10/1/2013 CONTROVERSIES IN PSYCHOPHARMACOLOGIC MANAGEMENT OF PERIPARTUM MOOD DISORDERS LEARNING OBJECTIVES CLINICAL MISUNDERSTANDINGS

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1 CONTROVERSIES IN PSYCHOPHARMACOLOGIC MANAGEMENT OF PERIPARTUM MOOD DISORDERS ALISON REMINICK, MD CENTER FOR WOMEN S MENTAL AND BEHAVIORAL HEALTH RUSH UNIVERSITY MEDICAL CENTER LEARNING OBJECTIVES -Understanding of the limitations of FDA labeling categories in pregnancy -Gain knowledge about the risk of untreated mood disorders during pregnancy and postpartum -Review safety data of psychotropic medications for mood disorders during pregnancy -Gain knowledge of clinical management of women with histories of psychiatric illness during pregnancy and postpartum CLINICAL MISUNDERSTANDINGS Common belief that pregnancy is protective Concerns about liability and malpractice Reliance on FDA category labeling Advising patients to abruptly stop psychotropics to avoid risk to the fetus Limited knowledge and comfort level regarding the safety data of psychotropic medications 1

2 TIME TO RELAPSE IN PATIENTS WHO MAINTAINED VS DISCONTINUED ANTIDEPRESSANT 4 Percentage of Patients Remaining Well Gestational Age Maintained (N = 82) Discontinued (N = 65) Cohen LS, Reminick et al. JAMA. 2006:295; RISK OF RELAPSE OF BIPOLAR DISORDER IN PREGNANCY Study of 89 pregnant women with bipolar I (69%) or II (31%) Maintained medications 37% relapse Discontinued medications 85% relapse Viguera, A.C. et al. Risk of Recurrence in Women with Bipolar Disorder During Pregnancy: Prospective Study of Mood Stabilizer Discontinuation. Am J Psychiatry 2007; 164: RISK OF RECURRENCE IN PREGNANT WOMEN WITH BPD WHO CONTINUED VS DISCONTINUED LAMOTRIGINE (LTG) Newport et al Bipol Disorders, 2008;10:

3 RISK OF RELAPSE AFTER LITHIUM DISCONTINUATION Viguera, A. C. et al. Risk of Recurrence of Bipolar Disorder in Pregnany and Nonpregnant Women After Discontinuing Lithium Maintenance. Am J Psychiatry 2000; 157: BIPOLAR MORBIDITY DURING PREGNANCY: POLARITY, TIMING OF RECURRENCES, AND RATE OF DISCONTINUATION Subjects who discontinued the mood stabilizer spent over 40% of pregnancy in an illness episode vs 8.8% for those who continued Majority of recurrences were major depressive episodes Median time to 1 st recurrence was 9 weeks after discontinuation vs >40 weeks with continued treatment Timing of recurrence: 47.2% in 1 st, 31.9% in 2 nd and 18.8% in 3 rd trimester Gradual discontinuation (>14d) decreased risk of recurrence compared to rapid discontinuation (<14d) Viguera, A.C. et al. Risk of Recurrence in Women with Bipolar Disorder During Pregnancy: Prospective Study of Mood Stabilizer Discontinuation. Am J Psychiatry 2007; 164: CONTINUED MOOD STABILIZER TREATMENT REDUCES RECURRENCE RISK AND MORBIDITY DURING PREGNANCY Viguera et al 2007 % weeks ill Newport et al 2008 N %of women who stopped treatment and relapsed % of women who continued treatment and relapsed Ratio 89 85% 37% % 8.8% % 30% 3.3 Viguera et al Am J Psychiatr 2007;164: , Newport et al Bipolar Disord 2008;10:

4 TREATING W OMEN OF REPRODUCTIVE AGE 49% of pregnancies in the U.S. are unintended 80% of teen pregnancies are unintended 82% of U.S. women have children (by 44 years of age, census data for 2002) Center for Disease Control and Prevention DEPRESSION DURING PREGNANCY Leading cause of disease-related disability in women 10-15% of women found to be depressed during pregnancy SSRI use during pregnancy is 3-7% Routine screening for antenatal depression uncommon Antenatal depression is typically untreated or incompletely treated F lyn n et al. Rat es an d p red ictors of d ep res s ion t reat m en t am on g p reg n an t wom en in h os p it al affiliat ed ob s t et rics prac t ices. G en Hop s P s yc h Andrade SE, et al. Am J Obstet Gynecol. 2008;198:194.e1-194.e5. Marcu s S M, F lyn n HA. Int J Gynaecol Obstet ;100: K u m ar R, Rob s on K M. A p ros p ec t ive s t u d y of em ot ion al d isord ers in c h ild b earin g wom en. B r J P s y c h ia t ry ; : Dietz, P, et al. Clinically identified Maternal Depression Am J Psychiatry 2007; 164: ) 4

5 BIPOLAR DISORDER IN PREGNANCY Prevalence of bipolar I equal among genders but bipolar II is more common among women Triggering role of reproductive events causes clustering of mood episodes during reproductive years Rise in rate of hospitalization immediately following delivery % of women with bipolar have manic symptoms in early puerperium Liebenluft, E: Am J Psychiatry 1996;153: Hover et al: Br J Psychiatr 2000;176:76-82, Grant et al Baldassano et al 2005 RISK FACTORS OF MOOD DISORDERS IN PREGNANCY History of psychiatric illness** Family history Younger age/ Low SES/ Less education/ Medicaid Insurance Unplanned pregnancy Maternal anxiety Smoking Lacking Social Support/ Single status/ Poor relationship / DV Lancaster, et al. Risk factors for depressive symptoms during pregnancy : a systematic review Am J Obstet Gynecol J a n. MATERNAL RISKS OF UNTREATED MOOD DISORDERS Impaired functioning Abnormal BMI Use of tobacco, ETOH, illicit drugs Missed PNC visits Use of medications Suicide Termination of wanted pregnancy Postpartum depression/ psychosis S u r i e t a l A m J P s y c h i a t r ; : O Ha r a e t a l J A b n o r m P s y c h o l ; 9 3 : Reis and Kallen 2010 Psychol Med G o t l i b e t a l J C o n s u l t C l i n p s y c h o l ; 5 7 :

6 EPISODE OCCURRENCE RATES Viguera, A. C. et al. Episodes of Mood Disorders in 2,253 Pregnancies and Postpartum Periods. Am J Psychiatry 2011;168:

7 INCIDENCE OF POSTPARTUM PSYCHOSIS Harlow et al. Arch Gen Psychiatry IMPACT OF MATERNAL UNTREATED MOOD DISORDER ON INFANT Suicide/infanticide Failure to thrive Poor maternal child bonding / attachment disorders Lower global IQ / poor language/ cognitive and social delay Developmental delay on Bayley Scale at 1 year Behavioral problems / emotional dysregulation Early onset of ADHD, mood, anxiety conduct disorders as well as tendency towards violence McLearn, Minkovitz, Strobino, et al., 2006 Beck, 1998 Sohr-Preston 2006 Percentage MATERNAL DEPRESSION IN PREGNANCY: OBSTETRIC OUTCOME Orr and Miller, 1995 (N=186) Overall CES-D score <16 CES-D score >16 Preterm delivery Steer et al, 1992 BDI <21(N=389) BDI >21 Preterm=<37 weeks estimated gestational age; LBW=low birth weight (<2.5 kg); SGA=small for gestational age (<10th percentile); CES-D=Center for Epidemiologic Studies-Depression; BDI=Beck Depression Inventory. Percentage Preterm LBW SGA 21 Orr S, Miller C. Epidemiol Rev. 1995;17: Steer RA, et al. J Clin Epidemiol. 1992;45:

8 OBSTETRICAL RISKS OF MOOD DISORDERS DURING PREGNANCY Maternal vasoconstriction Miscarrage Gestational HTN, diabetes, pre-eclampsia Preterm/ Operative delivery Low birth weight and APGAR scores Infant admission to a SCN Ross and McLean, JCP 2006, Ram belli et al Chen at al 2010 FETAL RISKS OF EXPOSURE TO UNTREATED ILLNESS Higher cortisol Brains - aberrant EEGs/ decreased density prefrontal cortex Irritability, Less attentive, impaired activity, more cry Developmental delay at one year Field et al: Inf Behav Dev 2006;29:445-55, Lyons-Ruth K, et al. Child Dev 1990;61:85-98,. Murray L, Cooper P. Arch Dis Child. 1997;77:99-101; Downey G, Coyne JC. Psychol Bull. 1990;108:50-76; Weinberg MK, Tronick EZ. J Clin Psychiatry. 1998;59(Suppl 2):53-61 Grizenko N, Shayan YR, Polotskaia A, et al. J Psychiatry Neurosci 2008; 33(1): W EIGHING THE RISKS PSYCHOTROPICS DISORDER UNTREATED MOOD NO DECISION IS RISK FREE 8

9 FDA CATEGORY LABELING OF DRUGS A: Studies in humans show no risk B: No evidence of risk in humans; if no human data, animal data show no risk C: Risk cannot be ruled out D: Positive evidence of risk X: Contraindicated in pregnancy NOT HELPFUL OVERALL APA/ACOG JOINT RECOMMENDATIONS FOR DEPRESSION Psychotherapy: First line for mild-moderate illness Lifestyle components: nutrition, weight management, prenatal care, childbirth education. Women trying to conceive: Encourage period of euthymia Sustained remission may consider tapering and discontinuing. Recently with symptoms- consider remaining on medications, optimizing Pregnant women with severe illness: medication first line Pregnant women on AD during pregnancy: Take into account patient preference, previous course of illness Medication selection should be based on known safety information Yonkers et al, APA/ACOG guidelines, Obstetric and Gynecology,2009 SSRI EARLY PREGNANCY: CONGENITAL MALFORMATIONS SSRIs as a group : are not considered teratogenic. No consistent evidence of increased malformations Consistent conclusions that the absolute risk of SSRI exposure in pregnancy is small Possible exception, Paroxetine (Paxil): cardiac defects 1.2% vs control 0.8% Reproductive safety data on SSRI exceed what is known about most other medicines used in pregnancy Simon et al. Am J Psych 2002;159:2055 Malm Ob Gyn 2005;106:1289 Einarson et al. Pharmacoepidemiol Drug Saf Kallen et al Birth Defects Res 2007;79:301-8 Louik et al N Engl J Med :2675. Alwan et al. N Engl J Med :356:2684 Einarson et al. Can J Psychiatry 2009;54:242-6 Wichman et al. Mayo Clinic 2009;84:23-7 Andrade et al Pharmacoepidemiol Drug Saf 2008 Wisner et al. Am J Psych

10 SSRI EARLY PREGNANCY: MISCARRIAGE RISK SSRIs increased risk of SAB 12.4% exposed vs 8 % control RR of 1.6 Another study: only implicated Paroxetine (paxil) Rates within normal range: 7-15% No control for illness 1. Broy P, Bérard A. Gestational exposure to antidpressants and the risk of spontaneous abortion: a review. Curr Drug Delivery 2010; 7(1): Einarson A, Choi J, Einarson TR, Koren G. Rates of spontaneous and therapeutic abortions following use of antidepressants in pregnancy: results from a large prospective database. J Obstet Gynaecol Can May;31(5): Gentile S. Pregnancy exposure to serotonin reuptake inhibitors and the risk of spontaneous abortions. CNS Spectr. 2008; 13(11): Hemels ME, Einarson A, Koren G, Lanctot KL, Einarson TR. Antidepressant use during pregnancy and the rates of spontaneous abortions: a meta-analysis. Ann Pharmacother 2005; 39: Santone G, Ricchi G, Rocchetti D, Tofani S, Bellantuono C. Is the exposure to antidepressant drugs in early pregnancy a risk factor for spontaneous abortion? A review of available evidences. Epidemiol Psichiatr Soc. 2009; 18(3): RECOMMENDATIONS IF AD NEEDED IN FIRST TRIMESTER Close monitoring by psychiatrist and OB High level ultrasound Fetal echocardiogram Fluoxetine (Prozac) best characterized in pregnancy Paroxetine (Paxil) best avoided if possible SSRI LATER PREGNANCY CONSIDERATIONS: PPHN Three studies: increased risk of PPHN in SSRI-exposed OR 2-4 Three studies: no association FDA given the conflicting results from different studies, it is premature to reach any conclusion about a possible link between SSRI use in pregnancy and PPHN Association between SSRI exposure and PPHN is weak 50/25,000 exposed found to have PPH The absolute risk is very small (2-3/1000 exp vs 1/1000 un-exp) Andrade SE, Pharmacoepidemiol Drug Saf 2009;18(3 ): Ch am b ers CD New Engl J Med ; (6 ): Källén B, Olausson PO. Pharmacoepidemiology and Drug safety 2008; 17: Reis M, Källén B. Psychol Med 2010; 40: Wichman C, Moore K, Lang T, et al Mayo Clin Proc January; 84(1 ): Wilson KL Am J Perinatol 2011; 28:

11 LATER PREGNANCY CONSIDERANTIONS: NEONATAL ADAPTABILITY SYNDROME Late trimester exposure associated with transient irritability, agitation, jitteriness, tachypnea (10-25%) Data to support lowering AD proximate to delivery are sparse. Tapering does not appear to decrease occurrence when confounders are assessed Overall, studies did not control for maternal mental health. NEJM 1996;335:1010, Costei Arch Pediater Adol Med 2002;256 :1129, Kallen Arch Pediatr Adol Med 2004;158 : 312 Laine Arch Gen Psychiatr 2003;60 : 720, O b e r l a n d e r J C P ; 6 5 : S u r i e t a l Misri et al AJP 2006;163 : 1026 Moses Kolko et al 2005 Jordan et al 2008 W arburton et al, 2010 RECOMMENDATIONS IF TAKING AD IN THIRD TRIMESTER Safest AD is the medication that affords euthymia Advise NOT to taper med in third trimester! Possibly need to increase dose of AD due to volume dilution Monitor newborn for first two days after delivery for NAS LONG TERM SEQUELAE OF AD EXPOSURE Fluoxetine (prozac) (n=135) vs. non-exposed No significant differences up to age 7 : IQ, language, temperament, behavior, mood, distractibility, or activity level Nulman et al. N Engl Med 1997 Nulman et al. Am J Psychiatry

12 LACTATION AND SSRIS SSRIs: one of the best studied classes of medications Amount of drug in breast milk : very low Complications : exceedingly rare Do not change medications from pregnancy to postpartum Paxil (paroxetine), Zoloft (sertraline) lowest secreted concentrations Attempt to avoid if baby is premature/ renal/liver dysfunction Burt 2001, Weissman 2004 MOOD STABILIZERS IN PREGNANCY Lithium Lamotrigine*** Sodium Valproate Carbamazepine* Oxcarbamazepine* Topiramate* Gabapentin Atypical Antipsychotics All common mood stabilizers carry some: Teratogenic risk Potential Perinatal adverse effects LITHIUM: RISKS IN PREGNANCY 1970 s Lithium Baby Registry-risk for specific CV malformation: Ebstein s anomaly Revised risk based on meta-analysis: 1/1000 to 1/2000 (0.05%) Relative risk times the rate in general population Absolute risk vs. relative risk Altshuler et al Am J Psychiatr 1996;153: /Cohen et al JAMA 1994;271: /Briggs et al: Drugs in Pregnancy & Lactation. 5th ed. Williams and Wilkins. 12

13 LITHIUM RISKS IN PREGNANCY Late use: isolated reports of transient hypotonia, poor feeding, hypoglycemia, cyanosis, neonatal goiter, diabetes insipidus No apparent neurobehavioral sequelae Altshuler et al Am J Psychiatr 1996;153: /Cohen et al JAMA 1994;271: /Briggs et al: Drugs in Pregnancy & Lactation. 5th ed. Williams and Wilkins. LITHIUM IN THE BIPOLAR PREGNANT PATIENT Monitor fetal development: Nuchal translucency (12 weeks gestation) Structural ultrasound (week 18-20) Maintain maternal target lithium concentration at clinically effective level ( meq/l) Check levels q month 1 st half, q wk 2 nd half Newport, Viguera, Beach et al 2005 LITHIUM IN THE BIPOLAR PREGNANT PATIENT Monitor maternal serum levels carefully Maintain maternal hydration If possible avoid situations that increase Li levels NSAIDS, diuretics, ACE inhibitors, Ca channel blockers Sodium-restricted diet (eg, to manage preeclampsia, edema) Newport, Viguera, Beach et al

14 LITHIUM IN THE BIPOLAR PREGNANT PATIENT Watch for obstetrical difficulties that may case maternal Li toxicity: acute loss of fluids at delivery, hyperemesis, preeclampsia Watch for fetal kidney abnormalities: Oligohydramnios (Li-associated fetal nephrotoxicity?) Polyhydramnios (Li-associated fetal diabetes insipidus?) Newport, Viguera, Beach et al 2005 LITHIUM IN THE BIPOLAR PREGNANT PATIENT d/c of Li hrs before scheduled C-section or at induction or onset of labor or maintain fluids throughout labor and delivery Restart Li at preconception dose as soon as mother has been stabilized post-delivery Newport, Viguera, Beach et al 2005 LAMOTRIGINE IN PREGNANCY The International Lamotrigine Pregnancy Registry created by GlaxoSmithKline in 1992 data did not show an elevated risk of malformations associated with lamotrigine exposure North-American Anti-Epileptic Drug Registry prevalence of major malformations in a total of 564 children exposed to lamotrigine monotherapy was 2.7% Oral clefts : 10-fold increased incidence of oral clefts (8.9/1000 vs baseline 0.37/1000) 3 If this is true, the absolute risk of having a child with cleft lip or palate is about 0.9% C u n n i n g ton M et a l. Neu rol g y. 2005;64: M ea d or K J et a l. Neu rol ogy. 2006;67: H ol m es LB et a l. A b s t r p resen t ed a t 46 t h A n n M t g Tera tol ogy S oci ety, J u n e 24-29, 2006, Tucson, AZ, 4. Dolk et al Neurol 1008;71:

15 SUMMARY OF VPA FINDINGS ACROSS PREGNANCY REGISTRIES Valproic acid (VPA) is associated with highest risk for all major malformations >10% Spina bifida risk 1-5% (15-30 days postfertilization) Craniofacial defects [incl. oral clefts], heart defects, polydactyly, hypospadias, LBW Cognitive developmental delay Wyszynski DF et al.neurology 2005;64:961-5 Morrow J et al. J Neurolog Neurosurg Psychiatr2006;77:193-8 Cunnington M et al. Epilepsia. 2007;48: Meador KJ et al. Neurology. 2006;67: Holmes LB et al. Arch Neurol 2004;61:673-8 SUMMARY RECOMMENDATIONS Discuss family planning with patients and contraception Avoid psychotropics that are contraindicated in pregnancy in women of reproductive age Use lowest effective dose if needed in pregnancy Avoid polypharmacy The best antidepressant to use is the one that affords euthymia 15