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Keywords:

  • antidepressant response;
  • fluvoxamine;
  • major depressive disorder;
  • menopausal status;
  • milnacipran

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGMENTS
  9. REFERENCES

Abstract  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 (≥44 years of age) and men. Depressive symptoms were evaluated using the Montgomery and Åsberg 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.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGMENTS
  9. REFERENCES

Selective serotonin re-uptake inhibitors (SSRI) are the most widely used drugs for treating depression because they are as effective as tricyclic antidepressants (TCA) and have an advantage over them with respect to tolerability.1 Despite differences of chemical structure and activity, SSRI including fluvoxamine share several common features and there is no evidence for superior effectiveness of one agent over another within the class. Recently, new specific antidepressants, serotonin/norepinephrine re-uptake inhibitors (SNRI) have been introduced for the treatment of depression. Milnacipran is the sole SNRI available in Japan. This agent is as effective as TCA and has a more benign side-effect profile in comparison to TCA because of little or no affinity for post-synaptic receptors, which is thought to be responsible for its favorable tolerance profile.2,3

At this time it is still difficult to predict the clinical effects of antidepressants and we have few indexes with which to predict antidepressant effects for each individual. So, we do not have a perfect antidepressant therapy that is safe and effective for all patients because of individual specificity. Therefore, we previously performed association studies between antidepressant effects and serotonin transporter gene polymorphisms with fluvoxamine4,5 and also reported the relationship between antidepressant response and plasma concentrations of milnacipran in Japanese major depressive patients to investigate responsiveness,6 because amultitude of variables such as genetic polymorphisms and plasma concentrations contribute to an individualized antidepressant response in patients with depression in the clinical practice.

Depression occurs more often in women than in men, and differences are also observed between men and women in terms of the clinical features of depression and the response to treatments.7 Accordingly, gender differences are predominant factors associated with individual specificity. Gender differences in the treatment response to antidepressants have been extensively investigated. Kornstein et al. suggested that women had an advantage in terms of the response rate to sertraline, while men had a higher response rate to imipramine.8 In another study, depressive female patients treated with fluoxetine had a significantly superior improvement on Hamilton Depression Rating Scale and Clinical Global Impressions–Severity of Illness scale scores than patients treated with maprotiline, while no efficacy differences between the treatment groups were observed in depressive male patients.9 However, Hildebrandt et al. found similar clinical effects of antidepressant (clomipramine vs citalopram, paroxetine, and moclobemide) treatment for male and female patients with major and predominantly melancholic depression.10

As regards SNRI and SSRI, Thase et al. re-analyzed 2045 patients with major depressive disorder to compare remission rates following therapy with venlafaxine (n = 851), SSRI (n = 748), or placebo (n =446), and reported that the remission rate on venlafaxine therapy was not affected by age and sex.11 The authors also reported that the responsiveness of older women to SSRI is poorer than that of younger women and these differences of antidepressant response were not observed in male patients. In contrast, Morishita and Arita performed a retrospective cohort analysis with 169 depressed patients treated with milnacipran (n = 63), fluvoxamine (n = 43) or paroxetine (n = 63).12 The authors reported a tendency toward a higher frequency of the improvement among male depressive patients than female patients receiving milnacipran treatment, and there was no significant difference in the treatment effects between male and female patients with the treatment of fluvoxamine or paroxetine.

Thus, it is still not clear whether the clinical effects of antidepressants depend on gender. In particular, information was limited as to influence of gender and age on antidepressant effect with regard to milnacipran in this field. In order to resolve this issue, we investigated the differences between genders in the treatment response to fluvoxamine and milnacipran in Japanese major depressive patients.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGMENTS
  9. REFERENCES

Subjects and treatment

We performed secondary data analysis of our two previous trials.5,6 In each of the studies, depressed patients were selected using equal inclusion and exclusion criteria, and study designs were also equal except for the dose-setting schedule of each antidepressant. Each previous trial was carried out in different period of time. A total of 125 Japanese patients (fluvoxamine, n = 66; milnacipran, n = 59) who fulfilled DSM-IV criteria for a diagnosis of major depressive disorder and whose scores on the Montgomery and Åsberg Depression Rating Scale (MADRS)13 were ≥21 were included in the present study. Patients with other axis I disorders (including dementia, substance abuse, dysthymia, panic disorder, obsessive-compulsive disorder, and generalized anxiety disorder) and those with axis II disorders determined by clinical interview were excluded. Patients with a past history of childhood disorders were also excluded, as were patients with severe non-psychiatric medical disorders. The patients were 20–69 years of age and had been free of psychotropic drugs for at least 14 days before entry into the study. After complete description of the study to the subjects, informed consent was obtained.

Fluvoxamine was administered twice daily (after dinner and at bedtime in the same dose) for 6 weeks. The initial daily dose was 50 mg. The daily dose was increased to 100 mg after 1 week, up to 200 mg after another week. During this trial, all patients took the same dose of fluvoxamine. Milnacipran was administered twice daily (after dinner and at bedtime in the same dose) for 6 weeks. The initial daily dose was 50 mg. After 1 week, the daily dose was increased to 100 mg. During this trial, all patients took the same dose of milnacipran. Patients with insomnia were prescribed brotizoram, 0.25 mg or 0.5 mg, a benzodiazepine sedative hypnotic, at bedtime. No other psychotropic drugs were permitted during the study.

Among the 66 patients in the fluvoxamine group, five patients stopped visiting hospital without explanation. Four patients could not finish the study because of side-effects. Fifty-seven patients ended the 6-week study. Three patients were excluded from the current analysis because plasma samples showed very low fluvoxamine concentrations, indicating poor compliance. Therefore, the remaining 54 patients constituted the subjects; they included 32 women and 22 men (mean age ± SD, 51.2 ± 13.2 years); 43 outpatients and 11 inpatients. Among 59 patients in the milnacipran group, four patients stopped visiting hospital without explanation: two patients because of side-effects and one patient because of severe insomnia; they did not complete the study. Fifty-two patients finished the 6-week study. Three patients were excluded from the current analysis because plasma samples showed very low milnacipran concentrations, indicating poor compliance. Therefore, the remaining 49 patients constituted the subjects in the milnacipran group; they included 34 women and 15 men (mean age ± SD, 51.7 ± 12.3 years), 27 outpatients and 22 inpatients.

The characteristics of the patients of both study groups are given in Table 1. Patients treated with fluvoxamine or milnacipran were divided into three groups: women <44 years of age, women ≥44 years of age, and men. For the female patients we set a cut-off point at 44 years of age because women <44 years of age have a high potential of intact gonadotropin-releasing hormone (GnRH) pulse-pattern and functioning ovulation cycle.9

Table 1.  Patient clinical characteristics (mean ± SD)
 Fluvoxamine (n = 54)Milnacipran (n = 49)AnalysisP 
  •  

    χ2 test.

  •  

    Unpaired t-test.

  • MADRS, Montgomery and Åsberg Depression Rating Scale.

Sex (male/female), n22/3215/34χ2 = 1.1450.285n.s
Age (years)51.2 ± 13.251.7 ± 12.3t = −0.1810.857n.s
No. previous episodes0.18 ± 1.210.49 ± 1.29t = −0.1560.77n.s
Melancholia (yes/no)12/4214/35χ2 = 0.5490.459n.s
Baseline MADRS score28.4 ± 4.0728.5 ± 5.53t = −0.2480.806n.s

The normal pattern of pulsatile secretion of GnRH starts to change during the early 40s, as a consequence of the irregularity of the hypothalamic pacemaker function, therefore both phases of the ovarian cycle are affected in perimenopause.14,15 Several endocrine changes precede the clinical menopause, such as the pattern of pulsatile GnRH secretion,14 therefore we used 44 years as the cut-off for the split of fertile period from peri/postmenopause.

Data collection

Depression symptom severity was assessed with the MADRS. Assessments were conducted at baseline and at 1, 2, 4 and 6 weeks after initiation of antidepressant treatment. A single rater conducted each of the ratings for each patient. A clinical response was defined as a ≥50% decrease in the baseline MADRS.

Collection of blood samples was performed 4 weeks after starting fluvoxamine or milnacipran, 12 h after the bedtime dose. Plasma concentrations of fluvoxamine were quantified using high-performance liquid chromatography (HPLC) based on the method developed by Ohkubo et al.16 The concentrations of milnacipran were analyzed by HPLC using a fluorescent detector.6 Both quantifications were performed in duplicate and the mean was determined as the plasma concentrations.

Statistical analysis

The time course of MADRS score change (the mean score at each evaluation point minus the mean score at baseline) among women <44 years of age, women ≥44 years of age and men were analyzed by a repeated- measures analysis of variance (anova). The distribution of responders and non-responders to fluvoxamine or milnacipran in three groups were analyzed with χ2 test or Fisher's exact probability test where appropriate. Plasma concentrations of fluvoxamine and milnacipran in responders and non-responders were analyzed using an unpaired t-test. Plasma concentrations of fluvoxamine and milnacipran in three groups were analyzed with the use of a one-way factorial anova. P ≤ 0.05 was regarded as significant.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGMENTS
  9. REFERENCES

Fluvoxamine study

In this group 35 patients were responders and 19 were non-responders. The plasma concentrations of fluvoxamine were 178.8 ± 164.6 ng/mL and 110.7 ±73.3 ng/mL in responders and non-responders, respectively. There was no significant difference in the plasma concentrations of fluvoxamine between responders and non-responders (t = 1.7, d.f. = 52, P = 0.094). Between women <44 years of age and women ≥44 years of age, there was no significant difference in the plasma concentrations of fluvoxamine (with unpaired t-test, t = 0.691, d.f. = 30, P = 0.495). There was no significant difference in the severity of MADRS before trial (MADRS base line score; t = 0.392, P = 0.697), in the number of previous depressive episodes (t = 0.119, P = 0.906), in the proportion of inpatients and outpatients (χ2 = 0.035, P = 0.851), and in the proportion of melancholia and non-melancholia (χ2 = 1.485, P = 0.223) between responders and non-responders (Table 2). Table 3 shows the distribution of responders and non-responders in each group. Although most of the women in the <44 age group were responders (6/7), there was no significant difference in the distribution of responders and non-responders to fluvoxamine between women <44 years of age and women ≥44 years of age (χ2 = 2.1, d.f. = 1, P = 0.21), between women <44 years of age and men (χ2 = 0.82, d.f. = 1, P = 0.63), and between women ≥44 years of age and men (χ2 = 0.74, d.f. = 1, P = 0.55).

Table 2.  Comparison of responder and non-responder (mean ± SD)
 ResponderNon-responderAnalysisP 
  •  

    χ2 test.

  •  

    Unpaired t-test.

  • MADRS, Montgomery and Åsberg Depression Rating Scale.

Fluvoxamine
 Baseline MADRS score28.3 ± 4.1428.5 ± 4.05t = 0.3920.697n.s
 No. previous episodes0.49 ± 1.380.47 ± 0.84t = 0.1190.906n.s
 Inpatients/Outpatients, n12/23 7/12χ2 = 0.0350.851n.s
 Melancholia (yes/no), n 6/29 6/13χ2 = 1.4850.223n.s
Milnacipran
 Baseline MADRS score28.5 ± 4.8828.5 ± 7.0 t = 0.0190.985n.s
 No. previous episodes0.59 ± 1.500.27 ± 0.59t = −0.7990.428n.s
 Inpatients/Outpatients, n17/17 4/11χ2 = 2.3140.122n.s
 Melancholia (yes/no), n 9/25 5/10χ2 = 0.240.624n.s
Table 3.  Response status with regard to gender and age
 n (%)Women < 44 n (%)Women ≥ 44 n (%)Men n (%)
Fluvoxamine (n = 54)
 Responder35 (65)6 (86)14 (56)15 (68)
 Non-responder19 (35)1 (14)11 (44)7 (32)
Milnacipran (n = 49)
 Responder34 (61)5 (62.5)17 (63)12 (80)
 Non-responder15 (39)3 (37.5)10 (37)3 (20)

There was a significant difference in the time course of MADRS score change between women <44 years of age and women ≥44 years of age (= 5.0, d.f. = 4, P = 0.0009), and between women <44 years of age and men (= 5.18, d.f. = 4, P = 0.0007) on repeated-measures anova. However, there was no significant difference between women ≥ 44 years of age and men (= 0.81, d.f. = 4, P = 0.51) (Fig. 1). The mean plasma concentrations of fluvoxamine were 206.5 ± 121.7 ng/mL, 157.9 ± 173.7 ng/mL and 135.0 ± 105.8 ng/mL in women <44 years of age, women ≥44 years of age and men, respectively, and there was no significant difference among them (= 0.67, d.f. = 2, P = 0.52).

image

Figure 1. Time course of Montgomery and Åsberg Depression Rating Scale (MADRS) score change in women <44 years of age, women ≥44 years of age and men treated with fluvoxamine. (a) Each point represents the mean score ± SD. (b) Analysis performed with the use of a repeated-measures anova. (c) Asterisks indicate the significant differences in the time course of MADRS score change between women <44 years of age and women ≥44 years of age, and between women <44 years of age and men.

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Milnacipran study

In this group 34 patients responded to milnacipran and 15 patients did not respond. The plasma concentrations of milnacipran were 82.0 ± 29.4 ng/mL and 78.6 ±23.1 ng/mL in responders and non-responders, respectively. There was no significant difference in the plasma concentrations of milnacipran between responders and non-responders (t = 0.20, d.f. = 49, P = 0.70). Between women <44 years of age and women ≥44 years of age, there was no significant difference in the plasma concentrations of milnacipran (with unpaired t-test, t = −1.84, d.f. = 32, P = 0.075). There was no significant difference in the severity of MADRS before trial (MADRS base line score; t = 0.019, P = 0.985), in the number of previous depressive episodes (t = −0.799, P = 0.428), in the proportion of inpatients and outpatients (χ2 = 2.314, P = 0.122), and in the proportion of melancholia and non-melancholia (χ2 = 0.240, P =0.624) between responders and non-responders (Table 2). There was no significant difference in the distribution of responders and non-responders to milnacipran between women <44 years of age and women ≥44 years of age (χ2 = 0.001, d.f. = 1, P > 0.99), between women <44 years of age and men (χ2 = 0.83, d.f. = 1, P = 0.36), and between women ≥ 44 years of age and men (χ2 = 1.31, d.f. = 1, P = 0.25; Table 3). There was no significant difference in the time course of MADRS score change between women <44 years of age and women ≥44 years of age (= 0.30, d.f. = 4, P = 0.88), between women <44 years of age and men (= 0.61, d.f. = 4, P = 0.66), and between women ≥44 years of age and men (= 0.36, d.f. = 4, P = 0.84) (Fig. 2). The mean plasma concentrations of milnacipran were 68.5 ± 28.2 ng/mL, 90.1 ± 29.1 ng/mL and 71.6 ±18.1 ng/mL in women <44 years of age, women ≥44 years of age and men, respectively. The one-way factorial anova showed that there was no significant difference in the plasma concentrations of milnacipran among these three groups (= 1.42, d.f. = 2, P = 0.28).

image

Figure 2. Time course of Montgomery and Åsberg Depression Rating Scale (MADRS) score change in women <44 years of age, women ≥44 years of age and men treated with milnacipran. (a) Each point represents the mean score ± SD. (b) Analysis performed with the use of a repeated-measures anova.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGMENTS
  9. REFERENCES

The results of the present study show that fluvoxamine treatment produced a significant difference in the time course of MADRS score change in younger female depressive patients (women <44 years of age) compared with older female (≥44 years of age) and male patients. In contrast, these differences were independent of gender and age (menopausal status) in the milnacipran treatment. The present results are compatible with those reported by Thase et al.11 but are in contrast to the view held by Morishita and Arita.12 There are three possible reasons for the contradiction. First, Quitkin et al. suggested no gender difference in the response to TCA based on their meta-analysis.17 The antidepressant psychopharmacological profile of milnacipran is similar to that of imipramine. Inhibitory potency of milnacipran is nearly the same as that of imipramine for serotonin and norepinephrine re-uptake;3 therefore, the efficacy of milnacipran may be independent of gender, similar to the evidence of imipramine study. Second, the authors considered gender differences alone, in contrast to the present methods that included both gender and age (menopausal status). Finally, a study design using flexible dose setting and/or a retrospective analysis have a tendency to reduce reliability compared with controlled studies.

Kornstein et al. examined gender differences in the treatment response to sertraline and imipramine in 635 depressive patients.8 Their subgroup analysis showed that premenopausal women had a significantly superior response rate to sertraline than to imipramine. In contrast, postmenopausal women had similar response rates to both sertraline and imipramine. They hypothesized a mechanism of gender differences; female gonadal hormones, particularly estrogen, may play an important role in antidepressant activity, thereby enhancing the response to SSRI in younger women. Several studies have shown that estrogen enhances monoaminergic activity, augments serotonergic postsynaptic responsiveness18 and increases both the number of serotonergic receptors and the transport and uptake of the neurotransmitter.19,20 Preliminary studies have suggested that estrogen augments the response of SSRI in postmenopausal women.21 A significant reduction in the number of 5HT-2 sites, together with a decrease in the 5HT-2 binding affinity, have been found in the frontal cortex of a post-mortem human brain in relation to age.22 Our results suggest the possibility that estrogen gives a fluvoxamine treatment ‘the boost effect’ of its serotonergic potential.

The major limitations of the present study are lack of a placebo control; the fact that it is not a double blind study; and the small patient number, especially in women <44 years of age. SSRI and SNRI have a broad spectrum of clinical indications including obsessive-compulsive disorder, eating disorder, panic disorder, anxiety disorder, post-traumatic stress disorder, and pain syndromes in addition to depression.23 Therefore, exploring associations between gender/age-related differences and clinical response to SSRI and SNRI would be of interest.

CONCLUSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGMENTS
  9. REFERENCES

The present 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. Although clinicians can prescribe antidepressants irrespectively of gender and age (menopausal status), these two factors should be considered when deciding which antidepressant to use for the treatment of each depressive patient, especially in treating premenopausal women.

ACKNOWLEDGMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGMENTS
  9. REFERENCES

This study was supported in part by grants from the Japan Research Foundation for Clinical Pharmacology, the Ministry of Education, Culture, Sports, Science and Technology of Japan and Asahi Kasei Pharma.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGMENTS
  9. REFERENCES
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