Br. J. clin. Pharmac. (1978), 5, 35S-4 IS
CLINICAL STUDY OF MIANSERIN, IMIPRAMINE AND PLACEBO IN DEPRESSION: BLOOD LEVEL AND MHPG CORRELATIONS G.F. PERRY & B. FITZSIMMONS Department of Psychiatry, Mercy Hospital, Rockville Center, New York
L. SHAPIRO & P. IRWIN Department of Psychiatry, School of Medicine, State University of New York at
Stony Brook, New York 1 1794
I The clinical efficacy of mianserin, a tetracyclic compound, was compared with imipramine and placebo in 47 hospitalized depressed patients. 2 The clinical ratings showed that the three treatment groups improved equivalently during hospitalization. 3 Plasma levels of mianserin correlated with changes in the Hamilton Rating Scale for depression, total score and two of its factors (anxiety/somatization, and retardation) and the item 'late insomnia'. 4 Drowsiness was a more frequent side-effect among mianserin patients on day 4; no other sideeffect distinguished the treatments. S No relationship between MHPG levels and treatment or treatment outcome were observed.
Introduction
Methods
Mianserin is a novel compound with clinical antidepressant activity similar to established tricyclic antidepressant compounds. In initial clinical assessments, the activity of. mianserin has been compared with amitriptyline and imipramine, and the efficacy has been found to be equivalent without significant differences in side-effects (Vossenaar, 1975). In more recent published studies, the antidepressant efficacy of mianserin has been confirmed (Coppen et al., 1976; Murphy et al., 1976; Jaskari et al., 1977), and a lack of anticholinergic effects demonstrated (Ghose et al., 1976). To further define the antidepressant efficacy of mianserin, a placebo-controlled double-blind study was undertaken in depressed in-patients for whom the therapeutic environment remained the same. As earlier studies related the efficacy of antidepressants to the amount of urinary MHPG, suggesting the selection of specific antidepressants for specific types of depression, MHPG values were incorporated in this study (Schildkraut, 1973; Maas et al., 1974; Beckmann & Goodwin, 1975). As quantitative EEG analysis had predicted the antidepressant activity of mianserin (Itil et al., 1972), EEG recordings were included to measure the rate of onset of effects and to investigate EEG relationships with behavioural change and with plasma mianserin concentration. Plasma drug levels were also examined for correlations with clinical improvement.
Selection Adult males and females aged 18-70 yr, who consented to participate as in-patients in Mercy Hospital, were included in the study. Mercy Hospital is a 400-bed general hospital in a suburb of New York. The psychiatric unit is an open-door facility, well staffed by specially trained nurses and psychology graduate students. There is an active programme of individual, group, occupational, milieu, art, poetry, and drama therapies. Patients are seen at least three times a week for individual psychotherapy, and families participate activity in treatment sessions. One nickname for the unit is the 'Mercy Hilton'. The average duration of stay is 3 weeks for psychiatric inpatients. Of the participants in the study, all but six remained 3 weeks. Each patient was classified by the psychiatrist as suffering from depressive neurosis or psychotic depression; patients with schizophrenic features were excluded. A Hamilton Rating Scale (HRS) for depression score minimum of 20 was required for admission and was adhered to in 45 of the 47 cases. Exclusion criteria included suicide attempts made within 3 weeks of admission, a trial of at least 300 mg of a tricyclic antidepressant for at least 3 weeks, and overt physical disease. Treatment evaluation Medical history and examination, pregnancy test, EEG, CBC, SMA-12, blood tests, and ratings on the
36S
G.F. PERRY, B. FITZSIMMONS, L. SHAPIRO & P. IRWIN
Adult Personal Data Inventory (APDI), the HRS, Clinical Global Impression (CGI) scale, and the Dosage Record and Treatment Emergent Symptom Scale (DOTES), were carried out before and periodically during the treatment period. The rating scales form part of the ECDEU assessment battery prepared by the National Institute of Mental Health in America (Guy & Bonato, 1970). Blood samples were drawn in association with EEG recordings. Urines were collected for 24 h for MHPG assessments. Dose times and schedules were standardized, and no other antidepressant was used during the study. Evaluations were carried out by the same psychiatrist. Drug regimen Tablets of identical size, colour and appearance, numbered by the manufacturer, were given in serial order to the patients. Each tablet contained mianserin 10 mg, imipramine 25 mg, or placebo. The code was not in the possession of the hospital staff. Nurses administered the medication at the same times each day, beginning with one or two tablets three times daily. In a few instances, when hypotension occurred, the number of tablets was reduced and increased again after 1 week. The psychiatrist evaluated each patient, completing the HRS, CGI scale, and the DOTES, on days 3-4, 7, 14 and 21 of treatment. A termination record was completed on the last day of treatment. These measures were analysed by the Biometric Laboratory, Washington DC. Determinations of urinary MHPG were carried out on first and last days. Laboratory tests were carried out on admission and repeated weekly. The only additional medication allowed was Table 1
flurazepam 30 mg at bed-time. Although EEG recordings were attempted in all subjects, recordings were completed in about half the study group. Recordings were carried out on treatment days 1, 3-4, 7, 14 and 21. On day 1, 1 and 2 h after ingestion of the first study medication, EEG recordings were made and blood samples drawn. On days 3-4, 7, 14 and 21, blood samples were obtained immediately following each EEG recording; the control sample was taken before the first ingestion of medication. All the laboratory analyses were carried out in the hospital, except the measurements of plasma mianserin, which were carried out by Organon International BV, Holland. The MHPG determinations were carried out according to the methods of Dekirmenjian & Maas (1970); our values were confirmed by laboratory assay at the National Institute of Mental Health, Washington, DC. Results
Forty-six patients have been studied to date. Of these, 27 were classified as depressive neurosis and 19 as psychotic depression (Table 1). The average dosage of mianserin was 60mg daily and imipramine 150mg daily. There was a progressive reduction in depression symptoms Ln each drug group during hospitalization. The fall in mean HRS score (difference between pretreatment and final scores) was 18.4 for mianserintreated patients; 17.3 for imipramine-treated patients; and 18.8 for those who received placebo. There was a similar improvement in CGI scores with a similar lack of differential response among the treatments.
Distribution of patients
Sex Females Males
Age (yr) 18-20 20-30 30-40 40-50 50-60 60-70 Diagnosis Depressive neurosis Psychotic depression
n
Mianserin
Imipramine
Placebo
(38) (8)
13 2
12 2
13 4
(3)
(9) (5)
(14) (7)
2 2 4 1 5 1
2 2 3 5 2
1 4 3 1 4 4
(27)
8
9
10
(19)
7
5
7
(8)
* Eight incomplete cases not included.
37S
BLOOD LEVEL AND MHPG CORRELATIONS
Table 2
Therapeutic effect
Treatment
Side-effects None Some
Mianserin (n= 18)
Moderate Minimal Slight
0 7 4
Imipramine (n= 14)
Moderate Minimal
2 6 3
Slight Moderate Minimal
Placebo
(n= 19)
Slight
0 6 1
2 0 0 0 0
3 11 5
X2 for therapeutic effect 4.01 (NS); x2 for side-effects 8.90
Table 4
CGI scale (efficacy index) on days 3,4 or 5
(P
00
co 60
40
C-
4-.'
CO
8
0(
-
45E co
w
16
-
24
32r 0 0
4
8
12
16
0
20
4
8
12
16
20
30
10
15
0
0
20
~~~~~~~~~~~~~~~~~~~~~~~~-40
60
-30
45
8
30
16 --20 10 E
24
15~
-~~~~~~~~~~~~~~~~~~~~~~~Jo00 >
0)
3200 C
0
50
-c -404-
I 0
60
c' ~~~~~~~~~~~~ M
E ~~~~~~~~~~~~~~~~~~~~~~~-30
8
45 0..
30
16 --20
24
75
C (
10
-
15
3200 0
21 004
8
12
16
20
Time (d) Figurel1Mianserin plasma levels (0), EEG theta activity (0)and HRS scores (A) during 3weeks' treatment in eight patients.
BLOOD LEVEL AND MHPG CORRELATIONS
0i
I 2
I
H
-5 ©
-lo1
©
J
-101-
0
F
K
-15
-15
BE
0
0
b
C
la(
G
H
A ~~
~
(-F'.
F E
-20 [
-20
co
E 2
39S
-25
I
D
20
I
I
30
40
B
-25
a
50
60
70
1 )
20
30
50
40
60
70
C
0
~0 -
-a) ') 2
0 Il)
d
0
Or
-5
-5 D
-10
-10
C
0
IE
I
A
H
-151
-20
H
-15
E
1
-20F M
-25L: 10
MF
-251 I ,%-
20
30
40
50
60
70
10
20
30
40
50
60
70
Plasma mianserin level (pg/I) Figure 2 Linear regression of clinical improvement on plasma levels of mianserin. Encircled patients were withdrawn from the study before completion: L, N-adverse reaction, SGOT elevated; C,D-ineffective medication; P-against medical advice. a, Day 4: Y=-0.31X-3.4, r=-0.55, P
CLINICAL STUDY OF MIANSERIN, IMIPRAMINE AND PLACEBO IN DEPRESSION: BLOOD LEVEL AND MHPG CORRELATIONS G.F. PERRY & B. FITZSIMMONS Department of Psychiatry, Mercy Hospital, Rockville Center, New York
L. SHAPIRO & P. IRWIN Department of Psychiatry, School of Medicine, State University of New York at
Stony Brook, New York 1 1794
I The clinical efficacy of mianserin, a tetracyclic compound, was compared with imipramine and placebo in 47 hospitalized depressed patients. 2 The clinical ratings showed that the three treatment groups improved equivalently during hospitalization. 3 Plasma levels of mianserin correlated with changes in the Hamilton Rating Scale for depression, total score and two of its factors (anxiety/somatization, and retardation) and the item 'late insomnia'. 4 Drowsiness was a more frequent side-effect among mianserin patients on day 4; no other sideeffect distinguished the treatments. S No relationship between MHPG levels and treatment or treatment outcome were observed.
Introduction
Methods
Mianserin is a novel compound with clinical antidepressant activity similar to established tricyclic antidepressant compounds. In initial clinical assessments, the activity of. mianserin has been compared with amitriptyline and imipramine, and the efficacy has been found to be equivalent without significant differences in side-effects (Vossenaar, 1975). In more recent published studies, the antidepressant efficacy of mianserin has been confirmed (Coppen et al., 1976; Murphy et al., 1976; Jaskari et al., 1977), and a lack of anticholinergic effects demonstrated (Ghose et al., 1976). To further define the antidepressant efficacy of mianserin, a placebo-controlled double-blind study was undertaken in depressed in-patients for whom the therapeutic environment remained the same. As earlier studies related the efficacy of antidepressants to the amount of urinary MHPG, suggesting the selection of specific antidepressants for specific types of depression, MHPG values were incorporated in this study (Schildkraut, 1973; Maas et al., 1974; Beckmann & Goodwin, 1975). As quantitative EEG analysis had predicted the antidepressant activity of mianserin (Itil et al., 1972), EEG recordings were included to measure the rate of onset of effects and to investigate EEG relationships with behavioural change and with plasma mianserin concentration. Plasma drug levels were also examined for correlations with clinical improvement.
Selection Adult males and females aged 18-70 yr, who consented to participate as in-patients in Mercy Hospital, were included in the study. Mercy Hospital is a 400-bed general hospital in a suburb of New York. The psychiatric unit is an open-door facility, well staffed by specially trained nurses and psychology graduate students. There is an active programme of individual, group, occupational, milieu, art, poetry, and drama therapies. Patients are seen at least three times a week for individual psychotherapy, and families participate activity in treatment sessions. One nickname for the unit is the 'Mercy Hilton'. The average duration of stay is 3 weeks for psychiatric inpatients. Of the participants in the study, all but six remained 3 weeks. Each patient was classified by the psychiatrist as suffering from depressive neurosis or psychotic depression; patients with schizophrenic features were excluded. A Hamilton Rating Scale (HRS) for depression score minimum of 20 was required for admission and was adhered to in 45 of the 47 cases. Exclusion criteria included suicide attempts made within 3 weeks of admission, a trial of at least 300 mg of a tricyclic antidepressant for at least 3 weeks, and overt physical disease. Treatment evaluation Medical history and examination, pregnancy test, EEG, CBC, SMA-12, blood tests, and ratings on the
36S
G.F. PERRY, B. FITZSIMMONS, L. SHAPIRO & P. IRWIN
Adult Personal Data Inventory (APDI), the HRS, Clinical Global Impression (CGI) scale, and the Dosage Record and Treatment Emergent Symptom Scale (DOTES), were carried out before and periodically during the treatment period. The rating scales form part of the ECDEU assessment battery prepared by the National Institute of Mental Health in America (Guy & Bonato, 1970). Blood samples were drawn in association with EEG recordings. Urines were collected for 24 h for MHPG assessments. Dose times and schedules were standardized, and no other antidepressant was used during the study. Evaluations were carried out by the same psychiatrist. Drug regimen Tablets of identical size, colour and appearance, numbered by the manufacturer, were given in serial order to the patients. Each tablet contained mianserin 10 mg, imipramine 25 mg, or placebo. The code was not in the possession of the hospital staff. Nurses administered the medication at the same times each day, beginning with one or two tablets three times daily. In a few instances, when hypotension occurred, the number of tablets was reduced and increased again after 1 week. The psychiatrist evaluated each patient, completing the HRS, CGI scale, and the DOTES, on days 3-4, 7, 14 and 21 of treatment. A termination record was completed on the last day of treatment. These measures were analysed by the Biometric Laboratory, Washington DC. Determinations of urinary MHPG were carried out on first and last days. Laboratory tests were carried out on admission and repeated weekly. The only additional medication allowed was Table 1
flurazepam 30 mg at bed-time. Although EEG recordings were attempted in all subjects, recordings were completed in about half the study group. Recordings were carried out on treatment days 1, 3-4, 7, 14 and 21. On day 1, 1 and 2 h after ingestion of the first study medication, EEG recordings were made and blood samples drawn. On days 3-4, 7, 14 and 21, blood samples were obtained immediately following each EEG recording; the control sample was taken before the first ingestion of medication. All the laboratory analyses were carried out in the hospital, except the measurements of plasma mianserin, which were carried out by Organon International BV, Holland. The MHPG determinations were carried out according to the methods of Dekirmenjian & Maas (1970); our values were confirmed by laboratory assay at the National Institute of Mental Health, Washington, DC. Results
Forty-six patients have been studied to date. Of these, 27 were classified as depressive neurosis and 19 as psychotic depression (Table 1). The average dosage of mianserin was 60mg daily and imipramine 150mg daily. There was a progressive reduction in depression symptoms Ln each drug group during hospitalization. The fall in mean HRS score (difference between pretreatment and final scores) was 18.4 for mianserintreated patients; 17.3 for imipramine-treated patients; and 18.8 for those who received placebo. There was a similar improvement in CGI scores with a similar lack of differential response among the treatments.
Distribution of patients
Sex Females Males
Age (yr) 18-20 20-30 30-40 40-50 50-60 60-70 Diagnosis Depressive neurosis Psychotic depression
n
Mianserin
Imipramine
Placebo
(38) (8)
13 2
12 2
13 4
(3)
(9) (5)
(14) (7)
2 2 4 1 5 1
2 2 3 5 2
1 4 3 1 4 4
(27)
8
9
10
(19)
7
5
7
(8)
* Eight incomplete cases not included.
37S
BLOOD LEVEL AND MHPG CORRELATIONS
Table 2
Therapeutic effect
Treatment
Side-effects None Some
Mianserin (n= 18)
Moderate Minimal Slight
0 7 4
Imipramine (n= 14)
Moderate Minimal
2 6 3
Slight Moderate Minimal
Placebo
(n= 19)
Slight
0 6 1
2 0 0 0 0
3 11 5
X2 for therapeutic effect 4.01 (NS); x2 for side-effects 8.90
Table 4
CGI scale (efficacy index) on days 3,4 or 5
(P
00
co 60
40
C-
4-.'
CO
8
0(
-
45E co
w
16
-
24
32r 0 0
4
8
12
16
0
20
4
8
12
16
20
30
10
15
0
0
20
~~~~~~~~~~~~~~~~~~~~~~~~-40
60
-30
45
8
30
16 --20 10 E
24
15~
-~~~~~~~~~~~~~~~~~~~~~~~Jo00 >
0)
3200 C
0
50
-c -404-
I 0
60
c' ~~~~~~~~~~~~ M
E ~~~~~~~~~~~~~~~~~~~~~~~-30
8
45 0..
30
16 --20
24
75
C (
10
-
15
3200 0
21 004
8
12
16
20
Time (d) Figurel1Mianserin plasma levels (0), EEG theta activity (0)and HRS scores (A) during 3weeks' treatment in eight patients.
BLOOD LEVEL AND MHPG CORRELATIONS
0i
I 2
I
H
-5 ©
-lo1
©
J
-101-
0
F
K
-15
-15
BE
0
0
b
C
la(
G
H
A ~~
~
(-F'.
F E
-20 [
-20
co
E 2
39S
-25
I
D
20
I
I
30
40
B
-25
a
50
60
70
1 )
20
30
50
40
60
70
C
0
~0 -
-a) ') 2
0 Il)
d
0
Or
-5
-5 D
-10
-10
C
0
IE
I
A
H
-151
-20
H
-15
E
1
-20F M
-25L: 10
MF
-251 I ,%-
20
30
40
50
60
70
10
20
30
40
50
60
70
Plasma mianserin level (pg/I) Figure 2 Linear regression of clinical improvement on plasma levels of mianserin. Encircled patients were withdrawn from the study before completion: L, N-adverse reaction, SGOT elevated; C,D-ineffective medication; P-against medical advice. a, Day 4: Y=-0.31X-3.4, r=-0.55, P
