currently Novartis Pharmaceuticals, Basel, Switzerland
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, Indiana, USA
Correspondence: Apurva Prakash, Lilly Research Laboratories, Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA. Tel: (317) 277 8798; fax: (317) 277 9551
Declaration of interest This work was sponsored by Eli Lilly & Co.
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ABSTRACT |
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Aims To assess the efficacy and tolerability of fluoxetine in preventing PTSD relapse.
Method This was a double-blind, randomised, placebo-controlled study. Following 12 weeks of acute treatment, patients who responded were rerandomised and continued in a 24-week relapse prevention phase with fluoxetine (n=69) or placebo (n=62). The primary efficacy assessment was the prevention of PTSD relapse, based on the time to relapse.
Results Patients in the fluoxetine/fluoxetine group were less likely to relapse than patients in the fluoxetine/placebo group (P=0.027). There were no clinically significant differences in treatment-emergent adverse events between treatment groups.
Conclusions Fluoxetine is effective and well tolerated in the prevention of PTSD relapse for up to 6 months.
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INTRODUCTION |
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METHOD |
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The study was conducted from June 1998 to August 2000 at 18 study centres in Belgium, Bosnia, Croatia, Yugoslavia, Israel and South Africa. The ethical review board for each site reviewed the study; written informed consent was obtained from all participants.
Study design
After a 1- to 2-week evaluation period, participants were randomised to 12
weeks' double-blind acute treatment with fluoxetine or placebo.
Fluoxetine-treated patients initially received 20 mg/day. This dose could be
increased by 20-mg increments at each of three titration points based on
predefined response criteria (CGIS3) to a maximum dosage of 80
mg/day. Acute response to fluoxetine v. placebo has been described
elsewhere (Martenyi et al,
2002).
After 12 weeks of acute treatment with fluoxetine or placebo, participants
who responded to treatment by a 50% decrease in the eight-item Treatment
Outcome PTSD (TOP-8) score (Davidson &
Colket, 1997) from baseline, a CGIS score 2, and
failing DSMIV diagnostic criteria for PTSD continued in a 24-week
relapse prevention phase. Those patients who had received fluoxetine were
randomised either to continue without variation from final dosage in the acute
phase or to placebo treatment. In order to maintain blinding, patients
switching to placebo did not undergo a tapering regimen. This was possible
because fluoxetine is associated with significantly fewer and less-severe
discontinuation-emergent adverse events than are other SSRIs
(Rosenbaum et al,
1998).
Patients who responded to treatment with placebo during the acute treatment
phase were continued on placebo during the relapse prevention phase to
preserve blinding. Participants discontinued the trial if relapse criteria
were met (40% increase in TOP-8 score and an increase in CGIS score of
2 from the baseline at week 12 of acute treatment) at any time during the
relapse prevention phase. Relapse could also be determined by the clinical
judgement of the investigator.
Outcome measures
The primary efficacy measure for the relapse prevention phase was time to
relapse based on the TOP-8 scale and the CGIS scale. TOP-8 is an 8-item
clinician-rated instrument measuring the presence and severity of PTSD
symptoms in three major dimensions (intrusive, avoidant and hyperarousal
symptoms). Each item is rated from 0 to 4, with higher numbers indicating
greater severity.
Secondary assessments included the CAPSDX total, intrusive, avoidance and hyperarousal scores; the Clinical Global Impression of Improvement (CGII) scale (Guy, 1976); and the Davidson Trauma Scale (DTS) total, intrusive, avoidance and hyperarousal sub-scores (Davidson et al, 1997). Changes in comorbid psychiatric disorders were measured using the MADRS, the Hamilton Rating Scale for Anxiety (HRSA; Hamilton, 1959) and the Hopkins 90-Item Symptoms Checklist Revised (SCL-90-R; Derogatis, 1983; Rief & Fichter, 1992). Both the DTS and the SCL-90-R are patient-rated scales; all others are clinician-rated.
Safety was assessed by evaluating treatment-emergent adverse events, discontinuations for adverse events, vital signs measurements and clinical laboratory tests. Adverse events were ascertained by non-probing enquiry and were recorded regardless of perceived causality. An event was considered treatment-emergent if it occurred for the first time or worsened during the relapse prevention phase of the study. Investigators assessed patient compliance at each visit by direct questioning and by counting returned medication. Patients were considered non-compliant if they missed more than 4 consecutive days or more than 10 cumulative days of study medication. Patients were also considered non-compliant if the ratio of the number of capsules taken to the number of capsules prescribed was less than 0.8 or more than 1.2.
Statistical methods
Time to relapse was evaluated by plotting KaplanMeier survival
curves. A long-rank test was used to compare the time to relapse curves for
the fluoxetine/fluoxetine and fluoxetine/placebo treatment groups. Analyses of
change from baseline (week 12 of acute treatment) in TOP-8, MADRS, DTS,
SCI-90-R, CGIS and HRSA scores were conducted using a repeated-measures
model with visit, treatment, investigator and visit-by-treatment interaction
as effects in the model. The corresponding baseline score was included in the
model as a covariate. An unstructured covariance matrix was fitted to the
within-patient repeated measures. Change from baseline to each visit was
tested between treatment groups using contrasts within the repeated-measures
model. The comparison between groups of the difference from baseline to the
last visit (week 36) was considered the primary comparison. Analysis of
CGII was done in a similar manner using raw post-baseline values. For
the CAPS total scores and sub-scores, which were collected at baseline (week
12), mid-point (week 24) and end-point (week 36 or discontinuation), analyses
of the change from baseline to end-point (last observation carried forward,
LOCF) were conducted using analysis of variance with treatment and
investigator as effects in the model.
To investigate the possible effect of trauma type (combat-related v. non-combat-related trauma), a repeated-measures analysis of variance was conducted as described above, with the addition of trauma type in the model. In addition, the two-way interactions of trauma type by visit and by treatment were included along with the three-way interaction of treatment by trauma type and by visit.
Treatment differences in patient characteristics at baseline were assessed using Fisher's exact test for categorical variables and analysis of variance for continuous variables. The analysis of variance model included investigator and therapy. Treatment-emergent adverse events and treatment-emergent abnormal laboratory values were analysed using Fisher's exact test. The mean final dose of fluoxetine was summarised.
All analyses were based upon the intent-to-treat principle and were performed using SAS software (SAS Institute Inc., Version 6 (for MVS), Carey, NC, 1991). Tests of treatment effects were conducted at a two-sided alpha level of 0.05. Investigators with fewer than two randomised patients per treatment group were pooled for statistical analysis purposes.
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RESULTS |
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Medication compliance was high for both groups at all time points. The mean exposure to the study drug was 157 days during the 6-month relapse prevention phase for fluoxetine/fluoxetine-treated patients. The mean final dose was 53 mg/day.
Efficacy
An analysis of time to relapse showed that fluoxetine was statistically
significantly superior to placebo in relapse prevention (log-rank
2=4.88, P=0.027)
(Fig. 2).
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A higher percentage of fluoxetine/fluoxetine-treated patients (82.6%) completed the relapse prevention phase compared with fluoxetine/placebo-treated patients (66.1%) (Fisher's exact test, P=0.043). A higher percentage of fluoxetine/placebo-treated patients (16.1%) discontinued the study because of relapse compared with fluoxetine/fluoxetine-treated patients (5.8%) (P=0.087) (Table 2).
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Fluoxetine/fluoxetine-treated patients had statistically significantly greater mean improvement in TOP8 total score from baseline to end-point than did fluoxetine/placebo-treated patients (fluoxetine/fluoxetine, -1.8; fluoxetine/placebo +0.05; F=6.721,112, P=0.011) (Fig. 3). The effect size of 0.5, typically considered to be of medium size, implies that the median improvement in the fluoxetine/fluoxetine group exceeded the improvement of 69% of individuals in the fluoxetine/placebo group.
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The CGIS scores also showed statistically significant improvement for fluoxetine/fluoxetine-treated patients compared with fluoxetine/placebo-treated patients (F=8.391,112, P=0.005) (Table 3). In addition, fluoxetine-treated patients experienced greater improvement in CAPS score compared with placebo-treated patients. The difference between the two treatment groups was statistically significant for the avoidance sub-score (F=5.441,113, P=0.021) but was not statistically significant for the CAPS total score or the CAPS intrusive sub-score (total score: F=3.801,113, P=0.054; intrusive: F=3.111,113, P=0.080). The patient-rated SCL90R and DTS did not show statistically significant separations between treatment groups in total scores or any DTS sub-scores (Table 3). Fluoxetine/fluoxetine-treated patients experienced significantly greater improvement compared with fluoxetine/placebo-treated patients in symptoms of anxiety and depression as measured by the HRSA (F=6.731,112, P=0.011) and MADRS (F=5.131,112, P=0.026) scores (Table 3).
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When exploring the possible effect of trauma type (combat-related v. non-combat-related), a significant three-way interaction was detected between visit, treatment and trauma type (P=0.005). For the non-combat-related traumas, the mean change from baseline to last visit was -1.72 for the fluoxetine/fluoxetine group compared with -1.25 for the fluoxetine/placebo group (P=0.633). For the combat-related traumas, the mean change for the fluoxetine/fluoxetine group was -1.62 compared with +1.97 for the fluoxetine/placebo group (P=0.002). It should be noted that for patients with non-combat-related PTSD, placebo was associated with some improvement but for patients with combat-related PTSD, placebo was associated with a worsening of symptoms. Fluoxetine was associated with similar levels of improvement in both patient types.
Safety
There were no significant differences between the two groups in any vital
sign measure or laboratory result.
The difference between treatment groups in the number of patients reporting one or more treatment-emergent adverse events was not statistically significant (fluoxetine/fluoxetine 39%; fluoxetine/placebo 24%; Fisher's exact test P=0.091). There were no statistically significant differences in the numbers of patients reporting any single event. The adverse events most commonly reported by fluoxetine/fluoxetine-treated patients were insomnia (15%), anxiety (6%) and headache (6%); those most commonly reported by fluoxetine/placebo-treated patients were insomnia (10%), headache (5%) and pain (5%). Two patients, both in the fluoxetine/fluoxetine treatment group, experienced serious adverse events requiring hospitalisation (back pain and traffic accident). Only the patient involved in the traffic accident discontinued the trial early.
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DISCUSSION |
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Participants in the fluoxetine/fluoxetine treatment group continued to experience statistically significant improvement in mean TOP8 score throughout the 24-week relapse prevention period and showed statistically significant better improvement at end-point than did fluoxetine/placebo-treated participants.
Improvement in illness severity, as demonstrated by the CGIS scale, was also statistically significant (P=0.005).
Fluoxetine/fluoxetine-treated participants experienced significantly greater improvement compared with fluoxetine/placebo-treated participants in the CAPS avoidance sub-score. Both of the patient-rated scales (DTS and SCL90R) failed to show significant differences in the improvement of PTSD symptoms between the two treatment groups, possibly as a result of inconsistent patient self-rating.
Because comorbid psychiatric disorders such as anxiety and depression are commonly associated with PTSD, the HRSA and MADRS scores were collected throughout the relapse prevention phase to monitor changes in patients' comorbid symptoms. When compared with fluoxetine/placebo-treated participants, fluoxetine/fluoxetine-treated participants experienced significantly greater improvement in both HRSA and MADRS total scores.
The findings demonstrate the efficacy of pharmacotherapy with fluoxetine, an SSRI, in the prevention of PTSD relapse and continual improvement in PTSD symptoms for up to 6 months following response to 12 weeks of acute treatment. In addition, the study design excluded patients with comorbid major depression (patients with a MADRS score >20 were excluded), which differs from previous studies that allowed unlimited severity of depression (Davidson et al, 2001; Londborg et al, 2001). The results of this study, therefore, represent improvement and relapse prevention of PTSD rather than improvement and relapse prevention of a mixed state of PTSD and depression.
Safety
Safety and tolerability of fluoxetine in this study were comparable to
previous studies of fluoxetine in PTSD and to fluoxetine trials for other
indications. Fluoxetine was generally well tolerated, with no statistically
significant differences between treatment groups in either the incidence of
any individual adverse event, or the drop-out rate due to adverse events.
The mean fluoxetine dose at end-point, 53 mg/day, was consistent with fluoxetine doses in the upper range for the treatment of clinical depression and the recommended range for patients with OCD.
This study was designed to assess the effect of pharmacotherapy with fluoxetine for preventing PTSD relapse, and investigators were instructed to avoid providing any type of counselling or behavioural therapy to study participants during study visits. Numerous other studies, however, have shown that psychotherapy is effective in the treatment of individuals with PTSD, and various behavioural treatments have shown efficacy in the reduction of the core symptoms of PTSD (Ballenger, 1999). Results of the acute treatment phase of this trial show an increased placebo response for participants with dissociative symptoms at baseline, resulting in a statistically significant interaction between treatment group and participants with and without dissociative symptoms at baseline (Martenyi et al, 2002). These results suggest that different populations of individuals with PTSD may respond favourably to psychotherapy compared with pharmacotherapy. Indeed, the combination of psychotherapy and pharmacotherapy may yield the most significant therapeutic effect and warrants further study.
One limitation of this study was the duration of acute therapy. Both large national surveys (Kessler et al, 1995) and a pharmacotherapy study with sertraline (Davidson et al, 2001) suggest that PTSD may require a fairly lengthy acute treatment (in excess of 12 weeks) before maximum improvement of symptoms is achieved. In this study, the statistically significant continued improvement in PTSD symptoms (measured by the TOP-8 scale) after 12 weeks of acute therapy suggests that the full therapeutic effect of fluoxetine on the improvement of PTSD symptoms may not have been observed even after 9 months of therapy.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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Received for publication November 6, 2001. Revision received June 6, 2002. Accepted for publication June 6, 2002.
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