1. PERINATAL MOOD DISORDERS: Updates in Treatment Maya Bulman, MD Maine Medical Center April 29, 2011

2. Updates in Treatment During Pregnancy Depression Depression Bipolar Disorder Bipolar Disorder Psychosis Psychosis Insomnia Insomnia

3. DEPRESSION DURING PREGNANCY Between 10-20% of women will experience significant depression during pregnancy Between 10-20% of women will experience significant depression during pregnancy This will be a first episode for one third This will be a first episode for one third

4. Course of Depression During Pregnancy Women from 3 specialty centers stable on antidepressants for at least 3 months prior to pregnancy : 43% relapsed 43% relapsed 26% who continued meds relapsed (50% in first trimester) 26% who continued meds relapsed (50% in first trimester) 68% who discontinued meds relapsed 68% who discontinued meds relapsed (50 % in the 1st trimester, 90% by the end of the 2 nd trimester) (50 % in the 1st trimester, 90% by the end of the 2 nd trimester) Cohen LS, et al. JAMA. 2006:295;499-507.

5. Time to Relapse in Patients Who Maintained or Discontinued Antidepressants Cohen LS, et al. JAMA. 2006:295;499-507. 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 0122436 Gestational Age Percentage of Patients Remaining Well Maintained (N = 82) Discontinued (N = 65) 5

6. CONCLUSIONS: Pregnancy puts women with a history of depression at higher risk of recurrence and is not protective. Pregnancy puts women with a history of depression at higher risk of recurrence and is not protective. Pregnant women stable on antidepressants need to be aware of the relapse risk with stopping meds Pregnant women stable on antidepressants need to be aware of the relapse risk with stopping meds This should be discussed when weighing the risk/benefit ratio of using antidepressants during pregnancy This should be discussed when weighing the risk/benefit ratio of using antidepressants during pregnancy Cohen LS, et al. JAMA. 2006:295;499-507.

7. APA/ACOG Guidelines “The Management of Depression During Pregnancy: A Report from the American Psychiatric Association and The American College of Obstetricians and Gynecologists,” Obstetrics & Gynecology (September 2009) and General Hospital Psychiatry (September/October 2009). Obstetrics & Gynecology (September 2009) and General Hospital Psychiatry (September/October 2009).

8. Pregnant women currently on medication: Those who wish to stay on medication, consult with psychiatrists and OB/GYN to discuss the risks Those who wish to stay on medication, consult with psychiatrists and OB/GYN to discuss the risks Stable women may attempt discontinuation depending on their history. Women with a history of recurrent depression are at a high risk of relapse if medication is discontinued. Stable women may attempt discontinuation depending on their history. Women with a history of recurrent depression are at a high risk of relapse if medication is discontinued. Women with recurrent depression or who have symptoms despite their medication may benefit from psychotherapy to replace or augment medication Women with recurrent depression or who have symptoms despite their medication may benefit from psychotherapy to replace or augment medication Women with severe depression (with suicide attempts, functional incapacitation, or weight loss) should remain on medication. If a patient refuses medication, alternative treatment and monitoring should be in place, preferably before discontinuation Women with severe depression (with suicide attempts, functional incapacitation, or weight loss) should remain on medication. If a patient refuses medication, alternative treatment and monitoring should be in place, preferably before discontinuation

9. Pregnant and not currently on medication for depression: Psychotherapy may be beneficial in women who prefer to avoid antidepressant medication. Psychotherapy may be beneficial in women who prefer to avoid antidepressant medication. For women who prefer taking medication, risks and benefits of treatment choices should be evaluated and discussed, including factors such as stage of gestation, symptoms, history of depression, and other conditions and circumstances (eg, a smoker, difficulty gaining weight). For women who prefer taking medication, risks and benefits of treatment choices should be evaluated and discussed, including factors such as stage of gestation, symptoms, history of depression, and other conditions and circumstances (eg, a smoker, difficulty gaining weight).

10. All pregnant women: Regardless of circumstances, a woman with suicidal or psychotic symptoms should immediately see a psychiatrist for treatment. Regardless of circumstances, a woman with suicidal or psychotic symptoms should immediately see a psychiatrist for treatment.

11. Antidepressant Drug Treatment During Pregnancy SSRI’s most commonly used SSRI’s most commonly used Largest sample size exists for Fluoxetine (Prozac) and it is first line Largest sample size exists for Fluoxetine (Prozac) and it is first line Then Citalopram/Escitalopram (Celexa/Lexapro), then Sertraline (Zoloft) and TCA’s (favored are nortriptyline and desiprimine) Then Citalopram/Escitalopram (Celexa/Lexapro), then Sertraline (Zoloft) and TCA’s (favored are nortriptyline and desiprimine)

12. Non-SSRI’s During Pregnancy More limited reproductive safety data available for SNRI’s compared to SSRI’s, i.e.. venlafaxine, duloxetine Data on bupropion includes growing number of exposures ( >1000) supporting absence of increased risk for malformation (overall and cardiac) http://www.gsk.com/media/paroxetine/ingenix_study.pdf Chun-Fai-Chan B, Koren G, et al. Am J Obstet Gynecol, March 2005. 192(3). Cole JA, Modell JG, Haight BR, et al Pharmacoepidemiol Drug Saf. 9 August 2006 12

13. First Trimester Use of Selective Serotonin-Reuptake Inhibitors and the Risk of Birth Defects Retrospective study: Compared 9849 infants with and 5860 infants w/o birth defects for associations with 1 st trimester SSRI use SSRIs overall show no increased risk of craniosynostosis, omphalocoel, heart defects Individual SSRIs may confer some increased risks for specific defects which are rare and the absolute risks are small Louik et al. NEJM June 28,2007

14. Risk for PPHN Associated With Late Trimester Exposure to SSRI Inconsistent Findings: One report showed increased risk by 6-fold (Chambers 2006) One report showed increased risk by 6-fold (Chambers 2006) Lower association seen with Källén and Olausson, 2008 Lower association seen with Källén and Olausson, 2008 NO association seen by Andrade.et al., 2009 NO association seen by Andrade.et al., 2009Limitations: Small number of SSRI exposures Small number of SSRI exposures Recall bias with respect to early versus late SSRI exposure Recall bias with respect to early versus late SSRI exposure Recent data suggests lower risk than Chambers et al Recent data suggests lower risk than Chambers et al PPHN correlated with cesarean section, race, body mass index, and other factors not related to SSRI use** PPHN correlated with cesarean section, race, body mass index, and other factors not related to SSRI use** ** Hernández-Díaz S, et al. Pediatrics. 2007;120:e272-e282. Kallen, August 2008 ; Pharmacoepidemiol Drug Safety Chambers CD, et al. N Engl J Med. 2006;354:579-587. Hernández-Díaz S, et al. Pediatrics. 2007;120:e272-e282 14

15. “Poor Neonatal Adaptation” and SSRI Use During Pregnancy Consistent data: Late trimester exposure to SSRIs is associated with transient irritability, agitation, jitteriness, and tachypnea Consistent data: Late trimester exposure to SSRIs is associated with transient irritability, agitation, jitteriness, and tachypnea Studies do not control for maternal mental health condition, blinding of exposure in neonatal assessments Studies do not control for maternal mental health condition, blinding of exposure in neonatal assessments Effectiveness of discontinuing or lowering the dose late in pregnancy aimed at reducing the risk of neonatal toxicity has not been studied Effectiveness of discontinuing or lowering the dose late in pregnancy aimed at reducing the risk of neonatal toxicity has not been studied Lowering the dose of antidepressants does, however, increase the risk for maternal post partum depression Lowering the dose of antidepressants does, however, increase the risk for maternal post partum depression Levinson-Castiel R, et al. Arch Pediatr Adolesc Med. 2006;160:173-176. Chambers CD, et al. N Engl J Med. 2006;354:579-587. 15

16. No correlation between measures of umbilical cord levels of SSRIs and risk of developing neonatal symptoms No correlation between measures of umbilical cord levels of SSRIs and risk of developing neonatal symptoms No difference in symptoms between two groups compared: infants born to mothers who had taken SSRIs but tapered 2 weeks prior to delivery vs. those who discontinued No difference in symptoms between two groups compared: infants born to mothers who had taken SSRIs but tapered 2 weeks prior to delivery vs. those who discontinued This phenomenon may represent serotonergic dysfunction rather than medication withdrawal This phenomenon may represent serotonergic dysfunction rather than medication withdrawal

17. LONGTERM NEUROBEHAVIORAL EFFECTS Two studies demonstrating absence of neurobehavioral differences with TCAs versus fluoxetine in exposed vs nonexposed children Two studies demonstrating absence of neurobehavioral differences with TCAs versus fluoxetine in exposed vs nonexposed children Children ages 1 1/2 to 6 years exposed to antidepressants (Fluoxetine or TCAs) in utero had similar IQ’s language development, behavioral development, temperament, mood, as those not exposed Children ages 1 1/2 to 6 years exposed to antidepressants (Fluoxetine or TCAs) in utero had similar IQ’s language development, behavioral development, temperament, mood, as those not exposed No difference between those exposed during just the first trimester or throughout the pregnancy No difference between those exposed during just the first trimester or throughout the pregnancy However, depression in the mother was associated with lower cognitive and language achievement Nulman I, et al. N Engl J Med. 1997;336:258-262. Nulman I, et al. Am J Psychiatry. 2002;159:1889-1895. Oberlander TF, et al. J Clin Psychiatry. 2004;65:230-237. Oberlander TF, et al. Arch Pediatr Adolesc Med. 2007;161:22-29. Misri S, et al. Am J Psychiatry. 2006;163

18. If a woman is already on an SSRI antidepressant that is working well, continue her on that one. If a woman is already on an SSRI antidepressant that is working well, continue her on that one. TCA’s are safe, with nortriptyline being preferred TCA’s are safe, with nortriptyline being preferred Use an adequate dosage, this often increases during the pregnancy (There is no fetal benefit to decreasing dose prior to delivery, and this may increase risk of PPD in mother) Use an adequate dosage, this often increases during the pregnancy (There is no fetal benefit to decreasing dose prior to delivery, and this may increase risk of PPD in mother) Consider ECT for severely depressed or psychotic women – it is safe and very effective Consider ECT for severely depressed or psychotic women – it is safe and very effective

19. Cohen LS, et al. JAMA. 1994;271:146-150. Steer RA, et al. J Clin Epidemiol. 1992;45:1093-1099; Orr ST, et al. Am J Prev Med. 1996;12:459-466; Suppes T, et al. Arch Gen Psychiatry. 1991;48:1082-1088; Faedda GL, et al. Arch Gen Psychiatry. 1993;50:448-55; Baldessarini RJ, et al. Clin Psychiatry. 1996;57:441-448. Pharmacologic Treatment of Pregnant Women with Bipolar Disorder: Weighing the Risks Commonly used antimanic agents are either known teratogens or limited available reproductive safety data Commonly used antimanic agents are either known teratogens or limited available reproductive safety data Risks of untreated psychiatric illness Risks of untreated psychiatric illness Risk of discontinuing maintenance psychotropic medications Risk of discontinuing maintenance psychotropic medications 19

20. Cohen LS, et al. JAMA. 1994;271:146-150. Lithium and Teratogenicity 1970s Lithium Baby Registry—risk for specific cardiovascular malformation high; Ebstein’s anomaly 1970s Lithium Baby Registry—risk for specific cardiovascular malformation high; Ebstein’s anomaly Revised risk based on meta-analysis: 1/1000 to 1/2000 (0.05%) Revised risk based on meta-analysis: 1/1000 to 1/2000 (0.05%) Relative risk 10 to 20 times the rate in general population (1/20,000) Relative risk 10 to 20 times the rate in general population (1/20,000) Absolute risk vs relative risk Absolute risk vs relative risk

21. Summary of Findings Across Pregnancy Registries Valproic acid (VPA) is associated with the highest risk for all major malformations Valproic acid (VPA) is associated with the highest risk for all major malformations Risk estimates around 10% and higher 1 Risk estimates around 10% and higher 1 Risk appears to be dose-dependent (>1000 mg/d); may be with LTG 2,3 Risk appears to be dose-dependent (>1000 mg/d); may be with LTG 2,3 Folic acid supplementation may not be protective against VPA- associated neural tube defects Folic acid supplementation may not be protective against VPA- associated neural tube defects Risk is highest with anticonvulsant polytherapy, specifically with VPA 4,5, Risk is highest with anticonvulsant polytherapy, specifically with VPA 4,5, Carbamazepine (CBZ) and LTG are associated with lower risk than VPA Carbamazepine (CBZ) and LTG are associated with lower risk than VPA 1. Wyszynski DF, et al. Neurology. 2005;64:961-965. 2. Morrow J, et al. J Neurol Neurosurg Psychiatry. 2006;77:193-198. 3. Cunnington M, et al. Epilepsia. 2007;48:1207-1210. 4. Meador KJ, et al. Neurology. 2006;67:407-412. 5. Holmes LB, et al. Arch Neurol. 2004; 61:673-678. 21

22. Neurobehavioral Teratogenicity and Anticonvulsants Data from several studies suggest VPA exposure is associated with increased risk for adverse cognitive and neurodevelopmental effects compared with other anticonvulsants Data from several studies suggest VPA exposure is associated with increased risk for adverse cognitive and neurodevelopmental effects compared with other anticonvulsants Neurobehavioral risk with LTG unknown Neurobehavioral risk with LTG unknown Adab N, et al. J Neurol Neurosurg Psychiatry. 2004;75:1575-1583. Adab N, et al. J Neurol Neurosurg Psychiatry. 2001;70:15-21. Vinten J, et al. Neurology. 2005;64:949-954. Gaily E, et al. Neurology. 2004;62:28-32. 22

23. Lamotrigine (LTG) Monotherapy Exposure: Increased Risk for Oral Clefts Overall risk for major malformations with LTG approximately 2.7% across several studies 1,2 Overall risk for major malformations with LTG approximately 2.7% across several studies 1,2 North American Antiepileptic Pregnancy Registry showed an increased incidence of a specific malformation North American Antiepileptic Pregnancy Registry showed an increased incidence of a specific malformation Oral clefts: 8.9/1000 vs baseline 0.37/1000 3 Oral clefts: 8.9/1000 vs baseline 0.37/1000 3 Finding not corroborated in other registries; further data needed Finding not corroborated in other registries; further data needed Absolute risk remains small Absolute risk remains small 1. Cunnington M, et al. Neurology. 2005;64:955-960. 2. Meador KJ, et al. Neurology. 2006;67:407-412. 3. Holmes LB, et al. Abstract presented at the 46th Annual Meeting of the Teratology Society. June 24-29, 2006; Tucson, Arizona.

24. Treatment of Bipolar Disorder in Pregnancy Mild to moderate bipolar disorder: Gradual taper and discontinuation of antimanic prophylaxis (lithium, sodium valproate) prior to pregnancy can be considered Gradual taper and discontinuation of antimanic prophylaxis (lithium, sodium valproate) prior to pregnancy can be considered Reintroduce mood stabilizer as needed or during second trimester; except for sodium valproate given data suggesting behavioral teratogenicity. Reintroduce mood stabilizer as needed or during second trimester; except for sodium valproate given data suggesting behavioral teratogenicity. Cohen LS, J Clin Psychiatry 2007;68 ( suppl 9).

25. Moderate to severe bipolar disorder: Lithium may be the safest alternative for women dependent on mood stabilizers For lithium nonresponders consider lamotragine monotherapy Consider lamotrigine and typical or atypical antipsychotic if lamotrigine monotherapy ineffective

26. Altshuler LL, et al. Am J Psychiatry. 1996;153: 592-606 Yaeger D, et al. Am J Psychiatry. 2006;163:2064-2070..McKenna K, et al. J Clin psychiatry. 2005;66:444-449. Kulkarni J, et al. Aust N Z J Psychiatry. 2008;42:38-44 Antipsychotic Use During Pregnancy Typicals and teratogenic risk: Data support safety of typical antipsychotics with respect to teratogenicity Atypicals and teratogenic risk: Atypicals and teratogenic risk: Postmarketing surveillance data for atypicals, case reports No increased risk for major malformations Postmarketing surveillance data for atypicals, case reports No increased risk for major malformations Conclusions regarding reproductive safety of these agents not possible with currently available data, though no sign of teratogenicity is evident based on limited studies Conclusions regarding reproductive safety of these agents not possible with currently available data, though no sign of teratogenicity is evident based on limited studies

27. Antipsychotic Use During Pregnancy Largest dataset documenting outcomes of use of Atypicals in Pregnancy Examined 713 pregnancies in women who were receiving Risperidone during pregnancy 21 cases of withdrawal-emergent syndrome including jitteriness, irritability, feeding problems and somnolence No increased rate of spontaneous abortions, structural malformations and fetal teratogenic risk above that of the general population. Evaluating the postmarketing experience of risperidone use during pregnancy: pregnancy and neonatal outcomes. Drug Saf. 2007;30(3):247-64.

28. Antipsychotic Use During Pregnancy On 2/22/11, the FDA issued a warning against use of antipsychotics during pregnancy, citing increased risk of withdrawal symptoms and EPS On 2/22/11, the FDA issued a warning against use of antipsychotics during pregnancy, citing increased risk of withdrawal symptoms and EPS Data obtained from FDA’s Adverse Event Reporting System up to 10/08, including use of typicals and atypicals (mostly typicals) Data obtained from FDA’s Adverse Event Reporting System up to 10/08, including use of typicals and atypicals (mostly typicals) A majority of the cases were confounded by other factors, such as malformations, other medications, prematurity and complications A majority of the cases were confounded by other factors, such as malformations, other medications, prematurity and complications

29. Antipsychotic Use During Pregnancy “The symptoms of EPS and withdrawal in newborns may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty in feeding. In some newborns, the symptoms subside within hours or days and do not require specific treatment; other newborns may require longer hospital stays.” “The symptoms of EPS and withdrawal in newborns may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty in feeding. In some newborns, the symptoms subside within hours or days and do not require specific treatment; other newborns may require longer hospital stays.” FFDA Drug Safety Communication: Antipsychotic drug labels updated on use during pregnancy and risk of abnormal muscle movements and withdrawal symptoms in newborns1 FFDA Drug Safety Communication: Antipsychotic drug labels updated on use during pregnancy and risk of abnormal muscle movements and withdrawal symptoms in newborns1 FDA Drug Safety Communication: Antipsychotic drug labels updated on use during pregnancy and risk of abnormal muscle movements and withdrawal symptoms in newbornsFDA Drug Safety Communication: Antipsychotic drug labels updated on use during pregnancy and risk of abnormal muscle movements and withdrawal symptoms in newborns

30. Sleep Disturbance in Pregnancy 25% of women in 1 st trimester 25% of women in 1 st trimester 75% in 3 rd trimester 75% in 3 rd trimester Poor sleep is strongly correlated with depression Poor sleep is strongly correlated with depression Insomnia is more prevalent in depressed women who are untreated vs. women who are treated in week 20 Insomnia is more prevalent in depressed women who are untreated vs. women who are treated in week 20 There is no difference at week 36, meaning most women experience sleep disturbance in the 3 rd trimester There is no difference at week 36, meaning most women experience sleep disturbance in the 3 rd trimester Speaks to the importance of treating underlying mood disorder Speaks to the importance of treating underlying mood disorder Field 2007, Katherine Wisner, MD, PhD

31. Zolpidem Use in Pregnancy Large Taiwanese study looked at 2,497 women without a history of mental illness, who used Zolpidem during pregnancy for at least 30 days (with an age matched comparison group) Large Taiwanese study looked at 2,497 women without a history of mental illness, who used Zolpidem during pregnancy for at least 30 days (with an age matched comparison group) This study showed increased rates of adverse pregnancy outcomes including: low birth weight, preterm delivery, small for gestational age babies and increased rates of C-section deliveries. This study showed increased rates of adverse pregnancy outcomes including: low birth weight, preterm delivery, small for gestational age babies and increased rates of C-section deliveries. There was no increase in congenital anomalies There was no increase in congenital anomalies

32. Zolpidem Use in Pregnancy Hypothesis include: Hypothesis include: Zolpidem causes the pituitary to release vasopressin and oxytocin resulting in uterine vasoconstriction GABAergic agonists cause respiratory depression Highest risk of adverse outcome in women who took Zolpidem >90 days Highest risk of adverse outcome in women who took Zolpidem >90 days Wang LH, Lin HC, Lin CC, Chen YH & Lin HC. Increased Risk of Adverse Pregnancy Outcomes in Women Receiving Zolpidem During Pregnancy. Clin Pharm Ther 88:3, 369-374 (2010). Increased Risk of Adverse Pregnancy Outcomes in Women Receiving Zolpidem During PregnancyIncreased Risk of Adverse Pregnancy Outcomes in Women Receiving Zolpidem During Pregnancy

33. Treatment of Sleep Disturbance in Pregnancy Due to these findings, the authors suggest avoiding use of Zolpidem in pregnancy when possible. Other medication options for sleep with safety data in pregnancy are the tricyclic antidepressants and the benzodiazepines. Other options for addressing sleep problems during pregnancy include cognitive behavioral therapy, improving sleep hygiene and addressing underlying mood disorders. Due to these findings, the authors suggest avoiding use of Zolpidem in pregnancy when possible. Other medication options for sleep with safety data in pregnancy are the tricyclic antidepressants and the benzodiazepines. Other options for addressing sleep problems during pregnancy include cognitive behavioral therapy, improving sleep hygiene and addressing underlying mood disorders.

34. Summary of Treatment of Mood Disorders During Pregnancy

35. Thank You Questions?