Bipolar Disorder in Women Meeting the Challenge

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Bipolar Disorder in Women Meeting the Challenge

• Nicole Harrington Cirino M.D.
• Wildwood Psychiatric Resource Center
• Beaverton, Oregon
• www.wildwoodpsych.com

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Disclosure

• GlaxoSmithKline
• Speakers Bureau
• Pfizer Pharmaceuticals Inc.
• Speakers Bureau
• Educational Grants
• Off label use of products will be discussed

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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.

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Prevalence

• Bipolar I with equal gender distribution
• Bipolar II more common in women (3.2 to 1 ratio)

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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

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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

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Seasonal Pattern

• Seasonal pattern more common in women
• Bimodal peak of admissions in Spring and Fall for
  women only

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Gender Distribution of Rapid Cycling Bipolar
Disorder
Leibenluft E . Am J Psychiatry 1996153163-173.
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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

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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)

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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

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Reproductive Cycle Influences on Bipolar disorder

• Menses
• Pregnancy
• Postpartum
• Menopause

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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

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Progesterone

• Elevated in pregnancy with rapid drop postpartum,
  premenstrually, during perimenopause
• GABA agonist properties
• Progesterone causes dysphoria, irritability in
  postmenopausal women

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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
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Impact of Reproductive Cycle Childbearing Years

• Most women (n50), 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
20021592102-2104. 2 Freeman MP, et al. J Clin
Psychiatry 200263264-267. 3 Bouffard S et al.
Presented at the American Psychiatric Association
Meeting, 2001.
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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 LIlt14 days.

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Pregnancy and Bipolar DisorderPostpartum 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
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I killed my children. -Andrea Yates
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Impact of Reproductive Cycle Psychiatric
Admissions in the 2 Years Preceding Following
Childbirth
70 60 50 40 30 20 10
All admissions n 120 (of 54,087 births)
Admissions / month
Pregnancy
-2 Years -1 Year Childbirth 1 Year 2 Years
Kendall RE et al. Br J Psychiatry
1987150662-673. Grof P et al. J of Affect
Disorders 20006131-39. Viguera AC, et al.
Can J Psych 200247426-436.
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Postpartum Relapse Rates

• Nonacs, APA 1998
• Euthymic during pregnancy 27.8
• (n18)
• Illness during pregnancy 68.8
• (n14)
• Cohen, Am J Psychiatry 1995
• With Li prophylaxis 10
• (n14)
• Without Li prophylaxis 60
• (n 13)

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Impact of Reproductive Cycle Menopause

• 20 of postmenopausal BPI women worsened (n56)1
• 30 of women converted to continuous cycling (no
  euthymia) (n256)2
• Some report no change3
• Women not using HRT more likely to report
  perimenopausal worsening of mood (n50)4
• New onset Bipolar Disorder during 5th decade more
  common in women.

1 Blehar MC et al. Psychopharmacology Bull.
199834239-243. 2 Kukopulos A et al.
Phamakopsychiatr Neuropsychophamakol.
198013156-167. 3 Wehr TA et al. Am J
Psychiatry 1988145179-84. 4 Freeman MP et al. J
Clin Psychiatry 200263284-287.
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The Effect of Bipolar Disorder on the
Reproductive cycle

• Menstrual irregularities
• PCO, PCOS
• Prolactin levels
• OCP efficacy
• Reproduction (infertility,
• unplanned pregnancy)

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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
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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

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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. 200061(3)173-178
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PCOS Possible Sequelae

• Decreased fertility
• Miscarriage
• Insulin Resistance
• Gestational Diabetes
• Pregnancy Induced HTN

• Hyperlipidemia
• Cardiovascular Disease
• Ovarian Cancer
• Obesity
• Hirsutism

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Clinical Features of PCOSHyperandrogenism
Hirsutism
Lobo RA et al, Ann Intern Med 2000
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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)
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Prolactin effects

• Risperidone, others increase Prolactin
• Anovulation
• Infertility
• Sexual dysfunction

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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

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Is it Worth the Challenge?
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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

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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

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Treatment During Pregnancy

• Introduction to the Risk/Benefit Ratio

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Pre-pregnancy Consult!

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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.
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Pharmacologic Risks during Pregnancy

• 1ST Trimester- Morphologic risk
• lt2 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

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Risk Benefit
?
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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

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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)

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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.
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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 199960356-364.
• 2Holmes LB, et al. N Engl J Med
  2001344(15)1132-8.
• 3Morrow JI, et al. Epilepsia 200142(Suppl
  2)125.
• 4Morrow JI, et al. Epilepsia 200344(Suppl 8)60.
  
• 5Samren EB, et al. Ann Neurol 199946739-46.
• 6Lamotrigine Pregnancy Registry. Interim Report.
  1 September 1992 through 31 March 2006.

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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 200676(5)318
• Bille C et al. Epidemiology. 2005 16 311-16
• Croen LA et al. J Med Genetics 19987942-47.
• Kallen B et al. Cleft Palate Craniofacial Journal
  200340(6)624-8.

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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

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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

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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

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Typical AP agents during pregnancy

• Low doses of High-potency agents show relative
  safety in pregnancy-drugs of choice haloperidol
  (Haldol)/ trifluoperazine (Stelazine) n2900
• 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

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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 (n60)
• Risperidone (n49)
• Quetiapine (n36)
• Clozapine (n6)

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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)

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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

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Treatment in the Postpartum Period
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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

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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.

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Psychotropics and Lactation

• Valproic Acid/ Carbamazepine -AAP considers it
  compatible.
• Low infant serum levels.
• Reports of neonatal toxicity, hepatic failure
  infants lt2, fetal valproate syndrome
• Atypical Antipsychotics Little data (nlt25)
• Low infant serum levels (except clozapine).
• Reports of jaundice, sedation, lethargy.

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Postpartum Guidelines Dos and Donts

• 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
• Dont routinely taper or change postpartum
• Dont wait for patient to call for PP follow up

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Resources

• www.wildwoodpsych.com
• www.motherisk.com
• www.womensmentalhealth.org