182
Combined Treatment with Imipramine and Mianserin A Controlled Pilot Study L. Lauritzen, L. Clemmesen. R. Klysner. D. Loldrup. M. Lunde. E. Schaumburg. S. Waarst. P. Bech Department ofPsychiatry, Frederiksborg General Hospital, Hillemd, Denmark
The effect of imipramine plus mianserin and imipramine plus a placebo was compared in 40 depressed patients with a median age of 60 years. The imipramine dosage was flexible to give a plasma concentration around 200 nmol/I and mianserin was given at a fIxed dosage of 30 mg daily. After six weeks of treatment the results showed that the scores on the Hamilton Depression Scale as weil as on the Melancholia Scale were signifIcantly more improved in the imipramine-plus-minaserin group than in the group of patients receiving imipramine alone (P 15 (7).
needed, otherwise no concomitant psychotropic drugs were prescribed. The Newcastle Depression Scale (9, 10) was used as a diagnostic tool for the subc1assification of patients into endogenous and nonendogenous depressives. The DSMIII (11) was used as standard c1assification system for categories of current major depression and less than-major depression currently (dysthymia and atypical depression).
Statistical Analysis It was decided to accept a type-l error risk of 5 %. Furthermore, the smallest difference not to be overlooked at end-point was a Hamilton score of 6 points. The acceptable type-2 error was 10%. Accodingly, the number needed in each group was 21 patients. In the statistical testing of the null hypothesis and other statistical inferences, nonparametric tests were used. Intention-to-treat approach: in this part of the analysis all patients allocated to treatment have been considered. For patients who did not complete the planned treatment period of six weeks, it was decided to carry forward the last observations. Explanatory approach: in this part of the analysis only patients who had completed all six weeks of treatment were considered. The levels of statistical significance were 5 percent and I percent. Only two-tailed analyses were considered apart from the Fisher test, where the exact percentage is shown.
Results
Procedure Depressed patients requiring treatment were examined with regard to inc1usion and exc1usion criteria and e1igible patients were started on a three-day wash-out period. Patients still fulfilling inc1usion criteria were randomly allocated to treatment with either imipramine plus mianserin (group A) or imipramine plus placebo (group B). Informed consent to treatment was obtained. Imipramine was started at a dosage of 50 mg twice daily for patients under 60 years of age, and 25 mg twice daily for patients over 60 years of age; thereafter it was administered at flexible dosages in order to maintain a plasma level of imipramine of around 200 nmolfl. This was done without violating the double-blindness principle. Group A was treated with a fixed dosage of 30 mg mianserin daily and imipramine, group B was treated with placebo and imipramine, the study being a controlled double-blind study. The duration of treatment was six weeks. All patients were examined prior to treatment and once a week in the following period by a psychiatrist who was trained in the rating procedure as member of the DUAG group (6). The interrater reliability was 0.76 for the Newcastle scale, 0.73 for the Hamilton Depression Scale, and 0.75 for the Me1ancholia Scale. At each examination the Hamilton Scale (17 items), Hamilton's subscale (6 items), and the Melancholia scale were used for assessment (7). Side-effects were registered according to the UKU side-effect scale (8). Finally, hematologic according profiles, to determinate renal and hepatic functions as weil as leucocytes, and standard electrocardiograms were obtained prior to treatment and at maximum dosage. Oxazepam was used when a hypnotic was
183
In total, 46 depressive patients were inc1uded. During the wash-out period of three days, six patients dropped out. This was due to the need for concomitant treatment with neuroleptics (2), switch to mania (1), and concomitant somatic illnesses (3). A total of 40 patients (10 men and 30 women) thus started active treatment; of those, 22 patients were randomly allocated to treatment with imipramine and mianserin (8 men and 14 women, ranging from 44 to 75 years of age, median age = 52), and 18 patients were allocated to imipramine alone (2 men and 16 women, ranging from 44 to 84 years of age, median age = 63). Of these 40 patients, 29 completed the treatment period of six weeks. In group A, six patients dropped out: two were transferred to electroconvulsive therapy (ECT) due to a worsening of their conditions, one patient committed suicide, one patient attempted suicide, one patient developed intolerable side-effects, and one patient showed noncompliance. Hence, a total of 16 ofthe 22 patients (73%) in group A completed the treatment. Of the 18 patients in group B, five patients dropped out. The reasons for dropping out were the following: two patients were transferred to ECT due to a worsening of their conditions, one patient developed mania, one patient developed intolerable side-effects, and one patient showed noncompliance. Hence, a total of 13 of the 18 patients (or 73%) in group B completed the six weeks oftreatment. Within the group of completers no significant difference was seen in the diagnostic c1assification between the two groups of patients, neither on the Newcastle scale
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tions the antidepressive effect of imipramine alone versus imipramine and mianserin in elderly depressed patients, the null hypothesis being the following: there is no difference in the efficacy of imipramine and the efficacy of imipramine plus mianserin in the treatment of elderly patients suffering from depression.
Pharmacopsychiat. 25 (1992)
L. Lauritzen et al.
184 Pharmacopsychiat. 25 (1992) -plus mianserin, N = 22); group B (imipramine plus placebo, N = 18). HDS = Hamilton Depression Scale, MES = Melancholia Scale. Median score (25 -75 percent). Day
Scale
GroupA
Group B
0
HDS
25.2 (21.0- 27.0) 23.6 (21.0- 28.0) 19.2 (17.0-23.0) 20.3 (19.0-24.0) 14.2 (12.0-18.0) 15.0 (13.0-20.0) 14.2 (10.0-19.0) 16.0 (10.0-22.0) 11.6 (7.0-16.0) 12.6 (6.0-17.0) 7.5 (5.3-14.0) 8.5 (4.0-14.0) 8.0 (2.0-11.0) 9.0 (2.0-13.0)
22.4 (19.0 - 29.0) 21.6 (19.0 - 25.0) 18.3 (14.0-23.0) 17.5 (14.0-22.0) 15.7 (10.0-20.0) 13.8 (10.0 - 22.0) 14.4 (10.0-17.0) 12.5 (9.0-17.0) 11.2 (9.0-17.0) 11.4 (7.0-18.0) 11.0 (8.0-18.0) 12.0 (7.0-20.0) 14.0 (9.0-23.0) 14.9 (8.0-20.0)
MES 7
HDS MES
14
HDS MES
21
HDS MES
28
HDS MES
35
HDS MES
42
HDS MES
p Mann-Withney ns
Table 2 The explanatory approach: group A (imipramine plus
mianserin, N = 16); group B(imipramine plus placebo, N = 13). HDS = Hamilton Depression Scale, MES = Melancholia Scale. Median score (25-75 percent). Day
Scale
GroupA
Group B
0
HDS
25.5 (21.0- 28.0) 23.5 (20.5-28.0) 19.0 (17.0-23.0) 20.0 (19.0 - 24.0) 14.0 (12.0-17.0) 14.0 (11.0-19.0) 14.0 (8.0-19.0) 15.0 (9.0-21.0) 11.0 (9.0-14.0) 10.0 (6.0-16.0) 7.0 (5.0-13.0) 6.0 (4.0-14.0) 7.0 (1.0- 9.0) 8.0 (1.0-10.5)
22.0 (18.0-24.0) 20.0 (16.0-25.0) 17.0 (13.5-20.5) 17.5 (12.5-21.0) 14.5 (9.5-18.5) 12.5 (9.0-17.0) 14.0 (10.0-15.0) 12.0 (8.0-15.0) 11.0 (9.5-16.0) 11.0 (7.5-16.5) 11.0 (8.5-16.5) 11.5 (7.0-17.5) 13.0 (9.0-17.0) 14.0 (8.0-17.0)
ns ns
MES 7
ns ns
MES 14
ns ns
21
28
Combined Treatment with Imipramine and Mianserin A Controlled Pilot Study L. Lauritzen, L. Clemmesen. R. Klysner. D. Loldrup. M. Lunde. E. Schaumburg. S. Waarst. P. Bech Department ofPsychiatry, Frederiksborg General Hospital, Hillemd, Denmark
The effect of imipramine plus mianserin and imipramine plus a placebo was compared in 40 depressed patients with a median age of 60 years. The imipramine dosage was flexible to give a plasma concentration around 200 nmol/I and mianserin was given at a fIxed dosage of 30 mg daily. After six weeks of treatment the results showed that the scores on the Hamilton Depression Scale as weil as on the Melancholia Scale were signifIcantly more improved in the imipramine-plus-minaserin group than in the group of patients receiving imipramine alone (P 15 (7).
needed, otherwise no concomitant psychotropic drugs were prescribed. The Newcastle Depression Scale (9, 10) was used as a diagnostic tool for the subc1assification of patients into endogenous and nonendogenous depressives. The DSMIII (11) was used as standard c1assification system for categories of current major depression and less than-major depression currently (dysthymia and atypical depression).
Statistical Analysis It was decided to accept a type-l error risk of 5 %. Furthermore, the smallest difference not to be overlooked at end-point was a Hamilton score of 6 points. The acceptable type-2 error was 10%. Accodingly, the number needed in each group was 21 patients. In the statistical testing of the null hypothesis and other statistical inferences, nonparametric tests were used. Intention-to-treat approach: in this part of the analysis all patients allocated to treatment have been considered. For patients who did not complete the planned treatment period of six weeks, it was decided to carry forward the last observations. Explanatory approach: in this part of the analysis only patients who had completed all six weeks of treatment were considered. The levels of statistical significance were 5 percent and I percent. Only two-tailed analyses were considered apart from the Fisher test, where the exact percentage is shown.
Results
Procedure Depressed patients requiring treatment were examined with regard to inc1usion and exc1usion criteria and e1igible patients were started on a three-day wash-out period. Patients still fulfilling inc1usion criteria were randomly allocated to treatment with either imipramine plus mianserin (group A) or imipramine plus placebo (group B). Informed consent to treatment was obtained. Imipramine was started at a dosage of 50 mg twice daily for patients under 60 years of age, and 25 mg twice daily for patients over 60 years of age; thereafter it was administered at flexible dosages in order to maintain a plasma level of imipramine of around 200 nmolfl. This was done without violating the double-blindness principle. Group A was treated with a fixed dosage of 30 mg mianserin daily and imipramine, group B was treated with placebo and imipramine, the study being a controlled double-blind study. The duration of treatment was six weeks. All patients were examined prior to treatment and once a week in the following period by a psychiatrist who was trained in the rating procedure as member of the DUAG group (6). The interrater reliability was 0.76 for the Newcastle scale, 0.73 for the Hamilton Depression Scale, and 0.75 for the Me1ancholia Scale. At each examination the Hamilton Scale (17 items), Hamilton's subscale (6 items), and the Melancholia scale were used for assessment (7). Side-effects were registered according to the UKU side-effect scale (8). Finally, hematologic according profiles, to determinate renal and hepatic functions as weil as leucocytes, and standard electrocardiograms were obtained prior to treatment and at maximum dosage. Oxazepam was used when a hypnotic was
183
In total, 46 depressive patients were inc1uded. During the wash-out period of three days, six patients dropped out. This was due to the need for concomitant treatment with neuroleptics (2), switch to mania (1), and concomitant somatic illnesses (3). A total of 40 patients (10 men and 30 women) thus started active treatment; of those, 22 patients were randomly allocated to treatment with imipramine and mianserin (8 men and 14 women, ranging from 44 to 75 years of age, median age = 52), and 18 patients were allocated to imipramine alone (2 men and 16 women, ranging from 44 to 84 years of age, median age = 63). Of these 40 patients, 29 completed the treatment period of six weeks. In group A, six patients dropped out: two were transferred to electroconvulsive therapy (ECT) due to a worsening of their conditions, one patient committed suicide, one patient attempted suicide, one patient developed intolerable side-effects, and one patient showed noncompliance. Hence, a total of 16 ofthe 22 patients (73%) in group A completed the treatment. Of the 18 patients in group B, five patients dropped out. The reasons for dropping out were the following: two patients were transferred to ECT due to a worsening of their conditions, one patient developed mania, one patient developed intolerable side-effects, and one patient showed noncompliance. Hence, a total of 13 of the 18 patients (or 73%) in group B completed the six weeks oftreatment. Within the group of completers no significant difference was seen in the diagnostic c1assification between the two groups of patients, neither on the Newcastle scale
Downloaded by: University of British Columbia. Copyrighted material.
tions the antidepressive effect of imipramine alone versus imipramine and mianserin in elderly depressed patients, the null hypothesis being the following: there is no difference in the efficacy of imipramine and the efficacy of imipramine plus mianserin in the treatment of elderly patients suffering from depression.
Pharmacopsychiat. 25 (1992)
L. Lauritzen et al.
184 Pharmacopsychiat. 25 (1992) -plus mianserin, N = 22); group B (imipramine plus placebo, N = 18). HDS = Hamilton Depression Scale, MES = Melancholia Scale. Median score (25 -75 percent). Day
Scale
GroupA
Group B
0
HDS
25.2 (21.0- 27.0) 23.6 (21.0- 28.0) 19.2 (17.0-23.0) 20.3 (19.0-24.0) 14.2 (12.0-18.0) 15.0 (13.0-20.0) 14.2 (10.0-19.0) 16.0 (10.0-22.0) 11.6 (7.0-16.0) 12.6 (6.0-17.0) 7.5 (5.3-14.0) 8.5 (4.0-14.0) 8.0 (2.0-11.0) 9.0 (2.0-13.0)
22.4 (19.0 - 29.0) 21.6 (19.0 - 25.0) 18.3 (14.0-23.0) 17.5 (14.0-22.0) 15.7 (10.0-20.0) 13.8 (10.0 - 22.0) 14.4 (10.0-17.0) 12.5 (9.0-17.0) 11.2 (9.0-17.0) 11.4 (7.0-18.0) 11.0 (8.0-18.0) 12.0 (7.0-20.0) 14.0 (9.0-23.0) 14.9 (8.0-20.0)
MES 7
HDS MES
14
HDS MES
21
HDS MES
28
HDS MES
35
HDS MES
42
HDS MES
p Mann-Withney ns
Table 2 The explanatory approach: group A (imipramine plus
mianserin, N = 16); group B(imipramine plus placebo, N = 13). HDS = Hamilton Depression Scale, MES = Melancholia Scale. Median score (25-75 percent). Day
Scale
GroupA
Group B
0
HDS
25.5 (21.0- 28.0) 23.5 (20.5-28.0) 19.0 (17.0-23.0) 20.0 (19.0 - 24.0) 14.0 (12.0-17.0) 14.0 (11.0-19.0) 14.0 (8.0-19.0) 15.0 (9.0-21.0) 11.0 (9.0-14.0) 10.0 (6.0-16.0) 7.0 (5.0-13.0) 6.0 (4.0-14.0) 7.0 (1.0- 9.0) 8.0 (1.0-10.5)
22.0 (18.0-24.0) 20.0 (16.0-25.0) 17.0 (13.5-20.5) 17.5 (12.5-21.0) 14.5 (9.5-18.5) 12.5 (9.0-17.0) 14.0 (10.0-15.0) 12.0 (8.0-15.0) 11.0 (9.5-16.0) 11.0 (7.5-16.5) 11.0 (8.5-16.5) 11.5 (7.0-17.5) 13.0 (9.0-17.0) 14.0 (8.0-17.0)
ns ns
MES 7
ns ns
MES 14
ns ns
21
28
