J Int Med Res (1975) 3 , 108

A Comparison Between Maprotiline (Ludiomil) and Amitriptyline

in the Treatment of Depressive Reaction in General Practice
J M u r p h y , L R C P I , L R C S I , L M , M R C G P , General Practitioner, Northampton,
W A F o r r e s t , M B , B S , Senior Medical Adviser, CIBA Laboratories,

England

Horsham, Sussex,

England

In this trial in depressive reaction in general practice, maprotiline

and
amitriptyline,
in a fixed dosage regime of 50 mg three times daily for three
weeks, were equally effective therapeutic agents; all but two of the patients
improving during the trial.
Thirteen patients (lS of the group) withdrew from the study due to the
.severity of side-effects, predominantly because of drowsiness.
In those patients who completed the trial both compounds were relatively
well tolerated. The general pattern of side-effects {'mild' drowsiness
and
dry mouth) was similar for both treatments, although maprotiline
appeared
to cause more dizziness than
amitriptyline.

Introduction

Maprotiline (Ludiomil) is a dibenzo-bicyclooctadiene dervate with a tetracyclic system,

differing chemically from current tricyclic
anti-depressants (Fig 1).

CHj-CHj-CHj-NH-CH) .HCl

Fig 1 Structural formula of Maprotiline

l-(3-methylaminopropyl)-dibenzo
2, 21-octadiene hydrochloride

[b, e] bicycio [2,

tion, being effective in agitated and retarded

patients. A rapid onset of action was ob
served, a clear-cut effect being evident as
early as the fifth day of treatment. Un
wanted effects were of minor importance and
well tolerated. Balastrieri et al (1971) con
cluded, after a controlled study, that mapro
tiline was an effective, powerful and well
tolerated anti-depressant drug, both in endo
genous and in neurotic depression. Further
confirmation of this therapeutic effect has
been shown in other double-blind, compara
tive trials (Welner 1972, Pinto et al 1972,
Levin 1974).
The aim of this study was to compare the
efficacy and tolerability of maprotiline and
amitriptyline in the treatment of depressive
reaction in general practice conditions.

T h e study
In preliminary open studies (Griiter
1970), maprotiline appeared active on de
pressed mood and on psychomotor retarda

This trial was conducted as a double-blind,

between patient comparison in eighty-two
patients. Patients were treated for three

J Murphy, and W A Forrest

weeks, with a fixed dose regime, 50 mg tid,
of maprotiline or amitriptyline. Twelve
general practice centres were involved in the
study, each entering between three and ten
patients.
Patient Population

Patients of either sex, with depressive illness

considered suitable for treatment with a
tricyclic anti-depressant were included in the
trial. At the start of the trial profiles of the
two groups were compiled for sex, age, type
and severity of depression and the history of
previous depressive episodes of illness. The
two groups were well matched, with no
significant differences.
The female: male ratio was almost exactly
3 - 5 : 1 , and the mean age of the group (-^se)
was 37 years 1 - 5 . Sixty-one per cent of the
patients were described as moderately de
pressed, with 12% assessed as seriously
depressed. In 7 0 % of the group no previous
therapy had been given for depressive illness.
Of the eighty-two patients who entered the
study, fifty-nine completed, with twentythree withdrawals.

Fig 3

109
Exclusions

Patients treated during the previous three

months with ECT, or an adequate course of
anti-depressant, patients with a history of
organic cerebral disease, an associated major
disease of a progressive nature and patients
in the first trimester of pregnancy were
excluded.
Measurements
1. Physicians'' assessments
At Day 7, 14 and 21 the doctor assessed
the patient's clinical response, in relation
to the previous visit using a five-point
scale shown in Fig 2.
Much better
Marginally better
Efficacy
compared with
previous visit

The s a m e
Marginally w o r s e
Much worse

Fig 2

Scale

Symptoms

Code

None

No side-effects at all

Mild

Occasionally troublesome. Nuisance value

Moderate

Persistently troublesome

Severe

Physician or patient s t o p s treatment

Tolerability

Put a c r o s s on the line at the point which Indicates how you feel T O D A Y .

1 don't feel
sad or
miserable
at all

Fig 4

Patients' visual analogue scale

I am s o
unhappy and
miserable
that I can't
stand it

The Journal of Internallonal

no

Medical

Research

Table 1
Physicians' assessments, compared with previous visit
Day 7

Day 14

Day 21

17

19

14

18

13

II

12

The same

Marginally worse

Much worse

Much better
Marginally better

Significance

ns

ns

= Maprotiline
A = Amitriptyline

ns

Significance assessed using chi-squared test

ns
> 0 I

The degree of tolerability was assessed

using the four-point scale illustrated in
Fig 3. The physician used an open-ended
question to elicit side-effects and adverse
reactions. If the patient volunteered
symptoms, these were recorded.
2. Patient assessment
At each visit, (Day 0, 7, 14 and 21),
before seeing the doctor, the patient
recorded his condition on the 10 cm visual
analogue scale shown in Fig 4.
Results

Efficacy
By the physicians' assessments there was no
significant difference between the two treat

ments (Table 1). Only two patients, both in

the amitriptyline group, failed to show any
improvement at all during the study, while
nineteen patients in the maprotiline group
and eleven in the amitriptyline group showed
continual improvements over the threeweek period.
Akhough maprotiline looks more effective
than amitriptyline at Days 14 and 21, there is
insufficient evidence to conclude that the
treatments are different.
The patient's ratings in Table 2 show a
significant improvement compared with Day
0, at all the follow-up visits. If the reduction
in score is considered as a percentage of the
previous weeks score, there is a reasonably
constant 25"/ reduction each week. This is

Table 2
Patients' assessments on visual analogue scale (scores measured from left-hand end of scale)
Day 0

Day 7

Day 14

Day 21

Maprotiline

7-32

5-35

3-74

2-74

Amitriptyline

7-35

4-84

3-87

2-90

< 0 001
(vs Day 0)

< 0 001
(vs Day 7)

< 0 01
(vs Day 14)

Significance*

Both scores using analysis of variance

No significant difference between scores, on a given day

/ Murphy and W A Forrest

111

Table 3
Withdrawals from study (n - 23)
Reason

Maprotiline

Lost to follow-up
Deterioration of
clinical condition
Severe side-effects
Total

1
6

0
7

10

13

Table 4
Side-effects causing withdrawal from study

Symptom

Maprotiline

Amitriptyline

Drowsiness
Skin rash
Headache

5
1
0

6
0
1

Total

6(14%)

7(18%)

Amitriptyline

in sliglit contrast to ttie phiysicians" assess

ments, which sbiowed ttiat more patients
improved during the last two weeks of the
study.

These assessments, like the physicians',

showed no difference in amount or rate of
improvement between the two treatments.
Tolerability and withdrawals
Table 3 shows the details of the twenty-three
patients who withdrew from the study. The
reasons for withdrawal are very similar in the
two groups, and the patient profile for this
group follows the pattern for those patients
who completed the study. Table 4 shows the
symptoms causing withdrawal.
The physicians' assessments of tolerability
are shown in Table 5, and the incidence of
side-effects volunteered by patients in Table
6. Again, there is no significant difference

Table 5
Physicians' assessment of tolerability (n ^ 72)
Number of patients
Degree of tolerability
No side-effects at all during
the study

Maprotiline

Amitriptyline

12

13

12

Moderate (persistently
troublesome), side-effects
piersistent throughout

Severe side-effects
Treatment withdrawn

39

33

Mild side-effects reported,

(occasionally troublesome),
but none at Day 21
Mild side-effects
persistent throughout

Total

112

The Journal of International

Medical

Research

Table 6
Incidence of side-effects in patients completing the study (n - 59)

Number of reports recorded

Symptoms reported

Maprotiline

Amitriptyline

Drowsiness
Dry mouth
Dizziness
Headache
Gastro-intestinal
Miscellaneous

14
12
9
6
6
18

15
11
2

Number of patients
reporting side-effects

25

21

9
11

p < 0 1 (Chi-squared test)

The majority of patients reporting side-effects reported more than one

between the two treatments in degree of

tolerability.
Patients who reported side-effects usually
reported more than one. Those most com
monly volunteered were drowsiness and dry
mouth, the incidence being very similar for
the two treatments. Dizziness as a sideeffect was more commonly reported in the
maprotiline group ( < 0 1).
Discussion

The limitations of formal clinical trials as

predictors for the population at large are
considerable. Early clinical studies with new
compounds are conducted in hospitals and
provide only limited information on how
the drug will fare in the conditions of general
practice.
Controlled hospital studies with mapro
tiline (Balastrieri et al 1971, Levin 1974)
indicate that in a daily dose of 150 mg it is an
effective and well tolerated anti-depressant;
and for this reason 150 mg daily was selected
as a fixed dose regime for this first general
practice trial in the United Kingdom.
Controlled studies with amitriptyline also
suggest that in a hospital environment
physicians record a relatively low incidence
of side-effects (Forrest el al 1964, Haider
1967, Hanton et al 1964).

In this trial, while the incidence of sideeffects between the two active compounds
was very similar, it was at a higher level than
reported in the hospital studies for both
maprotiline and amitriptyline, but compar
able to the level noted by the General
Practitioner Research G r o u p (1972) for
amitriptyline-treated patients in general prac
tice.
This study indicates that maprotiline is an
effective anti-depressant at this dose level,
and further trials in general practice, at vary
ing dose levels, are in progress to evaluate
its position in the spectrum of anti-depressant
drugs.

Acknowledgements

Our grateful appreciation is due to the

following General Practitioners in the United
Kingdom who participated in the study:
R Bruce, Chester-le-Street; Clyne,
Southall; W Cole, Bradford; J F Donald,
Northampton; C Lawson, Nottingham;
Levy, Kirkby; D Lomas, London; R
Midha, Gowerton; S D Moss, London; A
Smith, Cumbernauld; A S Veeder,
Gosforth; J D A Whitelaw, Worcester; G
Mann, T r o o n ; A L Molla, N o r t h a m p t o n ;
L Oldershaw, London.

J Murphy and W A Forrest

113

REFERENCES
Balastrieri A, Benassi P, Cassano G B, Castrogiovanni
, Catalano A, ColombI A, t onforto C, Del Soldato G,
Gilberti F, Luchelli , Muratorio A, Nistri M ,
& Sarteschi
(1971) Clinical comparative evaluation of Maprotiline,
a new anti-depressant drug. International
Pharma
copsychiatry

6, 2.36

Forrest A D, Affleck J W, Giflf I A McL & Priest R G

(1964) Comparative trial of nortriptyline and
amitriptyline. Scottish

MedicalJournal9,

341

Grter W
(1970) A new tetracyclic anti-depressive (CIBA
34,276-Ba): observations in more than 500 cases. CINP
Vll Congress

Abstracts

(Prague)

Vol II, 482

Haider I
(1967) A comparative trial of RO4-6270 and
amitriptyline in depressive illness. British Journal of
Psychiatry.

113. 993

Hanlon , Nussbaum , Wittig , Haninn D D &

Kurland A
(1964) The comparative effectiveness of amitriptyline,
perphenazine and their combination in the treatment
of chronic psychotic female patients. Journal of New
Drugs 4, 52

Levin A
(1974) Maprotiline and amitriptyline in the treatment
of depressive illness. A double-blind comparison.
Soiah African Medical Journal 48, 47

Pinto O de S, Afeiche S P, Bartholini & LousUlot

(1972) International Experience with Ludiomil
Depressive illness, diagnosis, assessment, treatment'
Kielholz cd. An International

Symposium

253

Welner J
(1972) A multinational multicentre, double-blind trial
of a new antidepressant. 'Depressive illness, diagnosis,
assessment, treatment'. Kielholz ed. An International
Symposium

209

General Practitioner Research Group

(1972) A long-acting amitriptyline
Practitioner 209, 700, Report No 176

preparation.