Predictors of antidepressant response to fluvoxamine obtained using the three-factor structures of the Montgomery and Åsberg Depression Rating Scale for major depressive disorders in Japanese patients

Authors


*Hisashi Higuchi, MD, PhD, Department of Neuropsychiatry, St Marianna University School of Medicine, 2-16-1 Sugou, Miyamae-ku, Kawasaki City 216-8511, Japan. Email: h5higuchi@marianna-u.ac.jp

Abstract

Aims:  Fluvoxamine, a selective serotonin reuptake inhibitor, is widely used to treat major depression. However, the symptomatological predictors of the response to fluvoxamine have not been studied.

Methods:  This study included 100 Japanese patients who fulfilled the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria for the diagnosis of major depressive disorders and whose score on the Montgomery and Åsberg Depression Rating Scale (MADRS) was 21 or higher. Eighty-one patients were included. Patients with a pretreatment MADRS score of ≥31 were defined as ‘severe’ (n = 32) and the rest were defined as ‘non-severe’ (n = 49). The three-factor model of MADRS was used for analysis: the first factor was defined by three items, the second factor was defined by four items, and the third factor was defined by three items representing dysphoria, retardation, and vegetative symptoms, respectively. Fluvoxamine (100–200 mg/day) was administered twice daily for 6 weeks.

Results:  In the non-severe patients, the mean factor 3 score of the non-responders at pretreatment was significantly higher than that of the responders. However, a significant difference was observed in the mean factor 3 scores from 1 week onwards between the non-severe responders and non-responders. Furthermore, the fluvoxamine response rate in the severe patients was 75% and higher than that of the non-severe patients (65.3%).

Conclusions:  This study suggested that a low factor 3 score at pretreatment was a good predictor of the response to fluvoxamine in non-severe patients. The marked efficacy of fluvoxamine in the treatment of severe patients was also confirmed.

FLUVOXAMINE, A SELECTIVE serotonin reuptake inhibitor (SSRI), is widely used to treat various psychiatric disorders including major depressive disorder (MDD), obsessive-compulsive disorder and panic disorder.1 In a comparative study of fluvoxamine versus imipramine for major depressive patients, no difference between these two antidepressants was indicated in 12 trials, while fluvoxamine was found to be superior in two trials.2 Morishita and Arita reported that age, the frequency of episodes, and the daily dose of fluvoxamine might be considered as predictors of the response to fluvoxamine treatment for depression.3 In contrast, it has been reported that the responders to fluvoxamine or paroxetine had significantly higher plasma-free 3-methoxy-4-hydroxyphenylglycol (pMHPG) levels before administration of fluvoxamine or paroxetine than did the non-responders.4,5 Therefore, patients with hyper noradrenergic activity might respond to SSRIs because pMHPG may provide valuable information regarding central noradrenergic activity.6 However, the symptomatological characteristics of patients responding to fluvoxamine treatment have not been studied.

The Montgomery and Åsberg Depression Rating Scale (MADRS) is a 10-item clinical rating scale that measures the severity of several depressive symptoms.7 Several studies addressed factor analysis of MADRS based on the scores of patients with various psychiatric disorders; however, the number of factor structures varied across studies and ranged from two to four.8–10 Recently, Suzuki et al.11 analyzed the pretreatment MADRS scores in 132 Japanese patients with unipolar MDD and followed the three-factor model of the MADRS: the first factor was defined by three items representing dysphoria, including reported sadness, pessimistic thoughts, and suicidal thoughts; the second factor was defined by four items representing retardation, including lassitude, inability to feel, apparent sadness, and concentration difficulties; and the third factor was defined by three items representing vegetative symptoms, including reduced sleep, reduced appetite, and inner tension.

Prediction of the antidepressant response to fluvoxamine would represent an important advance in the pharmacotherapy of MDD patients. In the present study, we investigated the symptomatological predictors of the response to fluvoxamine in Japanese patients with MDD by using the three-factor structure of the MADRS proposed by Suzuki et al.11

MATERIALS AND METHODS

Subjects and treatment

A total of 100 Japanese patients who fulfilled the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria for the diagnosis of an MDD with or without melancholia and whose total MADRS score at pretreatment was 21 or higher were included in this study. Patients with other axis I disorders (including dementia, substance abuse, dysthymia, panic disorder, obsessive-compulsive disorder, and generalized anxiety disorder) and axis II disorders as determined by a 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 the study was completely described to the subjects, their informed consent was obtained.

Fluvoxamine was administered twice daily (at the same dose after dinner and at bedtime) for 6 weeks. The initial daily dose was 50 mg. It was increased to 100 mg after 1 week. After another week, the dose was set to 100 mg, 150 mg or 200 mg depending on the judgment of each clinician, and this fixed dose was maintained until the end of the study. Patients with insomnia were prescribed 0.25 mg or 0.5 mg brotizolam, a benzodiazepine sedative hypnotic, at bedtime. No other psychotropic drugs were permitted during the study.

Among the 100 patients, 10 stopped visiting our hospitals without providing an explanation. Six patients could not complete the study because of side-effects (three patients with nausea or vomiting; three patients with severe insomnia and inner tension). Eighty-four patients completed the 6-week study. Three patients were excluded from the current analysis because of poor compliance. Therefore, the remaining 81 patients constituted the subjects, this included 44 females and 37 males (mean age ± SD = 48.0 ± 13.7 years). The characteristics of these patients are shown in Table 1. The final daily dose of fluvoxamine was 100 mg for 10 patients, 150 mg for eight patients, and 200 mg for 63 patients.

Table 1.  Clinical characteristics of the total patients, responders and non-responders
 Total
(n = 81)
Responders
(n = 56)
Non-responders
(n = 25)
Analysis  
  • Date are expressed as mean ± SD.

  • Analysis performed with the use of a χ2 test between the responders and non-responders.

  • §

    Analysis performed with the use of an unpaired t-test between the responders and non-responders.

  • Analysis performed with the use of Mann–Whitney U-test between the responders and non-responders.

  • MADRS, Montgomery and Åsberg Depression Rating Scale.

Sex (male/female)37/4427/2910/15χ2 = 0.47P = 0.49n.s.
Age (years)48.0 ± 13.747.4 ± 13.349.5 ± 14.6t = −0.66P = 0.51n.s.§
Nunber of previous episodes0.42 ± 1.050.41 ± 1.130.44 ± 0.77t = 0.12P = 0.91n.s.§
Melancholia (yes/no)31/5020/3611/14χ2 = 0.50P = 0.48n.s.
Pretreatment total
 MADRS score29.7 ± 4.929.6 ± 5.129.8 ± 4.6z = −0.27P = 0.79n.s.
 Final dosage of fluvoxamine (mg/day)182.7 ± 34.6179.5 ± 37.9190.0 ± 25.0t = −1.27P = 0.21n.s.§

Data collection

The characteristics and severity of the depressive symptoms were assessed by the total and three-factor scores of MADRS. We defined patients with a pretreatment total MADRS score of ≥31 points as ‘severe’ patients12 and those with a pretreatment total MADRS score of ≤30 points as ‘non-severe’ patients. The patients were assessed at pretreatment and at 1, 2, 4, and 6 weeks after the initiation of fluvoxamine treatment. A single rater conducted each of the ratings for each patient. A clinical response was defined as a 50% or greater decrease in the pretreatment total MADRS score.

Statistical analysis

The clinical characteristics of the patients, responders, and non-responders were analyzed by a χ2 test or an unpaired t-test where appropriate. The Mann–Whitney U-test was used to compare the total MADRS, factor 1, factor 2 and factor 3 scores in the responders and non-responders at pretreatment and 1, 2, 4 and 6 weeks after treatment initiation. All the tests were two-tailed, and a P-value of <0.05 was regarded as significant.

RESULTS

Fifty-six patients were responders and 25 were non-responders. No significant difference was observed in the severity in MADRS at pretreatment (z = −0.27, P = 0.79), the number of previous depressive episodes (t = −0.12, P = 0.91), and the proportion of melancholia and non-melancholia (χ2 = 0.50, P = 0.48) between the responders and non-responders (Table 1). Although there was no significant difference in the number of previous depressive episodes between the non-severe and severe patients (t = −0.76, P = 0.45), the average age of the ‘non-severe’ patients was significantly higher than that of the severe patients (t = 3.29, P = 0.015) (Table 2). Table 3 shows the rate of response to fluvoxamine observed in this study. There was no significant difference in the distribution of responders and non-responders between severe and non-severe patients (χ2 = 0.38, P = 0.54).

Table 2.  Clinical characteristics of ‘severe’ patients and ‘non-severe’ patients
 Severe
(n = 32)
Non-severe
(n = 49)
Analysis  
  • *

    P < 0.05,

  • **

    P < 0.01.

  • Date are expressed as mean ± SD.

  • Analysis performed with the use of a χ2 test.

  • §

    Analysis performed with the use of an unpaired test.

  • Analysis performed with the use of Mann–Whitney U-test.

  • MADRS, Montgomery and Åsberg Depression Rating Scale.

Sex (male/female)13/1924/25χ2 = 0.55P = 0.46n.s.
Age (years)42.2 ± 13.151.8 ± 12.7t = 3.29P = 0.015*§ 
Nunber of previous episodes0.31 ± 0.640.49 ± 1.21t = 0.76P = 0.45n.s.§
Melancholia (yes/no)20/1211/38χ2 = 13.3P < 0.01** 
Pretreatment total
 MADRS score34.6 ± 3.026.4 ± 2.6z = −7.57P < 0.01** 
Table 3.  The response rate of fluvoxamine in this study
 Total
(n = 81)
Severe
(n = 32)
Non-severe
(n = 49)
  1. There was no significant difference in the distribution of responders and non-responders between ‘severe’ patients and ‘moderate and mild’ patients in fluvoxamine (χ2 = 0.38, P = 0.54).

  2. Analysis performed with the use of a χ2 test.

Responder56 (69.1%)24 (75.0%)32 (65.3%)
Non-responder25 (30.9%)8 (25.0%)17 (34.7%)

The mean total and three-factor structure MADRS scores at pretreatment and at each evaluation point for the responders and non-responders among the severe patients are shown in Table 4. In the severe patients, no significant difference was observed in the pretreatment total MADRS (z = −0.83, P = 0.77), factor 1 (z = −0.29, P = 0.77), factor 2 (z = −0.64, P = 0.52), and factor 3 (z = −0.76, P = 0.45) scores between the responders and non-responders. However, there was a significant difference between the responders and non-responders in terms of the total MADRS (z = −2.67, P = < 0.01) and factor 1 (z = −2.50, P = 0.012) scores from 1 week onwards and in terms of the factor 2 (z = −1.87, P < 0.01) and factor 3 (z = −3.01, P < 0.01) scores from 2 weeks onwards. The mean total and three-factor structure MADRS scores at pretreatment and at each evaluation point for the responders and non-responders among the non-severe patients are shown in Table 5. In the non-severe patients, a significant difference was noted in the factor 3 scores (z = −2.80, P = < 0.01), while no significant difference was observed in the total MADRS (z = −1.77, P = 0.08), factor 1 (z = −0.51, P = 0.61), and factor 2 (z = −0.01, P = 0.99) scores at pretreatment between the responders and non-responders. There was a significant difference in the total MADRS (z = −3.17, P = < 0.01), factor 2 (z = −2.55, P = 0.011), and factor 3 (z = −3.81, P < 0.01) scores from 1 week onwards and in the factor 1 (z = −3.54, P < 0.01) scores from 2 weeks onwards.

Table 4.  The mean scores of total Montgomery and Åsberg Depression Rating Scale (MADRS), factor 1, factor 2 and factor 3 during the 6-week study in the responders and non-responders in the ‘severe’ patients
 Pretreatment1 week2 weeks4 weeks6 weeks
  • *

    P ≤ 0.05,

  • **

    P ≤ 0.01.

Total MADRS
 Responder (n = 24)34.426.919.812.57.1
 Non-responder (n = 8)35.332.931.032.830.8
 P0.40<0.01**<0.01**<0.01**<0.01**
Factor 1
 Responder (n = 24)9.16.95.02.91.5
 Non-responder (n = 8)9.19.18.39.08.8
 P0.770.012*<0.01**<0.01**<0.01**
Factor 2
 Responder (n = 24)14.612.39.16.13.7
 Non-responder (n = 8)15.114.413.513.812.8
 P0.520.06<0.01**<0.01**<0.01**
Factor 3
 Responder (n = 24)10.37.85.73.52.2
 Non-responder (n = 8)10.89.49.310.09.4
 P0.45≤0.051≤0.01**≤0.01**≤0.01**
Table 5.  The mean scores of total Montgomery and Åsberg Depression Rating Scale (MADRS), factor 1, factor 2 and factor 3 during the 6-week study in the responders and non-responders in the ‘non-severe’ patients
 Pretreatment1 week2 weeks4 weeks6 weeks
  • *

    P ≤ 0.05,

  • **

    P ≤ 0.01.

Total MADRS
 Responder (n = 32)26.020.914.38.95.4
 Non-responder (n = 17)27.326.123.922.221.3
 P0.08<0.01**<0.01**<0.01**<0.01**
Factor 1
 Responder (n = 32)7.15.63.72.21.1
 Non-responder (n = 17)6.86.76.05.55.4
 P0.610.10<0.01**<0.01**<0.01**
Factor 2
 Responder (n = 32)11.99.86.94.42.8
 Non-responder (n = 17)11.911.310.610.09.2
 P0.990.011*<0.01**<0.01**<0.01**
Factor 3
 Responder (n = 32)7.25.53.72.41.5
 Non-responder (n = 17)8.68.17.26.66.7
 P≤0.01**≤0.01**≤0.01**≤0.01**≤0.01**

DISCUSSION

The present study demonstrated that the mean factor 3 score of the non-responders at pretreatment was significantly higher than that of the responders among the non-severe patients. Furthermore, in the non-severe patient group, there was a significant difference in the mean factor 3 score from 1 week onwards between the responders and non-responders. Therefore, it is suggested that for patients with non-severe MDD, the therapeutic response to fluvoxamine is predicted by the pretreatment factor 3 score (i.e. the severity of the vegetative symptoms (reduced sleep, reduced appetite, and inner tension)). In addition, the improvement of vegetative symptoms is thought to be a good indicator of the response to fluvoxamine in the acute treatment of patients with non-severe MDD.

Mendels reported that the profile of depressed patients who responded to sertraline, an SSRI similar to fluvoxamine, was broad and that it was not affected by variables such as the severity of illness and concomitant anxiety, insomnia or agitation as assessed by the Hamilton Depression Rating Scale (HAM-D).13 With regard to fluvoxamine, no report has addressed the symptomatological predictive factor of clinical response. In our study, the factor 3 score at pretreatment was found to be a predictive factor of the response to fluvoxamine only in non-severe patients and not in severe patients. The reason for this discrepancy is unknown. The severe depressive patients in the present study (n = 32) was small sample sized. It is necessary to examine whether the factor 3 score at pretreatment is a predictive factor of the response to fluvoxamine in large numbers of severe depressive patients or patients with melancholia alone. The average age of the non-severe patients was significantly higher than that of the severe patients. Therefore, it is suggested that the low factor 3 score at pretreatment is a good predictor of the response to fluvoxamine in older non-severe MDD patients.

The next important finding of this study was that no significant difference was observed in the response rate to fluvoxamine between the severe and non-severe patients. Fukuchi and Kanemoto reported that a significantly higher response was recorded in severe depressive patients administered milnacipran, a serotonin and norepinephrine reuptake inhibitor (SNRI), than in those administered fluvoxamine.14 In our study, the response rate to fluvoxamine in severe patients was 75% and is higher than that of the non-severe patients (65.3%). We reported that the response rate to milnacipran in severe major depressive patients whose total MADRS scores at pretreatment were 31 or higher, similar to the present study, was 72%. This was almost equal to that in moderate major depressive patients.15 These facts suggest that the response rate to fluvoxamine in severe major depressive patients is sufficiently high and almost equal to that of milnacipran, an SNRI, in similar severe major depressive patients.

Fabre et al. reported that severely depressed patients (21-item HAM-D score ≥30) responded better to fluvoxamine than imipramine in five of six measures.16 Furthermore, a double-blind multicentre study was conducted with 86 severely depressed inpatients (total score ≥25 in 17-item HAM-D) to compare the efficacies of fluvoxamine and clomipramine.17 At the end of this study, 71% of the fluvoxamine group and 69% of the clomipramine group responded (≥50% decrease in the 17-item HAM-D total score). Our results regarding fluvoxamine were in agreement with those of previous studies in which a marked effect of fluvoxamine was observed in severe major depressive patients.

In conclusion, the present study reveals that the factor 3 score of MADRS (i.e. the severity of vegetative symptoms), is a good predictor of the response to fluvoxamine in the acute treatment of patients with non-severe MDD. Furthermore, the marked efficacy of fluvoxamine in the treatment of severe patients with a baseline MADRS score of ≥31 points was confirmed. The limitation of the present study is that it was not a double-blind placebo-controlled study. Another study is required to confirm our findings on the predictor of the response to fluvoxamine in major depressive patients.

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