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Bipolar Disorder in Women –Meeting the Challenge. Nicole Harrington Cirino M.D. Wildwood Psychiatric Resource Center Beaverton, Oregon Disclosure. GlaxoSmithKline Speakers Bureau Pfizer Pharmaceuticals Inc. Speakers Bureau Educational Grants

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bipolar disorder in women meeting the challenge

Bipolar Disorder in Women –Meeting the Challenge

Nicole Harrington Cirino M.D.

Wildwood Psychiatric Resource Center

Beaverton, Oregon

  • GlaxoSmithKline
    • Speakers Bureau
  • Pfizer Pharmaceuticals Inc.
    • Speakers Bureau
    • Educational Grants

Off label use of products will be discussed

the challenge
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 I with equal gender distribution
  • Bipolar II more common in women (3.2 to 1 ratio)
age of onset
Age of Onset
  • Women more commonly present with 1St episode depression
  • Women have later age of onset than men
  • First Depressive Episode
    • 22 YEARS IN MEN
  • First Manic Episode
    • 22 YEARS IN MEN
bipolar depression in women
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
  • Seasonal pattern more common in women
  • Bimodal peak of admissions in Spring and Fall for women only
gender distribution of rapid cycling bipolar disorder
Gender Distribution of Rapid Cycling Bipolar Disorder

Leibenluft E . Am J Psychiatry 1996;153:163-173.

medical co morbidity higher in women with bipolar
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 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
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
Reproductive Cycle Influences on Bipolar disorder
  • Menses
  • Pregnancy
  • Postpartum
  • Menopause
estrogen effects on mood
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
  • 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
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
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.


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
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

impact of reproductive cycle psychiatric admissions in the 2 years preceding following childbirth
Impact of Reproductive Cycle: Psychiatric Admissions in the 2 Years Preceding & Following Childbirth








All admissions

n =120 (of 54,087 births)

Admissions / month


-2 Years-1 Year Childbirth +1 Year +2 Years

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.

postpartum relapse rates
Postpartum Relapse Rates

Nonacs, APA 1998

  • Euthymic during pregnancy = 27.8%


  • Illness during pregnancy = 68.8%


Cohen, Am J Psychiatry 1995

With Li prophylaxis = 10%


Without Li prophylaxis = 60%

(n= 13)

impact of reproductive cycle menopause
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

The Effect of Bipolar Disorder on the Reproductive cycle

Menstrual irregularities


Prolactin levels

OCP efficacy

Reproduction (infertility,

unplanned pregnancy)

polycystic ovary syndrome pcos
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
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


Irregular Cycle


OligomenorrheaIrregular Cycle













No Illness


Prevalence of Menstrual Disturbances in Bipolar Women

Lithium Group(N = 10)

Divalproex Sodium Group

(N = 10)

Rasgon NL, Altshuler LL, Gudeman D et al. J Clin Psychiatry. 2000;61(3):173-178

pcos possible sequelae
Decreased fertility


Insulin Resistance

Gestational Diabetes

Pregnancy Induced HTN


Cardiovascular Disease

Ovarian Cancer



PCOS: Possible Sequelae
clinical features of pcos hyperandrogenism
Clinical Features of PCOSHyperandrogenism


Lobo RA et al, Ann Intern Med 2000

effect of mood stabilizers cyp3a4 reduction on oral contraceptive efficacy
Reduce Efficacy:




No effect:





Atypical Antipsychotics

Effect of Mood Stabilizers (CYP3A4 reduction) on Oral Contraceptive Efficacy

*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
Prolactin effects

Risperidone, others increase Prolactin

  • Anovulation
  • Infertility
  • Sexual dysfunction
women with bipolar the challenge
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
mood stabilizer xx the ideal agent for women
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
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

Treatment During Pregnancy

Introduction to the Risk/Benefit Ratio

fda categories in pregnancy
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
Pharmacologic Risks during Pregnancy

1ST Trimester- Morphologic risk

  • <2 weeks No maternal/ fetal exposure
  • 1-5 weeks Neural Tube Development
  • 3-8 weeks Cardiac
  • 6-9 weeks 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
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
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.
  • 2Holmes 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.
rates of non syndromic oral clefts associated with lamotrigine
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
  • 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
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
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
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 postpartum- Lithium and thyroid levels checked frequently
    • Doses given in three to four daily doses to prevent nausea
typical ap agents during pregnancy
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 pregnancy data
Atypical AP in Pregnancy-Data
  • 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
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
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
bipolar disorder and breastfeeding risk benefit
Bipolar Disorder and Breastfeeding- Risk/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
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 161:4 April 2004

psychotropics and lactation1
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
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