Expert: Ivan Goldberg, M.D. - 10/14/2008

Question
i'm 26 weeks pregnant,i have bipolar but i haven't took my meds (seraquel) since i found out i was pregnant,but lately i haven't been feeling to good,just really down sometimes to anxtious.is it safe for me to take seraquel while i'm pregnant.

Answer
Hi Jacqueline . . .

There is not a yes or no answer to your question as the use of every drug involves some risk. Below are abstracts of some articles from the medical literature on the topic. I hope you find then useful.

In my practice I've had three women who took Seroquel throughout their pregnancy. All give birth to healthy babies.

Best regards . . .

Ivan
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1: Arch Womens Ment Health. 2007;10(5):235-6. Epub 2007 Aug 6.

Quetiapine use for the treatment of manic episode during pregnancy.

Cabuk D, Sayin A, Derinöz O, Biri A.

Department of Psychiatry, Gazi University Faculty of Medicine Hospital, Ankara,
Turkey. fduygu@gazi.edu.tr

The foregoing is a case report about a 30-year-old woman, who was referred to our
psychiatry clinic with a clinical picture of manic episode, at the 21st week of
her first pregnancy. She had a history of bipolar affective disorder for 12
years, had two previous manic episodes and had stopped taking lithium 6 months
ago because of her plans to become pregnant. Quetiapine was begun and the dose
was slowly increased to 1200 mg/day after 2 weeks. She continued to receive
quetiapine throughout her pregnancy. Her obstetrical and perinatal examinations
were done by a consultant obstetrician. At the follow-up, she had given birth to
a boy, at 39th week of her pregnancy, with an Apgar score of 10. Follow-up of the
infant up to 3 months reveals normal physical and psychomotor development. The
pros and cons of quetiapine use during pregnancy are discussed.

Publication Types:
   Case Reports

PMID: 17676430 [PubMed - indexed for MEDLINE]

2: Am J Psychiatry. 2007 Aug;164(8):1214-20.

Atypical antipsychotic administration during late pregnancy: placental passage
and obstetrical outcomes.

Newport DJ, Calamaras MR, DeVane CL, Donovan J, Beach AJ, Winn S, Knight BT,
Gibson BB, Viguera AC, Owens MJ, Nemeroff CB, Stowe ZN.

Department of Psychiatry & Behavioral Sciences, Emory University School of
Medicine, Atlanta, GA 30322, USA. jeff.newport@emory.edu

OBJECTIVES: There are limited data regarding the use of atypical antipsychotic
medications in pregnancy. The objectives of the current study were to quantify
placental permeability to antipsychotic medications and to document obstetrical
outcomes for women taking these agents proximate to delivery. METHOD: The authors
conducted a prospective observational study of women treated with an atypical
antipsychotic or haloperidol during pregnancy. Maternal and umbilical cord plasma
samples collected at delivery were analyzed for medication concentrations.
Placental passage was defined as the ratio of umbilical cord to maternal plasma
concentrations (ng/ml). Obstetrical outcome was ascertained through maternal
reports and reviews of obstetrical records. RESULTS: Fifty-four pregnant women
with laboratory-confirmed antipsychotic use proximate to delivery were included
in the analysis. Complete maternal-infant sample pairs were available for 50
participants. Placental passage ratio was highest for olanzapine (mean=72.1%,
SD=42.0%), followed by haloperidol (mean=65.5%, SD=40.3%), risperidone
(mean=49.2%, SD=33.9%), and quetiapine (mean=23.8%, SD=11.0%). There were
tendencies toward higher rates of low birth weight (30.8%) and neonatal intensive
care unit admission (30.8%) among neonates exposed to olanzapine. CONCLUSIONS:
All four antipsychotics demonstrated incomplete placental passage. Quetiapine
demonstrated the lowest placental passage of the medications studied. These novel
data provide an initial quantification of the placental passage of antipsychotics
and fetal exposure in humans, demonstrating significant differences between
individual medications.

Publication Types:
   Comparative Study
   Research Support, N.I.H., Extramural

PMID: 17671284 [PubMed - indexed for MEDLINE]

3: J Psychopharmacol. 2007 Sep;21(7):751-6. Epub 2007 Jan 26.

Placental transfer of quetiapine in relation to P-glycoprotein activity.

Rahi M, Heikkinen T, Härtter S, Hakkola J, Hakala K, Wallerman O, Wadelius M,
Wadelius C, Laine K.

Department of Pharmacology and Clinical Pharmacology, Joint Clinical Biochemistry
Laboratory of University of Turku, Turku University Central Hospital, Turku,
Finland. melissa.rahi@tyks.fi

Atypical antipsychotic drugs are well tolerated and thus often preferred in women
of fertile age; yet the information on their placental transfer and use during
the prenatal period is limited. The aim of this study was to study the placental
transfer of quetiapine, a widely used atypical antipsychotic, with special
reference to the role of the placental transporter protein, P-glycoprotein
(P-gp). This was performed in 18 dually perfused placentas, using the well
established P-gp inhibitors PSC833 (valspodar) and GG918 to inhibit the function
of P-gp. We also aimed to clarify the significance of two potentially functional
ABCB1 single nuclear polymorphisms (SNPs), 2677G>T/A and 3435C>T, on the
transplacental transfer (TPT) of quetiapine. The placental transfer of quetiapine
in the control group as measured by TPT(AUC) % (absolute fraction of the dose
crossing placenta) was 3.7%, which is 29% less than the transfer of the freely
diffusible antipyrine, which was 5.2%. The P-gp inhibitors had no significant
effect on the transfer of quetiapine as measured by TPT(AUC) % (P = 0.77). No
correlation was found between the transplacental transfer of quetiapine (TPT(AUC)
%) and placental P-gp expression (P = 0.61). The 3435T allele in exon 26 was
associated with significantly higher placental transfer of quetiapine (P = 0.04).
We conclude that quetiapine passes the human placenta but that the
blood-placental barrier partially limits the transplacental transfer of
quetiapine. Administration of P-gp inhibiting drugs with quetiapine is not likely
to increase fetal exposure to quetiapine, although the ABCB1 C3435T polymorphism
may contribute to inter-individual variation in fetal exposure to quetiapine.

Publication Types:
   Comparative Study
   In Vitro

PMID: 17259208 [PubMed - indexed for MEDLINE]

4: Drug Saf. 2006;29(7):587-98.

Second-generation antipsychotics: is there evidence for sex differences in
pharmacokinetic and adverse effect profiles?

Aichhorn W, Whitworth AB, Weiss EM, Marksteiner J.

Department of General Psychiatry, Medical University Innsbruck, Innsbruck,
Austria.

Six second-generation antipsychotics (SGAs), aripiprazole, clozapine, olanzapine,
quetiapine, risperidone and ziprasidone, are currently US FDA approved. The aim
of this review is to investigate whether sex differences exist for efficacy and
adverse effects of these drugs.Sex-related differences have been shown in the
pharmacokinetics of cytochrome P450 (CYP), with a higher activity in females for
CYP3A4 and CYP2D6. However, even if there are pharmacokinetic differences between
females and males, significantly higher plasma concentrations in women have been
demonstrated only for olanzapine and clozapine.To date, sex differences in
adverse effects have not been well studied, but some adverse effects such as
weight gain, hyperprolactinaemia and cardiac effects are reported to be
particularly problematic for women. Most of the studies reviewed indicate that
clozapine and olanzapine are associated with greater bodyweight gain than the
other atypical antipsychotics, and that serious adverse effects such as metabolic
syndrome, which includes increased visceral adiposity, hyperglycaemia,
hypertension and dyslipidaemia induced by SGAs, are more frequent in females.
According to most studies, the risk for cardiac adverse effects induced by SGAs
is the same in male and female patients. Although women are at a lower risk of
sudden cardiac death, they have a higher risk of induced long QT syndrome from
antiarrhythmic and, probably, antipsychotic drugs. The propensity of sexual
dysfunctions is higher with conventional antipsychotics than with SGAs.
Additionally, there is some evidence that female sexual dysfunction is associated
with high prolactin levels; however, whether the degree of prolactin level
elevation is different between female and male patients remains controversial.
There is no evidence for sex differences for any of the SGAs to cause a higher
rate of extrapyramidal symptoms, acute dystonia or any other movement
disturbance. Knowledge of the risks and benefits associated with the use of SGAs
during pregnancy and lactation is limited, although the direction of dose
adjustments during pregnancy depends on the drug and the enzyme that is
responsible for its metabolism.In general, data on sex differences were mostly
obtained by posthoc analysis and, therefore, the conclusions that can be drawn
are limited. For a better understanding of the basic mechanisms of sex
differences, future studies with a primary focus on this topic are required. Data
that are more specific will help determine the extent to which these differences
will have implications for clinical management.

Publication Types:
   Review

PMID: 16808551 [PubMed - indexed for MEDLINE]

5: Bipolar Disord. 2006 Jun;8(3):207-20.

Prophylactic treatment of bipolar disorder in pregnancy and breastfeeding: focus
on emerging mood stabilizers.

Gentile S.

Department of Mental Health ASL Salerno 1, Operative Unit District n 4, Salerno,
Italy. salvatore_gentile@alice.it

OBJECTIVES: Bipolar disorders are reported to have a high incidence during
childbearing years and the need may arise to start or continue a pharmacological
treatment during pregnancy and the postpartum period. In the last few years
several investigations have evaluated the efficacy of emerging mood-stabilizing
agents in the treatment of bipolar disorders, such as lamotrigine, olanzapine,
risperidone, quetiapine, aripiprazole and ziprasidone. A number of studies, which
examined the use of oxcarbazepine, point to its potential usefulness in
prophylactic treatment. The aim of this review is to compare information from the
literature on the safety of lamotrigine, oxcarbazepine, risperidone, olanzapine,
and quetiapine to the safety data on classic mood stabilizers during pregnancy
and the postpartum period. METHODS: A computerized search carried out from 1980
to April 5, 2006 led to the summarization of the results. (References were
updated after acceptance and prior to publication.) RESULTS: Emerging mood
stabilizers show uncertain safety parameters in pregnancy and lactation. Limited
information on lamotrigine and oxcarbazepine does not suggest a clear increase in
teratogenicity, while olanzapine appears to be associated with a higher risk of
metabolic complications in pregnant women. Data about risperidone and quetiapine
are still inconclusive. Finally, the literature on the safety of these compounds
in breastfeeding is anecdotal. CONCLUSIONS: Untreated pregnant bipolar women are
at an increased risk of poor obstetrical outcomes and relapse of affective
symptoms. On the other hand, classic antiepileptic drugs are well-known human
teratogens, whereas data on lithium are partially ambiguous. The safety of
emerging mood stabilizers in pregnancy and breastfeeding has not been examined
extensively. Therefore, when approaching bipolar disorder, if possible, each
episode must be considered separately.

Publication Types:
   Review

PMID: 16696822 [PubMed - indexed for MEDLINE]

6: Encephale. 2006 Jan-Feb;32(1 Pt 1):97-105.

[Atypical antipsychotics and sexual dysfunction: five case-reports associated
with risperidone]

[Article in French]

Haefliger T, Bonsack C.

Unité de Psychiatrie Communautaire, Sévelin, 18, 1004 Lausanne.

LITERATURE FINDINGS: Sexual and reproductive function side effects of atypical
antipsychotics are frequent, often underestimated and badly tolerated. They
contribute to the 50% rate of non-compliance reported for treated patients.
Prevalence of sexual dysfunction associated with atypical antipsychotic treatment
is high, varying from 18 to 96%. Atypical antipsychotics aren't, as a group, much
better than typical antipsychotics, and among them, risperidone seems to induce
more and quetiapine less sexual dysfunction. Most atypicals are non-selective,
and have actions on multiple central and peripheral receptors. Among these,
dopaminergic blockade could have a direct - altering motivation (desire) and
reward (orgasm) - and an indirect negative influence on sexuality. Actually, the
secondary hyperprolactinemia induced by some antipsychotics (typical
antipsychotics, risperidone and amisulpiride), is dose-dependent, more pronounced
for female patients, and may have a detrimental effect on sexual function. It
also may result in hypogonadism, particularly for female patients. The long-term
consequences of this secondary hypogonadism are subject to debate but potentially
severe. Furthermore, the blocking and/or modulating actions of atypical
antipsychotics on adrenaline, serotonine, histamine or acetyl-choline receptors
all have the potential to contribute to secondary sexual problems. The
pharmacological profile of risperidone, characterized by a strong affinity for D2
and alpha1 receptors, correlates with his tendency to significantly elevate
prolactin levels and to produce ejaculatory disturbances. FIVE CASE-REPORTS: We
describe five case-reports of sexual or hormonal disturbances associated with
risperidone treatment: two cases of ejaculatory disturbance, one case of
galactorrhea and two cases of amenorrhea. Alberto and David are two young male
schizophrenic patients, treated with risperidone, and complaining of a total
absence of ejaculation despite a preserved orgasm. Many recent case-reports
describe the occurrence of retrograde ejaculation associated with risperidone but
the exact prevalence is unknown. Retrograde ejaculation is thought to be related
to the strong adrenolytic activity of risperidone. Alberto refused his medication
because the ejaculatory dysfunction was unbearable for him. A switch to
haloperidol depot was eventually well tolerated, without any sexual complaints.
His case emphasizes the importance of sexual function for self-esteem and how
this may amplify the intolerance to side-effects. David is on depot-risperidone
in a setting of a legally forced treatment. Though he - reluctantly - accepts his
medication, this side effect exacerbates his pre-existing delusions, strongly
focused on sexual themes. His case illustrates how intolerance to sexual
side-effects may be amplified by nature of delusions. Mireille is a 58 year old
psychotic female patient, whose 2 mg risperidone treatment produced a unilateral
galactorrhea. This sign became problematic because potentially visible at a time
when Mireille started an activity in a sheltered occupation in town. Lowering
dosage of antipsychotic allowed disappearance of the problem. Subjective
responses to galactorrhea have been reported to be highly individual. Apart being
a potentially visible side-effect, it may be misinterpreted as evidence of
pregnancy or of a tumoral process. The cases of Ermina and Denise illustrate two
contrasted situations in terms of subjective tolerability of reproductive
function side-effects. Both were pre-menopausal patients with hyperprolactinemia
secondary to risperidone treatment, resulting in amenorrhea. This was unbearable
for Ermina. A switch to olanzapine allowed, one month later, the menses to
resume. For Denise, on the other hand, the amenorrhea was a positive event,
freeing her of unpleasant menses. DISCUSSION: Amenorrhea occurs in about 30% of
pre-menopausal women treated with risperidone. It is a consequence of
hyperprolactinemia, which, although often silent, is not devoid of potential
negative consequences (ie increased risk of osteoporosis or neoplasia, worsening
of psychopathology) (34). When hyperprolactinemia is symptomatic, lowering of the
dose of the antipsychotic, or switching to a prolactin-sparing agent (olanzapine,
quetiapine, aripiprazole and clozapine) is recommended. Before this, women with
amenorrhea secondary to antipsychotic-induced hyperprolactinemia should be
advised that menses may resume. Especially after long-standing amenorrhea they
may assume being menopaused, hence may believe birth control measures are no
longer required. The prevalence of antipsychotic-induced sexual and reproductive
function side-effects is high. Clinicians should be aware of them, because they
are often badly tolerated, are associated with a low satisfaction and may
therefore result in low adherence with treatment. This implies for the clinician
to overtly discuss with the patient of his sexuality and the potential negative
impact of antipsychotic treatment on it. The recognition of these problems allows
the searching together for a solution. CONCLUSION: The described cases indicate
that solving the problem is often possible, provided that individual preferences
and subjective impact are taken in account. Antipsychotic treatment is often
prescribed for very long periods. A better knowledge of - and attention to - the
associated side effects, particularly on the sexual and reproductive functions,
is necessary in order to reduce some potentially negative long-term effects and
to improve the adherence to treatment of our patients.

Publication Types:
   Case Reports
   English Abstract

PMID: 16633296 [PubMed - indexed for MEDLINE]

7: J Clin Psychiatry. 2005 Apr;66(4):444-9; quiz 546.

Comment in:
   Evid Based Ment Health. 2005 Nov;8(4):115.

Pregnancy outcome of women using atypical antipsychotic drugs: a prospective
comparative study.

McKenna K, Koren G, Tetelbaum M, Wilton L, Shakir S, Diav-Citrin O, Levinson A,
Zipursky RB, Einarson A.

Motherisk Program, The Hospital for Sick Children, Toronto, Ontario, Canada.

BACKGROUND: A substantial number of women of childbearing age suffer from
schizophrenia and other mental illnesses that require the use of antipsychotic
drugs. Atypical antipsychotics have been on the market since the mid-1990s, and
to date there are no prospective comparative studies regarding use during
pregnancy. OBJECTIVES: (1) To determine whether atypical antipsychotics increase
the rate of major malformations above the 1% to 3% baseline risk seen in the
general population. (2) To examine rates of spontaneous and therapeutic
abortions, rates of stillbirths, birth weight, and gestational age at birth.
METHOD: The cohort was composed of pregnant women who contacted the Motherisk
Program in Canada or the Israeli Teratogen Information Service in Israel and
women who were recruited from the Drug Safety Research Unit database in England.
Women who had been exposed to atypical antipsychotics were matched to a
comparison group of pregnant women who had not been exposed to these agents.
RESULTS: Data were obtained on 151 pregnancy outcomes that included exposure to
olanzapine (N= 60), risperidone (N = 49), quetiapine (N = 36), and clozapine (N =
6). Among women exposed to an atypical antipsychotic, there were 110 live births
(72.8%), 22 spontaneous abortions (14.5%), 15 therapeutic abortions (9.9%), and 4
stillbirths (2.6%). Among babies of women in this group, there was 1 major
malformation (0.9%), and the mean +/-SD birth weight was 3341 +/-685 g. There
were no statistically significant differences in any of the pregnancy outcomes of
interest between the exposed and comparison groups, with the exceptions of the
rate of low birth weight, which was 10% in exposed babies compared with 2% in the
comparison group (p = .05), and the rate of therapeutic abortions (p = .003).
CONCLUSION: These results suggest that atypical antipsychotics do not appear to
be associated with an increased risk for major malformations.

Publication Types:
   Comparative Study
   Multicenter Study
   Research Support, Non-U.S. Gov't

PMID: 15816786 [PubMed - indexed for MEDLINE]

8: Bipolar Disord. 2005;7 Suppl 1:16-24.

Women are not the same as men: specific clinical issues for female patients with
bipolar disorder.

Curtis V.

Institute of Psychiatry and Maudsley Hospital, De Crespigny Park, London, UK.
v.curtis@iop.kcl.ac.uk

Women are not the same as men. While this observation can be considered to
subjectively manifest in many different ways, objectively a greater tendency for
bipolar II disorder, depressive symptoms, a rapid cycling course, and the
consequences of being of child-rearing age can all represent additional
challenges for female patients. Despite much recent interest in improving the
management of patients with bipolar disorder, relatively little guidance exists
relating to female-biased gender-specific issues. This review article will
explore how female gender can influence bipolar disorder and its treatment and
will focus on epidemiologic differences, the relevance to clinical presentation
of events unique to women (particularly contraception, pregnancy, and lactation),
and the importance of considering gender when making decisions about the
pharmacological management of mood. All female patients should receive counseling
regarding family planning and sexually transmitted diseases, as well as the risks
of and treatment options during pregnancy and postpartum. Wherever possible,
treatment choices should be made in a partnership between patient and clinician.
Copyright Blackwell Munksgaard, 2005

Publication Types:
   Comparative Study
   Review

PMID: 15762865 [PubMed - indexed for MEDLINE]

9: Ann Pharmacother. 2004 Jul-Aug;38(7-8):1265-71. Epub 2004 May 18.

Clinical utilization of atypical antipsychotics in pregnancy and lactation.

Gentile S.

ASL Salerno 1, Head of Mental Health Center District n. 4 Piazza Galdi, 84013
Cava de' Tirreni (SA), Italy. salvatore_gentile@libero.it

OBJECTIVE: To analyze the available literature regarding the safety of atypical
antipsychotics in pregnancy and lactation in order to recommend evidence-based
strategies for pharmacologic management of psychosis in these conditions. DATA
SOURCES: We summarized the results from articles identified via
MEDLINE/PubMed/TOXNET (1993-January 31, 2004), using the key terms pregnancy,
lactation, breast-feeding, human milk, psychotropic drugs, atypical
antipsychotics, olanzapine, quetiapine, risperidone, clozapine, ziprasidone, and
aripiprazole. STUDY SELECTION AND DATA EXTRACTION: Retrospective studies,
clinical observations, and case reports regarding the 6 atypical antipsychotics
mentioned above were selected and analyzed. Extensive manual review of pertinent
journals and textbooks was also performed. DATA SYNTHESIS: Reviewed studies show
that olanzapine and clozapine apparently do not increase the teratogenic risk if
administered to pregnant women, while evidence on quetiapine, risperidone,
aripiprazole, and ziprasidone is still limited. In contrast, available
information is not able to exclude unwanted serious effects associated with the
use of all atypical antipsychotics on mother-infant dyads. Furthermore, more than
a few studies suggest increased hyperglycemic risk for pregnant women related to
atypical antipsychotic therapy during gestation. Finally, published evidence
about the effects on long-term infant neurodevelopment of drug exposure through
both placenta and breast milk is represented only by sporadic case reports.
CONCLUSIONS: It is well known that potential consequences of an untreated
psychotic episode may be severe and may lead to the mother attempting suicide
and/or infanticide. For these reasons, clinicians need to help mothers weigh both
fetal and neonatal risks of exposure to drugs against the potential risk they and
their infant may incur if the psychiatric illness is not treated. On the other
hand, atypical antipsychotics in pregnancy and breast-feeding do not show evident
advantages in safety when compared with typical neuroleptic agents. Therefore, we
suggest that the most relevant parameters for selecting the best clinical option
for pregnant and breast-feeding women with schizophrenia and related disorders
remain strongly related to 3 main points: (1). cautious evaluation of the
risk/benefit ratio of fetal and neonatal drug exposure, (2). degree of severity
of maternal psychiatric illness, and (3). careful preliminary choice of drugs
characterized by a balanced safety/efficacy profile.

Publication Types:
   Review

PMID: 15150376 [PubMed - indexed for MEDLINE]

10: Prog Neuropsychopharmacol Biol Psychiatry. 2004 May;28(3):603-5.

Use of polypharmacotherapy in pregnancy: a prospective outcome in a case.

Yaris F, Yaris E, Kadioglu M, Ulku C, Kesim M, Kalyoncu NI.

Department of Family Medicine, Karadeniz Technical University School of Medicine,
Trabzon TR 61187, Turkey. fyaris@meds.ktu.edu.tr

PURPOSE: Little is known about the risks associated with prenatal exposure to
atypical antipsychotics. Our objective is to present a case of exposure to
risperidone and quetiapine in pregnancy, and additionally to some other drugs.
CASE: Our case (36-year old) has suffered schizophrenia (DSM-IV) for 5 years and
used these drugs (risperidone, quetiapine, mirtazapine, thioridazine, diazepam,
hydroxyzine, clomipramine, fluvoxamine, alprazolam, carbamazepine, biperiden,
haloperidol, ampicillin+sulbactam, enoxaparin, oxerutine) in her third pregnancy.
Because of her psychotic condition, Mrs. N.B. was not aware of her pregnancy
until 22nd week and the pregnancy could not be terminated. She had a female
infant (3000 g, 50 cm) with APGAR scores of 8-9 at the first and fifth minutes at
37th week with an uncomplicated vaginal delivery. The baby was normal.
CONCLUSION: This case may contribute to the existing knowledge regarding use of
atypical antipsychotics in pregnancy.

Publication Types:
   Case Reports

PMID: 15093969 [PubMed - indexed for MEDLINE]