A Placebo-Controlled Study of Fluoxetine in Continued Treatment of Bulimia Nervosa

Article
A Placebo-Controlled Study of Fluoxetine
in Continued Treatment of Bulimia Nervosa
After Successful Acute Fluoxetine Treatment
Steven J. Romano, M.D.
Katherine A. Halmi, M.D.
Neena P. Sarkar, Ph.D.
Stephanie C. Koke, M.S.
Julia S. Lee, M.S.
Objective: The efficacy of fluoxetine in
the acute management of bulimia nervosa
is well established; however, few controlled studies have examined whether
continuation of pharmacotherapy provides protection from relapse. This study
compared the efficacy and safety of treatment with fluoxetine versus placebo in
preventing relapse of bulimia nervosa during a 52-week period after successful acute
fluoxetine therapy.
Method: Patients who met DSM-IV criteria for bulimia nervosa, purging type,
were assigned to single-blind treatment
with 60 mg/day of fluoxetine. After 8
weeks of treatment, patients were considered responders if they experienced a decrease ≥ 50% from baseline in the frequency of vomiting episodes during 1 of
the 2 preceding weeks. Responders were
randomly assigned to receive 60 mg/day
of fluoxetine or placebo and were monitored for relapse for up to 52 weeks. Patients met relapse criteria if they experienced a return to the baseline vomiting
frequency that persisted for 2 consecutive
weeks.
Results: Of the 232 patients who entered
the acute phase, 150 patients (65%) met
response criteria and were randomly assigned to receive fluoxetine (N=76) or placebo (N=74). Fluoxetine-treated patients
exhibited a longer time to relapse than
placebo-treated patients. Quantitative
analysis of other efficacy measures, including frequency of vomiting episodes,
frequency of binge eating episodes, Clinical Global Impression severity and improvement scores, the patient’s global impression score, and Yale-Brown-Cornell
Eating Disorder Scale score, indicated that
the efficacy of fluoxetine treatment was
statistically superior, compared to placebo. There were no clinically relevant
differences in safety between groups. Attrition in this study was high, especially in
the first 3 months after random assignment to treatment groups.
Conclusions: Continued treatment with
fluoxetine in patients with bulimia nervosa who responded to acute treatment
with fluoxetine improved outcome and
decreased the likelihood of relapse.
(Am J Psychiatry 2002; 159:96–102)
B
ulimia nervosa, characterized by uncontrolled
binge-eating and self-induced purging or other compensatory behaviors to prevent weight gain, is associated with
substantial rates of psychiatric and medical comorbidity
(1). Its lifetime prevalence is estimated to be as high as
2.8% (2). Although the causal mechanisms underlying bulimia nervosa are not completely understood, evidence
suggests that it is associated with abnormalities in central
serotonergic function. Women with bulimia nervosa have
a blunted prolactin response and a normal cortisol response to the postsynaptic serotonergic agonist m-chlorophenylpiperazine given orally and to the serotonin precursor L -tryptophan given intravenously, suggesting
alteration of receptor activity at or above the hypothalamus (3). A blunted prolactin response to fenfluramine has
also been demonstrated (4). Since satiety in response to
food intake is mediated in part by serotonergic input to
the ventromedial hypothalamus, a defect in serotonin
96
function may produce impaired recognition of satiety,
thus contributing to binge eating (5).
A number of antidepressants have been effective in the
short-term treatment of bulimia nervosa. Overall, medication treatment decreases binge frequency by an average of
56%, compared with an average decrease of 11% with placebo treatment (6). Decreases in the frequency of self-induced vomiting appear to be similar. Tricyclic antidepressants, monoamine oxidase inhibitors, bupropion, and
trazodone have all been shown to be therapeutically superior to placebo (7–16). Fluoxetine has proven to be effective in reducing bulimic symptoms in two 8-week doubleblind trials (17, 18) and in one longer term, 16-week double-blind trial (19).
Fewer data are available regarding the long-term efficacy of pharmacotherapy, as well as its impact on relapse
prevention. Uncontrolled follow-up studies have suggested that patients with bulimia nervosa often remain
symptomatic for 4–6 years, although they may maintain
Am J Psychiatry 159:1, January 2002
ROMANO, HALMI, SARKAR, ET AL.
improvements achieved during treatment (6). A review of
eight studies with follow-up periods of 6 months to 6 years
showed that approximately one-third of the patients who
improved acutely experienced a resurgence of bulimic
symptoms. The probability of relapse appears to be highest during the first year after recovery, with the risk declining after 4 years (20).
The present study was designed to prospectively evaluate the efficacy and safety of treatment with fluoxetine
versus placebo in preventing relapse of bulimia nervosa
over a 52-week double-blind treatment period after response to acute fluoxetine treatment.
Method
Study Population
The study was conducted at 16 sites in the United States. All investigators were psychiatrists or physicians specializing in psychiatry. The protocol was approved by the institutional review board
at each site. Patients’ participation in the study was voluntary, and
all patients gave written informed consent before enrollment.
The study population included male and female outpatients, at
least 18 years old, with a psychiatric diagnosis of bulimia nervosa,
purging type, as defined by the DSM-IV criteria. Purging must
have included self-induced vomiting. Patients were excluded if
they had participated in a prior fluoxetine study or taken fluoxetine within 5 weeks before enrollment or if they had been previously treated with 60 mg/day of fluoxetine for longer than 8
weeks. Patients were excluded if they had coexisting schizophrenia or bipolar disorder, mood-congruent or mood-incongruent
psychotic features, serious suicidal risk, organic brain disease, a
history of seizures, a medically unstable condition, or a history of
an alcohol and/or other substance abuse disorder within 3
months before enrollment. Patients who had used a monoamine
oxidase inhibitor within 2 weeks before enrollment or had used
other investigational drugs or psychoactive medications within 4
weeks before enrollment were excluded. Patients who had received cognitive behavior therapy within 4 weeks of enrollment or
who planned to begin a structured, focused therapy at any time
during the study were excluded.
Study Design
After a 1-week no-therapy screening phase, patients who continued to meet entry criteria were assigned to single-blind treatment with 60 mg/day of fluoxetine. Dosage adjustment, at the clinician’s discretion, was allowed during the first 2 weeks of
treatment to accommodate patients who were initially unable to
tolerate 60 mg/day of fluoxetine. After 8 weeks of acute treatment,
responders were randomly assigned to receive 60 mg/day of fluoxetine or placebo for up to 52 weeks. Nonresponders and patients who were unable to tolerate a dose of 60 mg/day were discontinued from the study.
Study medication was packaged in blister packs and contained
either 20-mg fluoxetine capsules or matching placebo capsules.
At each visit, the patient returned the blister packs so that the remaining capsules could be counted. Patients who missed their
medication for 5 consecutive days or who failed to attend visits
within the stated periods were deemed noncompliant and were
withdrawn from the study. The treatment group to which the patient was assigned was determined by a computer-generated randomization sequence. No one at the study site had access to the
study randomization list. Emergency labels, generated by a computer drug-labeling system, were available to the investigator.
These labels, which revealed the patient’s treatment group, were
Am J Psychiatry 159:1, January 2002
opened only if the choice of follow-up treatment depended on the
patient’s therapy assignment or in medical emergencies.
Study Procedures
During the screening phase and the 8-week single-blind acute
therapy phase, patients were seen by the investigators each week.
During the 52-week, double-blind therapy period, visits occurred
at 2-week intervals during the first 8 weeks and at 4-week intervals thereafter.
Efficacy was measured by the change in the number of vomiting and binge-eating episodes per week and by ratings on the Eating Disorder Inventory (21), Yale-Brown-Cornell Eating Disorder
Scale (22), and Clinical Global Impression (CGI) severity and improvement scales (23) and by the patient’s global impression,
which uses a 7-point scale identical to the Clinical Global Impression improvement scale. The 17-item Hamilton Depression Rating Scale (24) was used to measure the presence and severity of
depression. Information about bulimic behaviors was obtained
by using a daily diary in which patients recorded their episodes of
binge eating, vomiting, and other purging behaviors.
The CGI severity measure was obtained at the beginning of
acute therapy (visit 2). The Eating Disorder Inventory, YaleBrown-Cornell Eating Disorder Scale, CGI improvement scale,
the patient’s global impression, and Hamilton depression scale
were completed at the beginning of acute therapy (visit 2), at the
end of acute therapy (visit 10), and at 4-week intervals throughout
the double-blind relapse-prevention period. The patients’ diaries
were collected at each visit. Data on adverse events were collected
by open-ended questioning about general well-being and problems with medication and were recorded at each visit regardless
of the perceived relationship to therapy.
Statistical Analyses
The primary efficacy measure was the change in the number of
vomiting episodes per week. This measure was also used to determine the patient’s eligibility for continuation into the doubleblind therapy period and to assess relapse during the double-blind
period. To be designated a treatment responder at the end of the
acute therapy period, patients must have experienced a decrease
of ≥50% in the frequency of vomiting episodes during at least 1 of
the 2 preceding weeks, compared to the baseline (screening) week.
Patients were considered relapsers during the double-blind period
if they experienced a return to the baseline frequency of vomiting
for 2 consecutive weeks. For ethical reasons, patients who experienced a return to the baseline frequency of vomiting for a single
week and whose condition had deteriorated significantly could
also be designated as relapsers at the clinician’s discretion.
Time-to-relapse curves were estimated for each treatment
group by using the product-limit (Kaplan-Meier) method for the
data for all patients with at least one postrandomization measurement. A two-sided log-rank test was used to compare the
time-to-relapse distributions. Confidence limits for estimated cumulative relapse rates were constructed for the 3- , 5- , and 12month time points by using Greenwood’s estimate of the variance
(25), and the difference in estimated relapse rates was tested at
these time points by using the proportions test proposed by Gray
and Tsiatis (26). In addition, a Cox proportional hazards model
stratified by investigative site was used to assess the relationship
between baseline covariates (frequency of vomiting and binge
eating) and time to relapse.
Endpoint analysis of continuous efficacy and safety data (vital
signs and laboratory data) evaluated change from randomization
to the last visit in the postrandomization period (last observation
carried forward). An analysis of variance model with treatment,
investigator, and the treatment-by-investigator interaction was
used to compute the summary statistics for normally distributed
measurements. A rank-transformed nonparametric model pro-
97
FLUOXETINE FOR BULIMIA
TABLE 1. Characteristics of Patients With Bulimia Nervosa
Before Acute Treatment With Fluoxetine and at Random
Assignment to Continued Treatment or Placebo After
Acute Response to Fluoxetinea
Characteristics at baseline
Sex
Female
Male
Ethnicity
Caucasian
Other
Age (years)b
Body mass index
Age at diagnosis
Vomiting episodes/weekb
Binge eating episodes/weekb
Clinical Global Impression severity score
Hamilton Depression Rating Scale score
Eating Disorder Inventory total score
Yale-Brown-Cornell Eating Disorder
Scale score
Characteristics at random assignment
Vomiting episodes/week
Binge eating episodes/week
Clinical Global Impression severity
score
Hamilton Depression Rating Scale
scoreb
Eating Disorder Inventory total score
Yale-Brown-Cornell Eating Disorder
Scale score
Patients
Receiving
Placebo
(N=74)
N
74
2
73
1
71
5
65
9
Patients Remaining at Risk
3 months
6 months
12 months
(N=42)
(N=26)
(N=13)
(N=16)
(N=10)
(N=6)
100
Mean
SD
Mean
SD
29.5
22.5
25.3
12.1
10.3
4.5
10.5
76.6
7.0
3.9
7.7
8.7
7.7
0.6
6.1
26.9
30.0
23.0
26.3
14.0
12.5
4.5
10.5
78.4
9.3
3.8
9.3
11.7
10.1
0.7
5.9
29.9
18.8
4.1
18.3
5.1
4.1
3.0
5.5
4.8
4.5
3.9
6.1
5.1
2.9
1.0
2.9
0.9
4.6
37.0
3.9
22.0
6.1
39.1
5.3
27.2
9.4
4.8
9.4
5.4
a
No statistically significant differences between treatment groups.
Baseline age was determined at the beginning of a 1-week notherapy screening phase (visit 1); all other baseline measurements
were assessed at the end of the no-therapy screening phase
(visit 2).
b Unequal variance.
posed by Akritas et al. (27) was used for measurements that failed
the normal assumption. Data from three sites with two or fewer
patients per treatment group were pooled together for the analysis of continuous efficacy and safety.
Data on patients’ characteristics were summarized at baseline
and at random assignment to the treatment groups. Treatment
differences were assessed with Fisher’s exact test for categorical
variables and Student’s t test for continuous variables. Reasons
for discontinuation from the study and adverse events that first
occurred or worsened during double-blind therapy were compared between treatment groups by using Fisher’s exact test.
Statistical significance was set at p<0.05. All statistical tests
were two-sided.
Results
Acute Response
Of the 265 patients who participated in psychological
and physical screening, 33 did not meet entry criteria and
were excluded. Of the 232 patients who received singleblind acute therapy, 150 patients (64.7%) met response criteria and were randomly assigned to double-blind ther-
98
0 months
Fluoxetine
(N=76)
Placebo
(N=74)
Percentage of Patients
Remaining Relapse Free
Characteristic
Patients
Receiving
Fluoxetine
(N=76)
N
FIGURE 1. Kaplan-Meier Estimates of the Percentage of
Patients With Bulimia Nervosa Remaining Relapse Free in
a Randomized, Placebo-Controlled Study of Continued
Treatment After Acute Response to Fluoxetinea
80
60
40
20
0
0
a
100
200
300
Days From Randomization
to Relapse or Discontinuation
400
Two-sided log-rank test applied to the Kaplan-Meier survival function (χ2=5.79, df=1, p<0.02).
apy. The treatment groups were comparable at baseline
with respect to age, gender, race, body mass index, and
severity of illness. At random assignment to treatment
groups, the patients’ severity of illness was comparable.
The majority of the patients were women and Caucasian
(Table 1).
Of the 232 patients who received single-blind acute
therapy, 94 patients (40.5%) had comorbid depression
(Hamilton depression scale total ≥12). There was no significant difference in response rates between depressed
and nondepressed patients (62.8% versus 65.7%) (χ2=0.21,
df=1, p=0.65). Of the 232 patients who received singleblind acute therapy, 41 patients (17.7%) had complete remission of symptoms, that is, no vomiting episodes during
the final week of acute therapy.
Time to Relapse
The primary hypothesis, that fluoxetine treatment prolongs the time to relapse, was assessed by a log-rank test
applied to the Kaplan-Meier survival function. The test
was statistically significant (χ2=5.79, df=1, p<0.02). The
survival curve shows that most of the relapses among placebo-treated patients occurred during the first 3 months
after randomization (Figure 1). Compared with the placebo group, the fluoxetine-treated group had a lower
number of relapses during the first 3 months and a more
gradually decreasing probability of remaining relapse free
(Figure 1). The estimated relapse rates and differences in
relapse rates (the rate for the placebo group minus the rate
Am J Psychiatry 159:1, January 2002
ROMANO, HALMI, SARKAR, ET AL.
TABLE 2. Estimated Relapse Rates of Patients With Bulimia Nervosa at 3, 6, and 12 Months of a Randomized, PlaceboControlled Study of Continued Treatment After Acute Response to Fluoxetine
Patients Receiving Fluoxetine
Time
3 months
6 months
12 months
a
N
42
26
11
Estimated
Relapse Rate (%) 95% CI (%)
19
9 to 29
29
16 to 42
33
19 to 48
Patients Receiving Placebo
N
17
9
5
Estimated
Relapse Rate (%) 95% CI (%)
37
23 to 51
43
26 to 59
51
30 to 71
Difference (%)a
18
14
18
95% CI (%)
1 to 35
–7 to 35
–8 to 42
p
<0.04
0.19
0.17
Analysis of differences conducted with the proportions test proposed by Gray and Tsiatis (26).
TABLE 3. Mean Change in Efficacy Measures from Randomization to Endpoint for Patients With Bulimia Nervosa in a
Placebo-Controlled Study of Continued Treatment After Acute Response to Fluoxetine
Efficacy Measure
Vomiting episodes/week
Binge eating episodes/week
Clinical Global Impression
Severity score
Improvement score
Patient’s global impression score
Hamilton Depression Rating Scale total score
Eating Disorder Inventory total score
Yale-Brown-Cornell Eating Disorder Scale
Total score
Preoccupation score
Ritual score
Patients Receiving Fluoxetine
Mean
SD
Na
Patients Receiving Placebo
Mean
SD
Na
2.92
2.47
7.08
6.58
74
74
4.82
4.11
Mean
SD
Na
0.45
0.77
0.72
2.03
7.79
1.33
1.43
1.54
5.66
25.49
2.92
1.53
1.35
7.91
3.82
4.51
χ2b
8.43
6.70
71
71
10.34
5.91
Mean
SD
Na
Fc
75
75
75
75
71
0.97
1.37
1.37
3.23
17.41
1.21
1.39
1.49
6.60
24.45
71
71
71
71
69
63
64
63
7.38
3.63
3.75
6.80
3.74
3.79
60
60
60
Analysis
df
1
1
p
0.001
<0.02
df
p
8.43
7.13
4.94
1.74
2.30
1, 118
1, 118
1, 118
1, 118
1, 113
0.004
0.009
<0.03
0.19
0.13
9.75
7.28
8.51
1, 95
1, 96
1, 95
0.002
0.008
0.004
a
Number of patients with a measurement at the randomization visit and at least one postrandomization visit. Last observation was carried
forward.
b Asymptotic chi-square distribution from rank-transformed nonparametric model by Akritas et al. (27).
c Type III sum of squares analysis of variance with treatment, investigator, and treatment-by-investigator interaction.
for the fluoxetine group) were computed at 3- , 6- , and 12month time points (Table 2). The difference in relapse
rates was statistically significant at the 3-month time
point and remained approximately constant from 3–12
months, although the difference was not statistically significant at the 6- and 12-month time points because of the
high attrition rate in the study. The Cox proportional hazards model indicated that the relapse rate did not depend
on the baseline frequency of vomiting or binge eating.
Endpoint Analysis of Change in Efficacy Measures
Analysis of mean change in efficacy measures from randomization to endpoint shows that both the fluoxetinetreated group and the placebo-treated group worsened
over time in each measure. However, statistically significant differences favoring fluoxetine were observed for
vomiting episodes, binge-eating episodes, CGI severity
score, CGI improvement score, patient’s global impression
score, and Yale-Brown-Cornell Eating Disorder Scale total
score, including statistically significant differences in both
the preoccupation and ritual subtotals (Table 3).
Safety
Adverse events that were first reported or that worsened
during double-blind therapy were compared between
treatment groups. The only event with a statistically significant difference in frequency between groups was rhinitis
(31.6% for the fluoxetine group, compared to 16.2% for the
Am J Psychiatry 159:1, January 2002
placebo group) (p<0.04, Fisher’s exact test). The rate of discontinuation because of an adverse event was also similar
between treatment groups, and the only adverse event
leading to discontinuation in ≥2% of patients was unintended pregnancy (2.6% for the fluoxetine group, compared to 4.1% for the placebo group).
There were no statistically significant differences between groups in change from randomization to endpoint
for systolic or diastolic blood pressure, heart rate, temperature, or weight. Although there were statistically significant differences in mean changes in certain laboratory
analytes from baseline to endpoint (magnesium, bicarbonate, and urine pH; all with a negative change in the fluoxetine-treated group and a positive change in the placebo-treated group), the mean endpoint values were not
indicative of drug-related toxicity.
Reasons for discontinuation were analyzed by time intervals after randomization (0–3 months, 3–6 months, and
6–12 months) (Table 4). Although the overall number of
patients who discontinued for various reasons was similar
among treatment groups, there were some interesting
trends that appeared to be time-related. In the first 3
months of the study, a large number of patients (11 fluoxetine-treated patients and 20 placebo-treated patients) discontinued for reasons of either patient decision or physician decision. Further inspection of individual study
comments for these patients revealed that eight fluoxe-
99
FLUOXETINE FOR BULIMIA
TABLE 4. Reasons for Attrition of Patients With Bulimia
Nervosa From a Randomized, Placebo-Controlled Study of
Continued Treatment After Acute Response to Fluoxetine
Reason for Attrition and
Treatment Group
Adverse event
Fluoxetine
Placebo
Lost to follow-up
Fluoxetine
Placebo
Patient decision
Fluoxetine
Placebo
Physician decision
Fluoxetine
Placebo
Protocol variance
Fluoxetine
Placebo
Relapse
Fluoxetine
Placebo
Noncompliance
Fluoxetine
Placebo
All reasons
Fluoxetine
Placebo
Months After Randomization
0–3
3–6
6–12
Total
2
3
2
0
0
0
4
3
4
6
2
3
3
1
9
10
8
14
4
4
6
2
18
20
3
6
0
1
0
0
3
7
1
1
1
0
2
0
4
1
12
20
2
0
3
2
17
22
3
5
3
0
2
0
8
5
33
55
14
8
16
5
63
68
tine-treated patients and 15 placebo-treated patients appeared to discontinue because of poorer than expected efficacy in this time period. None of these patients met the a
priori relapse criteria and were considered censored in the
time-to-relapse analysis.
Relapse as a reason for discontinuation occurred in 17
fluoxetine-treated patients and 22 placebo-treated patients. Within the fluoxetine-treated group, there was no
significant difference in relapse rates between depressed
and nondepressed patients (24.1% versus 21.2%) (χ2=0.09,
df=1, p=0.77).
Discussion
The results of the single-blind therapy phase confirm the
efficacy of fluoxetine in the acute management of bulimia
nervosa, with the response rate of 64.7% consistent with
previous reports (6). The remission rate of 17.7% is also
consistent with literature reports, which cite low abstinence rates during acute therapy (28). The comparable response rates among depressed patients and nondepressed
patients (62.8% versus 65.7%) further suggest that the absence or presence of comorbid depression does not affect
response in patients with bulimia nervosa, consistent with
results reported in a previous multicenter study (18).
During 52 weeks of double-blind relapse prevention
monitoring, patients who were randomly assigned to continued treatment with fluoxetine had a significantly longer
time to relapse than patients who received placebo. Analyses of mean change from randomization to endpoint for
each primary and secondary efficacy measure provided
further evidence of the beneficial effect of fluoxetine.
100
Within the group randomly assigned to continued fluoxetine treatment, the comparable relapse rates among depressed patients and nondepressed patients (24.1% versus
21.2%) suggest that comorbid depression is not a predictor of relapse among responders to acute treatment for
bulimia nervosa.
The majority of patients who received placebo relapsed
within the first 3 months after randomization, in contrast
to the more gradual loss of fluoxetine-treated patients due
to relapse during the course of the trial. This finding suggests that there may be a subgroup of pharmacologically
responsive bulimic patients who are highly sensitive to
medication discontinuation. Future research may help
elucidate traits of this subgroup and potentially determine
clinical strategies. It is noteworthy that the pharmacokinetic profile of fluoxetine and norfluoxetine, its active metabolite, parallels this observed pattern of relapse, as approximately 5–6 weeks are required for drug clearance.
To our knowledge, the present study is the largest placebo-controlled, double-blind trial evaluating relapse
prevention associated with maintenance pharmacotherapy for bulimia nervosa. However, the study had several
limitations. This study utilized patient diaries to assess
the primary outcome variable of weekly episodes of vomiting. Although no independent method to assess the reliability of these self-reports was used, one would expect
equal distribution of unreliable measures across treatment groups. It is important to note that vomiting is reported with greater clarity than is binge eating, the latter
tending to be assessed more variably by patients. Although limited by the accuracy and veracity of self-report,
and in light of the absence of a more objective index of
measurement, this method of recording is an improvement over retrospective account. Patient diaries have
been used extensively in studies assessing bulimia nervosa, including the large multicenter fluoxetine trial referenced earlier (18).
Determining operational definitions of response and relapse in bulimia nervosa trials represents a challenge, and
efforts in this area may be viewed as evolving. On the basis
of the results of the large multicenter trial (18), which reported a median reduction of 56% in weekly vomiting episodes in the group who received 60 mg/day of fluoxetine
and which calculated response as ≥50% improvement in
weekly vomiting episodes, a reduction of at least 50% was
felt to represent a clinically meaningful improvement to a
single treatment intervention. Similarly, a sustained return to the frequency of vomiting experienced at the time
of acute study entry was considered an appropriate criterion for relapse. Clearly, the definition of response used in
this study allows for persistence of symptoms, even for the
maintenance of syndromal criteria by some patients.
However, considering the negative consequences, both
psychological and medical, of persistent bulimic behavior,
a 50% reduction in frequency of vomiting episodes benefits clinical status.
Am J Psychiatry 159:1, January 2002
ROMANO, HALMI, SARKAR, ET AL.
Attrition during the relapse prevention phase of the
trial was high in both treatment groups, although there
was a trend for more fluoxetine-treated patients to complete the protocol. The largest amount of patient attrition
occurred in the first 3 months after randomization. Relapse, patients’ decisions, and physicians’ decisions were
the most common reasons for discontinuation. Investigators’ study notes for the patients who discontinued participation because of the patient’s decision or the physician’s decision revealed that eight of the fluoxetinetreated patients and 15 of the placebo-treated patients
were discontinued for worsening disease condition. None
of these patients met the formal relapse criteria and were
therefore considered as censored observations in the
time-to-relapse analysis. It is important to note, even in
light of the large attrition rate, that the estimated difference in relapse rates at 1 year was virtually the same as the
estimated difference after 3 months. This finding indicates that the observed benefit of fluoxetine treatment
occurs in the first 3 months and that this cumulative benefit remains constant after this time period. As clinical experience underscores the difficulty of maintaining patients with bulimia in longer-term therapy, the extended
period in which fluoxetine-treated patients remained in
the study, even in light of the noted attrition rate, suggests
the benefit of continued treatment.
Although fluoxetine treatment was associated with a
significantly lower rate of relapse, there was worsening
over time on all measures of efficacy, reflecting symptomatic regression. This finding suggests that fluoxetine alone
may not be an adequate treatment after acute response in
most patients and that additional management strategies
may be required to augment or to sustain initial improvement. Several studies have addressed the utility of combined approaches in an effort to establish effective treatment regimens (17, 29–32). Fichter and associates (17),
Goldbloom and associates (29), and Mitchell and associates (30) were unable to show greater improvement with
the combination of pharmacologic therapy and counseling than with counseling alone. Agras and associates (31)
studied 71 patients randomly allocated to treatment with
desipramine, cognitive behavior therapy, and a combination of the two interventions. At 16 weeks, both cognitive
behavior therapy and combined therapy were superior to
medication alone in reducing binge-eating and purging.
Continuing cognitive behavior therapy appeared to prevent relapse for up to 72 weeks in the patients who discontinued medication treatment. In addition, 77% of the patients with combined therapy achieved abstinence from
binge eating and purging, compared with 54% of those receiving cognitive behavior therapy alone. Walsh and associates (32), in a placebo-controlled study of 120 women,
found that cognitive behavior therapy plus medication
Am J Psychiatry 159:1, January 2002
(desipramine followed by fluoxetine if the desipramine
was poorly tolerated or ineffective) was superior to medication alone in reducing binge eating and vomiting, but
supportive psychotherapy plus medication was not.
Mitchell and associates (30), in a review of controlled trials
of pharmacotherapy and psychotherapy in the treatment
of bulimia nervosa, hypothesized that a longer course of
pharmacologic therapy in combination with counseling
would be of greatest benefit. Given the high attrition rate
observed in this fluoxetine trial and the known benefits of
cognitive behavior therapy, the latter should play a primary role in both acute and continuation treatment of patients with bulimia.
To our knowledge, the current study represents the largest relapse prevention trial to date assessing a pharmacotherapy treatment for bulimia nervosa. This study demonstrated that continued treatment with fluoxetine in
patients who responded to acute therapy was well tolerated and associated with a significant reduction in the
likelihood of relapse during a 52-week monitoring period.
An important finding, which is consistent with clinical experience and reported research results, was the gradual
worsening of symptom severity in both the fluoxetinetreated and placebo-treated groups. Although fluoxetine
treatment was statistically and clinically superior to placebo treatment in multiple measures of outcome, the latter observation suggests the benefit of a multimodal
approach. Additional outcome data on the long-term benefits of combined therapeutic approaches in improving
the likelihood of sustaining initial gains and in reducing
the rate of relapse should influence future treatment
guidelines. The findings of this study suggest that clinicians should consider providing acute responders to fluoxetine with maintenance fluoxetine treatment for up to 1
year, with psychotherapeutic interventions implemented
on the basis of individual need.
Acknowledgments
This study was completed with the participation of the following
investigators: Anne Becker, M.D., Massachusetts General Hospital, Boston; Barton Blinder, M.D., Ph.D., Newport Beach, Calif.;
Harry Brandt, M.D., Center for Eating Disorders, Towson, Md.;
Lynn Cunningham, M.D., Vine Street Clinical Research, Springfield, Ill.; Brenda Erikson, M.D., University of New Mexico, Albuquerque; James Ferguson, M.D., Pharmacology Research Corporation, Salt Lake City; Tana Grady, M.D., Duke University,
Durham, N.C.; Harry Gwirtsman, M.D., Vanderbilt University
Medical Center, Nashville, Tenn.; James Hudson, M.D., McLean
Hospital, Belmont, Mass.; Walter Kaye, M.D., University of Pittsburgh Western Psychiatric Institute, Pittsburgh; John Lauriello,
M.D., University of New Mexico, Albuquerque; Russell Marx,
M.D., San Luis Rey Hospital, Encinitas, Calif.; Pauline Powers,
M.D., University of South Florida College of Medicine, Tampa; Jeffrey Simon, M.D., Northbrooke Research Center, Brown Deer,
Wis.; B. Timothy Walsh, M.D., New York Psychiatric Institute, New
York; and Kathyrn Zerbe, M.D., Menninger Clinic, Topeka, Kan.
101
FLUOXETINE FOR BULIMIA
Presented in part at the 11th Congress of the European College of
Neuropsychopharmacology, Oct. 31–Nov. 4, 1998, Paris, and the
37th annual meeting of the American College of Neuropsychopharmacology, Dec. 14–18, 1998, Las Croabas, Puerto Rico. Received Feb.
1, 2001; revision received June 4, 2001; accepted July 31, 2001. From
Pfizer Inc, New York; Weill Medical College of Cornell University,
White Plains, NY; Lilly Research Laboratories, Eli Lilly and Company,
Indianapolis; and Cleveland Clinic, Cleveland. Address reprint requests to Ms. Koke, Lilly Research Laboratories, Lilly Corporate Center
2200, Indianapolis, IN 46285; skoke@lilly.com (e-mail).
Supported by a clinical research grant from Eli Lilly and Company.
The authors thank Roy Tamura of Eli Lilly and Company for statistical assistance.
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