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A Double-Blind Placebo-Controlled Study of Fluvoxamine and Imipramine in Out-Patients with Primary Depression T.M

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A Double-Blind Placebo-Controlled Study of Fluvoxamine and Imipramine in Out-Patients with Primary Depression T.M Br. J. clin. Pharmac. (1983), 15, 433S-438S A DOUBLE-BLIND PLACEBO-CONTROLLED STUDY OF FLUVOXAMINE AND IMIPRAMINE IN OUT-PATIENTS WITH PRIMARY DEPRESSION T.M. ITIL, R.K. SHRIVASTAVA, S. MUKHERJEE, B.S. COLEMAN' & S.T. MICHAEL New York Institute for Research into Contemporary Medicine, Tarrytown, N.Y., affiliated with the Department of Psychiatry, New York Medical College, Valhalla, N.Y. and 'Kali-Duphar Laboratories, Inc., Columbus, Ohio 43229, U.S.A. 1 A double-blind placebo-controlled study of fluvoxamine and imipramine was performed in a group of depressed patients. Twenty-two patients received fluvoxamine (mean dose 101 mg/day), 25 received imipramine (mean dose 127 mg/day) and 22 received placebo. 2 Apart from an increase in the SGOT and SGPT values offour imipramine patients, no statistically significant changes in haematology or urinalysis were judged to be medically relevant. Fluvoxamine exhibited fewer anticholinergic side effects than imipramine. 3 Both fluvoxamine treated patients and imipramine-treated patients exhibited a statistically sig- nificant improvement at the end ofthe 28-day treatment period with respect to the placebo patients, as measured using the Hamilton Rating Scale for Depression, and the Clinical Global Impression Scale. Evaluations ofthe results of the Beck Depression Inventory and the Profile ofMood States revealed a statistically significant improvement for imipramine patients with respect to placebo at week 4, but not for fluvoxamine patients. It is postulated on the basis of quantitative pharmaco-EEG findings, that the slight superiority of imipramine over fluvoxamine was due to underdosing of the latter. Introduction Despite the development of a series of new anti- study in human volunteers (Menon & Vijvers, 1974) depressants, there is still a need to develop an anti- confirmed the absence of anticholinergic effects. In depressant with early onset of therapeutic action but view of the 5-HT hypothesis of depression (Coppen et without side effects. Furthermore, recent studies al., 1972; Maas, 1974), plus the toxicological and suggest that an antidepressant with a 'special' bio- pharmacological characteristics of fluvoxamine, it chemical profile may be more effective in the treatment would seem that the drug is a member of a new class of certain types of depressed patients. of antidepressants. In a quantitative pharmaco-EEG Fluvoxamine maleate [5-methoxy-4-(trifluoro- (Itil, 1974) study in healthy subjects, the 'typical' methyl)valerophenone (E)-O-(2-aminoethyl)oxime antidepressant computer-(EEG (EEG) profile of maleate(1:1) Duphar B.V., The Netherlands] fluvoxamine was established (Itil et al., 1977) and (Figure 1) is a member of a series of 2-aminoethyl- early Phase II open studies confirmed the anti- oximethers of aralkylketones. Fluvoxamine has been depressant properties of fluvoxamine (Gaber & shown in animal studies to inhibit 5-hydroxytryp- Doogan, 1981, Wakelin & Schurer, 1981). tamine (5-HT) re-uptake at the synapses of animal The objectives of this study were to ascertain and brains (Claassen & Post, 1974; Claassen et al., 1977) compare the antidepressant properties and possible with little or no effect on noradrenaline (NA) re- unwanted effects of fluvoxamine relative to uptake. In animals there were no sedative or imipramine and placebo, in a double-blind, con- amphetamine-like stimulating effects. There was no trolled study in a group of depressed patients. inhibition ofmonoamine oxidase (MAO). A tolerance Methods F C \ C C-CHi-CHiCHiCHi-O-CH3 HCCOOH N .11 Sixty-nine out-patients, suffering from primary HCCOOH depression, were admitted to the study after giving O-CHOCH-NH2 their written informed consent. Pregnant women and Figure 1 The chemical structure of fluvoxamine maleate women of childbearing potential were excluded, as 0264-3334/83/0400-4330$02.00 © 1983 Blackwell Scientific Publications 434S T.M. ITIL, R.K. SHRIVASTAVA, S. MUKHERJEE, B.S. COLEMAN & S.T. MICHAEL were patients whose depression was secondary to took chlordiazepoxide, codeine, alcohol, fluraze- another illness. Patients receiving the following pam, ampicillin, aspirin or tetracycline. therapy were also excluded: imipramine, MAO Before and during the study, safety evaluations inhibitors within 2 weeks of study commencement, were conducted at weekly intervals. These included electroconvulsive therapy within 4 weeks of study blood chemistry, haematology, urinalysis, ECG, commencement, lithium carbonate, or any short- or EEG and vital signs. Psychopathological assessments long-term medication which might interact with were made pre-study and at weekly intervals. These either study drug. included the Clinical Global Impression Scale (CGI, Patients were between the ages of 21 and 68; 39 Guy, 1976), the HAMD, Self-Report Symptom were males with a mean age of41.6 years, and 30were Inventory (SCL-90), Beck Depression Inventory females whose average age was 40.9 years. None was (Beck & Beamesderfer, 1974), and Profile of Mood drug-dependent or had any significant organic States (McNair et al., 1971). A Dosage Record and disease. All patients had normal EEGs. Patients were Treatment Emergent Signs and Symptoms scale with selected who reported an episode of primary depres- 33 items were used weekly and whenever concurrent sion of at least 2 weeks duration, in which the signs or symptoms were observed (Guy, 1976). alteration of mood exceeded customary sadness and could not be relieved by social contact. Patients all attained a minimum of 15 points on the first 17 items Results of the Hamilton Rating Scale for Depression (HAMD; Hamilton, 1967). Premature terminations All patients had a minimum offour overt symptoms, thus complying with the Research Diagnostic Criteria Four of the first five study patients (two each in the for depressive disorders (DSM, 1980). All patients fluvoxamine and imipramine groups) entered were met the criteria for major affective disorder; three discontinued owing to emergence of unwanted signs were classified as bipolar depressed; the remainder and symptoms, probably because dosage titration were divided between single episode (n = 20) and was too rapid to allow adjustment to its effects. In recurrent major depressive disorder (n = 46). subsequent study patients, the titration of dose of Patients were randomly assigned to fluvoxamine, study drugs was done at a slower speed. Altogether, imipramine or placebo after a 1 week placebo 35 patients stopped the study medication before day washout period. The drug administration period 28 of the double-blind drug administration period lasted 28 days. Starting with an initial dose of 1 (see Table 2). Patients dropping out due to in- capsule (50 mg fluvoxamine or 50 mg imipramine, or effectiveness were included in the end-point analysis placebo) the amount of drug was increased gradually ifthey had received at least 14 days medication. In the during the first week; thereafter the increments fluvoxamine group, the most common complaints depended on the patient's response. In the usual recorded among patients dropping out for reasons of schedule, drug was administered three times daily intolerance were insomnia (five), nausea (three) and during the third day of the study, the largest dosage was 300 mg or six capsules daily. The dosage of each drug is shown in Table 1. Table 2 Reasons given for premature termination Only a few patients received concurrent medication. of treatment Three patients in the fluvoxamine group took bismuth subsalicylate, paracetamol, multivitamins, or flurazepam during the study. Four patients in the Flu Imi Placebo imipramine group took aspirin, isosorbide dinitrate, Patients entered 22 25 22 or acetaminophen. Five patients in the placebo group Patients completing 28 days treatment 10 13 11 Patients failing to Table 1 Mean dosage statistics (mg/day) complete 28 days 12 12 11 Reasonsfor drop-out: Flu Imi Placebo* Ineffectiveness* 0 1 5 Intolerance 9 7 1 Mean + s.d. 101 ± 46 127 ± 46 173** ± 136 Intercurrent illness 0 3 0 Range 50- 209 50- 210 50-750 Suicide attempt 0 0 1 n 22 25 22 Refused to continue 3 1 4 *For purposes of comparison, one capsule of placebo is *Patients dropping out due to ineffectiveness were said to contain 50 mg included in the end-point analysis if they had ** Includes 15 capsules overdose received more than 14 days medication. Flu fluvoxamine, Imi imipramine Flu fluvoxamine, Imi imipramine PLACEBO-CONTROLLED STUDY OF FLUVOXAMINE VS IMIPRAMINE 435S drowsiness (three). In the imipramine group, 10 Table 4 Frequency distributions showing the change in different complaints were recorded for the seven patient's condition at the end of treatment compared to his patients who discontinued for reasons of intolerance; condition at admission (end of treatment data missing for no one complaint was reported by more than two one patient on FLU and two on placebo) patients. The patient terminating prematurely in the Flu Imi Placebo placebo group for reasons of intolerance reported Category insomnia and tension. None of the 22 fluvoxamine Very much improved 3 6 1 patients withdrew for lack of effect; this is significant- Much improved 2 2 2 ly less than the corresponding percentage in the Minimally improved 0 3 2 placebo group (P = 0.028). No change 2 3 8 Minimally worse 2 0 1 Clinicalfindings Much worse 0 0 0 Very much worse 0 0 0 n 9 14 14 The severity of illness was evaluated using the CGI P values scale. As seen in Table 3, at the end of treatment both Flu vs placebo 0.051* active drug groups showed less severe illness than Imi vs placebo 0.009* placebo (fluvoxamine, P = 0.018 and imipramine, P Flu vs Imi 0.56** = 0.005). No significant differences were found between fluvoxamine and imipramine (P = 0.72). * one-sided Wilcoxon test, * * two-sided Wilcoxon test Global improvement at the end of treatment is Flu fluvoxamine, Imi imipramine presented in Table 4. Both fluvoxamine-treated patients (P = 0.051) and imipramine-treated patients (P = 0.009) exhibited much greater improvement groups showed lower end-point scores.
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