New statistical proposals to evaluate the benefit/risk ratio of long-term treatment of depression: application to a one-year double-blind study comparing medifoxamine with fluoxetine

The aim of this study was to determine the benefit/risk ratio of long-term treatment with medifoxamine, a non-tricyclic, non-monoamine oxidase inhibitor agent, and fluoxetine in patients with acute depressive episode and at high risk of relapse and/or recurrence. The study involved a 12-month double-blind, randomised, parallel-group design with a multicentric trial setting conducted by 64 participating physicians. 155 and 158 patients of either gender, aged between 18 and 70 years, were allocated to fluoxetine and medifoxamine, respectively. All patients had an acute depressive episode defined by the presence of at least five of the DSM III-R criteria with a minimal score of 25 on the Montgomery and Asberg Depression Rating Scale (MADRS). All subjects had at least one previous documented depressive episode in their medical history. The main outcome criterion consisted of good therapeutic response defined by a sustained 50% reduction of the Clinical Global Impression (CGI) score combined with the absence of any serious or troublesome (i.e. intensity motivating study discontinuation) events. In the fluoxetine and medifoxamine groups, respectively, 45.2% and 43% of the randomised patients completed the 12-month follow-up period with no major differences between groups regarding the reasons for treatment withdrawal. With each treatment 58% of the patients reached at least a 50% decrease in their CGI score, with no differences on the evolution of the MADRS, Hamilton Anxiety Rating Scale (HARS), the Self Rating Depression Scale of Zung (Zung scale) and Scott depression visual analogue scale (VAS) scores on average. According to the main efficacy criterion, 26% of the patients in the fluoxetine group were considered as responders compared with 36% in the medifoxamine group (p = 0.047). When only serious adverse effects were considered in combination with CGI scores to define response rates, the respective percentages were in favour of medifoxamine but the difference (45 vs 53%) was not significant. Results with medifoxamine were better in the elderly whereas, with fluoxetine, best responses were observed in younger patients. In conclusion, medifoxamine was an active and well tolerated drug in the continuation and maintenance treatment of depression. Its benefit/risk ratio appeared to be superior to fluoxetine, but this difference was mainly based on the occurrence of less minor adverse effects, a potential advantage not sufficient to favour better compliance with long-term therapy. Nevertheless, efficacy and tolerance of medifoxamine merits further evaluation in specific elderly populations.