Eur J Clin Pharmacol

DOI 10.1007/s00228-015-1944-6

PHARMACOKINETICS AND DISPOSITION

Pharmacokinetics of clomipramine during pregnancy

P. G. J. ter Horst 1,5 & J. H. Proost 2 & J. P. Smit 3 & M. T. Vries 1 & L. T. W. de Jong-van de
Berg 4 & B. Wilffert 5,6

Received: 28 May 2015 / Accepted: 10 September 2015

# Springer-Verlag Berlin Heidelberg 2015

Abstract (mg). We compared differences in ratios between trimesters by

Purpose Clomipramine is one of the drugs for depression
during pregnancy; however, pharmacokinetic data of clomip-
ramine and its active metabolite desmethylclomipramine in
this vulnerable period are lacking. In this study, we describe
clomipramine and desmethylclomipramine concentrations in-
cluding their ratios during pregnancy. Second, we describe
Center for Epidemiologic Studies Depression scale (CES-D)
scores during pregnancy.
Methods During 13 pregnancies, every trimester and 3 months
after pregnancy, the clomipramine and desmethylclomipramine
concentrations were measured with LC-MSMS and the severity
of depression was assessed by taking the CES-D score. All
concentrations used in our calculations were in fact the ratio
between actual plasma concentration (μg/l) and the actual dose
* P. G. J. ter Horst
p.g.j.ter.horst@isala.nl
1
Department of Clinical Pharmacy, Isala Klinieken, Dr van Heesweg
2, 8025 AB Zwolle, The Netherlands
2
University Centre for Pharmacy, Unit of Pharmacokinetics,
Toxicology and Targeting, University of Groningen,
Groningen, The Netherlands
3
Department of Psychiatry, Isala Klinieken, Dr van Heesweg 2, 8025
AB Zwolle, The Netherlands
4
University Centre for Pharmacy, Unit of PharmacoEpidemiology and
PharmacoEconomics, University of Groningen,
Groningen, The Netherlands
5
University Centre for Pharmacy, Unit of Pharmacotherapy and
Pharmaceutical Care, University of Groningen,
Groningen, The Netherlands
6
Department of Hospital and Clinical Pharmacy, University Medical
Centre Groningen, Groningen, The Netherlands
using the Friedman test.
Results Studying 12 women and 13 pregnancies, we found no
changes in mean clomipramine concentrations, a statistically
significant decrease in mean desmethylclomipramine concen-
trations (p=0.014) and a significant decrease in the ratio of
desmethylclomipramine/clomipramine mean concentrations
during pregnancy (p=0.014) compared to the post-partum pe-
riod. Sub-therapeutic concentrations of clomipramine and
desmethylclomipramine were found in three patients during
whole pregnancy.
Conclusions The mean concentrations of the pharmaco-
logically active metabolite of clomipramine and
desmethylclomipramine changes during pregnancy, where a
decrease in mean concentrations was found during pregnancy.
In case of recurrent disease, we recommend to control clomip-
ramine and its metabolite concentrations, while both are
active.
Keywords Clomipramine . Desmethylclomipramine .
Pregnancy
Introduction
Drugs of choice for maternal depression during pregnancy are
SSRI’s and tricyclic antidepressants (TCAs), including clo-
mipramine [1–3]. Clomipramine is also indicated for anxiety
disorders because of the serotonergic activity of clomipramine
compared to other TCAs [4, 5]. Also, the metabolite,
desmethylclomipramine, has antidepressant actions due to its
noradrenergic activity [5]. The use of clomipramine during
pregnancy is limited, while the use of TCAs during pregnancy
is about 10 % of all antidepressant users, which means about
0.3 % of all pregnant women use TCAs [6].

In general, during pregnancy, an increase of the volume of
distribution (increase in plasma volume, total body water, and
amount of body fat), and lower concentrations of drug-
binding proteins are observed, as well as an increase in hepat-
ic, renal, and cardiac blood flow, and in the end, an increase of
metabolic clearance (possibly by induction of metabolizing
enzymes by progesterone and estrogen) [7, 8]. Clomipramine
is hydroxylized by CYP2D6 to hydroxyclomipramine [9].
CYP2C19, CYP3A4, and CYP1A2 are responsible for the
demethylation of clomipramine to desmethylclomipramine,
and CYP2D6 converts desmethylclomipramine to
hydroxydesmethylclomipramine. The half-lives of clomipra-
mine and desmethylclomipramine are between 16 and 60 h
[10]. So, the elimination of clomipramine concentration under
normal conditions is a combined effect of all mentioned cyto-
chrome P450 enzymes, while the elimination of the main me-
tabolite desmethylclomipramine is only dependent on
CYP2D6 activity. The hydroxyl metabolites are rapidly con-
jugated to glucuronides and excreted in the urine, and so, their
pharmacological activity is limited [9].
According to Kirchheiner, different genotypes of CYP2D6
and CYP2C19 are responsible for variations in plasma con-
centrations of clomipramine [11]. The activity of CYP1A2
and CYP2C19 decrease to 35–50 % at the end of pregnancy
compared to the first trimester, which possibly may lead to
increased plasma concentrations at the end of pregnancy
[12–14]. In contrast to CYP1A2, the activities of CYP3A4
and CYP2D6 are increased during pregnancy [14]. The un-
predictable net effects of changing activities of these enzymes
and the implications for the clomipramine concentration dur-
ing pregnancy need further investigations. For clomipramine
summed with the concentration of desmethylclomipramine,
an equipotent metabolite [15], a relationship between plasma
concentrations and the therapeutic effect and toxicity has been
established, and the target ranges from 50 to 600 μg/l [10, 16].
Recent literature supports the idea to conduct more re-
search into the field of pregnancy and pharmacokinetics [17,
18]. As an example, we know that plasma concentrations of
TCAs may be changed during pregnancy. A small study with
nortriptyline showed that the dose of nortriptyline to prevent
relapse was elevated 1.6-fold, when the first trimester was
compared to the third trimester; however, the number of pa-
tients was small (n=6) [19].
Taken into account the well-established therapeutic win-
dow of clomipramine concentrations, the variations of phar-
macokinetic parameters during pregnancy, and the changes in
activity of the main metabolizing enzymes during pregnancy,
it is of importance to investigate possible increases or de-
creases in clomipramine concentrations and the pharmacolog-
ically active metabolite desmethylclomipramine during preg-
nancy to prevent women from relapse of psychiatric disease or
possibly clomipramine toxicity. In this study, we describe clo-
mipramine concentrations including desmethylclomipramine
Eur J Clin Pharmacol
concentrations and their ratios during pregnancy. Secondary
we describe Center for Epidemiologic Studies Depression
scale (CES-D) scores during pregnancy.
Methods
Setting
This observational study was performed in Zwolle,
The Netherlands, with patients from the Isala Clinics, a large,
1000-bed, secondary teaching hospital with about 3000 deliv-
eries each year. The study was approved by the hospital’s
medical ethics committee and the central medical ethics com-
mittee of The Netherlands (CCMO). Once written informed
consent was obtained and the subject was enrolled in the
study, the subjects’ GP and pharmacist were informed that
his/her patient participated in this trial and that clomipramine
was dispensed by the hospital pharmacy. The study protocol
follows the guidelines (until now only draft guidelines are
available) of the US Food and Drug Administration (FDA)
on pharmacokinetic studies in pregnancy [20].
Inclusion and study scheme
At the decision of the patient and the psychiatrist (JPS) women
used clomipramine when the benefits of using this drug out-
weigh the possible concerns of using TCA during pregnancy,
especially clomipramine. In the first trimester of pregnancy,
women were asked by the psychiatrist (JPS) to participate in
this study. Inclusion criteria for the pregnant women were
written informed consent for the study protocol, expected un-
avoidable use of clomipramine during the whole pregnancy,
and age >18 years. We excluded women who were mentally
incapable, had twin pregnancies, used drugs of abuse (not
nicotine or alcohol), used additional antidepressants or anti-
psychotic drugs, used drugs with the same or higher terato-
genic risk classification, or used any additional drugs with any
influence on TCA metabolism. At the following times, data
were collected: time of inclusion, 6-months pregnancy, 8.5-
months pregnancy, time just prior to delivery, 1 week after
delivery, and 3 months after delivery. The following data were
then collected: CES-D score (Center for Epidemiologic Stud-
ies Depression scale, the only validated score to be used dur-
ing pregnancy) [21]; antidepressant and dose; demographic
data (only at inclusion); body height (only at inclusion) and
weight; plasma concentration of clomipramine; and
desmethylclomipramine. Extra blood was withdrawn at inclu-
sion time for pharmacogenetic analysis for the CYP2D6 and
CYP2C19 status, which are of importance for clomipramine
metabolism [12]. Pharmacogenetic analysis was performed by
real-time allelic discrimination polymerase chain reaction
(PCR) for the following polymorphisms: CYP2D6*3,
Eur J Clin Pharmacol
CYP2D6*4, CYP2D6*6, CYP2D6*7, CYP2D6*8,
CYP2D6*9, CYP2D6*10, CYP2D6*35, CYP2D6*41,
CYP2C19*2, CYP2C19*3, and CYP2C19*17 and by long-
distance PCR for the CYP2D6 duplicates and CYP2D6 dele-
tion (CYP2D6*5).
Dosing and sampling
Because the study was performed in an out-of-hospital setting,
we used Medication Event Monitoring System (MEMS)
packages to be sure about dosing times (MEMS-6 track
cap®, Aardex ltd, Switzerland). MEMS medication bottles
contain a microelectronic chip that registers the date and time
of every bottle opening. Assuming that bottle openings repre-
sent medication intake, MEMS provides a detailed profile of
the patient’s adherence behavior. Sampling times were record-
ed electronically at times blood was withdrawn at times of
through levels.
Plasma concentration analysis
Plasma samples were analyzed with a UPLC-MSMS tech-
nique (Acquity® UPLC system, Acquity® TQD detector,
and Acquity® UPLC BEH C18 column, and Masslynx v4.1
software for concentration calculations, all from Waters Chro-
matography, Etten-Leur, The Netherlands). Samples were
processed as follows: 50 μl plasma was added to 200-μl in-
ternal standard solution (nortriptyline-D3 0.1 mg/l in
acetonitril/methanol 2:1), mixed thoroughly and frozen for
10 min at −20 °C. One hundred fifty microliters of the super-
natant and additional 600 μl of Millipore water were mixed.
Injection volume was 20 μl. Samples were eluted with a flow
rate of 0.6 ml/min with a gradient elution system containing
200-ml Millipore water added to 200-μl formic acid (A) and
200-ml acetonitrile added to 200-μl formic acid (B). During
elution, the ratio A/B changed from 75:25 during the first 30 s,
to 60:40 until 2.5 min. Thereafter, a 0.5-min column cleaning
procedure was performed using 100 % acetonitrile to remove
interfering phospholipid structures from plasma. The linearity
of our developed method was between 5 and 450 μg/l for both
clomipramine and desmethylclomipramine, which was suit-
able for the expected plasma concentration range (50–
450 μg/l). Within day variations and between day variations
for three concentrations (75, 150, and 225 μg/l) were lower
than 4.8 %, and the lower limit of quantification was 5 μg/l for
both analytes. All reagents were of analytical grade.
Acetonitril (UV grade) and methanol were purchased from
Labscan® (Cuijck, The Netherlands), nortriptyline-D3 was
Fig. 1 Formula for normalizing plasma concentrations of clomipramine and desmethylclomipramine
purchased from LGC (Wessel, Germany), and formic acid
was purchased from Sigma-Aldrich Chemicals (Zwijndrecht,
The Netherlands).
Statistics
We divided the period in four trimesters of 91 days each,
where trimesters 1, 2, and 3 represent the trimesters of preg-
nancy and the post-partum period. When two concentrations
were measured during a particular pregnancy for a single pa-
tient in the same trimester, we used the mean of these values,
despite the fact that throughout a trimester, plasma concentra-
tions also may be changed. We normalized plasma concentra-
tions for the actual dose by dividing the actual plasma con-
centration by the actual dose, see Fig. 1. We justified these
calculations because of first-order pharmacokinetics of clo-
mipramine. Differences between trimesters in concentrations
of clomipramine and desmethylclomipramine and their ratio
were tested with the Friedman test using the software package
SPSS statistics (version 22, IBM inc, Armonk New York,
USA).
Smoking may affect steady-state clomipramine concentra-
tions [16]. Another covariate in our analysis was the pharma-
cogenetic status at the level of poor metabolizer, extensive
metabolizer, intermediate metabolizer, and fast metabolizer
according to the definition of the Dutch working group on
pharmacogenetics [20]. Possible relationships between CES-
D scores and clomipramine and desmethylclomipramine con-
centrations were tested using linear regression analysis.
Results
From 2004 until 2009, 12 mothers, all of Caucasian race and
using clomipramine, were eligible for this study and all wom-
en could be included. From these 12 mothers, the data of 13
pregnancies were included. Women started this study after
signing informed consent, and then the first blood samples
were collected. Demographic data and drug information are
presented in Tables 1 and 2. Three out of 13 pregnancies were
complicated by pre-eclampsia, and 1 pregnancy was compli-
cated by gestational diabetes mellitus. Four neonates were
born with help from a cesarean section.
None of the patients used grapefruit juice (a cytochrome
3A4 inhibitor), two patients smoked during their pregnancy
(see Tables 1 and 2), and two patients did not give informed
consent for pharmacogenetic screening. Four patients were
intermediate metabolizer for CYP2D6, and one patient was a
Table 1 Patient demographics

ID Age Pre-pregnancy Daily dose at Daily dose at Tablet formulation Indication Complianceb Co-medication CES-D score Complications
(years) weight (kg) time of inclusion in delivery in (%) (min-max)
milligrams (mg) milligrams (mg)

1 32 70 37.5 37.5 Immediate release Obsessive-compulsive 100 Novorapid® 11–27 Intra-uterine death
disorder (insulin)
2 36 90 37.5 37.5 Immediate release Panic disorder 100 – 0–11
3 41 84 75 75 Sustained release Major depressive 97 Multivitamin 1–7
disorder preparations
4 36 64 75 113 Sustained release Panic disorder 100 – 22–25 Cesarean section, due to
meconium containing
amniotic fluid, diabetes
gravidarum, pregnancy-
related hypertension
5 40 81 75 100 Sustained release Panic disorder 100 – 0–16 Pre-eclampsia, sec. cesarean
section due to delayed
delivery
6 32 80 60 60 Immediate release Major depressive 96 – 1–1 Cesarean section due to
disorder delayed delivery
7 30 63 50 50 Immediate release Major depressive 96 – 0–0 Diabetes, not pregnancy related
disorder
8 34 60 100 125 Immediate release Obsessive-compulsive 97 – 5–14 Cesarean section, due to
disorder unsuccessful vacuum
extraction and delayed
delivery
9a 26 50 50 50 Immediate release Panic disorder 100 – 3–3 Pre-eclampsia
10 26 50 50 50 Immediate release Panic disorder 100 – 7–20 Pre-eclampsia
11 31 125 20 25 Immediate release Panic disorder 100 – 9–17 –
12a 29 52 125 125 Immediate release Obsessive-compulsive 76 – 24–24 –
disorder
13 28 83 25 25 Immediate release Obsessive-compulsive 100 – 0–0 –
disorder
a
Same mother, second pregnancy in study period
b
Calculated with MEMS-recorded administration times
Eur J Clin Pharmacol
Eur J Clin Pharmacol

Table 2 Plasma concentrations and possible variables in plasma concentrations of clomipramine and desmethylclomipramine

ID Smoke Cytochrome P450 Cytochrome P450 Clomipramine plasma Desmethylclomipramine plasma Breast
D6 sub-enzyme b 2C19 sub-enzymeb concentration (μg/l; min-max) concentration (μg/l; min-max) feeding

1 N NC NC 22ƒ 8ƒ N.A.
2 N 4 3 13–30 5–20 N
3 N 1 1 57–97 5–34 Y
4 Y 1 1 74–156 140–193 N
5 N NC NC 63–86 11–62 N
6 N 1 1 12–20 23ƒ N
7 N 1 1 34–64 10ƒ Y
8 N 1 3 49–125 51–174 Y
9a N 4 1 23–29 27–66 Y
10 N 4 1 33–80 19–75 Y
11 N 2 2 11–37 7ƒ Y
12a Y 4 1 58–88 220 N
13 N 4 1 36–70 – Y

NC no consent for pharmacogenetic testing. ƒ only 1 observation > lower limit of quantification during pregnancy
a
Same mother, second pregnancy in study period
b
1 designates normal metabolizers, 2 poor metabolizers, 3 fast metabolizers, and 4 intermediate metabolizers according to the Dutch working group on
pharmacogenetics [10]

poor metabolizer for CYP2D6. For CYP2C19, we found two
fast metabolizers and 1 poor metabolizer (see Table 2). Three
patients (id 1, 2, and 6), had summed sub-therapeutic concen-
trations (range from 50 to 600 μg/L) [10, 16] of clomipramine
and desmethylclomipramine (see Table 2).
All samples were taken as trough concentrations at steady
state, which means that in more than 4 weeks, the same dose
was administered. During pregnancy, the concentrations of
clomipramine (normalized for ingested dose) decreased
slightly; however, not statistically significant, see Fig. 2 and
Table 3. The variation in clomipramine concentrations among
the 12 patients is high, and the number of included patients is
relatively low, which made us to decide that analysis with co-
factors like smoking, weight, height, and P450 enzyme status
would not contribute to the aims of our study. We depicted the
change in median concentrations of clomipramine and
desmethylclomipramine normalized for daily dose and their
ratio in Figs. 2 and 3. It can be seen that during pregnancy, in

Fig. 2 Median concentrations of desmethylclomipramine and clomipramine, normalized for ingested dose, during pregnancy and the first 3 months after
pregnancy (post-partum). Therapeutic range 50–600 μg/l [10, 16]
 Eur J Clin Pharmacol

Table 3 Median concentrations and ratio of clomipramine and desmethylclomipramine concentrations during pregnancy

Trimester Median concentration clomipramine Median concentration Ratio desmethylclomipramine/ Number of

normalized for ingested dose desmethylclomipramine normalized clomipramine concentration observations
(median (range)) for ingested dose (median (range)) (median (range))

1 0.89 (0.03–1.44) 0.51 (0.03–1.87) 0.96 (0.07–3.79) 6

2 0.72 (0.13–3.07) 0.41 (0.03–2.53) 0.77 (0.04–2.50) 12
3 0.7 (0.03–1.99) 0.1 (0.03–1.72) 0.23 (0.04–2.00) 19
Post-partum 0.7 (0.33–1.29) 0.58 (0.38–2.78) 1.29 (0.35–3.08) 6

Not all patients provided blood samples at all times due to pre-term delivery which was not congruent with sample times or post-partum loss of follow-up

contrast to clomipramine concentration, the
desmethylclomipramine concentration decreased during preg-
nancy and also the ratio (desmethylclomipramine/clomipra-
mine) decreased during pregnancy, both p=0.014. The nor-
m al i z e d c o n ce n t r a t i on d e c r e a s e d w i t h 8 0 % fo r
desmethylclomipramine during pregnancy. Details of the me-
dian concentrations and the ranges are given in Table 3.
Sub-therapeutic concentrations of clomipramine and
desmethylclomipramine were found in three patients during
whole pregnancy. CES-D of all patients were not related to
time of pregnancy, see Fig. 4.
Discussion
We present the first study on pharmacokinetics of clomipra-
mine and its main metabolite desmethylclomipramine during
pregnancy. We found that the mean plasma concentration of
clomipramine did not significantly change during the different
trimesters of pregnancy. We found a statistically significant
decrease in the mean concentration of the pharmacologically
active metabolite desmethylclomipramine during pregnancy.
The ratio of mean desmethylclomipramine and clomipramine
concentrations decreased with 80 % from 0.5 to 0.1. In the
post-partum period, the mean desmethylclomipramine con-
centrations returned to the situation before pregnancy.
Normal ratios for desmethylclomipramine/clomipramine
are between 0.8 and 2.6 [10]. The means of the ratios were
comparable with the normal population; however, as a whole,
ratios varied between 0.04 and 3.79. Although the number of
patients are small, it might be that pregnancy is of importance
in interpreting the ratios found in individual patients.
The CES-D scores did not change during pregnancy. Also,
we found no relation between the CES-D score and the con-
centrations of clomipramine and desmethylclomipramine.
This might suggest that individual therapeutic clomipramine
and desmethylclomipramine concentrations were maintained
during pregnancy. However, in four patients, the dose of clo-
mipramine was increased during pregnancy. This dose adjust-
ments were made by the psychiatrist not related to this study.
Covariates like body weight, smoking behavior, and phar-
macogenetics, were not tested in our analysis due to the large
variability in the data combined with a relative low number of
included patients. The presumed increase of body weight dur-
ing pregnancy might influence clomipramine metabolism;
however, from other studies, we know that body weight did
not have an effect on clomipramine concentrations [10, 22].
The absence of a weight effect, however, has never been tested

Fig. 3 Mean ratio of

desmethylclomipramine/
clomipramine during pregnancy
and the first 3 months after
pregnancy (post-partum). Normal
ratios for
desmethylclomipramine/
clomipramine are between 0.8
and 2.6 [10]
Eur J Clin Pharmacol
Fig. 4 CES-D scores during pregnancy. a CES-D(20) cutoff score of 16 is indicative of Bsignificant^ or Bmild^ depressive symptomatology, whereas
higher scores indicate greater symptoms
in pregnant women. As far as we know, no influence of
smoking on clomipramine metabolism was reported; howev-
er, we could not exclude this possible co-variable, because
some intermediates in the clomipramine metabolism are de-
pendent on CYP1A2 activity, which is known for its induc-
ibility by smoking [14].
From Ververs et al., we know that demethylation across
pregnancy is dependent of the specific genotype of CYP2D6.
Extensive metabolizers and ultra-rapid metabolizers showed
decreasing levels of paroxetine, while intermediate
metabolizers and poor metabolizers show higher paroxetine
concentrations during the course of pregnancy [23].
Clomipramine and desmethylclomipramine are also
metabolized by CYP2D6 into hydroxyclomipramine and
hydroxydesmethylclomipramine, respectively. In this study,
we found that the ratio desmethylclomipramine/
clomipramine decreased during pregnancy, suggesting de-
creased metabolism of clomipramine or increased clearance
of desmethylclomipramine. We cannot find a reasonable ex-
planation for this because of the complex metabolism of clo-
mipramine into different metabolites, which were not all ana-
lyzed. We only found a decrease in the concentration of
desmethylclomipramine, which has equal pharmacological
activity as the parent clomipramine [15].
Another important point of our observational study is the
high number of complications in our cohort. One intra-uterine
death because of placental infection, unlikely to be related to
clomipramine therapy, four cesarean sections, and three cases
of pre-eclampsia. These findings should be further studied.
Recent literature suggests that within the group of TCA, clo-
mipramine should be avoided because of septal defects [24].
Neonatal withdrawal symptoms of the 10 neonates from this
cohort were published earlier and will not be discussed here
[22].
All results and conclusions are hampered by a relatively
low number of patients and limited the generalization of the
data. We included only 12 patients (13 pregnancies) during the
5 years of our study. This means that more centers should be
included for patient recruitment to enlarge the study popula-
tion. The reasons for not doing this were the intensive logistics
(MEMS, refill of dose, sample transport from delivery rooms,
umbilical cord samples), while the time of delivery was almost
always during out-of-office time further complicated data col-
lection. In light of the safety discussion of clomipramine dur-
ing pregnancy, it is unlikely that a larger cohort will be studied
in this way.
Conclusion
Limited by the low number of patients, we could not demon-
strate a change in mean plasma concentration normalized by
actual dose of clomipramine during the whole pregnancy; how-
ever, we found a decrease in mean desmethylclomipramine
concentrations normalized for actual dose of clomipramine,
the equal pharmacologically active metabolite. Most patients

had therapeutic levels of clomipramine summed with
desmethylclomipramine during pregnancy; however, three did
not reach that level during the whole pregnancy. In case of
recurrent disease, we recommend to monitor clomipramine
and its metabolite concentrations to monitor for possible
super- and sub-therapeutic concentrations.
Author contributions P.G.J. ter Horst contributed to the design of the
study, data analysis, and preparing of the manuscript. J.H. Proost contrib-
uted to the pharmacokinetic analysis and preparing of the manuscript. J.P.
Smit contributed to the design of the study and preparing of the manu-
script. M.T. Vries contributed to the validation of assays, analysis of
samples, and preparing of the manuscript. L.T.W. de Jong-van de Berg
contributed to the design of the study, and preparing of the manuscript. B.
Wilffert contributed to the design of the study, data analysis, and prepar-
ing of the manuscript.
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