147

Psychiatry Research, 4, I47- I56 ( I98 1)

Elsevier/North-Holland

Biomedical

Pharmacokinetics

Press

of Clomipramine

in Depressive Patients

Hugo J.A. de Cuyper, Herman M. van Praag, Wilhelmina

R.E.M.
Hajonides, Herman G.M. Westenberg, and Rokus A. de Zeeuw
Received
1981.

January 17, 1980; revised version received

October

Mulder-

1, 1980; accepted January 12,

Abstract. Ten patients with a vital depressive syndrome were treated for 4 weeks
with clomipramine (CI), five receiving the drug by mouth and five receiving it first
intramuscularly
and then by mouth. Plasma concentrations
of CI and desmethylclomipramine
(DCI) were measured daily. Both concentrations
showed marked
interindividual
differences, especially after oral administration
of the drug. The
mean relative CI clearance after repeated i.m. injections was 0.441 kg-l hour-l. The
route of administration
proved to exert a marked influence on the plasma concentration ratio CI/ DCI. In this small population, no significant relationship could be
demonstrated
between plasma CI and DC1 concentrations,
or the sum of both, and

the clinical effect.

Key Words. Clomipramine,
effect, clinical response.

desmethylclomipramine,

plasma

level,

first-pass

Clomipramine
(Anafranil@), a tricyclic antidepressant
(TCA) that is structurally
related to imipramine,
is widely used in the treatment of certain types of depression.
Like other TCAs however, it has a relatively high nonresponse
rate: 40-50s of
depressive patients show no or no sufficient response to treatment with clomipramine
(CI) (Della Corte et al., 1979). One possible factor in this high nonresponse
rate might
be interindividual
differences in pharmacokinetics,
resulting in a marked interindividual variability in steady-state plasma concentrations
of the active substance on standard doses.
Data on the pharmacokinetics
of CI are sparse, in spite of its wide use. Faigle and
Dieterle (1973) studied the absorption
and excretion of 14C-labeled Cl after oral and
intravenous
administration
to volunteers.
Their findings indicate that CI is almost
entirely absorbed from the gastrointestinal
tract, and is excreted almost exclusively in
the form of metabolites.
Nagy and Johansson
(1977) and Westenberg et al. (1977~)
studied the pharmacokinetics
of CI after administration
of a single oral dose to
volunteers. These investigators reported a mean plasma half-life of 20.8 hours and 22.8
hours, respectively.
The mean plasma clearance after a single i.m. injection was
calculated to be 0.33/kg/ hr and the systemic availability of CI after oral administration proved to vary from 19% to 78% ofthat after i.m. injection(Nagy
and Johansson,

Hugo J.A. de Cuyper, M.D., is Resident Psychiatrist,

Psychiatric Clinic Salve Mater, Louvain, Belgium.
Herman M. van Praag, M.D., Ph.D., is Professor and Head, and Herman G.M. Westenberg,
Ph.D., is
Research Pharmacist,
Department
of Psychiatry,
University of Utrecht, The Netherlands.
Rokus A. de
Zeeuw, Ph.D., is Associate
Professor
of Toxicology,
and Wilhelmina
R.E.M. Mulder-Hajonides
is
! requests to Dr. Westenberg at
Research Psychologist,
University of Groningen, The Netherlands.
(Rey
echt, The Netherlands.)
Department
of Psychiatry,
Academic Hospital, Catharijnesingel
101,
0165-

1781/81/0000~0000~$02.50

0 Elsevier/North-Holland

Biomedical

Press

148

1977). Nagy and Johansson (1977) have also indicated that the route of administration
can influence the degree of N-desmethylation
of tertiary TCA.
The primary purpose of the present study was to investigate the pharmacokinetics
of CI and desmethylclomipramine
(DCI) after repeated administration
to depressive
patients.
In order to study the influence of the route of administration
on the
availability and metabolism of CI, some of the patients were given CI both orally and
intramuscularly.
Methods
Patients. The patients studied were six women and four men who had recently been hospitalized for treatment of depression. All showed a vital depressive syndrome (van Praag, 1978)
characterized
by at least the following cardinal symptoms: decreased level of mood, motor
disorders, hypoasthesia,
disturbed sleep, anorexia, and fatigue inconsistent with performance.
The average age was 38 (range 23-50), and the mean initial score on the Hamilton Rating
Scale for depression was 32 (range 20-43). (See Table I for sample characteristics.)

Table 1. Sample characteristics

kg

Initial
Hamilton
score

Etiology

75

40

P, end

Weight

Sex

Age

Height
cm

40

178

35

185

90

26

Unipolar

49

172

78

34

Bipolar

Patient

Course
Unipolar

39

161

96

20

P, end

Unipolar

50

165

a8

24

P, end

Bipolar

36

172

79

43

Unipolar

41

180

76

34

P, end

Unipolar

41

152

47

29

P, end

Bipolar

43

165

80

38

Unipolar

10

23

197

73

34

Unbolar

P = mainly psychogenic.
End = mainly endogenous hereditary

Dosage. This was an open study. During a 5-day washout period before the study began, and
throughout
the period of study, no other medication was given (with the exception of benzodiazepines as hypnotic). All patients were treated for 4 weeks with clomipramine
(Anafranila,
Ciba-Geigy).
The patients were randomly divided into two equal groups: Group l-patients
received Cl
orally in tablet form throughout the study, starting with 25 mg three times daily and gradually
increasing to 200 mg per day on day 6 of the study, whereafter the dose was kept constant.
Group 2-patients
were given Cl intramuscularly
for the first 14 days, starting with 25 mg twice
daily and increasing within 2 days to 100 mg per day in two injections. After 14 days, injections
were replaced by a daily dose of 200 mg, orally administered
in three fractional doses given at
0830, 1630, and 2200h (the i.m. injections were given at 0830 and 1600h).
Plasma Measurements. During the first 2 weeks ofthe study, twice-daily blood samples were
obtained immediately before the morning medication and 60 minutes (group I) or 30 minutes
(group 2) after the afternoon medication. During the third and the fourth weeks, blood samples

149
were obtained once a day in both groups, 60 minutes after the afternoon medication. The blood
was collected in heparinized glass tubes and, after centrifugation,
stored as plasma at -20C
until analysis.
The plasma Cl and DC1 concentrations
were determined
by the liquid chromatography
technique described by Westenberg et al. (1977b).
Behavior Rating. Two depression rating scales, the Hamilton Rating Scale (HRS; Hamilton,
1960) and the Zung Self-rating Scale (ZSRS; Zung, 1965) were used to evaluate therapeutic
effectiveness. The HRS was done by the attending psychiatrist, while the ZSRS was completed
by the patient. Both ratings were always made on the same day, in the morning hours before the
study began and every 4 days throughout
the study.
Data Analysis. The mean steady-state
(Wagner et al., 1965):
C=

plasma

concentration

D.F

is described

in the equation

(1)

Clp

plasma concentration,
F the systemic
in which c represents
the average steady-state
availability-that
is, the fraction of the dose that reaches the systemic circulation unchanged
(after i.v. injection, F = 1 by definition)&D
the dose, Clp the plasma clearance and T the dose
interval.
The systemic availability (F) of a drug is determined
by the amount absorbed from the
gastrointestinal
tract unchanged and the amount eliminated or metabolized
during the first
passage through the liver. The latter, so-called first-pass effect is of particular importance for
drugs cleared chiefly via the liver.
The systemic availability F during repeated oral administration
can be calculated with the aid
of the equation:
F=

c oral

oral

iv . .

i.v.

D i.v.
D oral

As no iv. doses were given in this study, plasma clearance and systemic availability during
repeated oral administration
were estimated with the aid of equations (1) and (2), respectively,
using i.m. data, assuming that the dose is completely systemically available.
The average steady-state plasma concentrations
were calculated during the second and the
fourth weeks of medication,
as the mean of the plasma concentrations
during the period in
question.
The therapeutic effect was established during the second and the fourth weeks of medication
by calculating for both depression scales the differences from the initial score. The percentage of
reduction on the HRS was also calculated.
For statistical analysis of the mean values of the average steady-state plasma concentrations of Cl, DCI, and CI + DCI, and of the therapeutic effects, use was made of an analysis of
variance with two factors: method of administration
(groups) and weeks with repeated measures on one factor (weeks).

Results
Pharmacokinetics.
The difference
between morning
and afternoon
plasma concentrations
of CI and DC1 was generally
rather small in Group 1 (see Fig. 1, upper panel,
days l-l 5). Day-to-day
fluctuations
were quite pronounced
in some subjects, but these
variations
were small compared
to the interindividual
variations
in the steady-state
plasma concentrations
(Table 2). DC1 appeared
in the plasma of all subjects after oral

150
administration
of Cl. The ratio between the plasma concentrations
of CI and DC1
varied from 0.3 to 2.0 during the second week and from 0.2 to 1.3 during the fourth
week of treatment in this group.
Fig. 1. Plasma concentration-time
curves of clomipramine (0) and desmethylclomipramine (0) in two representative patients from Group 1
plasma

concentration

( nglml ; log scale )

500.

subject

l-6.

jq,
4
0, ..* ,*w-.c*
:

/k*
200

d
/d
P

10.

,
0

plasma

,*/
\XW

*\ ,+
\d

1
5
concentration

10

15

20

25

days

( nglml ; log scale 1

500.

subject

B.U

200.

100.

50.

10;
0
Clomlpramine

5
was given by mouth

10

15

in daily doses increasing

20
up to 200 mg.

25

days

151
Table 2. Mean plasma clomipramine (Cl) and desmethylclomipramine
concentrations
in Groups 1 and 2 during weeks 2 and 41
DCI

Cl

(DCI)

Cl + DCI

Patient #

2nd

4th

2nd

4th

2nd

4th

Group
1
2
3
4
5

49
97
158
139
197

a0
93
195
209
296

143
48
122
239
110

344
187
la3
540
234

192
145
280
378
307

424
280
378
749
530

128
57

175
a9

132
69

298
150

260
93

472
179

156
115
142
131
151

191
75
131
la7
131

28
30
ND2
ND2
36

262
41
137
76
75

la4
145
142
131
la7

453
116
268
254
206

139
16

141
46

~23

118
aa

158
26

259
123

Mean
SD
Group
6
7
a
9
10
Mean
SD

Analyses of variance3
Cl
F
P

F
D

DCI

Groups

Weeks

<l
NS

4.06
NS

Groups
7.69
co.05

Cl + DCI
Weeks

Groups

Weeks

21.11
co.01

5.61
co.05

a.00
co.05

Groups X weeks

Groups X weeks

Groups X weeks

3.36
NS

1.51
NS

2.49
NS

1. Plasma concentration ng/ml.

2. ND = not detectable (~10 ng/ml-1
3. Degrees of freedom = 1. 8.

).

In the computations we used a value of 10 ng/ml-1

In Group 2 there was a considerable

difference between morning and afternoon
plasma concentrations
of CI after i.m. injection,
suggesting
substantial
24-hour
fluctuations
(Fig. 2). DC1 appeared in the plasma of three subjects 5 to 10 days after
i.m. administration
of CI. In two subjects no detectable amounts of DC1 (< 10 mg/ ml)
were observed during i.m. administration.
The switch from i.m. to oral administration
resulted in a substantial
increase in the plasma DC1 concentration
in four of the five
subjects (Table 2). The mean relative plasma clearance in Group 2 was 0.44 +
0.11 /kg/ hr (mean Ifr SD). The systemic availability
was estimated to average 50%
(32% to 67%).
There was no significant difference between the plasma concentrations
of CI in the
second week as compared
with the fourth week (Table 2). Neither was there a
significant difference between the plasma CI concentrations
of Group 1 as compared
to those of Group 2. The N-desmethylation
of CI, however, was significantly
less for
Group 2 than for Group 1 (F = 21.11, df = 1,8, p < 0.01). For both Groups 1 and 2,

152
there was a significant increase in the mean plasma DC1 concentration
from week 2 to
week 4 (F = 7.69, df = 1, 8, p < 0.05). The results for the sum of CI and DC1 are
identical to the results for DC1 alone.
Fig. 2. Plasma concentration-time
curves of clomipramine (0) and desmethylclomipramine (0) in two representative patients from Group 2
plasma

concentration

(nglml;

log scale)
subject

A.0.

500
I

101
0

10
i.m.

plasma

concentration

( nglml

-j-

1 15
oral

20

25

days

; log scale)
subject

5001

Z.L.

8p-..9

200.

loo50-

20-

lo-?

10

--l- 15
i.m .

Clomipramine
respectively.

was first given intramuscularly

20

25

days

oral

G.m.) and then by mouth, in daily doses of 100 mg and 200 mg,

153
Effects. Table 3 presents the differences in HRS and ZSRS scores from
the initial scores and the ?Jr reduction on the HRS (% improvement)
per individual
patient in Group 1 (patients l-5) and Group 2 (patients 6-10). All patients in Group 1
showed distinct improvement
on the HRS during CI medication.
The mean HRS
improvement
at completion
of medication
was 15.2 points, corresponding
to 49%
improvement.
The improvement
on the ZSRS was much less pronounced:
only two of
the five patients rated themselves as improved. In Group 2, HRS improvement
was
seen in four of the five patients. The mean HRS improvement
at completion
of
medication
in this group was 10.2 points (i.e., 27% improvement).
Three of the four
patients (one did not complete the ZSRS) rated themselves as slightly improved.
For all therapeutic
variables,
Groups
1 and 2 showed comparable
significant
increases from the second to the fourth weeks.

Therapeutic

Table

3. TheraDeutic

effects

in Groups

1 and 2

A ZSRS2

A HRS
Patient #
Group 1
1
2
3
4
5

SD
Group 2
6
7
6
9
10

Mean
SD

2nd

4th

-3

1
11

23
23
44
40
29

50

10

4th

9
6
15

20
11
30

12

15

a
7
9
3.5

2nd

-4

-2

-1

42
a3
40
29

2.6

5.4

32

49

7.7

7.1

10

21

17

40

-1

5
6
5

21

11

26

32

-4

11
-

32

39

15
9.7

9
9
0
12
6

Improvements

VO

4th

2nd

-1

15

7.2

10.2

4.6

7.0

ia

28

4.8

6.8

19

27

4.4

2.9

12

la

Analyses of variance

A ZSRSz

A HRS
Groups
F

Cl

df
D

13
NS

Weeks

13

1,7
NS

co.05

Groups X weeks
F
df
P

Groups

7.67

Weeks
6.54
1,7
dO.05

O/O

Improvements

Groups

Weeks

3.62

a.41

i,a

i,a

NS

co.05

Groups X weeks

Groups X weeks

Cl

1.23

i,a
NS

1,7

i,a
NS

1. A HRS = difference in HRS score from initial score.

2. A ZSRS = difference in ZSRS score from initial score.
3. % Improvement
= % reduction on the HRS.

NS

154

Discussion
It has become increasingly
evident in recent years that the clinical effect of many
medications
correlates better with the plasma concentration
than with the dose
administered.
The steady-state plasma concentration
at a given dosage is determined
by clearance and by the fraction of the dose administered
that reaches the systemic
circulation unchanged (equation 1). These pharmacokinetic
factors are usually determined after administration
of a single dose to volunteers. However, pharmacokinetic
factors can be time-dependent-i.e.,
subject to changes after repeated administration
of the compound in question (Westenberg et al., 1978). Study of the pharmacokinetics
during repeated administration
is therefore always advisable.
Currently available data on the pharmacokinetics
of Cl after repeated administration to depressive patients are in accord with data previously reported after administration of a single dose to volunteers (Nagy and Johansson,
1977). Both the mean
clearance after repeated i.m. injections
and the mean systemic availability
after
repeated oral administrations
were not significantly
different from the corresponding
values after a single dose. These pharmacokinetic
factors would therefore not seem to
be time-dependent.
However, because the range around these mean values was
substantial,
interindividual
variations in the disposition of CI are evidently significant.
The switch from i.m. to oral administration
resulted in a significant increase in
plasma DC1 concentration,
This is in line with a similar observation reported by Nagy
and Johansson
(1977). This fact, together with the low availability (mean value 500/c)
after oral administration,
suggests that a significant fraction of the oral CI dose is
metabolized
in the liver during the first passage after absorption.
Since CI is eliminated
almost exclusively
via metabolic
conversion,
including
N-desmethylation,
this so-called first-pass effect results in an influence of the route
of administration,
not only on the availability of the parent compound but also on the
plasma DC1 concentration.
Although CI and DC1 are both pharmacologically
active
(Sigg et al., 1963, 1965; Carlsson et al., 1969a), they differ in their effect on the central
monoamine
metabolism
(Carlsson et al., 1969~ 1969b; Traskman
et al., 1979): CI
proves to be a relatively selective inhibitor of 5-hydroxytryptamine
(5-HT) uptake,
whereas DCI-as
secondary
amine-is
a strong inhibitor
of noradrenaline
(NA)
uptake. The route of administration,
therefore, influences the clinical effect not only
quantitatively,
but possibly also qualitatively.
Biotransformation
chiefly takes place by the microsomal
enzymes in the liver.
Changes in the capacity of the drug-metabolizing
enzyme system (as a result of enzyme
inhibition
or enzyme induction and/ or changes in hepatic blood flow) can therefore
markedly influence plasma CI and DC1 concentrations.
When other drugs are administered simultaneously,
the possibility of changes in the plasma concentration
ratio
CI/DCI should always be taken into account.
The average plasma concentration,
as calculated by employing equation 1, equals
the area under the plasma concentration-time
curve between the doses divided by the
dose interval, and therefore must represent some value between the maximum
and
minimum steady-state concentration.
For this reason the mean values of the morning
and afternoon plasma concentrations
were used to estimate the average steady-state
concentrations
during the second week of treatment.
During the fourth week, only

155
afternoon
plasma concentrations
were available, but as the difference between the
morning and afternoon plasma concentrations
after oral doses appeared to be small,
these values closely approximate
the average steady-state
concentration.
The interindividual
variations in plasma CI and DC1 concentrations,
particularly
after oral CI administration,
might largely be ascribed to variability both in absorption and in first-pass effect. The differences in first-pass effect probably
reflect
differences in enzyme activity.
The intraindividual
day-to-day
fluctuations
observed in some subjects are less
readily explained.
Apart from patient noncompliance-a
factor that can never be
excluded with certainty in oral medication-the
fluctuations
might be caused by
physiological
variables such as blood flow or food uptake.
In this small population,
no statistically significant linear relation (product moment
correlation) could be demonstrated
between clinical effect and plasma CI, DCI, or CI
+ DC1 concentrations.
Because of the small number of patients involved, no tests for a
curvilinear relationship could be completed. Although the mean clinical effect, particularly as measured by the HRS, was more pronounced
at completion of the treatment
in Group 1 than in Group 2, this difference was not statistically
significant.
Comparison
of all mean values for Group 1 versus Group 2 reveals that only the
plasma DC1 and CI + DC1 concentrations
in Group 1 were significantly
higher than
those in Group 2. This might suggest that DC1 makes an important contribution
to the
overall clinical effect. A similar observation
has been recently reported by Della Corte
et al. (1979) and Trlskman
et al. (1979), who found a significant correlation between
amelioration
of depression and plasma DC1 concentration.
According to Traskman et
al. (1979), this correlation
was best in patients with high pretreatment
concentrations of 5-hydroxyindolacetic
acid in the cerebrospinal
fluid. Therefore, particularly
in this subgroup of depressive patients, the degree of desmethylation
and consequently
the route of administration
may be very important.

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