Chittaranjan

Andrade

BIPOLAR DISORDERS IN WOMEN

 50% of bipolar subjects

are women.
 Most of these are young!

Chittaranjan Andrade, MD
Professor in Psychopharmacology
National Institute of Mental Health
and Neurosciences
Bangalore, India
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Andrade

BIPOLAR DISORDERS IN WOMEN

 General issues
 Pregnancy
 Lactation

 Wisner et al, Am J Psychiatry 2000

 Burt and Rasgon, Bipolar Disorders
2004
 Yonkers et al, Am J Psychiatry 2004

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ISSUES AT STAKE: 1

 Women are more likely to experience rapid cycling,

mixed episodes, and antidepressant-induced mania.
 The course of illness may be influenced by the
menstrual cycle, pregnancy, puerperium, and
menopause.
 Treatment may need to be modified during
pregnancy and lactation.
 Adverse effects with drugs may be different in
women.
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ISSUES AT STAKE: 2

 The following may be more common in

bipolar women:
Depressive episodes
Mood fluctuations
Physical comorbidity
Migraine
Pain syndromes

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MENSTRUATION AND BIPOLAR

DISORDER
 The menstrual cycle may be
associated with:
1. Cycle abnormalities
(>normal)
2. Subsyndromal mood
fluctuations (>normal)
3. S. lithium fluctuations due
to premenstrual fluid retention
(implications for monitoring)
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PREGNANCY AND BIPOLAR

DISORDER
 It is a myth that pregnancy protects
against bipolar illness (or recurrent
depressive illness).
 Pregnancy does not protect against nor
predispose to recurrence in patients who
stop lithium after diagnosis of pregnancy.
 Patients who stop lithium, however, are
more likely to experience recurrence of
illness.
 (Viguera et al, Am J Psychiatry 2000) 6
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PREGNANCY AND BIPOLAR

DISORDER

 The risk of recurrence is greater

# In those with a larger number of previous
episodes
# In those who discontinued lithium rapidly: in
<2 weeks
 Bipolar subtype does not influence the risk.
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POSTPARTUM PERIOD AND

BIPOLAR DISORDER
 Unprotected patients are
especially at risk of recurrence
during the first 6 months
postpartum.

 Recurrences during pregnancy

or the postpartum period tend
to be depressive or dysphoric-
mixed rather than pure manic.

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PREGNANCY AND RECURRENT

DEPRESSIVE DISORDER
 Women who stop antidepressant
medication before conception are 5
times more likely to relapse than
those who continue drugs all through
pregnancy.
 Women with a longer history of
depressive illness, and those with a
larger number of previous episodes,
are at higher risk of relapse.
 Cohen et al, JAMA 2006
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PUERPERIUM AND BIPOLAR

DISORDER
 Risk of recurrence during
the first month postpartum
is 40-60%.

 Lithium protects against

postpartum recurrence;
efficacy of valproate is
uncertain; estrogen is
probably ineffective.
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MENOPAUSE AND BIPOLAR

DISORDER
 Data are scarce
 Menopause may
increase the risk of
rapid cycling.
 Subsyndromal mood
fluctuations are
common.
 New onset illness is
rare.
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DRUGS AND BIPOLAR DISORDER

 Increased risk of weight gain with lithium,

valproate.
 ? increased risk of hypothyroidism with lithium.
 ? increased risk of polycystic ovaries with
valproate, especially in young girls.

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MANAGEMENT OF BIPOLAR
DISORDER IN WOMEN

 Focus on pregnancy,
the postpartum period,
and lactation

 Practical issues

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CONSIDERATIONS

 About half of bipolar

patients are women.

 Most of these are of

childbearing age.

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IMPORTANT DOs
 Discuss pharmacological management with
patient, family:
Effect of pregnancy on illness
Effect of illness on pregnancy
Effect of drugs on pregnancy
Need for planned pregnancy
 Involve patient, family in decision-making.
 Review discussion, especially during euthymia.
 Document decision-making processes.
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ISSUES RELATED TO
CONTRACEPTION

 Oral contraceptives can diminish

lamotrigine levels by 50%.
 Carbamazepine and topiramate
can diminish the efficacy of oral
contraceptives.
 Hence, importance of liaising
with gynecologist.

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PLANNING FOR PREGNANCY: 1

 Individualize psychopharmacological
decision-making based on the history of:
Frequency of episodes
Duration of euthymia after
noncompliance
Severity of episodes
Speed and magnitude of response to
drug therapy
Course of illness during pregnancy and
the postpartum period.
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PLANNING FOR PREGNANCY: 2

 Taper and withdraw drugs, if possible during the
entire period, or at least during the first
trimester.
 Use lowest historically-effective doses???????
 Administer drugs in divided doses to lower
dosage peaks.
 Avoid polypharmacy.
 Supplement with psychotherapy, social support.
 Lower stress exposure, ensure adequate sleep.
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ISSUES RELATED TO PLANNED

WITHDRAWAL OF DRUGS

 Lithium, valproate can be withdrawn under

antipsychotic cover to reduce the risk of
withdrawal mania (but typical antipsychotics
may raise prolactin and prevent conception!).
 If mood stabilizers are abruptly withdrawn after
pregnancy is discovered, risk of emergent mania
is very high.
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BEFORE PREGNANCY
 Provide antenatal
counselling, liaise with
gynecologist.
 Supplement with folate
(0.4-4.0 mg/day) months
in advance.
 Enlist family supervision.

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RISK PERIODS

 Weeks 5-7: Neural tube defects

 Weeks 6-10: Cardiac defects
 Weeks 8-11: Lip and palate defects
 Weeks 10-22: Craniofacial anomalies
 (Anytime after week 12: Behavioral teratogenicity)
 Wisner et al, Am J Psychiatry 2000

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FIRST TRIMESTER
 If the discovery of an
unexpected pregnancy
requires the abrupt
withdrawal of mood
stabilizers, effect the
withdrawal of the mood
stabilizers under cover of
a typical antipsychotic.

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FIRST TRIMESTER
 Consider ECT.
 Prefer monotherapy.
 Use lowest historically
effective doses???????
 Administer in divided
doses to lower peak drug
levels.
 Prescribe folate: 0.4-4.0
mg/day.
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SECOND AND THIRD

TRIMESTERS
 Do ultrasound, fetal echocardiography by
week 16-18.
 Do alpha-fetoprotein estimation in maternal
serum, amniotic fluid (to detect neural tube defects).
 Raise drug doses to compensate for
increased blood volume, hepatic metabolism,
renal clearance.
 Monitor drug levels.
 Supplement with vitamin K during last
trimester if on valproate or carbamazepine.
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PUERPERIUM

 Shortly before delivery, lower drug doses

because the neonatal liver is not mature
in metabolism.
 Maintain pre-pregnancy doses after
delivery
 Monitor drug levels.

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RISKS WITH LITHIUM DURING

PREGNANCY
 The risk of Ebstein’s
anomaly increases 10-
to 20-fold after first
trimester exposure to
lithium.
 Should lithium be
avoided during the first
trimester?

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RISKS WITH LITHIUM DURING

PREGNANCY
 First trimester: 1 in 500-1000 risk of
Ebstein’s anomaly (base rate, 1 in
10,000-20,000): right ventricular
hypoplasia with downward displacement
of the tricuspid valve.
 Rest of pregnancy: increased risk of
polyhydramnios, premature delivery,
floppy baby syndrome, perinatal
mortality, nontoxic goiter, nephrogenic
diabetes insipidus
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LITHIUM: SPECIAL ISSUES

RELATED TO
 Hyperemesis during first
trimester (so what?)
 Increased body fluid volume as
pregnancy progresses (so what?)
 Decreased body fluid volume
immediately after delivery (so
what?)
 Implications for monitoring,
liaison with obstetrician.
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UK EPILEPSY AND PREGNANCY

REGISTER DATA (Morrow et al, JNNP 2006)
 N=3607
 Major congenital malformations:
Untreated epilepsy: 3.5%
Carbamazepine exposure: 2.2%
Lamotrigine exposure: 3.2% (>5% at doses over
200 mg/day)
Valproate exposure: 6.2% (>9% at doses over
1000 mg/day)
Monotherapy, 3.7%; polytherapy, 6.0%;
polytherapy containing valproate, 9.0%
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RISKS WITH VALPROATE

DURING PREGNANCY
 Valproate levels in the fetus may be
up to double those in the mother.
 Increased risk of miscarriage,
stillbirths.
 1-5% risk of neural tube defects
(some authors, 5-9%); these are
lumbosacral rather than anencephalic
(i.e., effect on neural crest closure)

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OTHER RISKS WITH VALPROATE

DURING PREGNANCY
 Anticonvulsant facies, intrauterine
growth retardation, mental
retardation.
 Neonatal toxicity: bradycardia,
irritability, jitteriness, refusal to feed,
hypoglycemia, abnormal tone
 Fetal valproate syndrome
 Vitamin K dependent coagulatory
abnormalities, liver toxicity
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VALPROATE:
RECENT STUDIES
 10% risk of major fetal
malformations after first trimester
exposure (Wyszynski et al, Neurology 2005).

 Greater risk of memory impairment,

lower verbal IQ, and mental
retardation after in utero exposure
to valproate relative to exposure to
other antiepileptic drugs (Vinten et al,
Neurology 2005).

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RISKS WITH CARBAMAZEPINE

DURING PREGNANCY

 Prospective study (n=35)

 Craniofacial defects, 11%
 Fingernail hypoplasia, 26%
 Developmental delay, 20%
 (Jones et al, NEJM 1989)

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ANTICONVULSANT FACIES

 Midface hypoplasia
 Short nose
 Anteverted nostrils
 Long upper lip

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RISKS WITH CARBAMAZEPINE

DURING PREGNANCY: GENERAL
 0.5-1.0% risk of neural tube defects
 Miscellaneous other abnormalities in
the newborn: about 250 g decrease in
birth weight, smaller head
circumference etc.
 Neonatal toxicity is very rare.
 No cognitive impairment
 Oxcarbazepine does not produce the
epoxide metabolite and may hence be
safer. 35
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RISKS WITH CARBAMAZEPINE

DURING PREGNANCY: OTHER

 Fetal carbamazepine levels

may be 50-80% those in the
mother. Nevertheless,
neonatal carbamazepine
toxicity is very rare.

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CARBAMAZEPINE AND
VITAMIN K
 Carbamazepine can cause vitamin K deficiency
during pregnancy.
 Vitamin K is required for normal mid-facial
growth.
 Vitamin K is required for clotting.
 Administer vitamin K (20 mg/day) during the
last month of pregnancy.
 Administer vitamin K (1 mg i.m.) to the
neonate.
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RISKS WITH LAMOTRIGINE

DURING PREGNANCY

 The worldwide
lamotrigine pregnancy
registry data so far
show no increase in
teratogenic risk
(Cunnington et al, Neurol
2005).

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TERATOGENICITY AFTER 1ST

TRIMESTER EXPOSURE
 Incidence of major birth defects
after 1st trimester exposure to
 Lamotrigine monotherapy: 12/414
(2.9%)
 Lamotrigine + valproate + others :
11/88 (12.5%)
 Lamotrigine + others but not
valproate: 5/182 (2.7%)
 General population: 2-3%
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LAMOTRIGINE DURING
PREGNANCY: further notes
 Lamotrigine exposure
during 2nd, 3rd trimesters:
no teratogenicity.

 Lamotrigine exposure
anytime during
pregnancy: no pregnancy
loss, fetal death.

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LAMOTRIGINE DOSING DURING

PREGNANCY
 Lamotrigine is metabolized by glucuronidation.
Glucuronidation is induced during pregnancy.
Therefore, >50-100% increase in dose may be
required as pregnancy progresses.
 The increased requirement peaks in the early
third trimester (week 32).
 The requirement drops to baseline levels within 2
weeks postpartum, as the liver normalizes.
 (Tran et al, Neurology 2002; Pennell et al, Neurology 2004)
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LAMOTRIGINE DOSING AT THE

END OF PREGNANCY
 Lower the dose close to
term to reduce fetal
exposure. This is because
the glucuronidation pathway
is immature in the neonate.

 This will also lower the risk

of maternal adverse effects
postpartum.

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RISKS WITH ATYPICAL ANTIPSYCHOTICS

DURING PREGNANCY

 Abnormal weight gain

 Gestational diabetes
 Insulin resistance
 Pre-eclampsia

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RISKS WITH BENZODIAZEPINES

DURING PREGNANCY

 11 in 10,000 risk of oral clefts

(base rate is 1 in 10,000)
 Intrauterine growth retardation
 Withdrawal symptoms in infant
postpartum
 Sedation during breastfeeding

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RISKS WITH SSRIs DURING

PREGNANCY: Overview
 SSRIs increase the risk of fetal waste in
the first trimester, and the risk of
premature labor late in pregnancy.
 The risk of congenital malformations is
marginally elevated.
 The risk, especially of CVS (esp. VSD)
malformations is doubled with paroxetine.
 The neonate may experience SSRI
withdrawal.
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SSRIs AND TERATOGENICITY

 SSRIs marginally increase the risk of
major malformations.
 Paroxetine doubles the risk of major
malformations relative to other
antidepressants. The absolute risk
of major malformations is 4%, and
of cardiovascular malformations
(especially VSD) is 2%.
 NNH with paroxetine is 50-100.
 (GSK, 2005)
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SSRIs AND TERATOGENICITY

(Sivojelezova et al, Am J Obstet Gynecol 2005)

 125 women took citalopram at least during the

1st trimester; 71 took it all through pregnancy.
 Spontaneous abortion, 11%; stillbirths, 1.5%;
major malformation, 1.5%.
 Duration of pregnancy, mean birth weight: no
different from controls.
 Babies exposed to citalopram close to term were
4 times more likely to require admission in
special care nurseries (?neonatal withdrawal
syndrome).
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SSRI-RELATED NEONATAL
WITHDRAWAL SYNDROME
 SSRIs treble the risk of a mild,
self-limiting neonatal behavioral
syndrome characterized by
nonspecific motor, respiratory,
gastrointestinal, and CNS
symptoms.
 The syndrome is best managed
supportively.
 Moses-Kolko et al, JAMA 2005

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SSRI WITHDRAWAL
IN NEONATES
 A mild to severe SSRI withdrawal
syndrome develops in about 30% of
neonates after prolonged exposure
to the drug in utero.
 The withdrawal syndrome peaks in
severity during the first two days
after birth; in some cases, however,
the peak may not occur until the
fourth day of life.
 (Levinson-Castiel et al, Arch Ped Adol Med 2006)
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PAROXETINE AND NEONATAL

WITHDRAWAL
 By Nov 2003, 93 cases of SSRI-
related neonatal withdrawal had
been identified.
 SSRIs were considered causal in
these.
 Paroxetine was implicated in 64
cases.
 Caveat: no data on the base rate
of paroxetine use.
 Sanz et al, Lancet 2005
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SSRIs AND PULMONARY

HYPERTENSION
 Use of SSRIs after week 20 has
been associated with a 6-fold
increased risk of persistent
pulmonary hypertension in the
newborn.
 The absolute risk may be as
high as 1%.
 Chambers et al, NEJM 2006

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RISKS WITH OTHER DRUGS

DURING PREGNANCY
 In a meta-analysis of 7 prospective studies
(pooled n=1774), Einarson and Einarson
(Pharmacoepidemiol Drug Saf 2005) found no increase in the
risk of major malformations after first trimester
exposure to newer antidepressants.
 Mirtazapine (n=104) was not associated with
major malformations but increased spontaneous
abortions and preterm birth (Djulus et al, J Clin Psychiatry
2006).
 In general, prefer older antidepressants and
antipsychotics to newer drugs.
(Why?)
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RISKS WITH ECT DURING

PREGNANCY
 Drug exposure and hence the
teratogenic risk is negligible.
 There is a small risk of
premature labor in later
pregnancy.
 There is a small risk of aspiration
of gastric contents because of
delayed gastric emptying.

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REDUCING THE RISK OF

ASPIRATION DURING ECT
 Avoid anticholinergic premedication
because this can reduce lower
esophageal sphincter tone.
 Intubate with a pediatric cuffed
endotracheal tube.
 Increase gastric pH with a
nonparticulate antacid such as
sodium citrate.

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BREASTFEEDING
 Advantage to baby:
emotional, immunological,
intellectual
 Advantage to mother:
self-esteem, bonding
 Disadvantage to mother:
sleep loss, risk of relapse

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DRUGS DURING
BREASTFEEDING: 1

 Mothers on lithium should not breastfeed because

lithium reaches unacceptable levels in the infant;
lithium toxicity in infants has been described.
 Valproate and carbamazepine levels are reasonably
low in infant sera. These drugs can hence be
prescribed during breastfeeding.
 Olanzapine levels are also low in infant sera. This
drug can also be prescribed during breastfeeding.
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DRUGS DURING
BREASTFEEDING: 2

 Lamotrigine levels in breastfed infants may be one

third of those in the mother. However, no adverse
effects in the infants have been reported.
 There is insufficient information on newer drugs.

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ANTIDEPRESSANT DRUGS
AND BREASTFEEDING

 Pooled analysis of 57 studies.

 For fluoxetine and citalopram, infant
levels >10% of maternal levels were
found in 22% and 17% of infants,
respectively. (Significance of 10%)
 Infant levels are undetectable for
nortriptyline, paroxetine, and sertraline.
 (Weissman et al, AJP 2004)

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SUGGESTIONS DURING
BREASTEEDING
 Breastfeed before dosing,
during serum troughs.
 Express and discard milk
associated with serum peaks.
 Use formula feeds to
decrease the need for breast
milk.
 Especially useful for women
receiving lithium.
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RECOMMENDED READING
 Wisner et al, Am J
Psychiatry 2000
 Burt and Rasgon,
Bipolar Disorders 2004
 Yonkers et al, Am J
Psychiatry 2004

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ENFIN…

 THANK
YOU!

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