1. Management of Perinatal Depression Laurel Romer, M.D. Primary Care Conference October 11, 2006

2. Financial Disclosure I have received no financial support for this presentation.

3. Learning Objectives Understand the scope of perinatal depression. Understand predictors of perinatal depression. Understand adverse effects/teratogenicity of antidepressant medications. Understand harms associated with untreated depression in pregnancy. Determine when to use antidepressant medication in the perinatal patient.

4. Common Patient Scenarios in Primary Care Patient is on antidepressant and is considering becoming pregnant. Patient is pregnant and has a relapse of depression, is not currently on antidepressant. Patient is postpartum and has depressive symptoms.

5. Outline Epidemiology Antidepressants in Pregnancy Untreated Depression in Pregnancy Relapse of Depression in Pregnancy Treatment of Depression in Pregnancy Treatment of Postpartum Depression

6. Epidemiology In the general population, women ages 18- 44 have highest rates of depression Up to 70% of pregnant women report depressive symptoms 10 – 16% meet criteria for major or minor depression 3, 9, 10

7. Epidemiology Prevalence of depression in pregnancy: –1 st trimester: 7.4% –2 nd trimester: 12.8% –3 rd trimester: 12.0% Prevalence of postpartum depression: 13% 3, 9, 10

8. Antidepressants in Pregnancy Research limited by: –Small sample sizes –No randomized, controlled trials –Reliance on case reports –Questionable controls –Difficulty controlling confounding variables

9. U.S. Food and Drug Administration (FDA) Use-in-Pregnancy ratings A Controlled studies show no risk. Adequate, well controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester of pregnancy. B No evidence of risk in humans. Adequate, well controlled studies in pregnant women have not shown increased risk of fetal abnormalities despite adverse findings in animals, or, in the absence of adequate human studies, animal studies show no fetal risk. The chance of fetal harm is remote, but remains a possibility. C Risk cannot be ruled out. Adequate, well-controlled human studies are lacking, and animal studies have shown a risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is administered during pregnancy; but the potential benefits may outweigh the potential risk. D Positive evidence of risk. Studies in humans, or investigational or post- marketing data, have demonstrated fetal risk. Nevertheless, potential benefits from the use of the drug may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective. X Contraindicated in pregnancy. Studies in animals or humans, or investigational or post-marketing reports, have demonstrated positive evidence of fetal abnormalities or risk which clearly outweighs any possible benefit to the patient.

10. Antidepressants in Pregnancy General Principles: –Avoid in 1 st trimester, if possible –Monotherapy –Lowest effective dosage

11. Antidepressants in Pregnancy Specific recommendations: –SSRIs No teratogenic effects with exposure at any time during pregnancy with fluoxetine, fluvoxamine, paroxetine and sertraline Above SSRIs have been associated with: –Increased premature delivery –Lower birth weight –Lower Apgar scores –Perinatal complications (with 3 rd trimester use) –Poor neonatal adaptation –Increased admission to special care nurseries 4,6

12. Antidepressants in Pregnancy Specific Recommendations: –TCAs No clear association with congenital malformations –Early studies suggested limb anomalies –2002 meta-analysis of >300,000 live births identified no increase in congenital malformations (TCA/1 st trimester) Desipramine is preferred TCA –Less anticholinergic –Less likely to cause orthostatic hypotension 1, 12

13. Antidepressants in Pregnancy Long term effects on child exposed to fluoxetine or TCAs in utero: –Nulman I, et al. NEJM 1997;336:258-62. Study followed children to 7 years old No diminishment in: –Global IQ –Language development –Motor/behavioral development

14. Untreated Depression During Pregnancy Harms to mother: –increased risk of self-injurious or suicidal behaviors –contributes to inadequate self-care –poor compliance with prenatal care –decreased appetite and consequently lower- than-expected weight gain –more likely to smoke and to use either alcohol or illicit drugs –Increased risk of postpartum depression 7

15. Untreated Depression During Pregnancy Harms to fetus: –preterm birth –lower birth weight –smaller head circumference –lower APGAR scores –Putative mechanisms: increased serum cortisol and catecholamine levels in depression may alter uterine blood flow and induce uterine irritability Dysregulation of the HPA may have a direct effect on fetal development Animal studies suggest stress causes neuronal death and abnormal development of neural structures in the brain 7

16. Untreated Depression During Pregnancy Harms to mother/fetus: –Increased interpersonal difficulties in the family unit –Disruption of mother-child interactions and difficulty with attachment –Behavioral problems in the child –Disruptions in cognitive and emotional development in the child 7

17. Relapse of Depression in Pregnancy Cohen LS, et al. JAMA 2006; 295:499-507 revealed: –43% relapse rate of depression in pregnancy 50% in 1 st trimester, 90% by end of 2 nd trimester 26% relapse in those who continued antidepressant during pregnancy 68% relapse in those who discontinued antidepressant Earlier studies purport higher rate of relapse (75%)

18. Relapse of Depression in Pregnancy Of the group of women who discontinued antidepressant medication prior to pregnancy –Had a 5-fold increased risk of relapse over those who maintained their medication therapy –60% resumed therapy during pregnancy

19. Predictors of Relapse Higher rates of relapse: –Single status (trend only) –<32 years old –Duration of depressive illness >5 years –Recurrent depressive illness, > 4 episodes 5

20. Relapse of Depression in Pregnancy Guiding principles from this study: –Women with history of longstanding recurrent depression may do better maintaining antidepressant therapy –With the knowledge that 50% of those women who discontinue antidepressant prior to conception do not relapse in the first trimester – might be able to avoid medication exposure during period of organogenesis

21. Consensus Guidelines Definitions: –Mild depression: Meets minimum diagnostic criteria Patient has mild disability or functions only with considerable effort –Severe depression: Meets most diagnostic criteria Patient has clear-cut, observable disability 2

22. Consensus Guidelines Survey methodology: –36 American experts in women’s mental health –1 OB/GYN, all others in psychiatry –Mean of 16 years in practice (4-35 years) –83% involved in a clinical trial for mood disorders in women in the past 5 years 2

23. Consensus Guidelines Written questionnaire: –Sought to identify key decision points in the treatment of depression in women as well as all the feasible treatment options –Requested ratings on 858 treatment options –Highlighted important clinical questions not yet definitively answered in the literature 2

24. Consensus Guidelines Treatment of Depression in a woman trying to conceive –Severe depression 90% would treat with antidepressant and psychotherapy –Single episode, in remission for 6 months (on antidepressant) 91% advised tapering prior to/during conception –Recurrent, severe depression Continue/switch to “safer” antidepressant 2

25. Consensus Guidelines Treatment of Depression in the 1 st trimester – psychotherapy recommended in all scenarios –Severe, recurrent depression 83% would continue antidepressant, switching to “safer” alternative –Single, mild episode Taper, discontinue antidepressant over several weeks –Single, severe episode No consensus; about half would stop antidepressant 2

26. Consensus Guidelines Treatment of Depression in 2 nd /3 rd trimesters –Severe, recurrent depression Continue antidepressant through delivery –Single, severe episode 63% would continue antidepressant through delivery 2

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28. Postpartum Depression Definition: –A major depressive episode that occurs within 4 weeks after delivery Prevalence: –12-16% during the 6-12 weeks after delivery

29. Predictors of Postpartum Depression Meta-analyses including >14,000 women plus additional studies of 10,000 women revealed strongest predictors: –Depression during pregnancy –Anxiety during pregnancy –Stressful life events during pregnancy –Marital discord –Low level of social support –Previous history of depression (25% risk) –Prior history of postpartum depression (50-62% risk) 11

30. Postpartum Depression Treatment recommendations: –Consensus Guidelines Severe nonpsychotic postpartum depression (regardless of breastfeeding status) –SSRI plus psychosocial interventions –Involve spouse in psychotherapy sessions (90%) –Full-time or live-in help for the mother (80-90%) Milder postpartum depression –Psychosocial strategies alone (65%) –Antidepressants (57%) 2

31. Postpartum Depression Treatment recommendations: –Prophylaxis in women with prior postpartum depression SSRI within 24 hours of delivery yielded marked reduction in depression recurrence Nortriptyline prophylaxis did not reduce rates of postpartum depression in RCT –Consensus Guidelines 83% recommended antidepressant medication and psychotherapy after delivery Sertraline, treatment of choice, followed by paroxetine 2, 13, 14

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33. Happy Halloween