LONG-TERM EFFICACY AND SAFETY OF MILNACIPRAN COMPARED TO CLOMIPRAMINEIN PATIENTS WITH MAJOR DEPRESSION

Milnacipran is a new antidepressive drug, a combined noradrenaline/ser otonin (NA/5-HT) reuptake inhibitor, which has been suggested to be as effective as and better tolerated than tricyclic antidepressants. Sin ce long-term studies are lacking, we compared the efficacy, safety and tolerability of milnacipran and clomipramine in a double-blind, rando mized, parallel-group study setting during 26 weeks of treatment in pa tients with major depression. A total of 107 patients were treated wit h either milnacipran (n=52) or clomipramine (n=55). Due to active trea tment of duration less than 12 days in four patients and protocol devi ation in one patient, in total 47 milnacipran-treated patients were el igible for efficacy analysis. Nine patients in the clomipramine group continued on active treatment for less than 12 days. Thus 46 clomipram ine-treated patients were finally included in the efficacy analysis. A fter 1 week of dose escalation, there was a fixed dosage regimen of ei ther milnacipran (200 mg daily) or clomipramine (150 mg daily) during weeks 2 to 10, followed by flexible dosing of milnacipran (100, 150 or 200 mg daily) or clomipramine (75, 100 or 150 mg daily) during weeks 11 to 26. A total of 53 patients (49%) completed the 26-week study per iod; 21% (11/52) of the patients in the milnacipran group and 38% (21/ 55) of the patients in the clomipramine group discontinued their medic ation prematurely due to adverse events, whereas 19% (10/52) of those on milnacipran and 7% (4/55) of those on clomipramine treatment withdr ew due to either lack of efficacy or clinical deterioration. The mean change (+/- SD) in the Hamilton Depression Rating Scale (HAMD) score b etween the baseline and the last rating ranged from 23.7 +/- 3.1 to 12 .0 +/- 9.5 in the milnacipran-treated patients and from 23.1 +/- 3.5 t o 8.0 +/- 8.5 in the clomipramine-treated patients, revealing a signif icant difference in favour of clomipramine. In total 58% of the milnac ipran-treated patients vs. 72% of the clomipramine-treated patients sh owed a greater than or equal to 50% reduction in their baseline HAMD s cores and 45% vs. 63% had an HAMD score of less than or equal to 7 at the last rating, respectively. Moreover, the time to the onset of the antidepressant action (defined as greater than or equal to 50% reducti on of the baseline HAMD score) showed a significant difference in favo ur of clomipramine. Ln addition, clomipramine was significantly more e fficacious in patients with a baseline HAMD score of greater than or e qual to 24 as evidenced by the analysis of the HAMD score at week 6 an d at the last rating. The Montgomery Asberg Depression Rating Scale (M ADRS) and the Clinical Global Impression (CGI) scale did not show sign ificant differences between the treatment groups. The safety analysis did not reveal any differences of clinical significance in cardiovascu lar variables between the study drugs. Dry mouth was significantly les s frequently reported by the milnacipran-treated patients during the e arly and later phases (weeks 6 to 26) of the study, while insomnia was more common in the milnacipran group during weeks 1 to 6. In conclusi on, milnacipran appeared to be less effective than clomipramine in the long-term treatment of depression. The side-effects of the drugs diff ered to a certain extent, and milnacipran tended to be somewhat better tolerated than clomipramine.