L’objectif de cet essai exploratoire multicentrique, randomisé, en double insu, était d’évaluer l’efficacité et la tolérance du milnacipran (MLN) et de la venlafaxine (VLF) administrés à posologie flexible (100, 150 ou 200mg/j en deux prises journalières) pendant 24 semaines (dont quatre semaines de titration croissante) dans le traitement ambulatoire de l’adulte présentant un épisode dépressif majeur modéré à sévère sans risque suicidaire élevé (MINI–DSM IV-TR). Parmi les 195 patients inclus, 134 (68,7 %) ont complété l’essai. Les caractéristiques basales des deux groupes étaient similaires hormis une proportion sensiblement supérieure de patients sous MLN présentant un épisode sévère-DSM IV (63,3 % versus 54,0 % de patients sous VLF). Le score MADRS initial (moyenne : 31,0) a progressivement diminué et de façon superposable dans les deux groupes analysés (n=177 : 90/MLN, 87/VLF) jusqu’à semaine 24 (S24-OC ; moyenne : –23,1/MLN ; –22,4/VLF). Les taux de réponse MADRS (réduction≥50 %) à S8 et S24-last-observation-carried-forward (LOCF) étaient similaires dans les deux groupes (S8 : 64,4 %/MLN, 65,5 %/VLF ; S24 : 70 %/MLN, 77 %/VLF), ainsi que les taux de rémission MADRS (score≤10) (S8 : 42,2 %/MLN, 42,5 %/VLF ; S24 : 52,2 %/MLN, 62,1 %/VLF). Dans les deux groupes, les événements indésirables les plus fréquents étaient nausées, sensation vertigineuse, céphalées, hyperhidrose et troubles urogénitaux masculins. MLN et VLF administrés à posologie flexible (jusqu’à 200 mg/j) ont montré des profils d’efficacité et de tolérance globalement similaires dans le traitement ambulatoire au long terme de l’épisode dépressif majeur de l’adulte.
Serotonin (HT) and noradrenaline (NA) reuptake inhibitors (SNRIs) are commonly used as first line treatment of major depressive disorders (MDD). As compared to tricyclic antidepressants, they have proved similar efficacy and better tolerability. Milnacipran (MLN) (Ixel®) and venlafaxine (VLF) (Effexor®) are two SNRIs pharmacologically differing by their NA/HT ratio of potency: 1:1 and 1:30, respectively.
To investigate the efficacy and safety/tolerability of MLN and VLF administered at flexible doses (100, 150 or 200 mg/day) for 24 weeks (including 4 weeks of up-titration) in the outpatient treatment of adults with moderate-to-severe MDD.
Multicentre, randomised, double blind, 2-parallel-arm, 24-week exploratory trial conducted in France by 50 psychiatrists.
Diagnosis and main inclusion criteria
Male or female outpatients, aged 18 to 70, meeting the DSM-IV-TR and related MINI criteria for recurrent, unipolar, moderate-to-severe MDD, with neither psychotic features nor severe suicidal risk. A Montgomery-Asberg depression rating scale (MADRS) score≥23 was required at inclusion.
Patients were randomised to receive either MLN or VLF (1:1 ratio) for 24 weeks in double-blind conditions. Regardless of the treatment received, the following dosing schedule was applied: during the initial 4-week up-titration phase, the dosage was progressively increased from 25 mg/day (qd administration) to 150 mg/day (bid administration). At week 4, the dosage was either maintained at 150 mg/day, or adapted to 100 or 200 mg/day, based on the investigator’s clinical judgement. At any time during the 20 following treatment weeks, the dose could be lowered for safety concerns until a minimal threshold of 100 mg/day. From Week24, the dosage was decreased by 50mg/day every five days. After randomisation, eight assessment visits were organised at 2, 4, 6, 8, 12, 18, 24 weeks, and at study end (after the 5–15 days of down-titration and 10 days free of treatment). Efficacy evaluation ratings included the MADRS and global disease severity (CGI-S) total scores. Rates of MADRS response (reduction of initial score≥50%) and remission (score≤10) were calculated at Week 8 and Week 24 in the full analysis set as well as in the subgroups of patients with depressive disorder of severe DSM-IV intensity and with a MINI evaluation of suicidal risk (rated as required ‘moderate’ at the worst).
Standard distribution statistics (including mean and standard deviation [S.D.]) of scores and their changes from baseline, were calculated using the observed-case (OC) approach at all assessment times for the MADRS score, and the last-observation-carried-forward (LOCF) at 8 and 24 weeks for both MADRS and CGI-S scores. MADRS response and remission rates at 8 and 24 weeks were calculated using the LOCF approach by normal approximation of the binomial distribution. Bilateral exploratory statistical tests at 5% significance level were performed for results at 8 and 24 weeks of: (i) MADRS score changes from baseline, based on the score progress at each visit (mixed model for repeated measurements [MMRM]), and (ii) global MADRS response and remission rates (Chi2).
Results and patients
A total of 195 patients were randomly assigned MLN (n=97) or VLF (n=98) and 134 (68.7%: 61.9%/MLN and 75.5%/VLF) completed the trial. At the end of the up-titration, patients received 100 mg/day (11.4%/MLN, 10%/VLF), 150 mg/day (30.4%/MLN, 43.8%/VLF), or 200 mg/day (58.2%/MLN, 46.3%/VLF). Totals of 177 patients (90/MLN and 87/VLF) and 181 patients (90/MLN and 91/VLF) were analysed for efficacy and safety, respectively. Treatment groups were similar for baseline characteristics except a higher proportion of MLN patients with a severe depressive episode (63.3% versus 54%).
Results and efficacy
MADRS score (mean [S.D.] initial score: 31 [4.5]) progressively decreased all along the treatment course and similarly in both groups (Week 8-OC : –18.8 [7.7]/MLN and –18.6 [7.3]/VLF, pMMRM=0.95 ; Week 24-OC : −23.1 [7.8]/MLN and –22.4 [7.3]/VLF, pMMRM=0.37 ).
At week 8-LOCF, MADRS response rates were similar in both groups (64.4%/MLN, 65.5%/VLF, pchi2=0.88) as well as remission rates (42.2%/MLN, 42.5%/VLF pchi2=0.97). At week 24 they remained non clinically and statistically different between groups (response rates: 70%/MLN, 77%/VLF, pchi2=0.29; remission rates: 52.2%/MLN, 62.1%/VLF, pchi2=0.19). In both “severe depressive episode” and “MINI mild or moderate suicidal risk” subgroups (n=104 and 75, respectively), response and remission rates were non clinically different at both time points, however in the “MINI mild-to-moderate suicidal risk” subgroup, MLN tended to be more rapidly active (remission rate at week 8-LOCF: 44.7%/MLN, 35.1%/VLF). The changes in CGI-S were also indicative of a significant improvement of the global illness severity with both treatments.
Results and safety/tolerability
The tolerability profile of both drugs was in line with their pharmacological activity. About 70% of patients in both groups experienced at least one adverse event (AE). In both groups, the most common AEs were nausea, dizziness, headache and hyperhidrosis, and, in the male patients, genito-urinary problems: orgasmic disorders (VLF only) and dysuria (MLN only). These AEs were mostly responsible for definitive treatment discontinuation for tolerability concerns. None of the 6 serious adverse events (SAEs) on MLN and 4 of the 8 SAEs on VLF were related to the test drug.
MLN and VLF at flexible doses up to 200 mg/day globally exhibited similar efficacy and tolerability profiles in the long-term treatment of adults with MDD.
Mots clés : Épisode dépressif majeur, Adulte, Inhibiteurs de la recapture de la sérotonine et de la noradrénaline, Milnacipran, Venlafaxine
Keywords : Major depressive disorder, Adult, Serotonin and norepinephrine reuptake inhibitors, Milnacipran, Venlafaxine
Vol 35 - N° 6P. 595-604 - décembre 2009 Retour au numéro
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