Mood Stabilizers and Antipsychotics During Breastfeeding: Focus On Bipolar Disorder

European Neuropsychopharmacology (]]]]) ], ]]]]]]
www.elsevier.com/locate/euroneuro
REVIEW
Mood stabilizers and antipsychotics during

breastfeeding: Focus on bipolar disorder
Isabella Pacchiarottia, Jordi Len-Caballeroa,b, Andrea Murrua,
Norma Verdolinia,c, Maria Antonietta Furioa,d,
Corinna Pancheria,e, Marc Valenta, Ludovic Samalina,f,
Eva Sol Roiga, Ana Gonzlez-Pintog, Jose Manuel Montesh,
Antonio Benabarrea, Jose Manuel Crespoi,
Consuelo de Dios Perrinoj, Jose Manuel Goikoleaa,
Luis Gutirrez-Rojask, Andr F. Carvalhol, Eduard Vietaa,n
a
Hospital Clinic, Institute of Neuroscience, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona,

Catalonia, Spain
b
Institut de Neuropsiquiatria i Addiccions, Parc de Salut Mar, CIBERSAM, Barcelona, Catalonia, Spain
c
Division of Psychiatry, Clinical Psychology and Rehabilitation, Department of Medicine, Santa Maria della
Misericordia Hospital, University of Perugia, Italy
d
UOC di Psichiatria Universitaria, Dipartimento di Medicina di base, Neuroscienze e Organi di senso,
University Aldo Moro, Bari, Italy
e
Policlinico Umberto I, Clinica delle Malattie nervose e Mentali, La sapienza Universit di Roma, Roma, Italy
f
CHU Clermont-Ferrand, Department of Psychiatry, EA7280, University of Auvergne, Clermont-Ferrand,
France
g
BIOARABA Health Research Institute. OSI Araba. University Hospital. University of the Basque Country,
CIBERSAM, Vitoria, Spain
h
Psychiatry Service, University Hospital Ramn y Cajal, University of Alcal, CIBERSAM, IRYCIS, Carretera
Colmenar km. 9.1, 28034 Madrid, Spain
i
Department of Psychiatry, University Hospital of Bellvitge, Bellvitge Biomedical Research Institute
(IDIBELL), CIBERSAM, Barcelona, Spain
j
University Hospital La Paz, IdiPAZ, CIBERSAM, Madrid, Spain
k
Psychiatry Service, San Cecilio University Hospital, Granada, Spain
l
Department of Clinical Medicine and Translational Psychiatry Research Group, Faculty of Medicine,
Federal University of Ceara, Fortaleza, CE, Brazil
Received 30 May 2016; received in revised form 27 July 2016; accepted 5 August 2016
n
Correspondence to: Hospital Clinic, Institute of Neuroscience, University of Barcelona, IDIBAPS, CIBERSAM, 170 Villarroel st., Barcelona,
Catalonia, Spain.
E-mail address: evieta@clinic.ub.es (E. Vieta).
http://dx.doi.org/10.1016/j.euroneuro.2016.08.008
0924-977X/& 2016 Published by Elsevier B.V.
Please cite this article as: Pacchiarotti, I., et al., Mood stabilizers and antipsychotics during breastfeeding: Focus on bipolar disorder.
European Neuropsychopharmacology (2016), http://dx.doi.org/10.1016/j.euroneuro.2016.08.008
I. Pacchiarotti et al.
1.
KEYWORDS
Abstract
Lactation;
Bipolar disorder;
Mood stabilizers;
Antipsychotics;
Breastfeeding
Breast milk is considered the best source of nutrients and provides much better protection
than immune modied milk. However, the postpartum period is a phase of increased risk for
all women to experience psychiatric symptoms and recurrences or new episodes of bipolar
disorder (BD), especially in those who have discontinued treatment. This is a systematic
review of the risks and benets of mood stabilizers and antipsychotics during breastfeeding
as they relate to the health and well-being of mothers and their infants. Evidence-based
treatment advice for women with BD during lactation is also provided. This systematic
review has been conducted according to the PRISMA (Preferred Reporting Items for
Systematic Reviews and Meta-Analyses) statement. We included studies examining the
exposure and the effects of antipsychotics and mood stabilizers used to treat BD on infants
during breastfeeding clearly reporting the estimated amount of drug or effects on infants.
The nal selection included 56 studies. The available data supports the use of lithium as a
possible treatment option during breastfeeding. Carbamazepine and valproic acid are also
considered relatively safe. Lamotrigine can be used but at the lowest doses and considered
for individual cases. Among the antipsychotics, quetiapine and olanzapine should be
considered as rst-line treatment options. Risperidone may be compatible with breastfeeding under medical supervision. Clozapine and amisulpiride are currently contraindicated.
Long-term outcome studies evaluating the infant's health and psychosocial and cognitive
functioning are needed.
& 2016 Published by Elsevier B.V.
Introduction
Breastfeeding is currently considered the primary and ideal

form of nutrition for infants throughout the postpartum
period by most professional medical groups (American
College of Obstetricians and Gynecologists, 2007; Stowe,
2007; American Academy of Pediatrics, 2012).
However, the postpartum period is considered a time of
heightened vulnerability for bipolar disorder (BD), since it is
a high-risk period for affective recurrences, especially in
bipolar women who have discontinued treatment (Viguera
et al., 2000, 2007, 2011; Pope et al., 2014a, 2014b; Maina
et al., 2014; Larsen et al., 2015). Patients with BD have an
increased risk of developing a post-partum psychosis, especially during the rst 4 weeks after the birth of the child
(Harlow et al., 2007). Moreover, several recent studies have
suggested that the presentation of any mental illness in the
early postpartum period, including a rst episode of postpartum depression or most cases of puerperal psychosis,
could hide a rst episode of BD (Pope et al., 2014b;
Chaudron and Pies, 2003; Azorin et al., 2012).
Almost all drugs commonly used for treating BD are
excreted into breast milk and the risk of toxicity for
breast-fed infants from certain psychotropic drugs used in
BD is signicant. Nonetheless, these risks should be carefully balanced against the increased risk of a breakthrough
episode of bipolar illness or affective recurrences if a
patient's medication is changed or discontinued (Viguera
et al., 2000, 2007, 2011).
Actually, there is a strong consensus on the fact that
mood stabilizers and antipsychotics should be considered as
rst line treatments for BD, both in acute and long-term
management of the illness (Samalin et al., 2016).
In this review, the evidence indicating the toxicity for the

breastfed infant of mood stabilizers and antipsychotics, the
drugs most commonly used in BD, is discussed, and
evidence-based treatment recommendations for women
with BD during lactation are provided.
2.
Experimental procedures
This review has been conducted according to the PRISMA (Preferred

Reporting Items for Systematic Reviews and Meta-Analyses) statement (Moher et al., 2009).
2.1.
Literature search
We systematically searched the MEDLINE/PubMed/Index Medicus,

EMBASE, and Cochrane Library databases from any time to 20
February, 2016, cross-checking the obtained references. The systematic search was performed by two blind independent research
teams (leaded by IP and JL), who searched as follows:
MEDLINE/Pubmed/Index Medicus: authors used the keywords

((lactation OR breast feeding OR postpartum)) AND (antipsychotic
agents OR lithium OR valproic acid OR carbamazepine OR lamotrigine
OR oxcarbamazepine OR anticonvulsants OR antiepileptic drugs OR
valproate OR atypical antipsychotic drugs OR typical antipsychotic
drugs OR haloperidol OR chlorpromazine OR clozapine OR risperidone
OR olanzapine OR quetiapine OR ziprasidone OR aripiprazole OR
paliperidone OR lurasidone OR asenapine OR iloperidone),
Cochrane library: keywords were (lactation OR breast feeding)
AND (mood stabilizer OR antipsychotic).
EMBASE: lactation, bipolar disorder and treatment.
clinicaltrials.gov: keywords were lactation, bipolar disorder and
treatment.
Mood stabilizers and antipsychotics during breastfeeding

2.2.
Study selection
We included studies examining the exposure and the effects of

antipsychotics and mood stabilizers used to treat BD on infants during
breastfeeding clearly reporting the estimated amount of drug or
effects on infants. We included experimental studies (randomized
clinical trials (RCT), quasi-RCTs, non-RCTs), quasi-experimental studies (controlled before and after studies, interrupted time series),
and observational studies (cohort, case-control, registry studies) of
breastfeeding women and their infants/children. We only included
papers in English and limited to human studies. Studies not aimed at
determining the risk of the treatments used for BD on infants exposed
during breastfeeding were also excluded. Meta-analyses and reviews
were used as evidence to support information that could not be
drawn from individual studies. Data were grouped as: 1. Of interest,
2. Duplicates, and 3. Of no interest, according to the above-described
criteria. After selection, full papers were retrieved and studied.
3.
3.1.
Results
Systematic search results
The search yielded 1137 studies, 100 studies were deemed

eligible for further assessment. Among them, 12 were
inaccessible and 32 unrelated to the aim of this review.
The nal selection included 56 studies. Figure 1 is a owchart of considered and nally selected studies, following
the PRISMA statements.
3.2.
General considerations
SCREENING
IDENTIFICATION
The amount of drug that passes into the mother's milk

depends on several factors related to the characteristics of
a single drug, including the route of administration, the
absorption rate, the size of the molecule, the pH of the
3
substrate, the solubility in water and lipids, the protein
binding, the bioavailability and the volume of distribution
(Marks and Spatz, 2003). The foremost parameter that
determines the degree of drug penetration into breast milk
is plasma protein-binding: the higher the percentage of
protein-binding, the less likely the drug is to enter maternal
milk. Regarding the volume of distribution, drugs with a large
volume of distribution are poorly excreted into breast milk
when compared to those with a small volume of distribution.
With regard to the solubility of medication, lipid-soluble
drugs readily diffuse across cell membranes by dissolving in
the lipid bilayer. Another important parameter to determine
the ability of a drug to be excreted in the breast milk is the
milk/plasma (M/P) ratio, which is the ratio of the concentration of drug in the milk to that in the plasma. The higher the
milk/plasma (M/P) ratio, the greater the amount of the drug
found in breast milk. An M/P ratio greater than 1.0 suggests
that the drug may be sequestered in breast milk in high
concentrations. However, the M/P ratio does not provide all
of the information about the absolute amount of a drug that
can be transferred to the infant from breast milk. Thus, a
high M/P ratio does not necessarily contraindicate the use of
a particular medication. Even if the medication has a high M/
P ratio, if the maternal plasma concentration of the drug is
low, then the absolute amount (i.e., dose) of a drug entering
breast milk will likely be small enough to be considered
subclinical for the infant. Thus, higher M/P ratios can be
misleading because they can provide the impression that
large amounts of a medication are transferred into breast
milk, and this may not be the case if the maternal dosage is
low. In fact, drugs transfer into human milk is a function of
the maternal plasma level. The higher the plasma level, the
higher the transfer into human milk (Rowe et al., 2015).
Another important parameter to evaluate the safety of a
drug while breastfeeding is the relative infant dose which is
1137 papers returned by database search:

- Clinicaltrials.gov: 0
- Cochrane library: 15
- EMBASE: 10
- Pubmed/Medline/Index Medicus: 1112
21 duplicated results:
- Clinicaltrials.gov: 0
- Cochrane library: 15
- EMBASE: 6
- Pubmed/Medline/Index Medicus: 0
1116 papers after duplicates removal
ELEGIBILITY
Excluded on the basis of title or abstract: 1016
100 Full studies examined and assessed for inclusion:
INCLUDED
Full studies excluded: 44

Causes for exclusion:
- No data access: 12
- Of no interest with the aim of the review 32
56 Included in the present review
Figure 1 Flowchart of considered and nally selected studies, according to the PRISMA statements.
Lithium and antiepileptic drugs during breast-feeding.
Drug
First author, Study design

year
Sample and drug dosage
Lithium
Bogen et al., Case series

2012
3 women, 4
900 mg/day)
Tanaka
et al., 2008
Case report
1200 mg/day)
Viguera
et al., 2007
Moretti
et al., 2003
Case series
Valproate
Case series
infants
Main outcomes
(600 Infants' lithium levels at 1 month postpartum ranged from 10% to 17% of maternal levels.
Two infants had early feeding problems, which were overcome with breastfeeding education.
No adverse events reported
2 mother-infant pairs (900 Spurious toxic levels were found (sampling device containing lithium heparin) Once sampling

10 mother-infant pairs (600

1200 mg/day)
1500 mg/day)
Sykes et al., Case report

1976
Schou et al., Case series
1973
1 mother-infant pair (800 mg/

day)
8 mother-infant pairs (Lithium
daily dose not available)
Meador
et al., 2014
Open label study
11 Children

Veiby et al., Open label study

2013
18 Children
Meador
Open label study
et al., 2010
Piontek
Case series
et al., 2000
Wisner and Case report
Perel, 1998
11 Children

Stahl et al., Case report

1997
Philbert
et al., 1985
Case series
Von
Unruh Case series
et al., 1984
was removed, lithium levels undetectable or o0.11 mmol/L

Serum lithium levels on average 0.16 mEq/L, ranging from 0.09 to 0.25 mEq/L
No signicant adverse effects
Wide inter-patient variability in lithium concentrations in breast-milk (from 0% to 30% of maternal
weight-adjusted dose).
No clinically overt adverse effects
Plasma lithium levels in the infant o0.2 mmol/L
No adverse effects
Serum lithium concentrations about one-half of the mothers' in the rst week of life, onethird (ranging from undetectable to 0.6 mmol/L) during the following weeks
No adverse effects of VPA exposure via breast milk were observed at age 6 years
Breastfed children exhibited higher IQs compared to children of mothers under VPA
treatment who did not breastfed
Breastfeeding in women using VPA was not associated with any harmful effects on child
development at 6 to 36 months of age
Breastfeeding protected against low weight during the postnatal period
No deleterious effects of breastfeeding during VPA therapy on cognitive outcomes in children
previously exposed in utero (at 3645 months old)
6 mother-infant pairs (750 and Infants serum levels from 0.7 to 1.5 g/ml (0.9 to 2.3% of maternal serum levels)
No adverse clinical effects were observed in the infants
1000 mg/day)
2 mother-infant pairs (250 Infants' serum levels at 1 month of age were 4 mcg/ml (maternal level was 65 mcg/ml).
Infant development was normal at 18 months of age
750 mg/day)
Infants' serum levels at 3 month of age were 1 mcg/ml (maternal level was 67 mcg/ml).


day)

11 mother, 12 infants (9.5

31 mg/kg)
4 mother-infant pairs
Development at 12 months was normal

A 3-month-old, development of trombocitopenic purpura and anemia.
Infant's serum VPA: 6.6 g/ml
Normalization of hemoglobin and the reticulocytes two weeks after stopping breastfeeding,
platelet count normalization 3 months after discontinuing breastfeeding.
VPA in breast milk 510% of the maternal serum concentration.
All children were healthy without any signs of intoxication.
The amount of VPA excreted into the breast milk was negligible
VPA levels in mother's milk were only 3% of maternal serum samples.
During the rst 12 months, four children with a slight retardation in psychomotor
development
Table 1
Carbamazepine Meador
et al., 2014
Case report
1 mother-infant pair (1600 mg/ VPA level in infant's serum not signicant 5 days after delivery and undetectable at 29 days
after delivery.
day)

Open label study
23 Children

2013
40 Children
Meador
Open label study
et al., 2010
Frey et al., Case report
2002
26 Children

Shimoyama
et al., 2000
7 Lactating
800 mg/day)
VPA in breast milk between 510% of that in the mother's serum.

No evidence of any abnormality in the infant.
No adverse effects of CBZ exposure via breast milk were observed at age 6 years
Breastfed children exhibited higher IQs compared to children of mothers under CBZ
Breastfeeding in women using CBZ was not associated with any harmful effect on child
No deleterious effects of breastfeeding during CBZ therapy on cognitive outcomes in children
previously exposed in utero.
1 mother-infant pair (400 mg/ Between the third and seventh week of life the infant presented transient cholestasis
Simultaneous CBZ blood concentrations in the infant and mother (while nursing) were 0.5 and
day)
12.4 mg/L
Case series
women
(250 Mean levels for CBZ in milk and plasma samples were 3.50 and 6.18 mg/L
Wisner and Case report

Perel, 1998

1 Mother-infant pair (500 mg/

day)
Merlob
et al., 1992
Case report

day)
Frey et al., Case report

1990

day)
Meador
et al., 2014
Open label study
27 Children


2013
46 Children
Meador
et al., 2010
Fotopoulou
et al., 2009
Nordmo
et al., 2009
Open label study
30 Children

Case series

mg/day)
day)
Lamotrigine
Case report

Mean milk/plasma ratio of CBZ was 0.64

Infant serum level at 3 month of age was 0.7 mcg/ml (maternal level was 4.7 mcg/ml).
Infant had normal liver function. Serial blood counts revealed a normal physiologic decrease
in hemoglobin at 3 months with later rebound
Infants presented transient hepatic dysfunction with spontaneous resolution
At 24 and 6 months of age infants had normal development and were in good general
condition.
A 3-week-old infant developed cholestatic hepatitis most likely due to CBZ exposure during
pregnancy and breast-feeding.
Cholestasis remitted after cessation of nursing.
Liver function test results and histological ndings were compatible with a drug-induced
hepatitis and other causes were excluded.
No adverse effects of LTG exposure via breast milk were observed at age 6 years
Breastfed children exhibited higher IQs compared to children of mothers under LTG
Breastfeeding in women using LTG was not associated with any harmful effects on children
No deleterious effects of breastfeeding during LTG therapy on cognitive outcomes in children
previously exposed in utero.
Alexander,
1979
Median ratio of breast milk to maternal serum of 0.59 (IQR 0.380.7)

No adverse effects in any of the infants
Sixteen days after birth several apnea episodes appeared during sleeping.
Three hours later the infant became cyanotic while nursing, requiring heart compressions.
At the admission, infant's LTG serum concentration was 4.87 g/ml
Apnea episodes disappeared after stopping breastfeeding
Normal development and no further episodes of apnea up to 7.5 months of age.
Drug

year
Sample and drug dosage
Main outcomes
Wakil et al., Case series

2009
Newport
Prospective
et al., 2008 observational
study
3 mother-infant pair (50 Intermittently occurring skin rash of scarce clinical signicance
The children all developed normally at the age of 15 and 18 months
250 mg/day)
30 mother-infant pairs (50 LTG milk/plasma ratio demonstrated wide variability, ranging from 5.7% to 147%
Elevated platelet counts were observed in 7 of 8 children (no clinical consequences were
800 mg/day)
observed)
No other adverse events were noted

6 mother-infant pairs (175 Mean absolute infant doses, relative infant doses and infant/maternal plasma LTG values
Page-Sharp
et al., 2006
Case series
Gentile,
2005
Liporace
et al., 2004
Case report
Ohman
et al., 2000
Case series
9 mothers and 10 infants (100

800 mg/day)
Rambeck
et al., 1997
Case report
1 mother-infant
300 mg/day)
800 mg/day)
Case series


day)

800 mg/day)

pair
(200

Case report

day)
Oxcarbazepine Lutz et al., Case report

2007
1 mother infant pair (600 mg/

day)
Tomson
et al., 1997
IQR=Inter Quartile Range.

IQs=Intelligence quotients.
VPA=Valproate.
CBZ=carbamazepine.
LTG=Lamotrigine.

were 0.45 mg/kg/day, 7.6% and 18%, respectively

No adverse effects were reported
Infant's development showed a normal progress during the rst 4 months of life
No detrimental events were recorded
Serum LTG levels in nursing newborns ranged from o1.0 to 2.0 g/ml on day 10 of life
LTG levels in newborns were on average 30% of the maternal drug level (range 2043%)
While levels of LTG were higher than expected, no short-term adverse effect were observed
in the exposed children
Median milk/ maternal plasma concentration ratio was 0.61 (range, 0.470.77)
Nursed infants maintained LTG plasma concentrations of 30% (median, range 2350%) of the
mother's plasma levels.
No adverse effects were reported in the infants.
Concentration ratio milk/serum of LTG of the mother was about 0.6
Infant's serum LTG concentration ranged from 0.75 to 2.79 g/ml during the rst three
months of breast-feeding
The infant showed normal development with no signs of mental retardation or neurological
decit.
The ratio of milk to plasma concentration was 0.6 two weeks after delivery.
The plasma concentration in the breast-fed child was 25% of the mother's plasma levels
No adverse effects were observed in the newborn.
Relative and absolute infant dose assessed in this case appears to be low
No delayed development of the child has been noticed in a 5-year follow-up period
Table 1 (continued )

a calculation that divides the dose offered to the infant via
milk (mg/kg/d) by the mother's weight-adjusted dose (mg/
kg/d). An infant dose via breast milk of less than 10% of the
maternal weight-adjusted dose is generally considered safe
in breastfeeding (Chad et al., 2013). The frequency of
feedings and the volume of breast milk that the infant
ingests must be considered. The infant who is exclusively
breastfed for long periods of time (e.g., eight or more times
a day) is more likely to be exposed to maternal medications
than is a child who is breastfed only once or twice a day and
takes supplemental nutrition such as solids and juices. The
evaluation of the infant includes taking into consideration
the age of the infant. Premature and newborn infants are at
greater risk than older infants for developing high plasma
drug concentrations because of their immature hepatic and
renal systems. Older infants may tolerate maternally
ingested medications better than the previously mentioned
infants because they are larger, and the drug will be more
diluted. Infant stability should also be evaluated. Infants
who are physiologically and behaviorally unstable or with
poor gastrointestinal stability, may be at a greater risk from
toxicity induced by maternal medications. The mother
should take the medication immediately after breastfeeding
and not before (Marks and Spatz, 2003).
3.3.
Lithium
Lithium is still considered the mainstay of treatment for BD

(Grande et al., 2015), and women with chronic bipolar
illness are candidates for continuing lithium during pregnancy in order to avoid relapses or starting again at the 2nd
or 3rd trimester to prevent postpartum recurrences. For
lithium, the evidence comes from several case series. On
the basis of the early reports, the use of lithium during
lactation has been discouraged and typically contraindicated, due to the high variability of the transfer into breast
milk (Sykes et al., 1976; Tunnessen and Hertz, 1972; Schou
et al., 1973; Schou and Amdisen, 1973; Fries, 1970;
Weinstein and Goldeld, 1969). Conversely, recent data
suggest that serum lithium levels in nursing infants were
low (ranging from 0.09 to 0.25 mEq/L) and no clinically
overt adverse effects were found in infants. Elevations of
thyroid-stimulating hormone, blood urea nitrogen, and
creatinine were few, minor, and transient; lithium levels
were measurable at approximately one quarter of the
concentration of that in the mother (mothers average levels
of 0.76 mEq/L) in breast-feeding newborns5. Thus lactation
can be permitted through an individualized approach to
breastfeeding in women receiving lithium (Viguera et al.,
2011; Moretti et al., 2003; Bogen et al., 2012; Tanaka et al.,
2008) (Table 1).
3.4.
Antiepileptic drugs (AEDs)
Together with lithium, several AEDs are considered as "mood

stabilizers" and represent widely prescribed drugs for the
treatment of BD in its different phases and as prophylaxis
(Viguera et al., 2000, 2011; Pope et al., 2014a, 2014b;
Maina et al., 2014).
All AEDs pass into the breast milk, even if in different
amounts. Data on the use of AEDs by nursing women ae
7
scarce and mainly represented by single pharmacologic or
pharmacokinetic studies and/or by case reports or case
series on the side effects attributed to their presence in
breast milk (Davanzo et al., 2013).
Generally, the available data suggest that the use of most
AEDs in monotherapy does not preclude exclusive breastfeeding. In an open-label study of 82 mother-infant pairs,
breastfeeding was carried out during monotherapy with
lamotrigine, carbamazepine, phenytoin or valproate and
compared to 112 non-breastfed infants of mother on AEDs
treatment. Both groups were previously exposed in utero to
these drugs. No differences were found between the two
groups in infant Intelligence Quotients (IQs) at the age of
three and six years (Meador et al., 2010, 2014) (Table 1).
3.4.1. Valproate
Valproate (VPA) is the most prescribed drug as an alternative to lithium or even as a rst choice treatment for BD,
being its efcacy for acute manic episodes and for prevention of recurrences. For VPA, the evidence comes from case
reports and series and three open-label studies. In contrast
to the ndings of treatment with VPA during pregnancy, the
limited passage of VPA into breast milk makes it theoretically safe during lactation, with concentrations less than 1%
and no evidence of any cognitive impairment or signs of
intoxication in the infants (Meador et al., 2010, 2014;
Alexander, 1979; Philbert et al., 1985; Wisner and Perel,
1998; Piontek et al., 2000; Veiby et al., 2013), except from
one case of trombocitopenic purpura and anemia, that
promptly disappeared after stopping breastfeeding (Stahl
et al., 1997), and a slight retardation in the psychomotor
development in 4 out of 12 infants exposed to VPA also
during the entire pregnancy (von Unruh et al., 1984)
(Table 1).
3.4.2. Carbamazepine
Like lithium and VPA, carbamazepine (CBZ) has shown
efcacy for the treatment of manic phases of BD and during
the maintenance treatment (Chen and Lin, 2012). For CBZ,
there are three open-label studies and few case reports.
Despite the variability in the rate of transfer of CBZ into
breast milk (Wisner and Perel, 1998; Shimoyama et al.,
2000), no serious adverse events were reported in case
series, with the exception of transient toxic liver changes
(Merlob et al., 1992; Frey et al., 1990, 2002). Three openlabel studies found no deleterious effects of breastfeeding
during CBZ treatment on cognitive outcomes (Meador et al.,
2010, 2014; Veiby et al., 2013) (Table 1).
3.4.3. Oxcarbazepine
In BD, oxcarbazepine (OXC) has shown some effectiveness as
adjuvant treatment in preventing impulsive behavior in BD
and in the prevention of depressive recurrences (Popovic
et al., 2012; Vieta et al., 2008a, 2008b). Reports on the use
of OXC while on breastfeeding are limited to one case
report reporting a low relative infant dose and no signicant
side effects in a 5-year follow-up period (Lutz et al., 2007)
(Table 1).
Antipsychotics during breastfeeding.
Drug

year
Sample and maternal dose
Main outcomes
Olanzapine
Gilad et al., Prospective

2011
controlled
observational
study
Whitworth
Case report
et al., 2010
22 mothers breastfeeding while taking OLZ, 15 mothers taking OLZ Data on lactation and outcome at the age of 12 years
were obtained.
but did not breastfeed and 51 breastfeeding mothers using a drug
known to be safe during lactation (paracetamol) (Mean dose The rate of adverse outcomes in OLZ-exposed breastfed
infants did not differ from those of the control groups.
6.25 mg/day)
Relatively high plasma level in the infant aged four
1 mother-infant pair (515 mg/day)

Lutz et al., Case report
2008
Ambresin
et al., 2004
Gardiner
et al., 2003
Croke et al.,
2002
Goldstein
et al., 2000
Case report

Case series
7 mother-infant pairs (520 mg/day)
Case series
5 Mother-infant pairs (2.510 mg/day)
OLZ was not detected in the plasma of the 6 infants

No adverse effects were found in the infants.
There were no adverse effects on the infants as a
Case series
2 Mother-infant pairs (510 mg/day)
In one infant, the exposure to OLZ at 5 mg was
consequence of exposure to OLZ.
Aripiprazole
1 Mother-infant pair (10 mg/day)
Kirchheiner
et al., 2000
Case report
Watanabe
et al., 2011
Case report
Lutz et al., Case report

2010

Quetiapine
months (Maternal dosage 15 mg, infant's OLZ concentration 11 ng/ml) probably related to an immature hepatic
transformation system, especially CYP1A2
OLZ plasma levels decreased to very low or even
undetectable during the following four months
The infant developed normally and showed no side
effects during the treatment period
The relative infant dose was 0.3% and the OLZ concentration was below the limit of detection in the infant's
plasma sample (o5 ng/ml)
No adverse effects were noticed in the infant.
The relative amount of drug transferred to the infant
was about 4% of maternal weight-adjusted dose
Rampono
et al., 2007
Case report

associated with icterus and sedation; although bottlefed was initiated, icterus and sedation continued.
The second infant was exposed at 2 months to OLZ
10 mg. No adverse events were reported.
OLZ was not detected in the plasma of the infant either
2 or 6 weeks after lactation was started
At the age of 11 months and during the remaining
regular pediatric examinations there were no abnormal
ndings.
In the plasma of the 6-day-old baby 7.6 g/L of ARP was
measured
Neither ARP nor its metabolite was detected in any of
the 3 milk specimens obtained on day 27 after the
infant's birth.
In a 3-month follow-up period, the baby was growing
normally.
Infant's QTP plasma concentration was 1.4 g/L
No adverse effects were noted in the infant
Table 2
Risperidone
Amisulpride
6 mother-infant pairs (25400 mg/day)
QTP levels in breast-milk ranged from not detected to

32264 nmol/L depending on QTP doses.
4 out of the 6 babies scored as being within normal
Gentile, 2006 Case report

Lee et al., Case report

2004
Aichhorn
et al., 2005
Case report

Ilett et al., Case series

2004
3 mothers and 2 infants (1.54 mg/day)
Hill et
2000
1 mother (6 mg/day)

al., Case report
Teoh et al., Case report

2011

Ziprasidone
Ilett et al., Case report

2010
Werremeyer, Case report
2009
Breastfeeding was maintained up to 6 month, and the

Clozapine
Mendhekar,
2007
Case report
Barnas et al., Case report

1994
limits on the Bayley Scales of Infant Development,

whereas 2 showed a mild developmental delay.
Combination of QTP and uvoxamine (200 mg/day)
Mixed feeding was continued for 3 months and no
adverse events were observed in the baby.
An exclusively breast-fed infant would ingest only 0.09%
of the weight-adjusted maternal dose
Follow-up at 4.5 months indicated that the infant was
developing well, and no adverse effects were reported
Infant's serum concentration was 0 ng/ml for RIS and
0.1 ng/ml for its metabolite.
Three months after the initiation of breastfeeding the
infant did not show any adverse effects and psychomotor development was normal.
M/P concentration ratio for RIS and its metabolite was
o0.5
RIS and its metabolite were not detected in the plasma
of the 2 breast-fed infants studied
No adverse effects were noted.
The estimated infant exposure to RIS was calculated as
0.84% of the maternal dose as RIS and additional 3.46%
from its active metabolite.
Transfer of AMI into milk was high (5.188 mg/L AMI
concentration in milk and 266 mg/L in plasma).
The relative infant dose was 10.7% of the maternal
weight-adjusted dose.
The infant was in good health with an appropriate
Denver development score for her age.
The infant developed normally and no detectable drugrelated adverse effects were found
1 mother (50100 mg/day)

child was deemed healthy, with normal growth and

development at this age
ZIP was given in combination with citalopram (60 mg/
day)
Use of ZIP during lactation did not result in any
detectable outcome.
An infant who was exposed during pregnancy and breastfeeding (until the baby was 1 year old) to CZP experienced delayed speech acquisition possible related with
the drug-exposition.
Beside speech acquisition, development was normal.
CZP concentration in breast milk ranged from 63.5 ng/
ml (CZP dose 50 mg/day) to 115.6 ng/ml (CZP dose
100 mg/day)
Misri et al., Case series

2006
10
Drug

year
Sample and maternal dose
Main outcomes
Haloperidol
Yoshida
et al., 1998
9 mother-infant pairs and 18 controls bottle-fed infants whose HAL concentration in infants serum ranged from 0.8 to
8.0 ng/ml
mothers were taking HAL (in three cases in association with
Psychomotor development was assessed with the Bayley
chlorpromazine) (140 mg/day)
The infant was not exposed to breast-milk
Prospective
controlled
observational
study

Whalley
et al., 1981
Chlorpromazine Yoshida
et al., 1998
Case report
Prospective
controlled
observational
study

4 mother-infant pairs and 18 controls bottle-fed infants whose
mothers were taking neuroleptics or mood-stabilizing drugs. (50

600 mg/day)

Triuoperazine
Perphenazine
Yoshida
et al., 1998
Prospective
controlled
observational
study
Olesen et al., Case report

1990
2 mother-infant pairs and 18 controls bottle-fed infants whose

mothers were taking neuroleptics or mood-stabilizing drugs. (5

10 mg/day)

scale. All the breast-fed babies developed normally,

except 2 infants (both treated with HAL and clorpromazepine) whose scores fell to low borderline levels at 12
18 months.
All the infants were normal on the Amiel-Tison
neurological test.
There were no signicant differences in psychomotor
development between the breast-fed and the bottle-fed
infants at 14 months of age.
The baby did not appear to be sedated and was
feeding well.
HAL was stopped in the sixth week after birth.
The baby developed normally
CPZ concentration in infant serum ranged from o0.1 to
0.7 ng/ml
In three cases, CPZ was given in combination with HAL
Psychomotor development was assessed by the Bayley
scale. Two infants scored fell to low borderline levels at
1218 months. The other two infants were developing
normally
All the infants were normal on the Amiel-Tison
neurological test.
infants at 14 months of age
Infant serum concentration of TPZ was available for one
of the two infant exposed and was o2 ng/ml
The two infants developed normally
infants at 14 months of age
Expressed as micrograms per kilogram of body weight,
the dose passed on to the child with the milk was about
0.1% of that given to the mother.
The child developed normally, and no signs of druginduced symptoms were observed
OLZ=Olanzapine; ARP=Aripiprazole; RIS =Risperidone; AMI =Amisulpride; ZIP=Ziprasidone; CZP=Clozapine; HAL=Haloperidol.

CPZ=Chlorpromazine; TPZ=Triuoperazine; PFZ=Perfenazine; FPX=Flupenthixol; ZPX=Zuclopenthixol.
the corresponding maternal weight related dose
No adverse events were reported
normal motor development.
the corresponding maternal weight related dose.
The infant showed no specic drug effects and had a
The estimated daily infant exposure averaged 0.3% of

1 Mother-infant pair (1424 mg)
Zuclopenthixol
Flupenthixol
Matheson
Case report
and
Skjaeraasen,
1988
Matheson
Case report
and Skjaeraasen, 1988
The estimated daily infant exposure averaged 0.5% of
11
3.4.4. Lamotrigine
The efcacy of lamotrigine (LTG) in preventing depressive
recurrences of BD, mainly in bipolar patients with predominantly depressive polarity is considered the true strength of
this drug (Popovic et al., 2012; Reinares et al., 2014). Its
efcacy for the treatment of bipolar depression is still under
debate (Reinares et al., 2014).
The evidence on the safety of the treatment with LTG
during breastfeeding derives from one naturalistic, three
open studies and various case reports and series, reporting
high variability in infants plasma concentrations and in M/P
ratios but no serious adverse effects or cognitive and
development alterations (Meador et al., 2010, 2014; Veiby
et al., 2013; Tomson et al., 1997; Rambeck et al., 1997;
Ohman et al., 2000; Liporace et al., 2004; Gentile, 2005;
Page-Sharp et al., 2006; Newport et al., 2008; Fotopoulou
et al., 2009), with the exception of elevated platelet counts
in 7 out of 8 children without clinical consequences
(Newport et al., 2008), a case of mild apnea and cyanosis
with therapeutic values of LTG of 4.9 g/ml in infant's serum
(Nordmo et al., 2009) and another case of an intermittently
occurring skin rash of little clinical relevance (Wakil et al.,
2009) (Table 1).
3.5.
Antipsychotics
During the last years, an increased number of studies have

supported the use of antipsychotics (APs)- especially second
generation APs- as a valid therapeutic alternative for the
treatment of BD, both as monotherapy and as adjunctive
treatment to traditional mood stabilizers (Vieta et al.,
2008a, 2008b, 2010, 2011; Yildiz et al., 2011) (Table 2).
From the available studies, treatment with most APs does
not preclude breastfeeding. In fact, despite all the available
APs are excreted into human milk, only minimal concentrations of the active ingredients have been found in breastmilk (Larsen et al., 2015; Gentile, 2008; Klinger et al.,
2013; Parikh et al., 2014).
3.5.1. Quetiapine
For quetiapine (QTP) there are case reports and series,
showing low infant exposure to QTP, with a relative infant
dose from only 0.09% to a maximum of 0.43% of the weightadjusted maternal dose (Misri et al., 2006; Lee et al., 2004).
No adverse effects of QTP were reported from the available
studies (Lee et al., 2004; Gentile, 2006; Rampono et al.,
2007) (Table 2).
3.5.2. Olanzapine
For olanzapine (OLZ), there is sufcient documentation
deriving from several case series, reports and a prospective
study, showing low infant plasma concentrations and low
relative infant doses from 0.3% to 4% of the weight-adjusted
maternal dose (Kirchheiner et al., 2000; Croke et al., 2002;
Gardiner et al., 2003; Ambresin et al., 2004; Lutz et al.,
2008), except for one case with relatively high OLZ plasma
levels during the rst four months of age (Whitworth et al.,
2010). Generally, no adverse events were reported in the
exposed infants (Kirchheiner et al., 2000; Croke et al.,
2002; Gardiner et al., 2003; Ambresin et al., 2004; Lutz
12
et al., 2008; Whitworth et al., 2010; Goldstein et al., 2000;

Gilad et al., 2011) (Table 2).
3.5.3. Risperidone
For risperidone (RIS) during breastfeeding there are only
case reports, showing relative infant doses ranged from
2.3% to 4.7% and low or undetectable plasma levels, with no
adverse effects reported in the infants (Hill et al., 2000;
Ilett et al., 2004; Aichhorn et al., 2005) (Table 2).
3.5.4. Aripiprazole
Data on aripiprazole (ARP) exposure during pregnancy and
lactation are scarce. The only two case reports indicate that
the administration of ARP during lactation might be relatively safe (Lutz et al., 2010; Watanabe et al., 2011)
(Table 2).
3.5.5. Amisulpride
There are only two case reports for amisulpiride (AMI)
during breastfeeding showing a variability of relative infant
doses and a high transfer into breast milk, but no adverse
effects were found in the two infants (from 6% to 10.7%)
(Ilett et al., 2010; Teoh et al., 2011) (Table 2).
3.5.6. Ziprasidone
The use of ziprasidone during lactation did not result in any
detectable outcome from the only available case report
(Werremeyer, 2009) (Table 2).
3.5.7. Clozapine
Data on clozapine (CZP) use during lactation are anecdotal,
showing considerable CZP concentrations in breast milk and
M/P ratios and a possible delayed speech acquisition (Barnas
et al., 1994; Mendhekar, 2007). The general risk of agranulocytosis with CZP treatment might be one of the additional
reasons to avoid its use during lactation (Gentile, 2008)
(Table 2).
3.5.8. Typical antipsychotics
For haloperidol (HAL) there is a prospective study and a
case report, showing a high variability of HAL infant serum
and milk concentrations (Whalley et al., 1981; Yoshida
et al., 1998), with a possible impairment in psychomotor
development in two infants also exposed to chlorpromazine
(Yoshida et al., 1998). The aforementioned open label
controlled study (Yoshida et al., 1998) also evaluated the
transfer of chlorpromazine (CPZ) and triuoperazine (TPZ)
into breast milk, showing a high variability of milk concentrations for both drugs. There is only one case report for
perphenazine (PFZ), showing a low relative infant dose and
no adverse events (Olesen et al., 1990) (Table 2).
4.
Discussion
The postpartum is a period of signicantly increased risk for

severe mood episode recurrences in women with BD. eIn
several longitudinal studies, the postpartum psychosis was
shown not to be a discrete nosologic entity, but a postpartum presentation of an underlying mood disorder that
appears mainly within the bipolar spectrum (Chaudron and
Pies, 2003; Di Florio et al., 2013). A recent cohort study of a
long-term follow-up of a total of 120,378 women with a

rst-time psychiatric inpatient or outpatient admission with
any type of psychiatric disorder revealed a predictive effect
of symptoms occurring within the rst 14 days of delivery on
the subsequent conversion to BD (relative risk: 4.26; 95% CI:
3.11-5.85) (Munk-Olsen et al., 2012).
The clinical management of BD which recurs or starts
during the postpartum period is a complex issue that
highlights the need for balancing potential teratogenic
and other adverse effects of medication on the child,
against the consequences of untreated bipolar episodes,
rst of all the risk of suicide or even infanticide (Weinstein
and Goldeld, 1969; Pacchiarotti et al., 2001; Jones et al.,
2014). The assessment of the mother's intent to breast-feed
is critical to the discussion of treating a new postpartum
bipolar episode or continuing medication for BD. The
majority of women treated for BD need to continue
medication during postpartum, as this is a time of high
relapse risk. Some women may need treatment in the early
postnatal period due to onset of a new bipolar episode. In
this context, inherent benets of breast-feeding for a
mother with BD and her infant should be weighed against
risks of neonatal exposure to psychotropic drugs through
breast milk (Pope et al., 2014a).
Given ethical concerns, double-blind placebo-controlled
trials assessing the safety of mood stabilizers and antipsychotics during breastfeeding are not possible. Large-sample
retrospective studies following guidelines may provide more
information on safety concerns. Nevertheless, current ndings assessing this issue are mainly based on case reports
and/or case series, impeding a reliable ascription of any
reported side effect to medication taken by the breastfeeding mother.
Lithium, usually considered as contraindicated, has been
recently rehabilitated and can be considered as a possible
treatment option during breastfeeding. In fact, while
lithium passes through breast milk and is measurable in
breast-feeding newborns at approximately one quarter of
the concentration of that in the mother, a recent study
found no serious adverse events in breastfed infants
(Viguera et al., 2011). Nonetheless, following maternal
and infant lithium levels, a careful attention to infant
hydration and frequent monitoring of the infant's renal
and thyroid function are necessary, particularly if the infant
shows symptoms of lithium exposure (Viguera et al., 2011;
Pope et al., 2014a).
Regarding anticonvulsants, CBZ and VPA are considered to
have a good level of safety during lactation. LTG can be
used but at the lowest doses and considered for individual
cases, due to the highly variable transfer of this drug to the
child. Little data are available on the use of OXC (Davanzo
et al., 2013).
With respect to atypical APs during breastfeeding, QTP
and OLZ are cited as safe and should be considered as
rst-line treatment options in those patients in whom an
antipsychotic is indicated. RIS is categorized as possible
for breastfeeding under medical supervision due to
insufcient data. Finally, typical APs together with the
newer atypical APs such as aripiprazole, paliperidone,
lurasidone, ziprasidone, asenapine and loxapine are
currently not recommended due to the paucity or lack
of data.
Mood stabilizers, antipsychotics and their compatibility with breastfeeding.
Specic drugs
Efcacy/safety
in BD
Safety prole during breastfeeding
Lithium
Manic episode
Prophylaxis of BD
Suicide prevention
Breastfeeding could be permitted with lithium Careful observation of exposed infants (muscle tone, tremor, dehydration, Da
lethargy, feeding problems, weight gain) is needed.
through an individualized approach Moderately
Despite no signicant adverse effects were found in breastfed infants, a
safe
Valproate
Lamotrigine
Manic/mixed
episode
Prophylaxis of BD
Prophylaxis of
depressive
recurrences in BD
Carbamazepine Manic episode

Prophylaxis of BD
Quetiapine
Olanzapine
Risperidone
Manic/mixed
episode
Bipolar depression
Prophylaxis of BD
Manic/mixed
episode
Prophylaxis of BD
Manic/mixed
episode
Precautions
Level of
evidence
frequent monitoring of the infant's renal and thyroid function is

recommended.
With a close observation for possible side-effects, Thrombocytes count
D
the infant can be breastfed

Safe
Breastfeeding with LTG needs to be carefully con- It is advisable to check the presence of thrombocytosis and skin rush in the D
sidered by individual cases due to the wide varianursing infant.
bility of M/P ratio and infant's plasma The lowest dose should be prescribed (up to 200 mg/day)
concentrations.
Moderately safe
With a close observation for possible side-effects, Liver enzymes parameters
D
the infant can be breastfed
Safe
First line treatment in BD during breastfeeding.
Infant monitoring
D
Safe
Infant monitoring
Possible for breastfeeding under medical super- Infant monitoring

vision due to insufcient data
First line treatment in BD during breastfeeding.
Safe
Moderately safe
Amisulpiride
Manic/mixed
episode
Due to the considerable transfer into breast milk

other antipsychotic should be preferred.
Not recommended
Clozapine
Manic/mixed
episode
Clozapine is currently not recommended during

breastfeeding due to the lack of data and to its
side-effect prole.
Aripiprazole
Manic/mixed
episode
Paliperidone
Manic/mixed
episode
Not recommended
Despite the preliminary evidence seems to indicate
that the administration of ARP during lactation may
be relatively safe, breastfeeding cannot be currently recommended due to the paucity of studies.
Not recommended
Not recommended due to lack of data
13
Table 3

Not recommended due to the paucity of data
Loxapine
Typical APs
Manic/mixed
episode
Manic/mixed
episode
Agitation in BD
Asenapine
National Health and Medical Research Council (NHMRC) of the Australian Government. NHMRC levels of evidence and grades for recommendations for developers of guidelines. Canberra:
National Health and Medical Research Council, December 2009.
a
National Health and Medical Research Council (NHMRC) of the Australian Government's NHMRC levels of evidence and grades for recommendations for developers of guidelines Level of
evidence D: Body of evidence is weak and recommendation must be applied with caution.
D
D
D
Ziprasidone
Bipolar
depression (FDA)
Manic/mixed
episode
Prophylaxis of BD
as
adjunctive
treatment
Lurasidone
Safety prole during breastfeeding

Efcacy/safety
in BD
Specic drugs
Precautions
Level of
evidence
14
Since there are still no clear guidelines on the use of

mood stabilizers and antipsychotics in BD during breastfeeding, due to the dearth of evidence, only tentative treatment
advice can be made (Table 3). The decision to breastfeed
the child should be taken by the mother, after careful
assessment of the circumstances and the nature of the
treatment that she may be taking, and sensible medical
advice. From this systematic review, the benets of breastfeeding mostly appear to outweigh the cons, with few
exceptions. Combined breastfeeding with other supplementary nutrition is possible and reduces the risk of exposure to
high drug levels in the newborn. Breastfeeding should be
avoided or at least restricted in premature newborns.
Future reports are urgently needed assessing the safety of
these medications during breastfeeding such as long-term
follow-up studies evaluating the infant's health, psychosocial and cognitive functioning in order to allow clinicians
and patients to make informed treatment decisions.
Declaration of contribution of each author to

the manuscript
Dr. Pacchiarotti A, Dr. Len Caballero and Dr Murru: Conception and design of the study, acquisition of data, analysis
and interpretation of data, drafting the article.
Dr. Valent and Dr. Goikolea: Conception and design of the
study, acquisition of data, analysis and interpretation of
data, drafting the article.
Dr. Samalin and Dr. Carvalho: drafting the article, revising
critically for contents.
Dr. Sol Roig and Dr Benabarre: acquisition of data,
analysis and interpretation of data.
Dr. Furio, Dr. Verdolini and Dr. Pancheri: drafting the
article, revising critically for contents.
Dr. Gutirrez-Rojas and Dr. Crespo: acquisition of data,
analysis and interpretation of data.
Dr. Gonzalez-Pinto, Dr. Perrino and Dr. Montes: acquisition
of data, analysis and interpretation of data.
Dr Vieta: Conception and design of the study, revising
critically for contents, nal approval to the version.
Author disclosures/conict of interest

Dr. Pacchiarotti has received CME-related honoraria, or
consulting fees from
ADAMED, Janssen-Cilag and Lundbeck.
Dr. Len-Caballero has no conicts of interest.
Dr. Murru has received CME-related honoraria, or consulting fees from ADAMED AstraZeneca, Bristol-Myers
Squibb, Janssen-Cilag, Lundbeck and Otsuka.
Dr. Valent has received grants from Eli Lilly & Co.; and
has served as a speaker for Abbott, Bristol-Myers Squibb,
GlaxoSmithKline, and Janssen-Cilag.
Dr Samalin has served as consultant or speaker for the
companies: Astra-Zeneca, Bristol-Myers Squibb, Eli Lilly,
Janssen-Cilag, Lundbeck, Otsuka, Sano-Aventis, Takeda.
Dr. Goikolea has been a speaker or on the advisory board
for Astra-Zeneca, BristolMyers-Squibb, Eli Lilly, GlaxoSmith-Kline, Janssen-Cilag,Merck Sharpe and Dohme,
Otsuka, Pzer, Sano-Aventis.

Dr. Benabarre has served as consultant or speaker for the
companies: Janssen-Cilag, Otsuka, Ferrer, Lundbeck.
Dr. Montes has no conicts of interest.
Dr. Crespo has no conicts of interest.
Dr. Perrino has no conicts of interest.
Dr. Pancheri has no conicts of interest.
Dr. Verdolini has no conicts of interest.
Dr. Furio has no conicts of interest.
Dr. Carvalho has no conicts of interest.
Dr Sol Roig has no conicts of interest.
Dr L. Gutirrez-Rojas has been a spokesperson for and
advisory board member of Bristol-Myers Squibb, JanssenCilag, Astra-Zeneca, Rovi, Lundbeck, Otsuka, GSK and
Pzer.
Dr. Gonzalez-Pinto has received grants and served as
consultant, advisor or CME speaker for the following entities: Almirall, AstraZeneca, Bristol-Myers Squibb, Cephalon,
Eli Lilly, Glaxo-Smith-Kline, Janssen-Cilag, Ferrer, Johnson
and Johnson, Lundbeck, Merck, Otsuka, Pzer, Sano-Aventis, Servier, Shering-Plough, Solvay, the Spanish Ministry of
Science and Innovation (CIBERSAM), the Ministry of Science
(Carlos III Institute), the Basque Government, the Stanley
Medical Research Institute, and Wyeth.
Prof. Eduard Vieta has received research grants and:
Alexza, Almirall, Astra-Zeneca, Bial, Bristol-Myers Squibb,
Eli Lilly, Ferrer, Forest Research Institute, Gedeon Richter,
Glaxo-Smith-Kline, Janssen-Cilag, Jazz, Lundbeck, Merck,
Novartis, Otsuka, Pzer, Roche, Sano-Aventis, Servier,
Solvay, Shire, Takeda, United Biosource Corporation,
research funding from the Spanish Ministry of Science and
Innovation, the Stanley Medical Research Institute and the
7th Framework program of the European Union.
Role of funding and acknowledgments

This work was supported with funding from the Spanish
Ministry of Economy and Competitiveness, the Centro de
Investigacin en Red de Salud Mental, CIBERSAM, -Instituto
de Salud Carlos III Recerca del DIUE de la Generalitat de
Catalunya to the Bipolar Disorders Group (2014 SGR 398).
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Mood Stabilizers and Antipsychotics During Breastfeeding: Focus On Bipolar Disorder

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European Neuropsychopharmacology (]]]]) ], ]]]]]]

Mood stabilizers and antipsychotics during

Hospital Clinic, Institute of Neuroscience, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona,

Breastfeeding is currently considered the primary and ideal

In this review, the evidence indicating the toxicity for the

This review has been conducted according to the PRISMA (Preferred

We systematically searched the MEDLINE/PubMed/Index Medicus,

MEDLINE/Pubmed/Index Medicus: authors used the keywords

Mood stabilizers and antipsychotics during breastfeeding

We included studies examining the exposure and the effects of

The search yielded 1137 studies, 100 studies were deemed

The amount of drug that passes into the mother's milk

1137 papers returned by database search:

Excluded on the basis of title or abstract: 1016

100 Full studies examined and assessed for inclusion:

Full studies excluded: 44

56 Included in the present review

Lithium and antiepileptic drugs during breast-feeding.

First author, Study design

Sample and drug dosage

Bogen et al., Case series

Sykes et al., Case report

1 mother-infant pair (800 mg/ 

Open label study

Veiby et al., Open label study

Stahl et al., Case report

was removed, lithium levels undetectable or o0.11 mmol/L

Development at 12 months was normal

Open label study

Veiby et al., Open label study

VPA in breast milk between 510% of that in the mother's serum.

Wisner and Case report

1 Mother-infant pair (400 mg/ 

Frey et al., Case report

1 Mother-infant pair (600 mg/ 

Open label study

Veiby et al., Open label study

Open label study

4 mother-infant pairs (250900

Mean milk/plasma ratio of CBZ was 0.64

Mood stabilizers and antipsychotics during breastfeeding

Median ratio of breast milk to maternal serum of 0.59 (IQR 0.380.7)

First author, Study design

Sample and drug dosage

Wakil et al., Case series

 No other adverse events were noted

9 mothers and 10 infants (100 

1 mother-infant pair (300 mg/ 

Oxcarbazepine Lutz et al., Case report

1 mother infant pair (600 mg/ 

IQR=Inter Quartile Range.

were 0.45 mg/kg/day, 7.6% and 18%, respectively

Mood stabilizers and antipsychotics during breastfeeding

Lithium is still considered the mainstay of treatment for BD

Antiepileptic drugs (AEDs)

Together with lithium, several AEDs are considered as "mood

Antipsychotics during breastfeeding.

First author, Study design

Sample and maternal dose

Gilad et al., Prospective

1 mother-infant pair (5 mg/day)

1 mother-infant pair (20 mg/day)

1 mother-infant pair (800 mg/

1 Mother-infant pair (400 mg/

1 Mother-infant pair (600 mg/

No other adverse events were noted

9 mothers and 10 infants (100

1 mother-infant pair (300 mg/

1 mother infant pair (600 mg/

OLZ was not detected in the plasma of the 6 infants

In one infant, the exposure to OLZ at 5 mg was

QTP levels in breast-milk ranged from not detected to

4 out of the 6 babies scored as being within normal

Breastfeeding was maintained up to 6 month, and the

The infant was not exposed to breast-milk

2 mother-infant pairs and 18 controls bottle-fed infants whose

No adverse events were reported

The infant showed no specic drug effects and had a

The estimated daily infant exposure averaged 0.3% of

The estimated daily infant exposure averaged 0.5% of