Department of Liaison Psychiatry, Leeds General Infirmary, Leeds LSI 3EX, UK
Martenyi et al (2002) suggest that fluoxetine is effective and well-tolerated in the prevention of relapse of post-traumatic stress disorder (PTSD) for up to 6 months. I think that this statement needs careful consideration.
First, the authors start by randomising patients into a placebo group and a fluoxetine group; the latter is later subdivided into a fluoxetine/placebo group and a fluoxetine/fluoxetine group. We see the outcome results of both the groups initially treated with fluoxetine, but those of the placebo/placebo group are not included in the paper.
Second, the authors dismiss the issue of discontinuation-emergent adverse effects, referring to a study by Rosenbaum et al (1998). That study, also sponsored by Eli Lilly, concluded that fluoxetine had fewer adverse events than other selective serotonin reuptake inhibitors. However, fluoxetine was used up to a maximum dose of 60 mg/day with a mean dose close to 25 mg/day, whereas in the Martenyi et al study, the maximum dose was 80 mg/day and the mean close to 50 mg/day - double that in the Rosenbaum et al study. This is more significant as the results are not analysed on an intention-to-treat basis. Martenyi et al state that there were no significant differences when comparing drop-outs due to adverse events, but if we compare the total number of patients discontinuing the study, the percentages are almost double for those switched to placebo compared with those continued on fluoxetine (33.4% v. 17.3%).
Third, the authors mention that the reason behind the failure to show significant differences in the improvement of symptoms between the two treatment groups is the result of inconsistent patient self-rating. Could it not simply be that there are no differences?
The study addresses an important area, but the interpretation of the results should have been more rigorous.
REFERENCES
Martenyi, F., Brown, E. B., Zhang, H., et al
(2002) Fluoxetine v. placebo in prevention of
relapse in post-traumatic stress disorder. British Journal of
Psychiatry, 181,
315-320.
Rosenbaum, J. F., Fava, M., Hoog, S. L., et al (1998) Selective serotonin reuptake inhibitor discontinuation syndrome: a randomised clinical trial. Biological Psychiatry, 44, 77-87.[CrossRef][Medline]
Lilly Research Laboratories, Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA
This work was sponsored by Eli Lilly and Company. E.B.B., A.P. and C.M.M. are employees of Eli Lilly and Company.
Dr Agell raises concerns regarding the conclusions proposed in our original article (Martenyi et al, 2002a) that the results of our study suggest that fluoxetine is effective and well-tolerated in the prevention of PTSD relapse for up to 6 months. Dr Agell's concerns that (a) we do not discuss the results of the placebo/placebo group; (b) we do not adequately address the study results regarding SSRI discontinuation-emergent adverse events; and (c) the authors mention that the reason behind the failure to show significant differences in the improvement of symptoms between the two treatment groups is the result of inconsistent patient self-rating. We will attempt to address each of these concerns.
First, the results presented in our original article pertain to the relapse-prevention phase of a larger study. Results of the acute treatment phase (including the acute results of the placebo/placebo group) may be found in Martenyi et al (2002b). The primary objective of the relapse-prevention phase of our study and the focus of our original article was to assess the efficacy and tolerability of fluoxetine in the prevention of PTSD relapse. It then follows that the relevant results should come from acute phase fluoxetine responders who were continued on fluoxetine in the relapse-prevention phase or switched to placebo. The efficacy results from the placebo/placebo group would not address our question regarding the efficacy of fluoxetine in the prevention of PTSD relapse and, therefore, the full relapse-prevention efficacy results from the placebo/placebo group were not provided. We did, however, provide a breakdown of the reasons for discontinuation in the study for all treatment groups (Marteyni et al, 2002a, Fig. 1). Of the 31 patients in the placebo/placebo group (note that the sample size is small because the original randomisation was 3:1 fluoxetine:placebo), the discontinuation profile was quite similar to that of the fluoxetine/placebo group. Discontinuation profiles for the fluoxetine/placebo group v. the placebo/placebo group, respectively, were: 66.1% v. 61.3% completed the protocol; 0% v. 0% discontinued because of adverse events; 16.1% v. 16.1% discontinued because of clinical relapse; 4.8% v. 12.9% were lost to follow-up; 3.2% v. 0% discontinued because of patient decision; 9.7% v. 6.5% discontinued because of non-compliance; and 0% v. 3.2% discontinued because of lack of efficacy. These discontinuation data suggest that patients with an initial placebo response face a similar risk of recurrence of symptoms to those who had achieved an adequate pharmacological response and were then switched to placebo.
Second, it is true that approximately twice as many patients discontinued from the fluoxetine/placebo group compared with the fluoxetine/fluoxetine group. It is important, however, to note the reasons for discontinuations (Martenyi et al, 2002a, Table 2). The protocol specified that patients meeting pre-defined criteria for clinical relapse should be discontinued, which allowed the investigators to provide follow-up care at their discretion. Only one patient in the fluoxetine/fluoxetine group discontinued because of an adverse event compared with none in the fluoxetine/placebo group, and the primary difference between the two treatment groups with regard to reason for patient discontinuation was clinical relapse (5.8% v. 16.1% for the fluoxetine/fluoxetine and fluoxetine/placebo groups, respectively). Accounting for all reasons for discontinuation with the exception of clinical relapse, 8 patients (12%) v. 11 patients (18%) discontinued early for the fluoxetine/fluoxetine and fluoxetine/placebo groups, respectively (Martenyi et al, 2002a, Table 2). It should also be noted that there were no statistically significant differences in the numbers of patients reporting any single adverse event. The adverse events most commonly reported by patients in the fluoxetine/fluoxetine group were insomnia (15%), anxiety (6%) and headache (6%); those most commonly reported by patients in the fluoxetine/placebo group were insomnia (10%), headache (5%) and pain (5%). These data provide further support that the long half-life of fluoxetine and its active metabolite, norfluoxetine, provide benefit with regard to the minimisation of the risk of discontinuation-emergent signs and symptoms.
Third, statistically significant differences were detected between treatment groups for the a priori defined primary analysis (time to relapse, P=0.027; Martenyi et al, 2002a, Fig. 2). In addition, using repeated-measures analysis of variance (Martenyi et al, 2002a, Fig. 3), we can see that those patients in the fluoxetine/fluoxetine group continued to improve over time, with a statistically significant difference between groups occurring from week 28 to the study end-point (week 36), based on our primary efficacy measure, and other significant differences were detected between groups in several other illness severity measures (Martenyi et al, 2002a, Table 3). Other patient-rated secondary measures were used in this study and, as reported, failed to show a significant difference between groups (Martenyi et al, 2002a, Table 3).
We believe that the results of this study are robust and support our conclusions, and we maintain our opinion that the study results suggest that fluoxetine is effective and well-tolerated in the prevention of PTSD relapse for up to 6 months.
REFERENCES
Martenyi, F., Brown, E. B., Zhang, H., et al
(2002a) Fluoxetine v. placebo in prevention
of relapse in posttraumatic stress disorder. British Journal of
Psychiatry, 181,
315-320.
Martenyi, F., Brown, E. B., Zhang, H., et al (2002b) Fluoxetine versus placebo in posttraumatic stress disorder. Journal of Clinical Psychiatry, 63, 199-206.
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