Therapy, 34, 197 212.
Behav. Res. Ther. Vol. 35, No. 9, pp. 803-811, 1997 i 1997 Elsevier Science Ltd. All rights reserved Printed in Great Britain PII: S 0 0 0 5 - 7 9 6 7 ( 9 7 ) 0 0 0 4 1 - 7 0005-7967/97 $17.00 + 0.00
A RANDOMIZED CONTROLLED TRIAL OF FLUOXETINE AND COGNITIVE BEHAVIORAL THERAPY FOR BULIMIA NERVOSA: SHORT-TERM OUTCOME DAVID S. GOLDBLOOM,* MARION OLMSTED, RON DAVIS, JANET CLEWES, MARGUS HEINMAA, WENDI ROCKERT and BRIAN SHAW Clarke Institute of Psychiatry; Departments of Psychiatry and Psychology, The Toronto Hospital, and University of Toronto, Toronto, Ontario, Canada (Received II April 1997) S u m m a r y - - T h i s study compared and combined fluoxetine and individual cognitive behavioral therapy in the treatment of bulimia nervosa. Participants were 76 women who sought treatment at the Eating Disorders Program of the Toronto Hospital and who met DSM-III-R criteria for bulimia nervosa. Subjects were randomly assigned to receive fluoxetine alone, cognitive behavior therapy alone, or the two in combination and were treated over 16 weeks. Short-term outcome revealed that all three treatment conditions were associated with clinical improvement across a wide range of parameters. The combination of pharmacotherapy and psychotherapy was superior to pharmacotherapy alone on specific parameters and there was no statistically significant advantage to the combination over psychotherapy alone. Limitations to the study include the absence of a placebo pill group and a waiting list control group as well as a substantial dropout rate across all three treatment conditions. © 1997 Elsevier Science Ltd
INTRODUCTION
The treatment of bulimia nervosa (BN) has been the focus of numerous treatment studies since the disorder was described clinically in 1979 (Russell, 1979) and codified in DSM-III in 1980 (American Psychiatric Association, 1980); indeed, therapeutic research on BN has been far more prolific than that conducted on the related and long-recognized disorder anorexia nervosa. The principal domains of treatment have been individual and group psychotherapy and antidepressant pharmacotherapy (Garfinkel & Goldbloom, 1994; Kennedy & Goldbloom, 1995). Within the former, a variety of approaches has been studied, including psychodynamic, interpersonal, behavioral, and cognitive-behavioral modalities. Where waiting list controls have been employed, these active treatments have demonstrated superiority; when active forms of psychotherapy have been compared, short-term outcomes seldom differ, although long-term differences have been documented (Garfinkel & Goldbloom, 1994; Fairburn et al., 1995). Similarly, the vast majority of placebo-controlled trials of antidepressants have confirmed the antibulimic efficacy of the active medications, with benefits documented not only for behavioral symptomatology (Walsh & Devlin, 1995) but also for characteristic attitudinal patterns (Goldbloom & Olmsted, 1993). More recently, studies have compared and combined disparate forms of treatment for BN; these include trials of imipramine and intensive outpatient cognitive behavioral group therapy (Mitchell et al., 1990), fluoxetine and intensive inpatient eclectic behavioral therapy (Fichter et al., 1991), two trials of desipramine and outpatient individual cognitive-behavioral therapy (CBT) (Agras et al., 1992; Leitenberg et al., 1994), fluoxetine and nutritional counselling (Beumont et al., 1996), and a comparison of CBT and psychodynamically oriented supportive therapy with and without active pharmacotherapy using desipramine or, if it was ineffective or intolerable, fluoxetine (Walsh et al., 1997). In general, these studies have demonstrated a superiority of active drug over placebo and a superiority of individual CBT alone over drug alone. *Author for correspondence at: Clarke Institute of Psychiatry, 250 College Street, Toronto, Ontario, Canada M5T 1R8. 803
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The combination of psychotherapy and medication has not conferred major additional benefit over psychotherapy alone but this finding is most pronounced in studies where the psychotherapy is intensive and thus very costly to reproduce. Further, one of the leading exponents of CBT for BN has recently stated with regard to its effectiveness that "no more than roughly 50o of patients cease binge eating and purging. Of the remainder, some show partial improvement, whereas a small number derive no benefit at all. Current CBT for bulimia nervosa has significant limitations. Attention must now be focused on devising treatment strategies for those patients for whom CBT is ineffective or insufficiently helpful" (Wilson, 1996). Indeed, a recent effort to examine cost-effectiveness of different treatment options for BN-issues of availability of specific treatments notwithstanding--speaks to the economic benefits of drug therapy over psychotherapy or a combination (Koran et al., 1995); however, methodological limitations prevent more definitive interpretation of the data. To date, outpatient individual CBT is the most studied and effective form of psychotherapy for BN (Wilson, 1996). At the same time, it has not demonstrated unequivocal superiority to other forms of psychotherapy--notably, interpersonal therapy (Fairburn et al., 1995). Of the various antidepressants studied, fluoxetine has received the greatest scrutiny in placebo-controlled and fixed-dose comparison studies (Fluoxetine Bulimia Nervosa Collaborative Study Group, 1992; Goldstein, Wilson, Thompson, Potvin, Rampey & the Fluoxetine Bulimia Nervosa Research Group, 1995); it has been given an official indication for the treatment of BN by the health authorities of a number of countries. However, these two dominant forms of treatment have yet to be compared directly or combined in a published randomized clinical trial. The purpose of the present study was to compare fluoxetine therapy alone, individual CBT alone, and the two in combination in female outpatients with BN. Because of the previously well established efficacy of these treatments compared to pill placebo or waiting list controls in BN Ss, we elected not to include a placebo or waiting list condition in the randomization options; a similar decision has been taken in earlier randomized treatment trials in BN (Garner et aL, 1993). Based on review of existing clinical trials in BN, it was deemed important that this study maintain or improve the standard by including the following features: comparison of disparate active treatments; use of clearly specified diagnostic criteria; patient recruitment through clinical referral; identification of clinical subgroups in terms of psychiatric comorbidity; use of manualbased treatments for both pharmacotherapy and psychotherapy; audiotaping and review of all treatments to insure protocol adherence; use of experienced therapists; documentation of attrition rates; assessment and outcome data collection by evaluators independent of therapy delivery; multimodal and multidimensional assessment of outcome; assessment of beliefs about illness and expectations of treatment prior to randomization; and absence of a 'Mecca effect' with regard to a particular form of treatment (the Eating Disorders Program at the Toronto Hospital is recognized clinically and academically for its trials of both pharmacotherapy and psychotherapy as well as other interventions for BN).
METHOD Subjects
The Ss in the study were 76 females who were referred by health professionals for consultation and treatment to the Eating Disorders Program of the Toronto Hospital. This is a tertiary care program that offers evaluation as well as outpatient, day hospital, and inpatient treatment for people with eating disorders. It has also been the setting of numerous research studies into the etiology, clinical course, and treatment of eating disorders. Over 300 new referrals are seen annually in clinical consultation, and Ss in the current study were drawn from that pool. After a semi-structured clinical evaluation, potential participants were informed of the availability of this research trial in addition to standard clinical care options at the Toronto Hospital--which, in the Canadian health care system, are available to all citizens free of charge. Thus, there was no financial incentive to take part in the study.
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Female Ss who expressed an interest in the study and who met the following inclusion criteria were invited to participate: ages 18-45 yr, 85-125% matched population mean weight, DSMIII-R (American Psychiatric Association, 1987) diagnosis of BN on structured interview; binge and vomit frequency of at least twice per week as defined by the Eating Disorder Examination; minimum 6-month duration of illness; ability and willingness to provide informed consent. Exclusion criteria included: ongoing pharmacotherapy or psychotherapy or use of MAO inhibitots within 2 weeks prior to the onset of the study treatment; immediate suicide risk or psychosis; medical contraindications to drug treatment; and previous exposure to the research treatments. Procedure
Eligible Ss were referred to the study by the clinicians who conducted the initial consultation. The study coordinator explained the protocol, verified their eligibility, and obtained informed consent. Baseline structured diagnostic interviews and self-report measures were completed and then Ss were randomized to one of three treatment arms: Fluoxetine alone (FL), CBT alone (CBT), or the two in combination (FL-CBT), stratified for high (> 30 episodes per month) or low (< 30 episodes per month) frequency of vomiting and for presence or absence of a history of anorexia nervosa. Selected interviewer-based and self-report measures were repeated after 6weeks of treatment, at the end of treatment, and 4weeks after treatment had concluded. Additionally, Ss kept weekly symptom diaries documenting episodes of binge eating and purging. Treatments FL. Four psychiatrists (including the first author) with expertise in eating disorders met with Ss individually once a week for 4 weeks then biweekly for 12 weeks for a total of 10 sessions. The initial meeting allowed for a full clinical assessment by the psychiatrist but subsequent meetings were typically l0 min or less and focused on medication issues--both clinical response and side effects. Sessions were based on a format described in the Clinical Management--Fluoxetine Manual, a pharmacotherapy manual written expressly for this study and modeled on the Clinical Management--Imipramine Manual for the National Institute of Mental Health Collaborative Study on the Treatment of Depression (Fawcett, Epstein, Fiester, Elkin & Autry, 1987). It allows for the establishment of a generally supportive therapeutic relationship but proscribes specific psychotherapeutic techniques. Additionally, supervision of the pharmacotherapists was provided by the principal investigator (D.S.G.), who had previous experience in clinical trials with fluoxetine for BN. Subjects were prescribed 60 mg per day of fluoxetine based on previous fixed-dose comparison research which indicated the efficacy of this dose (Fluoxetine Bulimia Nervosa Collaborative Study Group, 1992); pharmacotherapists were able to adjust the dose if side effects emerged. Monthly plasma levels of fluoxetine were drawn to monitor compliance and all sessions were tape-audited to monitor for therapist adherence to the treatment manual. CBT. Subjects assigned to this condition met weekly with one of two psychologists for 16 weeks in a format previously described by Fairburn and others (Fairburn, 1985). Sessions were 1 hr in length and were based on a previously written manual specific to CBT in BN (Fairburn, Marcus & Wilson, 1993). The therapists met for weekly supervision by a senior clinicianresearcher experienced in the clinical and research applications of CBT for BN (R.D.) and all therapy sessions were tape-audited to monitor therapist adherence to the treatment protocol. FL-CBT. Subjects assigned to this condition met separately with pharmacotherapists and psychotherapists in a manner identical to the above two conditions but clearly involving a greater frequency of professional contacts than either of the non-combined treatments. Consideration of this time inequity in striking a balance between clinical reality and research equipoise has been discussed in previous psychotherapy-pharmacotherapy comparative trials (Elkin, Parloff, Hadley & Autry, 1985). Measures
Baseline measures were administered by an independent assessor prior to randomization. The Eating Disorder Examination (EDE) (Cooper & Fairburn, 1987) provided baseline data on a
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variety of bulimic behaviours and was repeated 4 weeks post-treatment; it captures the preceding 4 weeks of eating behaviour and was the principal measure of behavioral change. The Structured Clinical Interview for DSM-III-R (SCID) (Spitzer, Williams, Gibbon & First, 1992; Williams et al., 1992) was administered at baseline to determine a range of Axis I and Axis II psychiatric disorders. Secondary measures also repeated 4 weeks post-treatment included the Eating Disorder Inventory (EDI) (Garner, Olmsted & Polivy, 1983); the Hamilton Rating Scale for Depression (HRSD) (Hamilton, 1960); and the Beck Depression Inventory (BDI) (Beck, Ward, Mendelson, Mock & Erbaugh, 1961). Self-esteem was measured by the Rosenberg SelfEsteem Scale (RSE) (Rosenberg, 1979) and social adjustment by the Social Adjustment ScaleSelf-report (SAS-SR) (Weissman, Prusoff, Thompson, Harding & Myers, 1978).
Data analysis The principal analyses used only those Ss who were considered treatment completers (defined for these purposes as completion of 14 or more weeks of the 16-week protocol). Intent-to-treat analyses were also conducted for all 76 Ss enrolled. To ensure the initial comparability of Ss within the three treatment groups, univariate and multivariate analyses of variance were first conducted on baseline scores of the 76 enrolled Ss for all measures of eating disorder symptomatology, current psychological status, personality measures, psychosocial adjustment, and relevant demographic and clinical features. These analyses were repeated on Ss who completed treatment to ensure maintenance of comparability. Non-parametric chi square analyses were used to compare remaining sociodemographic features. The assessment measures were subjected to an analysis of covariance for the three treatment conditions 4 weeks post-treatment by using pre-treatment symptom frequencies as the covariates. A series of repeated-measures multivariate analyses of variance (MANOVA) was conducted on measures of psychological functioning to determine whether the three treatment groups evidenced changes over time on primary and secondary outcome measures. For this purpose, results are reported only for time effects observed. Significant omnibus time effects were followed by subsequent analyses of simple effects. RESULTS Seventy-six women with BN were enrolled in the study subsequent to their initial clinical consultation. It is impossible to determine factors which may have selectively influenced recruitment because of the large number of clinical consultants involved in the Eating Disorders Program, the clinical availability of fluoxetine and CBT to which potential Ss might have already been exposed (which were exclusionary criteria for entry into the study) as well as the presence of other ongoing research treatment protocols. Subjects were recruited over a 2 yr period, and the number of patients who participated in the study represents approximately 13% of all of the initial consultations for eating disorders conducted during the same period. Of the 76 enrolled Ss (FL = 23; CBT = 24; FL-CBT = 29), 43 (57%) completed at least 14 weeks of treatment. There were no group differences in the number of treatment completers in the FL group (n = 14; 60.9%), the CBT group (n = 16; 66.7%), and the FL-CBT group (n = 13; 43.8%). The number of patients who did not complete treatment is high in this study, and the reasons for treatment dropouts are as follows: almost all of the patients who discontinued FL (n = 9) did so because of either medication side effects (n = 4) or early termination of the course of treatment (n = 4). Although these two factors together also accounted for the majority of dropouts from FL-CBT (n = 16), most of these patients were not compliant with the attendance requirements of the combined treatment protocol (n = 10) and a relatively smaller number discontinued treatment because of medication side effects (n = 2). Of the 10 patients who did not comply with the FL-CBT protocol, 2 completed 16 weeks of FL but terminated early from CBT, 5 stopped taking their medication before 16 weeks had elapsed and were dropped from the study (CBT was continued on compassionate grounds but their data were not included beyond the point of drug discontinuation), and 3 discontinued both FL and CBT prior to the end of the protocol. Reasons for termination from CBT alone amongst the remaining 8 dropouts from the overall study were equally distributed amongst a variety of factors. Treatment completers and dropouts were compared on comorbid psychopathology to determine
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if these patient characteristics were related to dropout rates. They did not differ significantly with regard to pre-treatment levels of depression or the presence of Axis I or Axis II disorders. Of the patients who completed 14 weeks of treatment, one patient from FL-CBT and two each from FL and CBT did not attend their assessments 4 weeks post-treatment. Thus, the principal outcome analyses reported here are for the remaining 38 treatment completers for whom post-treatment symptom data were available (FL = 12; CBT = 14; FL-CBT = 12). An additional 3 patients in FL and 2 patients in FL-CBT did not complete questionnaires at the end of treatment, although their symptom status is available. The mean + SD age of the 38 Ss was 25.8 + 5.5 yr. 72.2% were single, 25.0% were married or in a common-law relationship, and 2.8% were separated or divorced. The majority (77.1%) were employed either full or part-time at entry into the study and 30.6% were attending school. 36.1% had attended some college or university, and 27.8% had completed high school or less. The sample had a mean __+SD body mass index (BMI; kg/m 2) of 23.0 + 2.5, a past highest BMI of 25.8 + 3.6, and a past lowest BMI of 19.8 + 2.2. Six Ss (15.8%) had met DSM-III-R criteria for anorexia nervosa in the past. In terms of other DSM-III-R psychiatric comorbidity, SCID interviews conducted pre-treatment showed that 13.2% had concurrent mood disorders, 10.5% had concurrent anxiety disorders, and 5.3% had concurrent substance use disorders. 18.4% of the sample met threshold criteria for at least one personality disorder diagnosis. None of the CBT patients met DSM-III-R criteria on the SCID for a current mood disorder, compared to 2 of FL and 3 of FL-CBT patients. Moreover, the groups did not differ in BDI mean levels of depression pre-treatment. Eight CBT patients, 8 FL patients, and 6 FL-CBT patients did, however, meet criteria for a lifetime mood disorder. Three CBT patients, 1 FL patient, and 2 FL-CBT patients had met DSM-III-R criteria for anorexia nervosa in the past. There were low rates of DSM-III-R Axis II disorders among the treatment completers and there were no group differences in rates of individual personality disorder diagnoses. Only one patient in FL met criteria for a Cluster A diagnosis, with none in the two other treatment groups. One patient in each of the three treatment groups met criteria for a Cluster B diagnosis. Three FL patients and 2 FL-CBT patients but no CBT patients received a Cluster C diagnosis. There were no significant between-group differences at baseline on any of the demographic or clinical variables, symptom frequencies, primary measures of eating disturbance, psychological distress, or personality functioning--with the sole exception of the Drive for Thinness subscale of the EDI. On this scale, CBT patients had significantly lower scores than did either the FL or FL-CBT patients 0r = 4.89, df = 2,35, P < 0.013). Pre-treatment and 4 weeks post-treatment frequencies of objective binge episodes, subjective binge episodes, vomit episodes and dietary restraint (as measured by the EDE) are provided in Table 1. An analysis of covariance (ANCOVA) was performed on each post-treatment symptom using pre-treatment levels as the covariate. Significant group differences were found for subjective binges, and differences approaching significance were identified for objective binges and vomit episodes. In the month following treatment, patients in the FL group reported a higher number of both objective binge and vomit episodes than did patients in the FL-CBT group, and there was a trend for FL patients to report a greater number of vomit episodes than CBT patients. Subjective binge episodes were significantly higher in FL patients than in CBT patients and a similar difference approached significance in comparison between FL and FL-CBT. Interestingly, the number of subjective binge episodes attenuated over the course of treatment in both CBT and FL-CBT, but actually increased in FL. Levels of dietary restraint reported at 4 weeks post-treatment were equivalent in the three treatment conditions and decreased equally across groups over the course of treatment. All three treatment groups evidenced similarly high reductions in objective binges following completion of treatment, with mean percentage reductions in binge frequency of 70% for FL, 80% for CBT, and 87% for FL-CBT. FL, however, had a lower percentage reduction in vomit episodes (37.4%) than CBT (79.2%) and FL-CBT (82.4%) ( f = 3.36, df = 2,30, P < 0.05). With regard to issues of abstinence and residual symptomatology separate from consideration of percentage symptom reduction, the distribution of patients within each treatment group in the following categories was: abstinent (no binges or vomit episodes in the 4 weeks posttreatment)--CBT 43%, FL 17%, and FL-CBT 25%; subthreshold (less than two binge or vomit
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Table I. A n a l y s i s o f c o v a r i a n c e on e a t i n g s y m p t o m s at 1 m o n t h p o s t - t r e a t m e n t
Objective binges Subjective binges Vomit episodes Dietary restraint
Pre Post Pre Post Pre Post Pre Post
CBT (n = 14)
FL (n = 12)
33.6 (29.5) 7.4 (16.6) 3.2 (5.5) 1.9 (3.8) 41.8 (34.4) 9.0 (16.8) 3.1 (1.5) 1.6 (1.6)
21.0 (12.2) 10.0 (15.9) 6.3 (9.6) 10.7 (13.3) 24.6 (20.4) 17.3 (27.2) 3.8 (1.0) 2.3 (1.5)
FL-CBT (n = 12) 29.6 (16.5) 1.8 (3.3) 9.7 (14.3) 4.7 (6.2) 30.9 (29.7) 3.3 (4.5) 3.7 (1.5) 1.6 (1.8)
f
df
P
3.03
2
0.061 a
3.37
2
0.046 c'a
2.92
2
0.068 b'a
0.58
2
NS
~FL > FL-CBT P < 0.03. bFL > CBT P < 0.07. CFL > CBT P < 0.02. dFL > FL-CBT P < 0.07.
episodes per week in the 4weeks post-treatment)--CBT 21% FL 25%, FL-CBT 50%; and threshold (two or more binge or vomit episodes per week in the 4 weeks post-treatment)--CBT 36%, FL 58%, FL-CBT 25%. The treatment groups did not differ statistically across these three outcome categories. Although patients did not deviate significantly from each other in terms of the magnitude of body weight change over the course of treatment, it is notable that in terms of mean + SD weight changes, FL patients lost 2.0 + 10.0 pounds, while CBT patients gained 5.0 + 7.7 pounds and FL-CBT patients gained 3.2 + 7.3 pounds. In terms of indices of psychological functioning, repeated-measures analysis of variance on the eight subscales of the EDI yielded a significant omnibus time effect [Hotelling's Tz = 86.11, F (8,22) = 8.17, P < 0.000]. Multivariate analyses of simple effects indicated that there were time effects for CBT [Hotelling's T2 = 37.92, F(8,22) = 3.60, P < 0.008], for FL [Hotelling's T2 = 49.41, F(8,22) = 4.69, P < 0.002], and for FL-CBT [Hotelling's T2 = 46.91, F(8,22) = 4.45, P < 0.003]. Univariate analyses indicated that in both CBT and FL-CBT all subscales decreased over treatment except Maturity Fears and also Ineffectiveness in FL-CBT. In FL, only Drive for Thinness and Bulimia declined significantly. ANCOVAs on each of the eight EDI subscales yielded only one significant group comparison at 4 weeks post-treatment, with FL patients reporting a higher degree of perfectionism than those in the other groups. On the EDE (Table 2), there was a significant omnibus time effect for the Shape Concerns subscale [Hotelling's T2 = 24.00, F(1,35) = 19.53, P < 0.0001] with FL and FL-CBT but not CBT demonstrating a significant reduction. Similarly, there was a significant time effect for the Weight Concerns subscale [Hotelling's T2 = 28.79, F(1,35) = 21.92, P < 0.0000], with significant univariate ANOVAs for FL and FL-CBT, and a trend for CBT to decline over treatment. ANCOVAs indicated that the groups did not differ at post-treatment on either of these scales. Secondary outcome measures examined more general psychological functioning in areas of depression, self-esteem, and social adjustment which are affected by BN. There were no significant outcome differences between groups on measures of depression (BDI, HRSD) (Table 2), selfesteem (RSE) or social adjustment (SAS-SR). There was no significant time effect on the H R S D and only a marginally significant omnibus time effect on the BDI [Hotelling's T2 = 374.76, F(1,29) = 3.50, P < 0.072]. Subsequent univariate ANOVAs revealed that self-reported levels of T a b l e 2. Analysis of c o v a r i a n c e on psychological functioning at 1 m o n t h p o s t - t r e a t m e n t
EDE Shape Concern EDE Weight Concern Beck Depression
CBT
FL
FL-CBT
f
df
P
n Pre Post
14 3.0 (1.8) 2.3 (2.0)
12 4.1 (l.0) 2.8 (1.8)
12 3.7 (1.7) 2.3 (1.9)
0.36
2
NS
n Pre Post
14 2.6 0.9) 1.8 (2.2)
12 3.4 (1.4) 2.1 (1.4)
12 3.3 (1.8) 1.8 (1.7)
0.35
2
NS
n Pre Post
13 18.4 (11.5) 13.8 (14.2)
9 16.3 (9.4) 13.6 (15.3)
10 14.8 (13.0) 7.5 (9.0)
0.58
2
NS
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depression on the BDI did not significantly decrease in any of the three treatment conditions. There was a significant time effect on the RSE [Hotelling's T2 = 374.64, F(1,29)= 28.31, P < 0.000] with all three treatment groups reporting significant improvements in self-esteem over the course of treatment. Finally, in addition to the above analyses, the data were analyzed using an intent-to-treat approach involving all 76 Ss initially enrolled in the protocol. Baseline and last-visit levels of symptoms and measures of psychological distress were used in place of 4 weeks post-treatment data for patients who did not complete at least 14 weeks of treatment. ANCOVAs failed to identify any significant differences between FL, CBT, and FL-CBT on any of the measures.
DISCUSSION The aim of this study was to compare two well-established but theoretically and therapeutically disparate treatments for BN alone and in combination. The results indicate that all three treatments are associated with improvements in objective binge eating, vomiting, dietary restraint and other disturbed eating attitudes, and a variety of measures of mood, social adjustment and self-esteem. While the absence of control groups limits interpretation of the statistical significance of the change, inspection of the data reveals the degree of change to be clinically meaningful for all three treatments. There is limited support for the superiority of the FL-CBT condition over FL and no statistically significant evidence that the combination of pharmacotherapy and psychotherapy is superior to psychotherapy alone. The results are compatible with those of Agras et al. (1992), who found evidence of superiority of combined psychopharmacological-psychotherapeutic treatment over its isolated components across a number of outcome parameters. An interesting finding is the apparent worsening of subjective binge eating in the context of FL treatment. It occurred against a backdrop of both a decrease in objective binge eating in this group and the absence of therapist-led relabelling of eating behaviour; in CBT, eating a small amount of food with a sense of loss of control would be therapeutically redefined as not being a binge. As the actual quantity of food consumed in binges may have decreased with FL treatment, the attitudinal and affective residua may have remained in the absence of psychotherapy, leading to an increase in the number of patient-defined qualitative binge eating episodes. The precise nature of the therapeutic effect of fluoxetine in BN awaits elucidation; its effectiveness is not related to the presence or absence of comorbid depression (Fluoxetine Bulimia Nervosa Collaborative Study Group, 1992) and its effects may be mediated through changes in brain serotonin activity, abnormalities of which have been documented in BN (Goldbloom & Garfinkel, 1990; Goldbloom, Garfinkel, Brown & Katz, 1996). Previously, Craighead and Agras (1991) have argued that tricyclic antidepressants appear to enhance dietary restraint in BN as reflected by measures in a trial of desipramine in non-purging BN Ss; because CBT seeks to decrease dietary restraint, they argued for the incompatibility of these treatments in combination. However, the data from the current study do not support an increase in dietary restraint as measured by the EDE in the context of FL treatment. At the same time, however, it is striking that the FL patients had a modest mean weight loss while CBT and FL-CBT patients experienced modest mean weight gain. We have previously demonstrated that FL alone in the context of a placebo-controlled multicentre study was associated with clinically significant attitudinal change as measured on the EDI (Goldbloom & Olmsted, 1993). In the current study, there were no significant post-treatment between-group differences in virtually all EDI subscale scores and all three forms of treatment were associated with a move toward healthier attitudes at the end of treatment. The issue of depression and response to the study treatments bears further consideration. As can be seen in Table 2, there was significant variability in levels of depression within each treatment condition. At pre-treatment, BDI scores ranged from 1 to 34 in CBT, and from 4 to 34 in both FL and FL-CBT. It is perhaps not surprising that we failed to find group differences in depression following treatment given this variability. Using a cutoff score of 17 on the BDI to examine the effect of treatment on pre-treatment depression, 7 CBT patients, 3 FL patients, and
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4 FL-CBT patients were classified as depressed pre-treatment. Of these, 3 CBT patients, 1 FL patient, and 3 FL-CBT patients fell below the cutoff for depression at the end of treatment. Patients were then categorized as 'improved' if they evidenced at least a 50% decrease in BDI scores over treatment, 'worse' if their BDI scores increased by 50% over treatment, or 'no change' if their BDI scores changed less than 50% in either direction. One CBT patient and 2 FL-CBT patients who had a pre-treatment BDI score of 1 and a post-treatment score of 0-3 were also considered to be in the 'no change' group. Three CBT patients, 4 FL patients, and 5 FL-CBT patients were categorized as 'improved'. Nine CBT patients, 4 FL patients, and 5 CBT patients were categorized as 'no change'. One patient from each of the three treatment groups was categorized as 'worse'; the patients in the 'worse' category had very low pre-treatment BDI scores and post-treatment scores above 17. There were no significant group differences in the percentage of patients whose presenting level of depression had improved, stayed the same, or worsened over the course of treatment. A number of limitations are evident to this study. First, at the design level we opted not to include a pill placebo or waiting list control. Second, the treatments were unequally weighted in terms of global amount of therapist contact. We felt there were ethical constraints on the basis of existing literature against randomization to inactive treatment versus treatments of established efficacy; we also felt that clinical verisimilitude was a more important component for this clinical treatment study than careful balancing of contact time. We realize this leaves the data vulnerable to the interpretation that better outcomes may reflect simply more time spent with a professional dealing with a problem. Another serious issue was the high dropout rate, which was higher than many pharmacological and psychotherapy studies for BN. The protocol was, in retrospect, demanding with regard to hours of assessment and follow-up and many patients found the repeat measures draining. Scheduling appointments, particularly for FL-CBT Ss, proved to be overly complex, especially when Ss found either one of the two components more helpful than the other and voiced reluctance to continue with combined treatment. This high dropout rate may well have significantly compromised the power of the data to detect significant differences. We are conducting a separate analysis of the dropouts with regard not only to their clinical outcomes but also their pre-randomization expectations of benefit and wishes for particular treatment. We are also examining the long-term effects of these short-term interventions through follow-up evaluations.
Acknowledgements--This study was supported by an operating grant from Eli Lilly Canada Inc. The authors gratefully acknowledge the efforts of Adrienne Bonello BA in the coordination and execution of the study. They also thank the therapists in the study: Joel Katz PhD, Venera Bruto PhD, Janet de Groot MD, Robert Levitan MD, and Mark Katz MD.
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