Efficacy of milnacipran in the treatment of chronic pain syndromes.

Abstract Eleven outpatients with chronic pain syndromes other than fibromyalgia were treated for 12 weeks with milnacipran, a novel serotonin noradrenaline reuptake inhibitor. The agent was administered at 50-150 mg/day, and the mean ± SD dose at 12 weeks or at the time drug treatment was stopped was 84.1 ± 32.2 mg/day. None of the patients met the DSM-IV criteria for a major depressive disorder. Abdominal, chest, back, arm, leg or glossal pain, or headache was involved. Pain was assessed clinically by means of a visual analog scale (VAS) before and 12 weeks after the start of milnacipran treatment, or at the time drug treatment was stopped. The mean ± SD decrease in VAS scores was 42.3 ± 31.6 (50.8 ± 49.2%). One patient discontinued treatment after 4 weeks because of nausea, whereas others tolerated the agent well. These results suggest that the use of milnacipran in patients with a variety of chronic pain syndromes is beneficial.

Differential clinical effects of fluvoxamine by the effect of age in Japanese female major depressive patients.

The effects of gender differences and age on the treatment response to fluvoxamine were investigated in major depressive Japanese patients. A total of 100 Japanese patients participated in this study. The daily dose of fluvoxamine was fixed to 100, 150 or 200 mg in the fourth week. This fixed dose was maintained until the end of the 6-week study. The patients were divided into 3 groups: younger females, older females, and males. Depressive symptoms were evaluated using the Montgomery and Asberg Depression Rating Scale (MADRS) at pretreatment and at 1, 2, 4, and 6 weeks after the commencement of the study. Seven of the 100 patients were excluded, and the remaining 93 patients constituted the subjects (50 females, 43 males). The number of intent-to-treat responders and non-responders was 55 and 38, respectively. There was a significant difference in the changes in the time course of the MADRS score and changes in the MADRS scores at each evaluation point between the younger and older females. Younger females demonstrated a significantly better response than older females. The results suggest that fluvoxamine is more effective in younger female patients than in older female patients.

Gender differences in the clinical effects of fluvoxamine and milnacipran in Japanese major depressive patients.

Gender differences in the treatment response to fluvoxamine (selective serotonin re-uptake inhibitor) and milnacipran (serotonin/norepinephrine re-uptake inhibitor) were investigated in Japanese major depressive patients. A total of 125 Japanese patients was included in the present study. Sixty-six patients received fluvoxamine treatment. The daily dose was 50 mg/day for the first week and increased to 100 mg after 1 week, up to 200 mg after another week. Fifty-nine patients were given milnacipran. The daily dose was 50 mg/day for the first week, and up to 100 mg/day thereafter. Patients were divided into three groups: younger women (<44 years of age), older women (> or =44 years of age) and men. Depressive symptoms were evaluated using the Montgomery and Asberg Depression Rating Scale (MADRS) before treatment and at 1, 2, 4 and 6 weeks after the beginning of the study. In comparison with other groups, younger women treated with fluvoxamine demonstrated a significant difference in the time course of MADRS score change. However, these gender/age-related differences of antidepressant response were not observed in the patients treated with milnacipran. The results suggest that fluvoxamine is more effective in younger female patients than older female patients and male patients, while milnacipran is generally effective irrespective of gender or age.

Response rate obtained using milnacipran depending on the severity of depression in the treatment of major depressive patients.

Milnacipran--a new specific serotonin and noradrenaline reuptake inhibitor--is as effective as tricyclic antidepressants and exhibits a higher remission rate for major depressive patients than selective serotonin reuptake inhibitors. However, the effectiveness of milnacipran for severe major depressive patients had not been studied adequately. The study included 96 Japanese patients who fulfilled the DSM-IV criteria for the diagnosis of major depressive disorders and whose score on the Montgomery-Asberg Depression Rating Scale (MADRS) was 21 or higher. Of these, 16 patients were excluded because 10 did not complete the study, and 6 showed poor compliance. Finally, 80 patients were included. We defined patients with a baseline MADRS score of > or = 31 points as "severe" (n = 25). The remaining patients were classified as "moderate" (31 > MADRS score > or = 25, n = 30) and "mild" (MADRS score < 25, n = 25) using the median score of those patients as the cutoff. Milnacipran was administered twice daily for 6 weeks. The initial total dose was 50 mg/d; after a week it was increased to 100 mg/d. The response rates were 72%, 70%, and 44% in the "severe," "moderate," and "mild," respectively. No significant differences were found between "severe" and the "moderate"; however, significant differences were observed between "severe" and "mild" and "moderate" and "mild." These results demonstrated that milnacipran is almost equally effective in "severe" and "moderate." This study suggested that milnacipran has a reliable antidepressant effect in treating severe and moderate major depressive patients.

Effectiveness of milnacipran for the treatment of chronic pain: a case series.

Milnacipran is a novel serotonin noradrenaline reuptake inhibitor. The authors describe the use of milnacipran for the treatment of chronic pain in a series of patients. There were 5 outpatients who suffered chronic pain for at least 3 months. None of these patients met the DSM-IV criteria for a major depressive disorder. Chronic pain was assessed clinically by means of a visual analog scale (VAS) before and 12 weeks after the start of the milnacipran treatment or at the time the drug was stopped. The duration of pain was 17.8 +/- 9.3 months (mean +/- SD), and the baseline VAS score was 88.2 +/- 6.3 points. Milnacipran was administered at 50 to 150 mg/day, and the dose at 12 weeks or at the time the drug was stopped was 85.0 +/- 31.3 mg/day. The mean +/- SD decrease in VAS at this time was 61.2 +/- 15.5%. Three patients showed marked improvement (decrease in VAS, >75%). Their decreases in VAS scores were 86.5%, 85.7%, and 77.6%. One patient showed mild improvement (42.0% decrease in VAS). These 4 patients tolerated the drug well. The fifth patient experienced nausea and discontinued treatment after 4 weeks. The VAS decrease for this patient was 14.3%. Results of this study show milnacipran to be beneficial in patients with chronic pain. This drug should be studied further for its effectiveness in the treatment of chronic pain.

Prediction of antidepressant response to milnacipran by norepinephrine transporter gene polymorphisms.

OBJECTIVE: With a multitude of antidepressants available, predictors of response to different classes of antidepressants are of considerable interest. The purpose of the present study was to determine whether norepinephrine transporter gene (NET) and serotonin transporter gene (5-HTT) polymorphisms are associated with the antidepressant response to milnacipran, a dual serotonin/norepinephrine reuptake inhibitor. METHOD: Ninety-six Japanese patients with major depressive disorder were treated with milnacipran, 50-100 mg/day, for 6 weeks. Severity of depression was assessed with the Montgomery-Asberg Depression Rating Scale. Assessments were carried out at baseline and at 1, 2, 4, and 6 weeks of treatment. The method of polymerase chain reaction was used to determine allelic variants. RESULTS: Eighty patients completed the study. The presence of the T allele of the NET T-182C polymorphism was associated with a superior antidepressant response, whereas the A/A genotype of the NET G1287A polymorphism was associated with a slower onset of therapeutic response. In contrast, no influence of 5-HTT polymorphisms on the antidepressant response to milnacipran was detected. CONCLUSIONS: The results suggest that NET but not 5-HTT polymorphisms in part determine the antidepressant response to milnacipran.

Monoamine oxidase A gene polymorphism, 5-HT 2A receptor gene polymorphism and incidence of nausea induced by fluvoxamine.

Selective serotonin reuptake inhibitors cause a side effect of nausea with high frequency, but there have been no accurate methods to predict its incidence. The authors first investigated whether a functional polymorphism in the monoamine oxidase A (MAOA-VNTR) and a -1438G/A polymorphism in the promoter region of the 5-HT(2A) gene were associated with the incidence of nausea induced by fluvoxamine. Fluvoxamine was administered for 6 weeks with a specific dosage plan (50-200 mg/day) in 66 Japanese major depressive patients. The frequency of MAOA-VNTR allele 1 was significantly higher in the patients without nausea than in ones with nausea in the statistical analysis including the patients whose plasma levels were below the average and who were considered to be pharmacodynamically more sensitive to nausea. This study showed that the genetic polymorphism of MAOA-VNTR might affect the incidence of nausea induced by SSRIs. If this finding is replicated in other studies with more subjects, MAOA-VNTR polymorphism would be of great clinical use to predict the incidence of nausea induced by SSRIs.

Milnacipran plasma levels and antidepressant response in Japanese major depressive patients.

The relationship between antidepressant effects and plasma levels of milnacipran was studied in 49 cases of major depression without psychotic features during 6 weeks of milnacipran treatment. The daily dose of milnacipran was 50 mg/day for the first week, and up to 100 mg/day thereafter. Depressive symptoms were evaluated by the Montgomery and Asberg depression rating scale (MADRS) before treatment and at 1, 2, 4 and 6 weeks after the beginning of this study. Thirty-four patients (69.4%) were responders (defined as a 50% or greater decrease in the baseline MADRS score). Significant differences of MADRS scores were seen from 1 week after the beginning of this study (p=0.004, unpaired t-test) between responders and nonresponders. The mean plasma milnacipran level of responders, 82.0 +/- 29.4 ng/ml, was similar to that of non-responders, 78.6+/-23.1 ng/ml; there was no significant difference between responders and nonresponders. Neither a significant linear nor a curvilinear relationship was obtained between the final MADRS score and the plasma levels of milnacipran. Although there was no significant relationship between the plasma levels of milnacipran and the antidepressant response, milnacipran should be considered an efficacious agent in the treatment of major depressive patients.

Monoamine oxidase: A gene polymorphism, tryptophan hydroxylase gene polymorphism and antidepressant response to fluvoxamine in Japanese patients with major depressive disorder.

Monoamine oxidase A (MAOA) and tryptophan hydroxylase (TPH) are the staple enzymes in the metabolism of serotonin (5-HT). The genetic polymorphisms of these two enzymes might individually alter the production, release, reuptake or degradation of 5-HT during the treatment of selective serotonin reuptake inhibitors (SSRIs), leading to the individual differences in the antidepressant effects of SSRIs. The authors investigated whether a functional polymorphism in the MAOA gene promoter (MAOA-VNTR) and a TPH gene polymorphism in intron 7 (TPH-A218C) were associated with the antidepressant response to fluvoxamine in 66 Japanese patients with major depressive disorder during a 6-week study with a specific dosage plan. Fifty-four patients completed the study. The present study fails to demonstrate that the genetic polymorphisms of MAOA-VNTR and TPH-A218C affect the antidepressant effect of fluvoxamine in Japanese patients with major depressive disorder.