PCN Psychiatric and Clinical Neurosciences 1323-13162003 Blackwell Science Pty Ltd 572April 2003 1098 Dose and duration of fluvoxamine S. Morishita and S. Arita 10.1046/j.1323-1316.2002.01098.x Original Article177181BEES SGML Psychiatry and Clinical Neurosciences (2003), 57, 177 181 Regular Article Suitable dose and duration of fluvoxamine administration to treat depression SHIGERU MORISHITA, MD, PhD 1 AND SEIZABURO ARITA, PhD 2 1 Department of Psychiatry, Kawasaki Medical School, Kurashiki, Okayama and 2 Department of Mathematics, Kansai Medical School, Hirakata, Osaka, Japan Abstract The purpose of the present paper was to determine the suitable dose and appropriate trial duration of fluvoxamine to treat for depression. A retrospective cohort analysis was performed among depression patients who were treated in the Department of Psychiatry, Kawasaki Medical School Hospital, Kurashiki, Japan, in 2000. A total of 72 patients received fluvoxamine to treat depression. The dose response was compared and the initial significant clinical action was examined. The percentage showing improvement after receiving a high daily dose (100 150 mg) of fluvoxamine was 73.7%, but that showing improvement on a low daily dose (50 75 mg) was 47.1%. A significant difference between the two groups was seen on Kaplan Meier analysis and log rank test (c 2 = 4.814; d.f. = 1; P = 0.0282). The cumulative percentage of responder patients was more than 80% at the end of a 6-week period. Fluvoxamine is recommended at a daily dose of 100 mg or 150 mg as the initial dose. If a patient does not show improvement by the end of 6 weeks the treatment regimen of fluvoxamine should be altered. Key words depression, dose response, fluvoxamine, onset, selective serotonin reuptake inhibitor. INTRODUCTION Depression is the most common of the major mental illnesses and affects 5 12% of men and 10 25% of women during their lifetime. 1 Of all medical disorders seen in primary care, depression appears to be the most common and has been found to cause more functional disability than diabetes, chronic lung diseases, hypertension, or arthritis. 2 Recently, many patients with depression have been successfully treated with antidepressants including tricyclic antidepressants, tetracyclic antidepressants and/or selective serotonin reuptake inhibitors (SSRI). The SSRI fluvoxamine is an effective antidepressant 3 that acts by facilitating serotonergic neurotransmission. 4 It has been approved for treatment of obsessive compulsive disorders in the USA Correspondence address: Shigeru Morishita, Department of Psychiatry, Kawasaki Medical School, 577 Matsushima, Kurashiki-city, 701 0192, Japan. Email: morisita@med.kawasaki-m.ac.jp Received 20 May 2002; revised 7 August 2002; accepted 12 August 2002. Regular Article since 1994 and for depression in several European countries since 1983. In Japan, fluvoxamine was introduced in 1999 as the first antidepressant SSRI. 5,6 However, there remain some questions regarding the clinical use of fluvoxamine for depression. The question of when fluvoxamine initiates significant clinical action in depressed patients is still unsettled. The suitable trial duration of SSRI has been much less studied. 7 The oral dose varies widely from the daily dose of 50 300 mg. 3 The suitable oral dose of fluvoxamine has not been determined. The purpose of the present study was to determine the suitable dose and the most suitable duration of fluvoxamine. METHODS Patients A retrospective cohort analysis was made among depression patients treated in the Department of Psychiatry, Kawasaki Medical School, Kurashiki, Japan, from January to December in 2000. During this study period 672 outpatients met the Diagnostic
178 S. Morishita and S. Arita et al. and Statistical Manual of Mental Disorders (4th edn; DSM-IV) criteria for major depressive disorder or bipolar disorder depression. Among 672 patients, 178 patients were receiving fluvoxamine to treat depression and their medical records were also reviewed. To be included in the present study, patients who were diagnosed with depression and were being treated with fluvoxamine were required to meet all of the following criteria. Inclusion criteria Patients who were already evaluated by the Hamilton Depression Rating Scale (HDRS), were reviewed. Before treatment, patients had a total HDRS score between 22 and 32 after at least 14 days without psychotropic medication. Fluvoxamine was administered once or twice a day without any other antidepressants, mood stabilizers and benzodiazepines. Use of hypnotics was not known. In many randomized clinical trials that tested the efficacy of fluvoxamine in depression a daily fluvoxamine dose of 100 mg or higher was administered. Therefore, we identified a low daily dose group and a high daily dose group. The low daily dose group was started with an initial dose of 50 mg of fluvoxamine and the dose was increased up to 75 mg. The high daily dose group was started with an initial dose of 100 mg of fluvoxamine and the dose was increased up to 150 mg. Patients with a 50% reduction from baseline total scores on HDRS were evaluated as improved 8 whiles others were evaluated as not improved. The efficacy of fluvoxamine was evaluated every week. Exclusion criteria Patients were excluded from the study if they had a history of seizure or myoclonus, comorbid anxiety, obsessive compulsive disorder or other psychiatric disorders. We identified 72 patients who met the aforementioned criteria and they were included in the analysis (Table 1). Patient characteristics did not differ between the two groups (c 2 test and Student s t-test). Statistical analyses To determine the suitable oral dose, the rates of improvement were compared between the low daily dose and the high daily dose. The probability plot for improvement was determined using the Kaplan Meier method and compared by log rank test and c 2 test. To determine the most appropriate duration, we observed the period at which the cumulative percentage of responders was > 80%. We selected 80% as the critical value because a lower probability with 1 standard deviation (SD) was 84.4% on statistical analysis. To determine the side-effects, the percentage was compared by ratio test. A computer software program, STATVIEW for Macintosh (version 4.11), was used for analyses in the present study. The level of significance was set at P < 0.05. RESULTS After the end of the 10-week treatment period 28 (73.7%) of 38 patients showed improvement in the high daily dose group (100 150 mg). However, only 16 (47.1%) of 34 patients showed improvement in the low daily dose group (50 75 mg). There was a significant difference between the two groups (Fig. 1) when the whole follow-up period was compared by Kaplan Table 1. Baseline characteristics of 72 patients Characteristics Fluvoxamin 50 75 mg (n = 34) Fluvoxamine 100 150 mg (n = 38) Age (years) Mean 53.0 ± 16.1 50.7 ± 16.1 Range 18 81 20 76 Gender Male/Female 13/21 22/16 Type of depression Unipolar/Bipolar 28/6 36/2 HDRS scores 26.4 ± 2.6 27.0 ± 2.5 HDRS, Hamilton Depression Rating Scale. Figure 1. Survival plot of response to treatment of fluvoxamine.
Dose and duration of fluvoxamine 179 Table 2. Cumulative percentage of depression patients showing improvement Treatment weeks % improved 50 75 mg % improved 100 150 mg Differences (c 2 test) 1 5.8 2.6 NS 2 14.7 28.9 NS 3 23.5 36.8 NS 4 29.4 47.4 NS 5 35.3 52.6 NS 6 41.2 65.8 P < 0.05 7 41.2 68.4 P < 0.05 8 47.1 73.4 P < 0.05 9 47.1 73.4 P < 0.05 10 47.1 73.4 P < 0.05 % improved: improved patients/total patients. NS, not significant. Meier analysis and log rank test (c 2 = 4.814; d.f. = 1; P = 0.0282). A significant difference in the cumulative improvement percentage between the high and low daily dose group appeared after 6 weeks (c 2 = 4.379; d.f. = 1; P = 0.0364; Table 2). Among the unipolar patients, 26 (72.2%) of 36 patients showed improvement in the high daily dose group while only 13 (46.4%) of 28 patients showed improvement in the low daily dose group. There was a significant difference between the two groups by Kaplan Meier analysis and log rank test (c 2 = 3.890; d.f. = 1; P = 0.0486). Regarding the responders (high daily dose, 28 patients; low daily dose, 16 patients), the cumulative improved percentage of responder patients is shown in Fig. 2. The cumulative improved percentage of responder patients in the high daily dose group was more than 80% after 6 weeks, as was that for the low daily dose group. Two patients in the low daily dose group and one patient in the high daily dose group experienced slightly nausea. Four of the low daily dose group and seven of the high daily dose group patients experienced slightly drowsiness. There was no significant difference between the two groups by ratio test. The other patients did not experience side-effects. DISCUSSION In drug treatments it is important to determine suitable dose and whether the regimen should be altered after several weeks. In the present study of fluvoxamine therapy for depression, we showed that a daily dose of 100 150 mg Figure 2. Cumulative improved percentage of patients showing response to fluvoxamine. was significantly more effective than a daily dose of 50 75 mg. Walczak et al. demonstrated a dose effect relationship and the minimal effective dose for fluvoxamine in a titrated fixed-dose study (25, 50, 100 and 150 mg) of major depressive disorder. 9 The minimal effective dose was 50 mg/day. Although they reported that fluvoxamine showed dose-related effectiveness in the treatment of major depressive disorder, they did not show a comparison between each dose of fluvoxamine. Many randomized clinical trials that tested the efficacy of fluvoxamine in depression administered a daily fluvoxamine dose of 100 mg or higher. 3 Those trials demonstrated good results but it is also certain that a daily dose of 50 mg of fluvoxamine has therapeutic efficacy. However, we think that the efficacy was not sufficient based on our findings. Side-effects severe enough to warrant discontinuation of medication were not seen at a daily dose of 100 150 mg of fluvoxamine. Therefore, we recommend a daily dose of 100 150 mg of fluvoxamine as the initial dose to treat depression. In contrast, data from studies relating the plasma concentration of fluvoxamine to its clinical effects do
180 S. Morishita and S. Arita et al. not support routine plasma concentration monitoring in depression. 10 12 These problems may be induced by the effects of fluvoxamine on specific cytochrome isozymes. 12 However, we do not have data on plasma concentration. It should be investigated in future studies. The second objective of the study was to examine the most appropriate duration of fluvoxamine administration. During the last few years, some investigators have studied the onset of the action of antidepressant medication. Stassen et al. found that 70% of subjects who showed improvement of at least 20% at 10 days reached the conventional 50% symptom reduction responder criterion at 4 weeks. 13 Quitkin et al. investigated the point at which a patient was not likely to receive any further benefit from the current antidepressant and should be switched to another medication. 14 They studied a total of 593 patients to determine the time at which patients who received drug therapy would have a better chance of being rated as responders versus patients who received a placebo. Nineteen (32%) of 59 drug-treated patients who were unimproved at 3 weeks were rated as responders at 6 weeks versus only six (10%) of the 57 placebo-treated patients. Patients who received drug therapy and whose conditions were unimproved but who had been minimally improved at some point had a superior prognosis with drug therapy versus a placebo at up to 4 weeks. On the basis of their findings, they recommend that patients who are tolerant of an adequate dose but whose conditions have not been even minimally improved by the end of 4 weeks should have their treatment regimen altered. The results of an open trial of fluoxetine by Nierenberg et al. 7 support these recommendations. They found that of the patients who showed no improvement at 2, 4, and 6 weeks, the percentages of responders at 8 weeks were 36.4%, 18.9% and 6.5%, respectively. Also, in a survey of treatment choice most clinicians chose to intervene after just 4 weeks of non-response. 15 These investigators recommended that if a patient with depression dose not show at least a 20% improvement within the first 2 4 weeks of treatment, the treatment regimen should be altered. However, our data showed that the cumulative improved percentage of responder patients was > 80% at the end of a 6-week period. and a significant difference of cumulative improved percentage between a high daily dose and a low daily dose appeared at the end of the 6-week period. Therefore, we recommend that a daily dose of 100 150 mg of fluvoxamine should be administered for at least 6 weeks to treat depression. These results should help guide clinicians in determining suitable oral dose and suitable duration of fluvoxamine for depression. However, the present report was a retrospective study; we did not have a placebo control group or randomized method. These limitations should be investigated using stricter methods in future studies. REFERENCES 1. Kessler RC, McGonagle KA, Zhao S et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Arch. Gen. Psychiatry 1994; 51: 8 19. 2. Panzarino PJ. The cost of depression: Direct and indirect; treatment versus nontreatment. J. Clin. Psychiatry 1998; 59 (Suppl. 20): 11 14. 3. Ware MR. Fluvoxamine: A review of the controlled trial in depression. J. Clin. Psychiatry 1997; 58 (Suppl. 5): 15 23. 4. Claasen V. Review of the animal pharmacology and pharmacokinetics of fluvoxamine. Br. J. Clin. Pharmacol. 1983; 15 (Suppl. 3): 49s 55s. 5. Murasaki M, Mori A, Asai M et al. An early clinical phase II study of SME3110, a selective serotonin reuptake inhibitor, in the treatment of depression and depressive state. Jpn. J. Clin. Psychopharmacol. 1998; 1: 185 198 (in Japanese). 6. Murasaki M, Mori A, Miura S et al. Clinical evaluation of SME3110 in the treatment of depression and depressive state. Rinshoigaku 1998; 14: 951 980 (in Japanese). 7. Nierenberg AA, McLean NE, Alpert JE, Worthington JJ, Rosenbaum JF, Fava M. Early nonresponse to fluoxetine as a predictor of poor 8-week outcome. Am. J. Psychiatry 1995; 152: 1500 1503. 8. Prien RF, Carpenter LL, Kupfer DJ. The definition and operational criteria for treatment outcome of major depressive disorder: A review of the current research literature. Arch. Gen. Psychiatry 1991; 48: 796 800. 9. Walczak DD, Apter JT, Halikas JA et al. The oral dose effect relationship for fluvoxamine: A fixed-dose comparison against placebo in depressed outpatients. Ann. Clin. Psychiatry 1996; 8: 139 151. 10. Kasper S, Dotsch M, Kick H et al. Plasma concentration of fluvoxamine and maprotiline in major depression: Implications on therapeutic efficacy and side effects. Eur. Neuropsychopharmacol. 1993; 3: 13 21. 11. Perucca E, Gatti G, Spina E. Clinical pharmacokinetics of fluvoxamine. Clin. Pharmacokinet. 1994; 27: 175 190. 12. DeVane CL, Gill HS. Clinical pharmacokinetics of fluvoxamine: Applications to dosage regimen design. J. Clin. Psychiatry 1997; 58 (Suppl. 5): 7 14. 13. Stassen HH, Angst J, Delini-Stula A. Severity of baseline and onset of improvement in depression. Meta-analysis of imipramine and moclobemide versus placebo. Eur. Psychiatry 1994; 9 (Suppl. 3): 129 136.
Dose and duration of fluvoxamine 181 14. Quitkin FM, McGrath PJ, Stewart JW et al. Chronological milestones to guide drug change: When should clinicians switch antidepressant? Arch. Gen. Psychiatry 1996; 53: 785 792. 15. Nierenberg AA. Treatment choice after one antidepressant fails: A survey of Northeastern psychiatrists. J. Clin. Psychiatry 1991; 52: 383 385.