Transcript Document
Bipolar Disorder in
Women –Meeting
the Challenge
Nicole Harrington Cirino M.D.
Wildwood Psychiatric Resource Center
Beaverton, Oregon
www.wildwoodpsych.com
Disclosure
GlaxoSmithKline
Speakers Bureau
Pfizer Pharmaceuticals Inc.
Speakers Bureau
Educational Grants
Off label use of products will be discussed
The Challenge
Women with Bipolar Disorder describe….
worse overall health and well-being
compared with men (MCOS-SF-20)
despite equivalent Global Assessment of
Function (GAF) scores.
Bipolar
Disorder
Reproductive
Cycle
Prevalence
Bipolar I with equal gender distribution
Bipolar II more common in women (3.2 to
1 ratio)
Age of Onset
Women more commonly present with 1St
episode depression
Women have later age of onset than men
First Depressive Episode
27 YEARS IN WOMEN
22 YEARS IN MEN
First Manic Episode
26 YEARS IN WOMEN
22 YEARS IN MEN
Bipolar Depression in
Women
Women: MDE predominate vs Mania,
often precede mania
DSM-IV Atypical features more common
in women, more common in Bipolar II
Longer , treatment refractory depressive
episodes in women
More commonly misdiagnosed as
Unipolar depressed
Seasonal Pattern
Seasonal pattern more common in
women
Bimodal peak of admissions in Spring
and Fall for women only
Gender Distribution of Rapid
Cycling Bipolar Disorder
Male
Female
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Medical Co morbidity
Higher in Women with
Bipolar
Migraine
Obesity*
May worsen course of illness
Thyroid Disease
May contribute to rapid cycling
Obesity and Bipolar illness
Obesity associated with a poorer outcome in
Bipolar patients
Increased recurrence of depressive episode in
obese vs. controls
LI induced weight gain more common in women,
others have not been specifically tested.
Obesity in Bipolar Women vs. Bipolar controls
Overweight (44% vs. 25%)
Obese (22% vs. 13%)
Psychiatric Clinics of North
America 26 (3) Sept 2003
Suicidality in Bipolar
Women
Higher rates of suicide attempts in
women with Bipolar D/O (and Unipolar)
Suicidality higher in patients with Bipolar
II
Lithium has been associated with marked
reduction in suicidality in both sexes
Reproductive Cycle
Influences on Bipolar
disorder
Menses
Pregnancy
Postpartum
Menopause
Bipolar
Disorder
Reproductive
Cycle
Estrogen – Effects on
Mood
Rapid fluctuations during postpartum,
premenstrual and menopausal periods.
Estrogen supports Serotonin
Increases synthesis (tryptophan)
Increased 5HT1 receptors in Dorsal Raphe
Reduces metabolism of serotonin
(Decrease MAO activity)
Estrogen potentiates Norepinephrine
Antidopaminergic effects
Progesterone
Elevated in pregnancy with rapid drop
postpartum, premenstrually, during
perimenopause
GABA agonist properties
Progesterone causes dysphoria,
irritability in postmenopausal women
Menses and Effect on
Mood
In a retrospective interview-based study, 2/3 of
BP women reported frequent premenstrual
mood disturbances, ¼ report depression
Prospective studies have not found a specific
relation between menstrual cycle and bipolar
disorder
Increased incidence of suicide attempts in
premenstrual-menstrual phase from autopsies
and suicide call center
Endo et al, 1978; Luggin et al, 1984; Abramowitz et al, 1982;
Jacobs and Charles, 1970; Blehar et al, 1998;
Wehr et al, 1988; Leibenluft et al, 1999
Impact of Reproductive Cycle:
Childbearing Years
Most women (n=50), did not receive accurate
diagnosis nor treatment for BP until AFTER they
had children1
Survey found health care practitioners and families
are biased against women with BP becoming
pregnant2
45% of BP women in 1 survey were advised to not
get pregnant
1 Viguera AC, et al. Am J Psych 2002;159:2102-2104.
2 Freeman MP, et al. J Clin Psychiatry 2002;63:264-267.
3 Bouffard S et al. Presented at the American Psychiatric Association Meeting, 2001.
Pregnancy
Considered to neither protect nor worsen
symptoms
Restrospective review of 101 Bipolar women
(after Li discontinuation) showed no difference
in pregnant vs nonpregnant controls for 40
weeks
Rate of recurrence for 40 weeks was 52% for
both groups after Li discontinuation
Higher if discontinuation of LI<14 days.
Pregnancy and Bipolar Disorder:
Postpartum Period
Postpartum period clearly destabilizes
mood
BP women have 100-fold higher risk than
women without a psychiatric illness history of
experiencing postpartum psychosis (1) (10-25%)
40%-67% of the female BP subject population
experienced postpartum mania or depression
within 1 month of delivery (2)
70 times higher rate of suicide in the first month
postpartum
1) Pariser, Ann Clin Psychiatry
1993 2) Jefferson et al, 1987
“I killed my children….” Andrea Yates
Impact of Reproductive Cycle:
Psychiatric Admissions in the 2
Years Preceding & Following
Childbirth
Admissions / month
70
60
All admissions
n =120 (of 54,087 births)
50
40
30
20
Pregnancy
10
-2 Years
-1 Year
Kendall RE et al. Br J Psychiatry 1987;150:662-673.
Grof P et al. J of Affect Disorders 2000;61:31-39.
Viguera AC, et al. Can J Psych 2002;47:426-436.
Childbirth
+1 Year
+2 Years
Postpartum Relapse Rates
Nonacs, APA 1998
Euthymic during pregnancy = 27.8%
(n=18)
Illness during pregnancy = 68.8%
(n=14)
Cohen, Am J Psychiatry 1995
With Li prophylaxis = 10%
(n=14)
Without Li prophylaxis = 60%
(n= 13)
Impact of Reproductive Cycle:
Menopause
20% of postmenopausal BPI women
worsened (n=56)1
30% of women converted to continuous
cycling (no euthymia) (n=256)2
Some report no change3
Women not using HRT more likely to report
perimenopausal worsening of mood (n=50)4
New onset Bipolar Disorder during 5th decade
more common in women.
1 Blehar MC et al. Psychopharmacology Bull. 1998;34:239-243.
2 Kukopulos A et al. Phamakopsychiatr Neuropsychophamakol. 1980;13:156-167.
3 Wehr TA et al. Am J Psychiatry 1988;145:179-84.
4 Freeman MP et al. J Clin Psychiatry 2002;63:284-287.
The Effect of Bipolar
Disorder on the
Reproductive cycle
Menstrual irregularities
PCO, PCOS
Prolactin levels
OCP efficacy
Reproduction (infertility,
unplanned pregnancy)
Bipolar
Disorder
Reproductive
Cycle
Polycystic Ovary
Syndrome (PCOS)
PCOS is among most common endocrine
disorders in women of reproductive age1
Stein-Leventhal Syndrome:
Clinical Triad: anovulation, hirsutism, obesity
PCOS affects 4-6% of reproductive age women
PCOS is the leading cause of anovulatory
infertility and hirsutism2
PCOS is characterized by increased
androgens and abnormal LH/FSH ratio
1) Franks, 1995
2) Bauer et al, 1995
Polycystic Ovarian
Syndrome (PCOS) and
Bipolar Disorder
Valproate and Carbamazepine are
associated with symptoms of menstrual
irregularity that may/may not lead to full
blown PCOS
Bipolar women prior to treatment also
show an increased risk of
Elevated LH
Menstrual irregularities
Polycystic Ovaries
Prevalence of Menstrual
Disturbances in Bipolar
Women
Lithium Group
(N = 10)
Divalproex Sodium Group
(N = 10)
Oligomenorrhea
Dysmenorrhea Irregular Cycle
50%
17%
Menorrhagia
37%
Oligomenorrhea
Irregular Cycle
37%
Miscarriages
17%
No Illness
8%
Infertility
8%
Stillbirth
13%
Rasgon NL, Altshuler LL, Gudeman D et al. J Clin Psychiatry. 2000;61(3):173-178
Amenorrhea
13%
PCOS: Possible Sequelae
Decreased fertility
Miscarriage
Insulin Resistance
Gestational
Diabetes
Pregnancy Induced
HTN
Hyperlipidemia
Cardiovascular
Disease
Ovarian Cancer
Obesity
Hirsutism
Clinical Features of PCOS
Hyperandrogenism
Hirsutism
Lobo RA et al, Ann Intern Med 2000
Effect of Mood Stabilizers
(CYP3A4 reduction) on Oral
Contraceptive Efficacy
Reduce Efficacy:
Carbamazepine
Topiramate
Oxcarbazepine
No effect:
Gabapentin
Lithium
Lamotrigine*
Valproate
Atypical Antipsychotics
*Oral Contraceptives stimulate metabolism of Lamotrigine,
and reduce plasma concentrations by 40-60%
-Toxicity may occur when OCP is discontinued (or pill free
week)
Prolactin effects
Risperidone, others increase Prolactin
Anovulation
Infertility
Sexual dysfunction
Women with Bipolar – The
Challenge
Rapid Cycling (predictor of non response for
many agents)
Preponderance of Depressive episodes
Co morbid Medical conditions
Increased risk of obesity
Fertility Issues
Birth Control Efficacy
Pregnancy/Teratogenesis
The Postpartum period
Is it Worth the Challenge?
Mood Stabilizer “XX” – The
Ideal Agent for Women
Rapid Cycling
Depressive episodes
Co morbid Medical conditions
Low risk of obesity
Fertility Issues
Birth Control Efficacy
Pregnancy/Teratogenesis
The Postpartum Period
Bipolar Disorder in Women
- Evaluation
Reproductive function
Menstrual diary: note cycle length, duration of flow
H/O infertility
Birth Control method
Plans for Childbearing
Quality of Parenting/Interpersonal relationships
Metabolic Status
Weight / Ideal Weight
Fasting glucose and lipid profile
Treatment During
Pregnancy
Introduction to the Risk/Benefit Ratio
Pre-pregnancy
Consult!
FDA Categories in
Pregnancy
A. Controlled studies fail to
demonstrate risk in humans
B. No controlled studies in
women, animal studies do
not show risk or adverse
effect in animal studies.
C Adverse effects in
animals, no controlled trials
in women
D Evidence of human risk
exist
X Contraindicated
FDA categories are not
necessary helpful.
Must rely on evidence based
information in the literature.
Pharmacologic Risks
during Pregnancy
1ST Trimester- Morphologic risk
<2 weeks
1-5 weeks
3-8 weeks
6-9 weeks
No maternal/ fetal exposure
Neural Tube Development
Cardiac
Lip and Palate
2nd-3rd Trimester
Behavioral/ functional risks
Neonatal effects (toxicity/withdrawal)
Preterm labor
Maternal side effects
=
?
VALPROIC ACID /
PREGNANCY
1st trimester - Major congenital
anomalies(8-11%)
2-3% background risk
Neural tube defects ,open spinal defects
Spina bifida most serious (1-2%)
2nd-3rd trimester “Fetal valproate
syndrome”
23% of children with significant
developmental delays/ low IQ
VALPROIC ACID
RECOMMENDATIONS
Reduce daily dose, 3-4 divided doses
4-5 mg folic acid before conception and
throughout pregnancy
Vitamin K (20/mg/day) first trimester and
last
Vitamin K (IM) 1mg at birth
High resolution ultrasound 16-18
weeks(92%)
Lamotrigine Pregnancy
Registry
As of March 2006:
2232 pregnancies involving exposure to
lamotrigine have been prospectively
registered
332 pending delivery
488 cases lost to follow-up
1412 prospectively registered pregnancies
with 1440 outcomes
Lamotrigine Pregnancy Registry. Interim Report. 1 September
1992 through 31 March 2006.
Lamotrigine Pregnancy Registry:
Risk With Monotherapy
Estimates of malformations risk in the general
population
2 to 3% 1
Frequency of birth defects in women with
epilepsy using AED monotherapy
3.3 to 4.5% 2,3,4,5
Major malformation rate associated with
lamotrigine monotherapy first trimester
exposure
23/831 = 2.8% (95% CI 1.8-4.2%)6
1Honein
MA et al. Teratology 1999;60:356-364.
LB, et al. N Engl J Med 2001;344(15):1132-8.
3Morrow JI, et al. Epilepsia 2001;42(Suppl 2):125.
4Morrow JI, et al. Epilepsia 2003;44(Suppl 8):60.
5Samren EB, et al. Ann Neurol 1999;46:739-46.
6Lamotrigine Pregnancy Registry. Interim Report. 1 September 1992 through 31 March 2006.
2Holmes
Rates of Non-Syndromic Oral Clefts
Associated with Lamotrigine
NAAED reported signal of increased risk of
non-syndromic oral clefts (cleft palate or
cleft lip)1
8.9 per 1,000 (5/564; 3 isolated cleft
palate and 2 isolated cleft lip) associated
with lamotrigine
0.37 per 1,000 in an unexposed
population group
24-fold increase with lamotrigine
1.
2.
3.
4.
Holmes LB et al (abstract). Birth Defects Research Part A: Clinical and Molecular Teratology
2006;76(5)318
Bille C et al. Epidemiology. 2005; 16: 311-16
Croen LA et al. J Med Genetics 1998;79:42-47.
Kallen B et al. Cleft Palate Craniofacial Journal 2003;40(6):624-8.
Guidelines for Lamotrigine
during Pregnancy
Increased lamotrigine clearance
documented during pregnancy
Higher doses may be required for clinical
response
4 mg Folic Acid prior to conception and
during pregnancy
Lithium in Pregnancy –
Treatment of Bipolar Disorder
Morphologic risks: Epsteins’ anomaly
Incidence 1 per 1000 (.05-.1%) associated
with Lithium
4 fold increase in risk
Diagnosed by a Level II US at 16 weeks.
Often surgically correctable.
Neonatal Toxicity
Floppy baby syndrome, Nephrogenic
Diabetes Insipidus in the fetus-(reversible),
Neonatal hypothyroidism
Lithium –Pregnancy
Dose adjustments
Require increase doses third trimester
Prior to Delivery -dose should be cut in half
48 hours prior to delivery (scheduled?)
Throughout pregnancy and postpartumLithium and thyroid levels checked
frequently
Doses given in three to four daily doses to
prevent nausea
Typical AP agents during
pregnancy
Low doses of High-potency agents show
relative safety in pregnancy-drugs of choice
haloperidol (Haldol)/ trifluoperazine
(Stelazine) n=2900
Increase minor abnormalities with Thorazine
Behavioral Teratogenicity – No effect on IQ
Perinatal syndrome rarely reported including
hypertonia, tremor, hyperreflexia-all of which
resolved without sequelae
Atypical AP in PregnancyData
No national database.
Case series, case reports and manufacturers data
make up a small sample size,
Olanzapine 129, Quetiapine 39, Risperidone 61,
Clozapine 6
Reports of gestational diabetes, obesity, seizures,
preeclampsia
McKenna J Clinical Psych 2006 -Only Prospective
study
Olanzapine (n=60)
Risperidone (n=49)
Quetiapine (n=36)
Clozapine (n=6)
Atypical AP in Pregnancy Conclusions
Not enough data to establish safety
No association thus far with major
malformations, stillbirth, prematurity,
neonatal complications.
Olanzapine, risperidone, quetiapine with
the most data
No data on ziprasidone (Geodon) or
aripiprazole (Abilify)
The Bipolar Pregnant
Patient: Treatment
Options
Mild to Moderate Illness
Trial of safer agent/ monotherapy prior to
pregnancy
Gradual taper of mood stabilizer before
pregnancy or when pregnancy test positive
Maintain drug free in first trimester with low
threshold for reintroduction of mood stabilizer
Severe Bipolar illness
Consider continuation of mood stabilizer in first
trimester and throughout pregnancy
Treatment in
the Postpartum
Period
Bipolar Disorder and
BreastfeedingRisk/Benefit
Due to limited and concerning lactation
data, BF generally discouraged in BP
women
Most important variable may be sleep
deprivation
Inform pediatrician so infant can be
monitored if infant is exposed
Psychotropics and
Lactation
Lithium –American Academy of
Pediatrics (AAP) -From Contraindicated
to Use With Caution
Reported cases of Li toxicity in infant.
Levels 5-200% of maternal serum.
Lamotrigine- AAP “may be a concern”.
Higher than expected levels (30-60%).
No adverse effects reported.
Chaudron, Jefferson. J Clin Psych
2000;61:79-90; Am J Psychiatry
Psychotropics and
Lactation
Valproic Acid/ Carbamazepine -AAP
considers it “compatible”.
Low infant serum levels.
Reports of neonatal toxicity, hepatic failure
infants <2, fetal valproate syndrome
Atypical Antipsychotics – Little data
(n<25)
Low infant serum levels (except clozapine).
Reports of jaundice, sedation, lethargy.
J Clinical Psychiatry 2002:63
Postpartum Guidelines –
Do’s and Don’ts
Do achieve euthymia in pregnancy
Do consider postpartum prophylaxis
Do discuss/”discourage” breastfeeding
Do discuss postpartum planning during
pregnancy with partner present
Do involve all providers in care plan
Don’t routinely taper or change postpartum
Don’t wait for patient to call for PP follow up
Bipolar
Disorder
Reproductive
Cycle
Resources
www.wildwoodpsych.com
www.motherisk.com
www.womensmentalhealth.org