Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA
Correspondence: Dr David Michelson, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Drop Code 6026, Indianapolis, IN 46285, USA. Tel: (317) 277 6443; fax: (317) 277 3262
Declaration of interest This study was funded by Eli Lilly and Company. Drs Michelson and Sarkar and Mr Pemberton are employees of Eli Lilly and Company. Drs Allgulander, Dantendorfer, Knezevic, Maierhofer, Micev, Paunovic, Timotijevic and Skoglund are paid consultans to Eli Lilly and Company.
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ABSTRACT |
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Aims To assess the efficacy of the usual antidepressant dose of fluoxetine in treating full panic attacks.
Method Patients with panic disorder were randomised to placebo or to fluoxetine initiated at 10 mg daily for 1 week and then increased to 20 mg daily. The trial lasted 12 weeks, but after 6 weeks patients who had failed to achieve a satisfactory response were eligible for dose escalation to a maximum of 60 mg of fluoxetine daily.
Results Fluoxetine was associated with a statistically significantly greater proportion of panic-free patients compared with placebo after 6 weeks and at end-point.
Conclusions Fluoxetine at a dose of 20 mg daily is safe and efficacious in reducing symptoms of panic disorder. Patients who fail to obtain a satisfactory response at 20 mg daily may benefit from further dose increases.
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INTRODUCTION |
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METHOD |
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Study design
Following a 2-week medication washout period, the study incorporated an
initial single-blind (patients) 2-week baseline evaluation period followed by
randomisation under double-blind conditions to either fluoxetine or placebo
for 12 weeks. Dosing was initiated at 10 mg daily for 1 week and then
increased to 20 mg daily. After 6 weeks, patients who had not achieved a
CGI-Severity score of 2 or less (minimal symptoms) were required to have a
dosage increase to 40 mg. If CGI-Severity at subsequent visits remained above
2 (indicating some residual symptoms), an additional increase to 60 mg was
required.
Patients were seen at 2-week intervals throughout the study. Panic frequency was assessed using an electronic diary that was completed by patients after each panic attack and included information on duration, severity and whether the attack was spontaneous or triggered by an external stimulus, as well as which symptoms were experienced during the attack. Other assessments included the PDSS, the 17-item HRSD, the Hamilton Rating Scale for Anxiety (HRSA; Riskind et al, 1987), the State Anxiety Inventory (SAI; Spielberger, 1983) and CGI-Severity. The Sheehan Disability Scales (Sheehan, 1983) were used to assess patients' functional impairment.
Statistical methods
All the analyses were based upon the intention-to-treat principle. The
sample size of 180 patients was calculated to provide a 90% likelihood of
detecting a 20% difference between treatment groups in panic-free status at
end-point (the protocol-specified primary outcome measure). Efficacy
evaluations were made at 6 weeks and at end-point for measures of panic
frequency and the PDSS. Other measures were assessed at end-point only. SAS
software, version 6.09 (SAS Institute, 1991) was used for all analyses.
Logistic regression methods were used to compare fluoxetine and placebo groups
after 6 weeks and during the final visit interval with respect to the odds of
being panic-free and of having a 50% reduction in panic frequency, and during
the final visit interval with respect to the odds of having a final
CGI-Severity score of 1 or 2. The logistic regression model included
treatment, site and treatment-site interaction (with provision to delete
treatment-site from the model if the term was non-significant). Likelihood
ratio tests were used to test the treatment effects. The GENMOD procedure of
the SAS system was used for logistic regression analyses.
Continuous data (PDSS, HRSD, HRSA, Sheehan Disability Scale, SAI and CGI-Severity) were analysed using an analysis of variance to test the null hypothesis of no difference in mean change from baseline to end-point between groups. Prior to analysis, panic frequency was rank-transformed because of non-normality of the data. Adverse events were compared between groups using Fisher's exact test.
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RESULTS |
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Efficacy
Outcomes are summarised in Table
2. For the protocol-specified primary outcome measure (panic-free
status at end-point), analysis did not demonstrate a treatment-site
interaction for the logistic regression comparison of likelihood ratios, and
this term was dropped from the model. Patients treated with fluoxetine
achieved significantly greater improvements than the placebo group at 6 weeks
and at end-point in panic-free status, 50% or more reduction in panic attacks
and proportion of patients with CGI-Severity scores or 1 or 2 (no or minimal
symptoms). The estimated odds of achieving panic-free status at 6 weeks and
end-point were 2.38 (95% CI=1.11-5.11) and 2.29 (95% CI=1.14-4.59) times
higher, respectively, for fluoxetine-treated patients compared with patients
receiving placebo. At 6 weeks, 29% of fluoxetine patients and 16% of patients
in the placebo group were panic free. Forty-two per cent of fluoxetine-treated
patients and 28% of patients in the placebo group were panic free at
end-point. The estimated odds of achieving at least a 50% reduction from
baseline in the number of full panic attacks at 6 weeks and at end-point were
1.94 (95% CI=1.04-3.62) and 3.23 (95% CI=1.57-6.63) times higher,
respectively, for fluoxetine-treated patients compared with patients in the
placebo group. At 6 weeks, 61% of fluoxetine patients and 47% of placebo
patients reported a 50% or greater reduction in the number of panic attacks.
The percentages of patients who demonstrated at least a 50% reduction at
end-point were 82% and 61% in the fluoxetine and placebo groups, respectively.
Mean reduction in panic attack frequency as measured by diary was not
statistically significantly different between the groups. However, mean
reduction in panic attack frequency as assessed by item 1 of the PDSS was
significantly greater among fluoxetine patients at both 6 weeks and end-point.
Reduction in global panic disorder symptom severity as assessed by the overall
PDSS score was statistically significantly greater for fluoxetine-treated
patients than for those treated with placebo. More general measures of
anxiety, including the HRSA and SAI, also demonstrated greater symptom
reduction by fluoxetine compared with placebo, as did measures of functional
impairment, including the Sheehan work and social impairment measures and the
social impairment item of the PDSS.
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The final median dose of the fluoxetine treatment group was 20 mg daily and the final mean dose was 29.8 mg daily. Among fluoxetine patients at end-point, 61 subjects (67.7%) were taking 20 mg daily, 14 (15.5%) were taking 40 mg daily and 15 (16.7%) were taking 60 mg daily.
Safety
Among randomised patients, the number of patients reaching the final visit
after 12 weeks of fluoxetine or placebo therapy was similar for both groups
(fluoxetine: n=75 (83.3%); placebo: n=80 (88.8%); NS). The
total number of discontinuations due to adverse events was similar for both
groups (fluoxetine: n=5 (5.5%); placebo: n=3 (3.3%);
P=0.72, Fisher's exact test). Other reasons for discontinuation
included lack of efficacy (fluoxetine: n=5 (5.5%); placebo:
n=3 (3.3%); P=0.72, Fisher's exact test), patients lost to
follow-up (fluoxetine: n=3 (2.2%); placebo: n=3 (2.2%);
P=0.99, Fisher's exact test), patient decision (fluoxetine:
n=2 (2.2%); placebo: n=0; P=0.50, Fisher's exact
test) and protocol requirement (fluoxetine: n=1 (1.1%); placebo:
n=2 (2.2%); P=0.99, Fisher's exact test). The total number
of adverse events reported was similar for both groups (fluoxetine:
n=25 (27.8%); placebo: n=19 (21.1%); P=0.37,
Fisher's exact test). No single adverse event occurred in more than 5% of
patients in either group, and no single event was statistically significantly
more common among patients in either group (summarised in
Table 3).
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DISCUSSION |
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We previously reported evidence of efficacy for fluoxetine at both 10 and 20 mg daily compared with placebo (Michelson et al, 1998), with evidence of a somewhat more robust pattern of response at 20 mg. In that study, however, neither dose was associated with an effect on full panic attack frequency. This finding could have been related to methodological issues associated with measuring panic attack frequency (Michelson et al, 1998) or to a need for higher doses to achieve a specific effect on panic attack frequency.
Efficacy of fluoxetine
The results of this study demonstrate a statistically significant
difference in treatment effects on multiple measures of panic attack frequency
after 6 weeks (when all patients were being treated with fluoxetine 20 mg
daily) and after 12 weeks (when daily doses ranged from 20 mg to 60 mg). The
initial 6-week period provided an opportunity to assess whether the usual
antidepressant dose of fluoxetine is effective in treating full panic attacks
as well as other symptoms of panic disorder. The study also provided an
opportunity to determine whether the number of patients who require higher
doses for optimal response is similar or dissimilar to that observed among
patients with depression.
Among patients who met DSM-IV criteria for panic disorder, fluoxetine was associated with statistically significant improvement in panic attack symptoms and a reduction in broader symptom measures both after 6 weeks of treatment with 20 mg daily and at end-point at doses up to 60 mg daily. These data provide further evidence that 20 mg is an efficacious dose in this disorder and suggest that the failure to demonstrate effects on panic attack frequency in the previous study was related to methodological issues rather than a need for higher doses of fluoxetine.
This study did not include an active comparator. The difference in numbers of panic-free patients observed in this study is comparable to that reported in some studies of other selective serotonin reuptake inhibitors (Oehrberg et al, 1995; Londborg, 1998; Pohl et al, 1998). Other studies, however, have failed to show a difference in panic-free status at end-point (Pollack et al, 1998) or have shown greater treatment differences for this variable between active drug and placebo (Ballenger et al, 1998). In this regard, we note that response rates are determined by many study-specific factors as well as by a drug's intrinsic effects, and that comparisons across different studies conducted under unique protocols and circumstances are difficult to interpret meaningfully. As a result, we cannot determine definitively from this study the relative effects of fluoxetine compared with other agents that have been reported to be efficacious.
A further question concerns the degree to which the observed statistically significant effects also represent clinically important change. Although the absolute response rate was high (82% of fluoxetine-treated patients had at least a 50% decrease in panic frequency at end-point), placebo response (i.e. improvement related to non-specific interventions) also was high (61% of patients assigned to placebo also had a 50% reduction in panic frequency). This is not unusual, because panic symptoms often are quite placebo-responsive and the magnitudes of observed treatment differences between active drugs and placebo can be limited. However, the clinical trial itself can affect non-specific responses through such variables as subject selection, visit frequency, intensity of evaluations and patient expectations of a novel or experimental treatment, making extrapolation to other settings difficult. Further, the clinical relevance of an effect depends not only on its magnitude but also on a number of other variables, including the discomfort and impairment associated with the disorder, the natural history of the disorder and any burdens associated with therapy. The results of measures such as the Sheehan Disability Scale that favour fluoxetine suggest that the greater symptomatic improvement observed among fluoxetinetreated patients was associated with improved functional outcomes compared with placebo. However, the study was designed primarily to assess efficacy (i.e. to determine whether or not fluoxetine has specific effects in this disorder compared with placebo) and definitive assessment of the clinical relevance of these effects will require further studies with designs specific to this issue.
Although dose-escalation designs can confound dose and time effects, it seems likely that responses observed after only 6 weeks among patients who had not responded initially are attributable more to increased dose than to time, because fluoxetine would have been at steady state and expected to have induced relevant physiological changes in the brain homoeostasis well within that period. We therefore hypothesise that a subgroup of patients required doses above 20 mg to attain optimal therapeutic responses. Overall, the final mean dose was 29.6 mg, a figure comparable to values found in many trials of similar design using fluoxetine in patients with depressive disorders (Beasley et al, 1991; Casacchia et al, 1993).
Methodological issues
Several methodological issues arose in the course of this study and are
also of interest. In designing this study, we chose to use an electronic
diary. Analyses were conducted directly on patient-entered data, unlike many
previous studies in which results were reviewed, interpreted and subject to
change based on the investigator's judgment. Because no control group with
investigator-reviewed data was included, it is not possible to determine
definitively which methodology provides more accurate data. We do note,
however, that the results suggest that using patients' reports without
investigator mediation provides sufficiently reliable data to demonstrate drug
effects, because the diary reports are consistent with the
investigator-administered assessments. In this context, item 1 of the PDSS,
which is an investigator assessment of panic frequency based on a review of
symptoms with the patient, demonstrated a similar outcome to the diary,
although the PDSS results on that item were somewhat more robust in separating
fluoxetine and placebo than the diary results (a finding potentially related
to measurement issues associated with transforming panic attack frequency into
a limited number of discrete categories).
We and others (Michelson et al, 1998) have suggested that, for multiple reasons, change in panic attack frequency is an unsatifactory method for assessing change in overall illness severity, and that measures that include panic attack frequency as well as a broader range of symptomatology appear to be more meaningful markers of change. In this study, two measures of effects on panic attacks (proportion of panic-free patients and 50% reduction in panic attack frequency) did show differences between fluoxetine and placebo. The treatment differences in mean change in panic attack frequency, although directionally consistent with the other measures, did not reach statistical significance. In this regard, the PDSS overall score has been suggested as a preferable alternative (Shear et al, 1997), because it reflects a multidimensional approach to assessment of panic disorder and has been validated psychometrically. The overall results of the PDSS and other measures (e.g. HRSA, Sheehan Disability Scale) provide evidence of fluoxetine-specific response across symptom domains other than panic associated with fluoxetine treatment, including improvement in illness-associated functional impairment.
Tolerability and safety
Fluoxetine was well tolerated in this study. Overall reports of adverse
events were similar among both placebo- and fluoxetine-treated patients, and
no individual adverse event was statistically significantly more frequent in
the fluoxetine group. Discontinuations due to adverse events among both groups
were also similar and low. Some authors have suggested that patients suffering
from panic disorder could be particularly sensitive to initiating fluoxetine
treatment and have advocated very low initial doses and gradual increases
(Giesecke, 1990;
Schneier et al,
1990). The results of this and previous work, however, provide
evidence that the tolerability of fluoxetine among patients with panic
disorder is similar to that among depressed patients.
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Clinical Implications and Limitations |
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LIMITATIONS
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Received for publication August 15, 2000. Revision received May 29, 2001. Accepted for publication June 14, 2001.
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