Acta psychiat. scand. (1977) 55, 10-20 Dept. of Psychiatry (Head: Prof. I.-0. Ottosson, M.D.), University of Gothenburg, Dept. of Psychiatry (Head: Prof. G. Wretrnark, M.D.), University of Linkoping, Dept. of Psychiatry (Head: Prof. C. Ferris, M.D.), University of Umefi, and the Research Laboratories, Leo AB, Helsingborg, Sweden
Comparative clinical evaluation of lofepramine and imipramine PSYCHlATRIC ASPECTS G. ~‘ELIA, S. BORG,L. HERMANN, G . LUNDIN,C. PERRIS,H.mom, G . ROMANAND B. SIWERS Lofepramine, an imipramine analogue, was compared with imipramine in a multicentre, double-blind clinical trial. The 62 patients (31 in each of two treatment groups) had a depressive syndrome that normally would have been treated with a tricyclic antidepressant. These patients had not received any adequate treatment for their present depressive episode. After a wash-out period and once a week during treatment (up to 5 weeks), routine laboratory tests and eIectrocardiograms were done. The dosage was 50 mg t.i.d. for imipramine and 70 mg t.i.d. for lofepramine. Depression ratings with the Cronholm-Ottosson depression rating scale were performed before treatment and once weekly for 3 weeks and then in the 5th week. The last four ratings were combined with rating of side-effects. In the 5th week of treatment 15 out of 31 in the lofepramine group and 18 out of 31 in the imipramine group had recovered. This difference was not significant, nor did the median values of individual symptoms differ between the groups. The side-effects were moderate and the two groups only differed significantly in the items “dry mouth” and accommodation disturbances in favour of lofepramine. The drug compliance was checked by plasma levels of desmethylimipramine in the imipramine group, parent compound, and “apparent” desmethylimipramine in the lofepramine group. The relationship between plasma drug levels, the effect on noradrenaline uptake in v i m and amelioration is discussed in Siwers et al. (1977)in this issue. The clinical outcome in the two groups did not differ significantly; interpretation of this result is discussed in relation to the reliability of rating and selection of patients.
Key words: Tricyclic antidepressant - lofepramine - imipramine depression rating
- side-effects.
Earlier investigations concerning the imipramine analogue, lofepramine, indicate that it has some favourable properties: fairly low toxicity, low cardiotoxicity (Boek (1972)), and weak anticholinergic effects (Eriksoo & Rohte (1970)).
11 Lofepramine has a high lipophilicity and a low base strength, which means a rapid absorption and distribution to the central nervous system (Plym Forshell (1975)). Its pharmacodynamic profile is in accordance with antidepressants in current use (Siwers et al. (1970)). In other clinical trials an antidepressive effect has been observed (Bucht et al. (1971), Angst et al. (1975)). In the present study, a controlled comparative trial of lofepramine and h i pramine was performed in depressed in- and out-patients with reference to the effect on various depressive symptoms, rapidity of action, and side-effects. The relationships between clinical effects and plasma concentrations of the drug as well as the noradrenaline uptake and the inhibitory capacity of patients’ plasma to inhibit noradrenaline uptake in nerve-endings are published in a succeeding paper (Siwers et al. (1977)).
PATIENTS AND METHODS Design and setting The study was a double-blind comparison with random allocation of the patients to the two treatment groups. The treatment was intended to last 5 weeks with ratings of symptoms before the start and 1, 2, 3 and, if possible, 5 weeks thereafter. The last four ratings were combined with rating of side-effects. The study was performed in three different psychiatric clinics. Many of the staff members of the departments have collaborated in previous projects. The psychiatric frame of reference was the same in the different departments, and may be characterized as eclectic. Patients Sixty-two in- and out-patients aged 20-60 years with a depressive syndrome of such an intensity that pharmacological treatment was required were included in the study. At least three symptom-free months should have elapsed since a preceding adequately treated depressive episode. The following patients were excluded: 1. Patients with a depressive syndrome of clearly psychotic dimension or with obvious suicidal intentions. 2. Patients who already had received adequate treatment with antidepressants during the present episode. Treatment given irregularly or for less than 7 days was not regarded as a basis for exclusion if it had been interrupted at least 7 days before the beginning of the trial and if the dosage of antidepressants had not exceeded 100 mg daily (for protriptyhe 30 mg daily). 3. Pregnant women. 4. Alcoholics and drug addicts. 5. Patients with relevant somatic diseases such as heart disorders, kidney or liver diseases, hypertrophy of the prostate, glaucoma, epilepsy, cerebral damage. In Table 1 patient characteristics are shown. The two groups (31 patients in each) were balanced as regards sex, age, and previous history of depression. All differences between the groups are within the range of chance. No patients received any formal psychotherapy during the study.
12 Table 1. The patient characteristics Lofepramine Imipramine (n = 31) (n = 31)
Variable Sex
Male Female
10 21
12 19
41.2 10.1 40.9 12.8
34.4 8.6 41.5 14.7
Unipolar Bipolar First episode
18 2 11
17 3 11
Endogenous Mixed
14 17
8 23
18
18
5
4
13 14 2 2
7 19 5 0
23 8
25 6
Male Female Type of depression
Antidepressant drugs during previous episodes ECT during previous
Mean s.d. Mean s.d.
episodes after antidepressant drugs had failed Duration of the present period (months)
In-patients Out-patients
6
Dosage The tablets contained 35 mg of lofepramine or 25 mg of imipramine, which are approximately equimolar quantities and considered equipotent as regards noradrenaline uptake inhibition in vitro (Tuck et aI. (1973)). The initial dose was one tablet t.i.d. increased by one tablet on each of the following days up to a total of six tablets daily. This dosage was to be kept as constant as possible during the 5 weeks of trial but could be reduced or augmented in relation to sideeffects and/or therapeutic effect. Addition of hypnotics (pentobarbital or methaqualone) was permitted if necessary. The treatment was preceded by a washout period of 7 days. Experimental method Depressive symptoms were rated by the doctors using an expanded version of Cronholm-Ottosson’s depression scale (CODS) (Ottosson (1960)) and by the patients themselves with the Zung self-rating scale (ZRS) (Zung (1965)). The Cronholm-Ottosson scale comprises 12 subscales, each with seven steps, when using half-points, from normal (0) to the most pronounced degree of the disturbance (3). On the basis of the assumption of common underlying variables the
13 Table 2. Coefficients of reliability for the CODS (three patients and eight raters) Item I
IIa I1 b I1 c I1 d I11 IV V
VI 2
I-VI VII
VIII IX 2 VII-IX 2
I-IX
Coefficient Mood
SO
Anxiety Restlessness Tension Vegetative disturbances Suicidal tendencies Depressive ideas Hypochondriac ideas Sleep disturbances
.51 .17 .51 .76
Depression-anxiety score
.89
Experience of intellectual and conative inhibition Experience of emotional indifference Psychomotor retardation
.47 .59 .81
Retardation score
.84
Total score
.91
.83
.35 .76 .62
symptoms were combined in a depression-anxiety syndrome and a retardation syndrome which together constitute the total depressive syndrome. The global changes in state were rated by the doctors, who considered depressive symptoms, side-effects, and general level of social functioning (Table 3). In order to test the reliability of the ratings, four joint training sessions for the participating psychiatrists were arranged during the study. The reliability of the rating from one of the training sessions is presented in Table 2, which shows that the reliability of the ratings is fair for the individual symptoms and high for the grouped depressive symptoms. By an unfortunate mistake the results from the other joint training sessions were lost. At each check-up a simple rating scale for side-effects was used. The patient was asked to rate changes during the last week. The ratings were made on a four-step scale: 0 = no side-effect; 1 = mild side-effect, no change needed; 2 = moderate side-effect, special steps must be taken, e.g. smaller doses or addition of some other drug; 3 = serious side-effect, treatment discontinued. Statistical methods As estimates of the effect of treatment, differences between the initial score and the score at later rating (sign and symptoms, syndromes, total score) were used, together with global ratings. Central values are given in medians and intergroup differences were tested with the Wilcoxon’s rank s u m test (Bradley (1968)). Differences in side-effects were tested with the Fisher’s four-field test. Coefficients of reliability were calculated by means of intraclass correlation according to the Ebel’s formula (Guilford (1954, p. 395)) which gives the mean reliability for one rater.
14 Table 3. Distribution of patients according to global ratings
~~
1week Lo Im
2 weeks Lo Im
3 weeks Lo Im
5 weeks Lo Im
4 2 11 12 1 6 1 6 0 0
6 14 8 1
7 15 6 1
12 10 4 1
12 9 5 0
11 7 2 0
16
31
30
29
29
27
26
20
21
0 0 0
0 0 0
0 0 0
0 0 1
1 1 0
1 0 2
4 2 2
2 0 2
0
1
2
1
2
2
3
6
2 5-8
0
1
2
2
4
5 1 1 1 0
2 1-8
31
31
31
31
31
~
~
~~
1 Recoveredormuchimproved 2 Slightly improved 3 Unchanged 4 Impaired
2 1-4
~
5 0
0
~
Drop-outs 5 Recovered 6 Impaired 7 Side-effects 8 Non-cooperation or other reason
31
31
31
Lo, lofepramine. Im,imipramine.
RESULTS As already mentioned, 62 patients fulfilled all selection criteria. Global effect The global ratings give the main results of the study and are shown in Table 3. Fifty-three patients completed 3 weeks of treatment. Thirteen patients in each group had recovered or were much improved. There were no significant differences between the two treatment groups either in the time for onset of improvement or in the therapeutic outcome. At the 5th week of treatment, 15 patients in the lofepramine group and 18 in the imipramine group (including recovered drop-outs) were recovered or much improved. This difference is not significant either.
E&ct on Cronholm-Ottosson’s depression scale Fifty-three patients were rated with CODS during 3 weeks’ treatment. Table 4 shows the results in median values from three ratings for the individual symptoms and syndromes. There are no significant differences between the two groups, the only exception being the symptom “intellectual and conative inhibition”, which may be explained by initial difference. A separate analysis of the actual rating scores at the 3rd week of treatment showed no differences between the two treatment groups. Because of the high number of drop-outs and different reasons for early termination (Table 3), the results at the 5th week of treatment (Fig. 1) cannot be considered for a comparison of the overall clinical effect. There are no statistically significant differences between the two
15
Table 4. Median values of initial rating scores and differences between the initial and later rating scores (n = 53, Lo = 27, Irn = 26) Initial score
1week
Symptom
Im
2weeks Im
Im
Lo
2.0 2.0 0.9 1.1 1.2 1.0 1.3 0.2 1.4
2.1 1.9 0.9 1.2 1.1 1.0 1.2 0.2 1.9
0.6 0.3 0.1 0.1 0.2 0.5 0.2 0.1 0.1
0.4 0.3 0.0 0.2 0.1 0.2 0.2 0.0 0.5
0.8 0.8 0.2 0.2 0.3 0.6 0.8 0.1 0.6
0.9 0.5 0.1 0.2 0.2 0.8 0.3 0.1 0.8
11.2
11.3
2.6
4.6
4.6
Experience of intellectual 1.8 and conative inhibition
2.0
0.2
0.6
0.6
Lo
Lo
3 weeks
Lo
Im
n=27 n=26 n=27 n=25 n=27 n=25 n=27 n=26
I I1 a I1 b I1 c I1 d I11 IV V
VI
Depression of mood Anxiety Restlessness Tension Vegetative disturbances Suicidal tendencies Depressive ideas Hypochondriac ideas Sleep disturbances
1.0 0.9 0.2 0.7 0.8 0.9 0.1 0.3
1.2 0.8 0.1 0.3 0.4 0.9 0.9 0.1 0.8
4.7
6.0
6.5
0.9
0.8
0.9
2 I-VI Depressionanxiety score VII
P VIII IX
Experience of emotional indifference Psychomotor retardation
1.8 1.1
0.9
0.3 0.2
0.9 0.4
0.4
0.8 0.9
1.0 0.8
0.9 1.1
4.3
1.0
1.9
1.9
2.0
2.7
3.0
13.8
14.6
3.3
5.9
5.9
6.8
8.5
9.5
Zung’s Index (Lo: n = 21, Im: n = 20) 75.0
71.7
3.2
3.8
2.5
11.3
7.5
10.0
P
Comparative clinical evaluation of lofepramine and imipramine PSYCHlATRIC ASPECTS G. ~‘ELIA, S. BORG,L. HERMANN, G . LUNDIN,C. PERRIS,H.mom, G . ROMANAND B. SIWERS Lofepramine, an imipramine analogue, was compared with imipramine in a multicentre, double-blind clinical trial. The 62 patients (31 in each of two treatment groups) had a depressive syndrome that normally would have been treated with a tricyclic antidepressant. These patients had not received any adequate treatment for their present depressive episode. After a wash-out period and once a week during treatment (up to 5 weeks), routine laboratory tests and eIectrocardiograms were done. The dosage was 50 mg t.i.d. for imipramine and 70 mg t.i.d. for lofepramine. Depression ratings with the Cronholm-Ottosson depression rating scale were performed before treatment and once weekly for 3 weeks and then in the 5th week. The last four ratings were combined with rating of side-effects. In the 5th week of treatment 15 out of 31 in the lofepramine group and 18 out of 31 in the imipramine group had recovered. This difference was not significant, nor did the median values of individual symptoms differ between the groups. The side-effects were moderate and the two groups only differed significantly in the items “dry mouth” and accommodation disturbances in favour of lofepramine. The drug compliance was checked by plasma levels of desmethylimipramine in the imipramine group, parent compound, and “apparent” desmethylimipramine in the lofepramine group. The relationship between plasma drug levels, the effect on noradrenaline uptake in v i m and amelioration is discussed in Siwers et al. (1977)in this issue. The clinical outcome in the two groups did not differ significantly; interpretation of this result is discussed in relation to the reliability of rating and selection of patients.
Key words: Tricyclic antidepressant - lofepramine - imipramine depression rating
- side-effects.
Earlier investigations concerning the imipramine analogue, lofepramine, indicate that it has some favourable properties: fairly low toxicity, low cardiotoxicity (Boek (1972)), and weak anticholinergic effects (Eriksoo & Rohte (1970)).
11 Lofepramine has a high lipophilicity and a low base strength, which means a rapid absorption and distribution to the central nervous system (Plym Forshell (1975)). Its pharmacodynamic profile is in accordance with antidepressants in current use (Siwers et al. (1970)). In other clinical trials an antidepressive effect has been observed (Bucht et al. (1971), Angst et al. (1975)). In the present study, a controlled comparative trial of lofepramine and h i pramine was performed in depressed in- and out-patients with reference to the effect on various depressive symptoms, rapidity of action, and side-effects. The relationships between clinical effects and plasma concentrations of the drug as well as the noradrenaline uptake and the inhibitory capacity of patients’ plasma to inhibit noradrenaline uptake in nerve-endings are published in a succeeding paper (Siwers et al. (1977)).
PATIENTS AND METHODS Design and setting The study was a double-blind comparison with random allocation of the patients to the two treatment groups. The treatment was intended to last 5 weeks with ratings of symptoms before the start and 1, 2, 3 and, if possible, 5 weeks thereafter. The last four ratings were combined with rating of side-effects. The study was performed in three different psychiatric clinics. Many of the staff members of the departments have collaborated in previous projects. The psychiatric frame of reference was the same in the different departments, and may be characterized as eclectic. Patients Sixty-two in- and out-patients aged 20-60 years with a depressive syndrome of such an intensity that pharmacological treatment was required were included in the study. At least three symptom-free months should have elapsed since a preceding adequately treated depressive episode. The following patients were excluded: 1. Patients with a depressive syndrome of clearly psychotic dimension or with obvious suicidal intentions. 2. Patients who already had received adequate treatment with antidepressants during the present episode. Treatment given irregularly or for less than 7 days was not regarded as a basis for exclusion if it had been interrupted at least 7 days before the beginning of the trial and if the dosage of antidepressants had not exceeded 100 mg daily (for protriptyhe 30 mg daily). 3. Pregnant women. 4. Alcoholics and drug addicts. 5. Patients with relevant somatic diseases such as heart disorders, kidney or liver diseases, hypertrophy of the prostate, glaucoma, epilepsy, cerebral damage. In Table 1 patient characteristics are shown. The two groups (31 patients in each) were balanced as regards sex, age, and previous history of depression. All differences between the groups are within the range of chance. No patients received any formal psychotherapy during the study.
12 Table 1. The patient characteristics Lofepramine Imipramine (n = 31) (n = 31)
Variable Sex
Male Female
10 21
12 19
41.2 10.1 40.9 12.8
34.4 8.6 41.5 14.7
Unipolar Bipolar First episode
18 2 11
17 3 11
Endogenous Mixed
14 17
8 23
18
18
5
4
13 14 2 2
7 19 5 0
23 8
25 6
Male Female Type of depression
Antidepressant drugs during previous episodes ECT during previous
Mean s.d. Mean s.d.
episodes after antidepressant drugs had failed Duration of the present period (months)
In-patients Out-patients
6
Dosage The tablets contained 35 mg of lofepramine or 25 mg of imipramine, which are approximately equimolar quantities and considered equipotent as regards noradrenaline uptake inhibition in vitro (Tuck et aI. (1973)). The initial dose was one tablet t.i.d. increased by one tablet on each of the following days up to a total of six tablets daily. This dosage was to be kept as constant as possible during the 5 weeks of trial but could be reduced or augmented in relation to sideeffects and/or therapeutic effect. Addition of hypnotics (pentobarbital or methaqualone) was permitted if necessary. The treatment was preceded by a washout period of 7 days. Experimental method Depressive symptoms were rated by the doctors using an expanded version of Cronholm-Ottosson’s depression scale (CODS) (Ottosson (1960)) and by the patients themselves with the Zung self-rating scale (ZRS) (Zung (1965)). The Cronholm-Ottosson scale comprises 12 subscales, each with seven steps, when using half-points, from normal (0) to the most pronounced degree of the disturbance (3). On the basis of the assumption of common underlying variables the
13 Table 2. Coefficients of reliability for the CODS (three patients and eight raters) Item I
IIa I1 b I1 c I1 d I11 IV V
VI 2
I-VI VII
VIII IX 2 VII-IX 2
I-IX
Coefficient Mood
SO
Anxiety Restlessness Tension Vegetative disturbances Suicidal tendencies Depressive ideas Hypochondriac ideas Sleep disturbances
.51 .17 .51 .76
Depression-anxiety score
.89
Experience of intellectual and conative inhibition Experience of emotional indifference Psychomotor retardation
.47 .59 .81
Retardation score
.84
Total score
.91
.83
.35 .76 .62
symptoms were combined in a depression-anxiety syndrome and a retardation syndrome which together constitute the total depressive syndrome. The global changes in state were rated by the doctors, who considered depressive symptoms, side-effects, and general level of social functioning (Table 3). In order to test the reliability of the ratings, four joint training sessions for the participating psychiatrists were arranged during the study. The reliability of the rating from one of the training sessions is presented in Table 2, which shows that the reliability of the ratings is fair for the individual symptoms and high for the grouped depressive symptoms. By an unfortunate mistake the results from the other joint training sessions were lost. At each check-up a simple rating scale for side-effects was used. The patient was asked to rate changes during the last week. The ratings were made on a four-step scale: 0 = no side-effect; 1 = mild side-effect, no change needed; 2 = moderate side-effect, special steps must be taken, e.g. smaller doses or addition of some other drug; 3 = serious side-effect, treatment discontinued. Statistical methods As estimates of the effect of treatment, differences between the initial score and the score at later rating (sign and symptoms, syndromes, total score) were used, together with global ratings. Central values are given in medians and intergroup differences were tested with the Wilcoxon’s rank s u m test (Bradley (1968)). Differences in side-effects were tested with the Fisher’s four-field test. Coefficients of reliability were calculated by means of intraclass correlation according to the Ebel’s formula (Guilford (1954, p. 395)) which gives the mean reliability for one rater.
14 Table 3. Distribution of patients according to global ratings
~~
1week Lo Im
2 weeks Lo Im
3 weeks Lo Im
5 weeks Lo Im
4 2 11 12 1 6 1 6 0 0
6 14 8 1
7 15 6 1
12 10 4 1
12 9 5 0
11 7 2 0
16
31
30
29
29
27
26
20
21
0 0 0
0 0 0
0 0 0
0 0 1
1 1 0
1 0 2
4 2 2
2 0 2
0
1
2
1
2
2
3
6
2 5-8
0
1
2
2
4
5 1 1 1 0
2 1-8
31
31
31
31
31
~
~
~~
1 Recoveredormuchimproved 2 Slightly improved 3 Unchanged 4 Impaired
2 1-4
~
5 0
0
~
Drop-outs 5 Recovered 6 Impaired 7 Side-effects 8 Non-cooperation or other reason
31
31
31
Lo, lofepramine. Im,imipramine.
RESULTS As already mentioned, 62 patients fulfilled all selection criteria. Global effect The global ratings give the main results of the study and are shown in Table 3. Fifty-three patients completed 3 weeks of treatment. Thirteen patients in each group had recovered or were much improved. There were no significant differences between the two treatment groups either in the time for onset of improvement or in the therapeutic outcome. At the 5th week of treatment, 15 patients in the lofepramine group and 18 in the imipramine group (including recovered drop-outs) were recovered or much improved. This difference is not significant either.
E&ct on Cronholm-Ottosson’s depression scale Fifty-three patients were rated with CODS during 3 weeks’ treatment. Table 4 shows the results in median values from three ratings for the individual symptoms and syndromes. There are no significant differences between the two groups, the only exception being the symptom “intellectual and conative inhibition”, which may be explained by initial difference. A separate analysis of the actual rating scores at the 3rd week of treatment showed no differences between the two treatment groups. Because of the high number of drop-outs and different reasons for early termination (Table 3), the results at the 5th week of treatment (Fig. 1) cannot be considered for a comparison of the overall clinical effect. There are no statistically significant differences between the two
15
Table 4. Median values of initial rating scores and differences between the initial and later rating scores (n = 53, Lo = 27, Irn = 26) Initial score
1week
Symptom
Im
2weeks Im
Im
Lo
2.0 2.0 0.9 1.1 1.2 1.0 1.3 0.2 1.4
2.1 1.9 0.9 1.2 1.1 1.0 1.2 0.2 1.9
0.6 0.3 0.1 0.1 0.2 0.5 0.2 0.1 0.1
0.4 0.3 0.0 0.2 0.1 0.2 0.2 0.0 0.5
0.8 0.8 0.2 0.2 0.3 0.6 0.8 0.1 0.6
0.9 0.5 0.1 0.2 0.2 0.8 0.3 0.1 0.8
11.2
11.3
2.6
4.6
4.6
Experience of intellectual 1.8 and conative inhibition
2.0
0.2
0.6
0.6
Lo
Lo
3 weeks
Lo
Im
n=27 n=26 n=27 n=25 n=27 n=25 n=27 n=26
I I1 a I1 b I1 c I1 d I11 IV V
VI
Depression of mood Anxiety Restlessness Tension Vegetative disturbances Suicidal tendencies Depressive ideas Hypochondriac ideas Sleep disturbances
1.0 0.9 0.2 0.7 0.8 0.9 0.1 0.3
1.2 0.8 0.1 0.3 0.4 0.9 0.9 0.1 0.8
4.7
6.0
6.5
0.9
0.8
0.9
2 I-VI Depressionanxiety score VII
P VIII IX
Experience of emotional indifference Psychomotor retardation
1.8 1.1
0.9
0.3 0.2
0.9 0.4
0.4
0.8 0.9
1.0 0.8
0.9 1.1
4.3
1.0
1.9
1.9
2.0
2.7
3.0
13.8
14.6
3.3
5.9
5.9
6.8
8.5
9.5
Zung’s Index (Lo: n = 21, Im: n = 20) 75.0
71.7
3.2
3.8
2.5
11.3
7.5
10.0
P
