PERINATAL MOOD DISORDERS: Update on Psychotropic Prescribing

1. PERINATAL MOOD DISORDERS: Update on Psychotropic Prescribing

2. www.mainepsych.org Postpartum Depression Project

3. Disclosures and Thanks Disclosures: I do not have any conflicts of interest that may have any direct bearing on this CME presentation. I wish to thank Lee Cohen, M.D. Director of the Perinatal Psychiatry Clinical Research Program at MGH, for lending me the slides of some of the graphics in this presentation

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

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

6. Time to Relapse in Patients Who Maintained or Discontinued Antidepressant 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Maintained (N = 82) Percentage of Patients Remaining Well Discontinued (N = 65) 0 12 24 36 Gestational Age Cohen LS, et al. JAMA. 2006:295;499-507.

7. CONCLUSIONS: • 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 • This should be discussed when weighing the risk/benefit ratio of using antidepressants during pregnancy Cohen LS, et al. JAMA. 2006:295;499-507.

8. Relapse of Bipolar Disorder During Pregnancy • 89 women with BPD stable at least 1 month prior to conception, 62 continued treatment, 27 discontinued (treatment was mood stabilizer =/- antidepressant and/or antipsychotic) • 71% had at least one mood episode ( usually depressed) --47% of episodes occurred in the 1st trimester --85.5 % of those who discontinued treatment --37% of those who continued treatment • Those who discontinued spent 40% of their pregnancy in an illness state; those who continued only 8.8% Viguera, et al , Am J Psychiatry, 2008

9. Relapse of Bipolar Disorder During Pregnancy Presented at NCDEU, Viguera et al, June 2006 Viguera, et al , Am J Psychiatry, 2008

10. RISKS OF UNTREATED DEPRESSION DURING PREGNANCY • Neonatal risks (low birth weight and small for gestational age infants • Obstetrical risks (higher rates of miscarriage, preterm labor, placental abruption, preeclampsia • Irritable babies (with high cortisol levels) • Lack of adequate prenatal care • Higher use of alcohol and drugs • SUBSEQUENT POSTPARTUM DEPRESSION • SUBSEQUENT RECURRENT EPISODES OF DEPRESSION • SUICIDE

11. GUIDELINES FOR TREATMENT OF DEPRESSION DURING PREGNANCY • Assess the overall risks through evaluation of the patient’s history, current risk factors and current presentation • For mild to moderate depression try non-pharmacologic intervention • Have an open discussion of the risks and benefits of treatment with medication • Consider the risks of inadequately treated depression

12. For women who are stable on antidepressants who wish to discontinue antidepressants, inform them of the risks and monitor closely. Intervene early at signs of recurrence • When the decision is made to use medication, select medications with the best established safety profile. • Medication decisions should be guided by the patient’s history of prior medication treatment

13. If a woman is already on an SSRI antidepressant that is working well, continue her on that one; pregnancy is not a time to change antidepressant s and risk relapse and exposure to two drugs. • TCA’s are safe, with nortriptyline being preferred • Use an adequate dosage, this often increases during the pregnancy because of the increase in blood volume • Consider ECT for severely depressed or psychotic women –it is safe and very effective

14. Regardless of circumstances, a woman with suicidal or psychotic symptoms should immediately see a mental health specialist for treatment. 

15. 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).   

16. FDA LABELING FDA Category labeling is often misunderstood and interpreted to mean that the risk increases from A to B to C, etc That is NOT the case. No distinction is made between human and animal data Often is not updated New FDA labeling will be released in 2013 and will eliminate the categories. Pregnancy and lactation subsections would have three components: a risk summary, clinical considerations and a data section. Standard language: “Use the medication in pregnancy when clearly needed”; when risk of treatment is outweighed by risk of underlying disorder Pregnancy registries are sparse across psychotropics

17. SSRI Use during Pregnancy • Recent findings and more data inform the pharmacologic treatment of depression during pregnancy • Consistent conclusions that the absolute risk of SSRI exposure in pregnancy is small1-3 • Recent case-control studies reveal inconsistent data regarding teratogenic risk of individual SSRIs4-9 • Reproductive safety data on SSRIs exceed what is known about most other medicines used in pregnancy 1 Louik C, et al. N Engl J Med 2007; 2 Einarson TR, Einarson A. Pharmacoepidemiol Drug Saf 2005; 3Einarson A, et al. Am J Psychiatry 2008; 4 Alwan S, et al. N Engl J Med 2007; 5 Greene MF. N Engl J Med 2007; 6Hallberg P, Sjoblom V. J Clin Psychopharmacol 2005; 7Wogelius P, et al. Epidemiology 2006; 8www.gsk.ca/english/docs-pdf/PAXIL_PregnancyDHCPL_E-V4.pdfDear Healthcare Professional (3/17/08); 9www.fda.gov/medwatch/safety/2005/Paxil_dearhcp_letter.pdf Dear Healthcare Professional (3/17/08)

18. Antidepressant Drug Treatment During Pregnancy • SSRI’s most commonly used • Largest sample size exists for Prozac and it is first line • Then Celexa/Lexapro, then Zoloft and TCA’s (favored are nortriptyline and desiprimine) • Accumulating safety data for Wellbutrin and Effexor

19. 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 supporting absence of increased risk for malformation Buproprion registry over 500 • Retrospective analysis of 1200 exposed infants • Prospective study of 105 infants 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

20. Evidence for Increased Risk of Cardiac Malformations Following Paroxetine Exposure? Some Epidemiologic data suggesting increased relative risk (1.5) associated with first trimester exposure to paroxetine (VSD, ASD) Absolute risk of 1/50 vs. background risk of 1/100 Resulted in labeling change from category C to D Recent data from global teratogen monitoring programs do no not support increased risks of overall cardiac malformations . Wogelius P, et al. Epidemiology. 2006;17:701-704. Lennestål R, Källén. J Clin Psychopharmacol. 2007;27:607-613. Cohen LS, Nonacs R. http://www.womensmentalhealth.org/information/newsletter_2.3.html. Accessed March 17, 2008. Einarson A, et al. Am J Psychiatry. 2008 Apr 1 [Epub ahead of print].

21. “Poor Neonatal Adaptation” and SSRI Use During Pregnancy 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 Effectiveness of discontinuing or lowering the dose late in pregnancy aimed at reducing the risk of neonatal toxicity has not been prospectively studied

22. “Poor Neonatal Adaptation” and SSRI Use During Pregnancy No correlation between measures of umbilical cord blood levels of SSRIS and the risk if 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 continued Lowering the dose of antidepressants does, however, increase the risk for maternal postpartum 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. Sit, D, et al. Pre-publication communication Warburton et al, Acta Psychiatr Scand 2010; 121(6): 471-9.

23. Risk for PPHN Associated With Late Trimester Exposure to SSRI Inconsistent Findings: One report showed increased risk by 6-fold (Chambers 2006) (with this highest estimate of 6-fold increase 1% of exposed infants would be affected) Lower association seen with Källén and Olausson, 2008 NO association seen by Andrade.et al., 2009 Limitations: Small number of SSRI exposures Recall bias with respect to early versus late SSRI exposure 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** ** 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

24. SSRI Use vs. Untreated Depression • Both continuous untreated depression and continuous SSRI use associated with 20% increase risk preterm birth • Women taking SSRIs vs. those with psych histories vs. controls: those taking SSRI had higher risk of preterm birth (by only 5 days) • Depression, SSRI exposure and stopping SSRIs during pregnancy have been associated with increased spontaneous abortions Wisner at al Arch Pediatr Adolesc Med. 2009;163:949–954. Lund N, Pedersen LH, Henriksen TB. Arch Pediatr Adolesc Med. 2009;163:949–954. Rahimi R, Nikfar S, Abdollah M. Reprod Toxicol. 2006;22:571–575. Hemels ME, Einarson A, Koren G, Lanctôt KL, Einarson TR. Ann Pharmacother. 2005;39:803–809. Gavin AR, Chae DH, Mustillo S, Kiefe CI. J Womens Health (Larchmt). 2009;18:803–811. Einerson et al, pre publication communication, Marce’ Sociaty Annual meeting, 2010

25. Zolpidem (Ambien) in Pregnancy • Evaluated 10,343 women prescribed zolpidem • Included if prescribed for > 30 days in pregnancy • Excluded women with prior mental disorders, diabetes, hypertension coronary artery disease • Extracted 2497 zolpidem exposed and compared to matched control group of 12, 485 • Zolpidem exposed had higher rates of LBW, PTD, SGA , highest in those receiving Zolpidem > 90 days • No increase in fetal malformations • Recommend using alternatives to Ambien for insomnia during pregnancy Wang et al, 2010

26. LONGTERM NEUROBEHAVIORAL EFFECTS • Two studies demonstrating absence of neurobehavioral differences with TCAs versus fluoxetine in exposed vsnonexposed children • Children ages 1 1/2 to 6 years exposed to antidepressants (Prozac 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 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 PediatrAdolesc Med. 2007;161:22-29. Misri S, et al. Am J Psychiatry. 2006;163

27. Pharmacologic Treatment of Pregnant Women with Bipolar Disorder: Considering the Risks Commonly used antimanic agents are either known teratogens or limited available reproductive safety data Risks of untreated psychiatric illness Risk of discontinuing maintenance psychotropic medications 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.

28. Lithium and Teratogenicity 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%) Relative risk 10 to 20 times the rate in general population (1/20,000) Absolute risk vs relative risk: absolute risk is small Cohen LS, et al. JAMA. 1994;271:146-150.

29. Pregnancy Registries for Anticonvulsants: and Teratogenic Risk North American Antiepileptic Pregnancy Registry Lamotrigine Pregnancy Registry United Kingdom Epilepsy and Pregnancy Register Central Registry of Antiepileptic Drugs and and Pregnancy (EURAP) Australian Pregnancy Registry Holmes LB, et al. Arch Neurol. 2004;61:673-678. Meador KJ, et al. Neurology. 2006;67:407-412.

30. Summary of Findings Across Pregnancy Registries Valproic acid (VPA) is associated with the highest risk for all major malformations Risk estimates around 10% and higher1 Risk appears to be dose-dependent (>1000 mg/d); may be with LTG2,3 Folic acid supplementation may not be protective against VPA-associated neural tube defects Risk is highest with anticonvulsant polytherapy, specifically with VPA4,5, 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.

31. Should Depakote (Valproate) be used in Pregnancy (or women of child bearing age)? • Three year old children of 309 women who took anticonvulsants studied: Valproate exposed had IQ’s 9 points lower than lamotrigine exposed Data from several studies suggest VPA exposure is associated with increased risk for adverse cognitive and neurodevelopmental effects compared with other anticonvulsants • 1565 pregnancies in which infants were exposed to valproic acid with 118 malformations • 14 malformations were more common in infants exposed to valproic acid in the 1st trimester.

32. Should Depakote (Valproate) be used in Pregnancy (or women of child bearing age)? • spina bifida, microcephaly, ventricular and atrial septal defects, tetralogy of Fallot, cleft palate, hypospadias, club foot and craniosynostosis • Use of valproic acid monotherapy in 37,154 women was associated with significantly increased risks for 6 of the 14 malformations: Spina bifida, Atrial septal defect , Cleft palate , Hypospadias , Polydactyly , Craniosynostosis         AMERICAN ACADEMY OF NEUROLOGISTS RECOMMENDS AGAINST THE USE OF VALPROATE IN PREGNANCY Kimford, JM et al, Cognitive function at 3 years of age after fetal exposure to antepileptic drugs, NEJM; 2009 , 360 (16) 1597-1605 Jentink, J. New England Journal of Medicine, 2010; vol 362: pp 2185-2193. • 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

33. Lamotrigine (Lamictal) Monotherapy Exposure: Increased Risk for Oral Clefts Overall risk for major malformations with lamotrigine approximately 2.7% across several studies; no significant difference from the general population North American Antiepileptic Pregnancy Registry showed an increased incidence of a specific malformation Oral clefts: 8.9/1000 vs baseline 0.37/1000 Finding not found in the pooled analysis of 19 other registries Absolute risk remains small Cunnington M, et al. Neurology.Neurology March 22, 2005 64:955-960. Holmes LB, et al. Neurology 2008 70 (22 part2) 2152-8 Dolk, H et . ;Neurology 2008, 71 (10) 714-22

34. Antipsychotic Use During Pregnancy Typical antipsychotics and teratogenic risk: Data support safety of typical antipsychotics with respect to teratogenicity Atypicals and teratogenic risk: 151 subjects exposed to different atypicals-60 to olanzapine, 49 to risperidone, 36 to quetiapine, and 6 to clozapine-with non-exposed controls, major malformation rates were not significantly different between the two groups Altshuler LL, et al. Am J Psychiatry. 1996;153: 592-606Yaeger 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 Newham, JJ et Br J Psych; 2008, 192(5) 333-7McKenna et al, J. Clin. Psychiatry 2005;66:444-9

35. Antipsychotic Use During Pregnancy Infants exposed to atypical antipsychotics are more likely to be large for gestational age Conclusions regarding reproductive safety of these agents are limited with currently available data, though no of teratogenicity is evident based on limited studies National Pregnancy Registry for Atypical Antipsychotics 1-866-961-2388 Altshuler LL, et al. Am J Psychiatry. 1996;153: 592-606Yaeger 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 Newham, JJ et Br J Psych; 2008, 192(5) 333-7McKenna et al, J. Clin. Psychiatry 2005;66:444-9

36. Antipsychotic Use During Pregnancy New FDA Black Box warning: • All antipsychotics have been updated to have a black box warning about the use in pregnancy regarding abnormal movements (EPS) or withdrawal symptoms in infants exposed in the third trimester • Data from FDA adverse Event Reporting System • 69 cases of withdrawal or EPS with antipsychotics • Some resolved within hours without treatment; others required longer hospital stays

37. Antipsychotic Use During Pregnancy Pitfalls: • This data does not reveal anything about the incidence • Typical antipsychotics have been used during pregnancy since the 1950’s • FDA noted that these cases were confounded by other variables—other meds, other neonatal and obstetrical complications Bottom line: Be aware of the potential for adverse effects Balance the benefits and risks , especially that of relapse of a psychotic illness

38. Benzodiazepine Use during Pregnancy • Some evidence for a slight increase in oral clefts with first trimester exposure • Infants born to mothers taking high doses in late pregnancy may show signs of toxicity • Anxiety is a risk factor for preeclampsia, preterm labor, low birth weight, PPD; long term, behavioral, cognitive, developmental and medical problems in the exposed fetus

39. Treatment of Bipolar Disorder in Pregnancy Mild to moderate bipolar disorder: Gradual taper and discontinuation of anti-manic 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 for behavioral teratogenicity. Moderate to severe bipolar disorder: Lithium may be the safest alternative for women dependent on mood stabilizers For lithium nonresponders consider lamotrigine monotherapy Consider lamotrigine and typical or atypical antipsychotic if lamotrigine monotherapy ineffective Cohen LS, J Clin Psychiatry 2007;68 ( suppl 9).

40. ECT During Pregnancy Treatment of choice when urgent management is necessary or illness is life threatening Especially recommended in delusional depression, mania External fetal monitoring, ultrasonography increases safety Requires a comprehensive treatment team

41. Treatment of Mood Disorders during Pregnancy • Pregnancy is not protective with respect to new onset or recurrent mood disorders • Thoughtful consideration needs to be given to the risks of untreated psychiatric illness • Thoughtful treatment decisions can be made regarding the use of psychotropics during pregnancy • Weighing the relative risks of medication treatment should be done on an individualized case by case basis. • Maintaining euthymic mood during pregnancy is crucial • NO DECISION IS PERFECT; NO TREATMENT IS RISK FREE.

42. PPD as a Public Health Problem • Over 4 million women give birth in America • One of every 8 new mothers experience depression • Over half a million women will suffer postpartum depression each year • Most common complication of childbearing • Causes serious and lasting effects on child health and family functioning 1 Wisner K et al. N Engl J Med. 2002;347:194-199; 2Wisner K et al. J Clin Psychiatry. 2001;62:82-86.

43. 70 60 50 40 Admissions/Month 30 20 Pregnancy 10 0 –2 Years – 1 Year Childbirth +1 Year +2 Years Epidemiology of Postpartum Episodes Kendell RE et al. Br J Psychiatry. 1987;150:662-673.

44. Spectrum of Postpartum Mood Disorders Postpartum Psychosis(0.1-0.2%) Postpartum Depression(10-15%) Postpartum Symptom Severity Postpartum Blues(50-85%) None

45. Risks of Untreated PPD To mother: • Stressful impact on relationship with partner • Kindling phenomenon---development of a chronic low grade depression with more susceptibility to repeated episodes of MDD • Severe postpartum psychiatric disorder is associated with a high rate of death from natural and unnatural causes, particularly suicide • Suicide risk in the first postnatal year is increased 70-fold

46. Risks of Untreated PPD To child: • Poor weight gain • Sleep problems • Less breastfeeding-depressed mothers more likely to discontinue breastfeeding • Impaired maternal health and safety practices • Disruption in the attuned infant-caregiver interactions which promote brain neurological “wiring”: • Future , hyperactivity, conduct disorders and school behavior problems • Delays in language and social development • Increased risk of depression • Maternal depression is an “Adverse childhood experience” ACE, often it is not the only adversity MATERNAL POST PARTUM MOOD IS ONE OF THE STRONGEST PREDICTORS OF NEUROCOGNITIVE DEVELOPMENT IN CHILDREN MEASURED UP TO AGE SIX

47. PRESENTATION OF PPD CLASSIC SYMPTOMS OF DEPRESSION WITH SOME FEATURES especially prominent with PPD: • Women are often unable to sleep even when given the opportunity to do so Anxiety symptoms are often a very prominent aspect of PPD • Frequently have intrusive, obsessional ruminations, or images, usually focused on the baby, often violent in nature, but they are egodystonic and there is not a problem with reality testing i.e. non-psychotic. One study showed 50% of women with PPD had these. Such obsessional thoughts do not increase the risk of harm to the baby and are important to distinguish from psychosis.

48. POST PARTUM PSYCHOSIS • Typical onset is within 2 weeks after delivery, first symptoms often within 48-72 hours • Earliest signs are restlessness, irritability and insomnia • Often very labile in presentation • Often looks “organic” with a lot of confusion and disorientation • Most often consistent with mania or a mixed state

49. POST PARTUM PSYCHOSIS • Includes agitation, paranoia, delusions, disorganized thinking and impulsivity • Thoughts of harming the baby are frequently driven by delusions—Child must be saved from harm, child is malevolent, dangerous, has special powers, is Satan or God • Rates of infanticide associated with untreated postpartum psychosis have been estimated to be as high as 4% and of suicide as high as 5 %.

50. TREATMENT OF PPD Selection of treatment: • First requires good evaluation, review of prior history and assessment for suicidality/dangerousness • individual psychotherapy--CBT /IP Interpersonal and cognitive behavioral therapy very effective for mild to moderate PPD • support group • community support programs • Medication • ECT • hospitalization O'Hara MW, et al. Arch Gen Psych. 2000;57:1039-1045. Stuart S, et al. J Psychother Pract Res. 1995;4:18-29. Appleby L, et al. BMJ. 1997;314:932-936.