Milnacipran

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Abstract
Milnacipran is a cyclopropane derivative which acts by inhibiting noradrenaline (norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT) reuptake at presynaptic sites; no postsynaptic receptor activity has been demonstrated. It is most commonly administered at a dosage of 50mg twice daily for the treatment of major depressive disorder. Improvement usually occurs within 2 weeks of treatment initiation, but some patients do respond sooner. Most studies which evaluated milnacipran were of short (4 to 8 weeks) duration and results were not published in full with rigorous peer review. Nonetheless, the drug is significantly more effective than placebo for the treatment of in-or outpatients with moderate to severe major depressive disorder. Limited data suggest that it may prevent relapse and be effective for long term use, although this requires confirmation. Milnacipran 200 mg/day is generally not significantly different from amitriptyline 150 mg/day in terms of onset and efficacy. However, when doses are titrated (not a requirement for milnacipran), milnacipran 50 or 100 mg/day has a slower onset than the tricyclic antidepressant. At a dosage of 100 mg/day for 4 to 12 weeks, milnacipran generally has similar efficacy to imipramine and clomipramine 150 mg/day, although milnacipran 50 to 150 mg/day had a faster onset of activity than imipramine 50 to 150 mg/day in Japanese patients. In a 6-month trial, milnacipran was less effective than clomipramine. Milnacipran 50 or 100mg twice daily was as effective as fluoxetine 20mg once daily or fluvoxamine 100mg twice daily in 4-to 12-week studies. At a dosage of 50 then 100mg daily it was also as effective as mianserin 30 then 60mg daily in a 4-week study. However, when administered once daily (in the evening), milnacipran 100 mg/day was not as effective as fluoxetine 20 mg/day after 6 weeks. The drug is generally well tolerated, producing no more adverse events (including anticholinergic events) than placebo, selective serotonin reuptake inhibitors or mianserin and fewer adverse events than tricyclic antidepressants in clinical trials. However, dysuria has been reported in 7% of male patients receiving milnacipran. Conclusions: Data from predominantly short term trials suggest that milnacipran generally has similar efficacy to tricyclic antidepressants and SSRIs. Although further published data are required to confirm its efficacy, good tolerability profile and pharmacokinetic profile which suggests a low potential for drug interactions, milnacipran should be considered a promising agent for the treatment of patients with major depressive disorder. Milnacipran is a cyclopropane derivative which appears to act at presynaptic sites to inhibit noradrenaline (norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT) uptake. The inhibitory capacity of milnacipran is of approximately the same order as that of imipramine for noradrenaline and serotonin uptake in vitro and in vivo. Milnacipran does not appear to act at any postsynaptic receptor in vitro or in vivo. In rats, it has no effect on β-adrenergic receptor density, function or affinity, postsynaptic 5-HT2 receptor numbers or sensitivity, adenylcyclase activity, α1-or α2-adrenergic, 5-HT1 or benzodiazepine receptors or monoamine A or B activity. Behavioural tests based on interactions with the noradrenergic or serotonergic system showed milnacipran to be very active. The effective oral doses of milnacipran producing inhibition in 50% of mice involved in these tests were generally lower than those of tricyclic antidepressants. Milnacipran 3 to 60 mg/kg produces dose-dependent antidepressant activity in the forced swimming test, in the conditioned fear stress test, after exposure to the uncontrollable aversion situation and during forced walking stress in rats and/or mice and reduces hyperactivity of olfactory bulbectomised rats in the ‘open field’ test. These effects, however, are usually significant only at doses of ≥30 mg/kg. Reductions in immobility time during the forced swimming test were associated with increases in interstitial serotonin levels in rats. Compared with placebo, milnacipran 100 mg/day for 7 days had nonsignificant effects on cognitive function but appeared to improve deferred visual memory in healthy volunteers. The same dose of milnacipran for 3 days also had no significant effect when volunteers were given a small amount of alcohol (blood concentration of 0.5 g/L) before performing simulated driving testing. Tests examining short term memory, choice reaction time and quality of awakening in elderly volunteers showed milnacipran 75 mg/day for 3 days to have effects that were not significantly different from those of placebo. However, milnacipran had less effect on choice reaction time than amitriptyline 50 mg/day and improved critical flicker fusion test performance significantly when compared with both amitriptyline and placebo. Milnacipran had negligible anticholinergic activity in behavioural models and this was reflected in studies of the cardiovascular effects of the drug. Intravenous milnacipran 0.2 to 0.8 mg/kg induced some cardiovascular changes in 10 healthy volunteers, but most were not considered important and occurred at plasma concentrations higher than those seen after a 100mg dose of the drug. Heart rate and systolic blood pressure increased, and the functional refractory periods of the atrium and atrioventricular node and the effective refractory period of the right ventricle decreased. The cardiovascular effects of milnacipran were usually less severe or less numerous than those induced by tricyclic antidepressants (predominantly imipramine) in animals. In general, trends in electrocardiographic changes induced by milnacipran were small and difficult to qualify, although heart rate tended to increase. The pharmacokinetics of single oral doses of milnacipran have been investigated in 2 groups of 12 healthy volunteers. Milnacipran 50mg has a bioavailability of 85%. Maximum serum concentrations (Cmax) are dose-proportional for single doses of milnacipran 25 to 200mg, with the Cmax of a 50mg dose being 134 μg/L after 2 hours (tmax). After a 50mg dose, volume of distribution is 5.3 L/kg, area under the concentration-time curve (AUC) is 1833 μg/L · h, elimination half-life (t1/2) is 6.1 or 8.1 hours and total clearance is 37.6 L/h/1.73m2. Interindividual variation is low (except for tmax) and good correlation is demonstrated between single-dose and steady-state pharmacokinetics. Oral milnacipran 50 or 100mg twice daily for 28 days had linear pharmacokinetics in 17 patients with major depressive disorder. At 2 hours, Cmax values of D- and L-milnacipran were 223 to 419 nmol/L after a 50mg dose and 381 to 690 nmol/L after a 100mg dose. Values of t1/2 (5 to 9 hours) appeared to be independent of dose and time. Steady-state concentrations of milnacipran are rapidly achieved (after 2 to 3 days with twice daily dosing) in healthy volunteers. Serotonin uptake inhibition parallels blood drug concentrations. Milnacipran has low and nonsaturable binding to plasma proteins. This, and the fact that the drug is not metabolised by the hepatic cytochrome P450 (CYP) system, reduces the number of likely drug interactions involving milnacipran. First-pass metabolism is low and no active metabolites have been identified in humans. 50 to 60% of the drug is excreted unchanged. Milnacipran does not accumulate after multiple dosages. The pharmacokinetics of milnacipran are not significantly affected by hepatic impairment. However, in patients with renal impairment [glomerular filtration rate of 9 to 85 ml/min (0.54 to 5.1 L/h)], changes in total and renal clearance are correlated with decreases in glomerular function. In these patients and in the elderly, Cmax values are increased and elimination is prolonged compared with in healthy volunteers and younger adults, respectively. To date, many of the trials assessing the efficacy of milnacipran in the treatment of depression, in particular those comparing the drug with other antidepressants, have been published only as abstracts or in summary papers. In 3 double-blind multicentre placebo-controlled trials, milnacipran 50mg twice daily was significantly more effective than placebo for the treatment of in-or outpatients with major depressive disorder. Efficacy was measured using the Montgomery-Åsberg Depression Rating Scale (MADRS), Hamilton Depression Rating Scale (HDRS) and Clinical Global Impression (CGI) rating. The largest and longest placebo-controlled trial showed significantly more milnacipran than placebo recipients to respond to treatment (>50% decrease in HDRS total score from baseline) after 8 weeks (65 vs 44%. Dosages of 25 and 100mg twice daily were not as effective as the 50mg twice daily dosage. Although some improvement has been observed with milnacipran as early as after 1 week, it usually occurs within 2 weeks of treatment initiation. Efficacy was maintained in 23 patients who received milnacipran 50 to 200 mg/day for 4 to 65 weeks. Limited evidence from 165 patients who received treatment for a mean of 21 weeks (all were treated for >8 weeks) also suggests that milnacipran may prevent relapse. Milnacipran 50 or 100 mg/day had a slower onset of action than amitriptyline 150 mg/day in multicentre double-blind trials which enrolled patients with major depressive disorder, but the efficacy of milnacipran 100 mg/day and amitriptyline were similar after 4 weeks. Dosages of both drugs were titrated to the levels specified over 5 days, although this is not necessary for milnacipran. A higher dosage of milnacipran (200 mg/day) was not significantly different from amitriptyline at any time according to total MADRS, HDRS, CGI severity of illness or efficacy index scores. However, improvements in CGI global improvement scores were significantly larger in milnacipran recipients than in amitriptyline-treated patients at 7 and 28 days. There were no significant differences in changes in HDRS and/or MADRS scores for milnacipran 100 mg/day and imipramine or clomipramine 150 mg/day recipients according to the results of individual 4-to 12-week studies and pooled data from 7 trials (842 patients with major depressive disorder). One trial included elderly (65 to 90 years) patients only, and there were also no significant between-treatment differences in efficacy in this population. However, results of a longer (26-week) trial indicated that although some advantages for milnacipran 200 mg/day were seen in terms of good tolerability, the drug was significantly less effective than clomipramine 150 mg/day in adult in-or outpatients with depression. Patients with melancholia appear to be particularly responsive to milnacipran. A trial, as yet published only as part of a review, showed no significant differences at 12 weeks between milnacipran 50mg twice daily (n = 93) and fluoxetine 20mg once daily (n = 100) according to HDRS and MADRS scores and the proportion of responders, although milnacipran had a faster onset of action. Unpublished results indicate that an additional 96 patients received milnacipran 100mg twice daily in this study; the efficacy of this regimen was not significantly different from that of the other two. However, milnacipran 100 mg/day, when administered as a single evening dose to patients with major depressive disorder, was not as effective as fluoxetine 20 mg/day after 6 weeks. The dosage regimen of milnacipran used in this study of 190 patients was unusual and probably sub-optimal (milnacipran has a short half-life and no active metabolites). No significant differences were noted between recipients of milnacipran 150mg twice daily for 2 weeks followed by 75mg twice daily (n = 41), milnacipran 100mg twice daily (n = 42) or fluvoxamine 100mg twice daily (n = 37) in 4-week MADRS, HDRS or CGI scores or the number of patients who responded to therapy. After 4 weeks, the efficacy of milnacipran 50 then 100mg daily was not significantly different from that of mianserin 30 then 60mg daily in Japanese patients, but efficacy was noted sooner in milnacipran recipients. Milnacipran, most commonly at a dosage of 100 or 200 mg/day, was generally well tolerated and usually produced no more adverse events (including anticho-linergic events) than placebo in clinical trials. In comparative trials, anticholinergic effects (dry mouth, blurred vision) occurred significantly more frequently with amitriptyline, clomipramine or imipramine than with milnacipran. However, insomnia during the first 6 weeks of treatment, dyspnoea and treatment for constipation were significantly more common with milnacipran than clomipramine in 26-week trials. Milnacipran had a better overall tolerability profile than tricyclic antidepressants, but its tolerability profile was not significantly different from that of fluoxetine, fluvoxamine or mianserin in a small number of trials. Analysis of several comparative trials showed that milnacipran was associated with significantly fewer cardiovascular events and withdrawals because of poor tolerability than tricyclic antidepressants. Events most frequently causing withdrawal of milnacipran were gastrointestinal disturbances, dysuria and palpitations. Indeed, dysuria, which occurred at ahigher frequency with milnacipran than with tricyclic antidepressants, has been reported to occur in 7% of male patients receiving milnacipran. A database of clinical trials involving milnacipran (n = 1871) showed that vertigo, increased sweating, anxiety, hot flushes and dysuria occurred in significantly more milnacipran than placebo recipients (n = 394). However, dry mouth, constipation, tremor, sweating, somnolence, tiredness and vertigo all occurred at a significantly greater incidence with tricyclic antidepressants (n = 940) than with milnacipran. The incidence of nausea was significantly higher with the SSRIs fluoxetine and fluvoxamine (n = 344) than with milnacipran. However, dysuria was significantly more common with milnacipran than with tricyclic antidepres-sants or SSRIs. In general, the most commonly reported adverse events in Japanese patients were anticholinergic (dry mouth, constipation and, less frequently, urinary retention, nasal obstruction or dryness and visual disturbances), gastrointestinal, or dizziness or headache. Less frequently, orthostatic hypotension, drowsiness and rash occurred. Laboratory abnormalities were infrequently reported and were not serious. Unpublished data show that milnacipran had no electrocardiographic effects in 939 patients. The optimal dosage of milnacipran is 50mg twice daily for the treatment of patients with major depressive disorder in European countries. However, in Japan, the optimal dosage is 25mg twice daily; 15mg twice daily is recommended for elderly patients in this country. Dosage reduction is necessary in patients with impaired renal function, but not in those with hepatic impairment.

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