- Email: [email protected]
Fluvoxamine maleate, a serotonergic antidepressant; A comparison with chlorimipramine
Prog. Neuro~Psychopharmacol & Biol. Psych/at 1982. Vo|. 6. pp. 475-478 Printed in Great Britain. All rights reserved.
0278-5846/82/060475-04503.00/0 Copyright © 1982 Pergamon Press Ltd.
FLUVOXAMINE MALEATE, A SEROTONERGIC ANTIDEPRESSANT; A COMPARISON WITH CHLORIMIPRAMINE
BERNARD S. COLEMAN and BARBARA A. BLOCK
Kali-Duphar Laboratories, Inc. Columbus, Ohio, USA
(Final form, August 1982)
Abstract Coleman, Bernard S. and Barbara A. Block: Fluvoxamine maleate, a serotonergic antidepressant; a cc~parison with chlorimipramine. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1982, 6(4-6) : 475-478. i. 2. 3.
4. 5.
Fluvoxamine is a potent serotonin re-uptake inhibitor, with little or no noradrenergic or anticholinergic activity. The results of three studies using an almost identical protocol with a prospectively randomized, double-blind design comparing fluvoxamine and chlorimipramine are presented. Tn a population of 98 subjects suffering from a variety of depressive conditions, there was a marked improvement over four weeks in both groups, dosage was maintained between 150 and 300 mg per day. There were no changes of clinical importance in vital signs, hematology or biochemistry, but pulse rates increased in the chlorimipramine group. There were fewer concurrent signs and symptoms in the fluvoxamine group, especially those attributable to anticholinergic activity.
Keywords:
anticholinergic activity, chlorimipramine, fluvoxamine, serotonin
Introduction
In the continuing search for "the right drug for the right patient", investigations into depression have focused upon several of the amine systems. Central serotonin (5-HT) metabolism has played a major role in such research (Praag, van 1980). Fluvoxamine maleate (DU 23000) has been shown in animal studies to inhibit serotonin re-uptake at the synapses of animal brains, with little or no effect on noradrenaline re-uptake (Claassen 1974; Claassen et al. 1977). This report describes the first three double-blind studies of fluvoxamine vs. chlorimipramine which were carried out between 1976 and 1978 by the following investigators: i. GJ Brouwer, MD and CJ Klok, ~P at "Her Groot Graffel", Warnsveld, The Netherlands 2. P Dick, MD at Bel Air Psychiatric Clinic, Geneva, Switzerland 3. JEM De Wilde, FD at Geneeskundig Instituut, Sleidinge, Belgium
475
B.S. Coleman and B.A. Block
476
Methods
Study design. Each of these studies was a double-blind four week comparison of fluvoxamine and chlorimipramine in hospitalized depressed patients. Ninety-eight patients were treated in all, with 36, 32 and 30 patients at the respective centers. Diagnoses included both unipolar and bipolar depression, with the dysphoric mood accompanied by at least five of Feighner's criteria (Feighner et al. 1972). Clinical assessments were performed at baseline and weekly thereafter and included: Hamilton Rating Scale for Depression, clinical global impression scale, and self ratings. Safety and tolerance were evaluated by routine laboratory tests, electrocardiograms and physical examinations. Drug Administration. Double-blind medication was administered according to the following schedules: #i: fixed dosing at 150 mg/day, #2: fixed-flexible dosing 100-150 mg/day, ~3: fixed-flexible dosing 150-300 mg/day. A summary of the efficacy of the two drugs: fluvoxamine and chlorimipramine is given in Table i.
Results
Ma~or Efficacy Variables Fluvoxamine produced over time a systematic reduction of depression, which was equivalent to that of chlorimipramine.
Table I
SUMMARY OF END POINT EFFICACY ANALYSIS Response Variable
Fluvoxamine Mean N
Chlorimipramine Mean N
P-value
HAM-D TOTAL Pre-treatment End-treatment % improvement
25.4 8.8
41 41 64.0
24.6 8.6
43 43 65.8
0.81 0.59
Clinical Global Impressions Severity Pre-treatment End-treatment Improvement End-treatment Improved No change Worse
Drop outs * Markedly ill ** Mildly ill # Much improved
5.8* 3.0**
41 41
5.5* 2.6**
43 43
0.13 0.13
1.95#
41 32 8 1
1.91#
43 31 ii 1
0.38
9
5
Fluvoxamine maleate - A comparison with chlorimipramine
477
Safety and Tolerance (Fig. i) Fewer fluvoxamine treated patients reported anticholinergic synptoms than those treated with chlorimipramine.
50 40
** P = 0.01 • P = 0.032
;
30
20-
10-
~ 23
Dry Mouth
Tremor
Nausea
One or More Anticholinergic Symptoms
40 30
~ [~-~'51
20 10 i5
0 Week
Pre 1 2 3 4
Insomnia
Pre 1 2 3
,
Pre
Pre 1 2 3
4
Sweating
Asthenia
Constipation
234
Week
Pre
1
2
3
4
[] Ruvoxamine
n =
47
47
45
45
41
[] Chlorimipramine
n =
44
44
44
43
41
Fig. i.
Side-effects of fluvoxamine and chlorimipramine. % incidence per week.
478
B.S. Coleman and B.A. Block
No systematic changes in laboratory test variables were noted with fluvoxamine. Fluvoxamine has little effect on blood pressure, while a statistically significant decrease (mean 7.9 mm HG) in systolic blood pressure was found after treatment with chlorimipramine. A decreased heart rate was noted in fluvoxamine-treated subjects in one study (Belgium). precipitation of hypomania was noted in any of the studies.
No
Conclusions
Fluvoxamine is comparable to chlorimipramine in antidepressant activity. There were fewer anticholinergic symptoms with fluvoxamine and no evidence of systemic toxicity.
References CLAASEN, V.
(1974) Pharmacological properties of DU23000
Duphar report no. 56648/30/74
CLAASSEN, V., DAVIES, J.E., HERTTING, G. AND PLACHETA, P. (1977) Fluvoxamine, a specific 5 hydroytryptamine uptake inhibitor Brit J Pharmacol 60, 505-516 FEIG~R~ER, J.P., ROBINS, E., GUZE, S.B., WOODRUFF, R.A., WINOKUR, G. AND MUNOZ, R. Diagnostic criteria for use in psychiatric research Arch Gen Psychiat 26, 57-63
(1972)
KLOK, C.J., BROUWER, G.J., VAN PRAAG, H.M. AND IX)OGAN, D.P. ( 1 9 8 1 ) Fluvoxamine and chlomipramine in depressed patients, a double-blind clinical study Acta Psychiat Scand 64f i-ii PRAAG, H.M. VAN ( 1 9 8 0 ) Central monoamine metabolism in depressions. I. serotonin and related compounds. Comprehens Psychiat 21, 30-43
Inquiries and reprint requests should be addressed to: Dr. Bernard Coleman Director of Clinical Research Kali-Duphar Laboratories, Inc. P.O. Box 29560 Colt~bus, Ohio 43229-1177
0278-5846/82/060475-04503.00/0 Copyright © 1982 Pergamon Press Ltd.
FLUVOXAMINE MALEATE, A SEROTONERGIC ANTIDEPRESSANT; A COMPARISON WITH CHLORIMIPRAMINE
BERNARD S. COLEMAN and BARBARA A. BLOCK
Kali-Duphar Laboratories, Inc. Columbus, Ohio, USA
(Final form, August 1982)
Abstract Coleman, Bernard S. and Barbara A. Block: Fluvoxamine maleate, a serotonergic antidepressant; a cc~parison with chlorimipramine. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1982, 6(4-6) : 475-478. i. 2. 3.
4. 5.
Fluvoxamine is a potent serotonin re-uptake inhibitor, with little or no noradrenergic or anticholinergic activity. The results of three studies using an almost identical protocol with a prospectively randomized, double-blind design comparing fluvoxamine and chlorimipramine are presented. Tn a population of 98 subjects suffering from a variety of depressive conditions, there was a marked improvement over four weeks in both groups, dosage was maintained between 150 and 300 mg per day. There were no changes of clinical importance in vital signs, hematology or biochemistry, but pulse rates increased in the chlorimipramine group. There were fewer concurrent signs and symptoms in the fluvoxamine group, especially those attributable to anticholinergic activity.
Keywords:
anticholinergic activity, chlorimipramine, fluvoxamine, serotonin
Introduction
In the continuing search for "the right drug for the right patient", investigations into depression have focused upon several of the amine systems. Central serotonin (5-HT) metabolism has played a major role in such research (Praag, van 1980). Fluvoxamine maleate (DU 23000) has been shown in animal studies to inhibit serotonin re-uptake at the synapses of animal brains, with little or no effect on noradrenaline re-uptake (Claassen 1974; Claassen et al. 1977). This report describes the first three double-blind studies of fluvoxamine vs. chlorimipramine which were carried out between 1976 and 1978 by the following investigators: i. GJ Brouwer, MD and CJ Klok, ~P at "Her Groot Graffel", Warnsveld, The Netherlands 2. P Dick, MD at Bel Air Psychiatric Clinic, Geneva, Switzerland 3. JEM De Wilde, FD at Geneeskundig Instituut, Sleidinge, Belgium
475
B.S. Coleman and B.A. Block
476
Methods
Study design. Each of these studies was a double-blind four week comparison of fluvoxamine and chlorimipramine in hospitalized depressed patients. Ninety-eight patients were treated in all, with 36, 32 and 30 patients at the respective centers. Diagnoses included both unipolar and bipolar depression, with the dysphoric mood accompanied by at least five of Feighner's criteria (Feighner et al. 1972). Clinical assessments were performed at baseline and weekly thereafter and included: Hamilton Rating Scale for Depression, clinical global impression scale, and self ratings. Safety and tolerance were evaluated by routine laboratory tests, electrocardiograms and physical examinations. Drug Administration. Double-blind medication was administered according to the following schedules: #i: fixed dosing at 150 mg/day, #2: fixed-flexible dosing 100-150 mg/day, ~3: fixed-flexible dosing 150-300 mg/day. A summary of the efficacy of the two drugs: fluvoxamine and chlorimipramine is given in Table i.
Results
Ma~or Efficacy Variables Fluvoxamine produced over time a systematic reduction of depression, which was equivalent to that of chlorimipramine.
Table I
SUMMARY OF END POINT EFFICACY ANALYSIS Response Variable
Fluvoxamine Mean N
Chlorimipramine Mean N
P-value
HAM-D TOTAL Pre-treatment End-treatment % improvement
25.4 8.8
41 41 64.0
24.6 8.6
43 43 65.8
0.81 0.59
Clinical Global Impressions Severity Pre-treatment End-treatment Improvement End-treatment Improved No change Worse
Drop outs * Markedly ill ** Mildly ill # Much improved
5.8* 3.0**
41 41
5.5* 2.6**
43 43
0.13 0.13
1.95#
41 32 8 1
1.91#
43 31 ii 1
0.38
9
5
Fluvoxamine maleate - A comparison with chlorimipramine
477
Safety and Tolerance (Fig. i) Fewer fluvoxamine treated patients reported anticholinergic synptoms than those treated with chlorimipramine.
50 40
** P = 0.01 • P = 0.032
;
30
20-
10-
~ 23
Dry Mouth
Tremor
Nausea
One or More Anticholinergic Symptoms
40 30
~ [~-~'51
20 10 i5
0 Week
Pre 1 2 3 4
Insomnia
Pre 1 2 3
,
Pre
Pre 1 2 3
4
Sweating
Asthenia
Constipation
234
Week
Pre
1
2
3
4
[] Ruvoxamine
n =
47
47
45
45
41
[] Chlorimipramine
n =
44
44
44
43
41
Fig. i.
Side-effects of fluvoxamine and chlorimipramine. % incidence per week.
478
B.S. Coleman and B.A. Block
No systematic changes in laboratory test variables were noted with fluvoxamine. Fluvoxamine has little effect on blood pressure, while a statistically significant decrease (mean 7.9 mm HG) in systolic blood pressure was found after treatment with chlorimipramine. A decreased heart rate was noted in fluvoxamine-treated subjects in one study (Belgium). precipitation of hypomania was noted in any of the studies.
No
Conclusions
Fluvoxamine is comparable to chlorimipramine in antidepressant activity. There were fewer anticholinergic symptoms with fluvoxamine and no evidence of systemic toxicity.
References CLAASEN, V.
(1974) Pharmacological properties of DU23000
Duphar report no. 56648/30/74
CLAASSEN, V., DAVIES, J.E., HERTTING, G. AND PLACHETA, P. (1977) Fluvoxamine, a specific 5 hydroytryptamine uptake inhibitor Brit J Pharmacol 60, 505-516 FEIG~R~ER, J.P., ROBINS, E., GUZE, S.B., WOODRUFF, R.A., WINOKUR, G. AND MUNOZ, R. Diagnostic criteria for use in psychiatric research Arch Gen Psychiat 26, 57-63
(1972)
KLOK, C.J., BROUWER, G.J., VAN PRAAG, H.M. AND IX)OGAN, D.P. ( 1 9 8 1 ) Fluvoxamine and chlomipramine in depressed patients, a double-blind clinical study Acta Psychiat Scand 64f i-ii PRAAG, H.M. VAN ( 1 9 8 0 ) Central monoamine metabolism in depressions. I. serotonin and related compounds. Comprehens Psychiat 21, 30-43
Inquiries and reprint requests should be addressed to: Dr. Bernard Coleman Director of Clinical Research Kali-Duphar Laboratories, Inc. P.O. Box 29560 Colt~bus, Ohio 43229-1177