PERINATAL MOOD DISORDERS: Update on Psychotropic Prescribing.

PERINATAL MOOD DISORDERS: Update

on Psychotropic Prescribing

www.mainepsych.orgPostpartum Depression Project

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

DEPRESSION DURING PREGNANCYDEPRESSION DURING PREGNANCY

• Between 10-20% of women will experience significant depression during pregnancy

• This will be a first episode for one third

Course of Depression During Course of Depression During PregnancyPregnancy

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.

Time to Relapse in Patients Who Maintained Time to Relapse in Patients Who Maintained or Discontinued Antidepressantor Discontinued Antidepressant

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

0 12 24 36

Gestational Age

Perc

enta

ge o

f Pati

ents

Rem

aini

ng W

ell

Maintained (N = 82)

Discontinued (N = 65)

6

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.

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

Relapse of Bipolar Disorder During PregnancyRelapse of Bipolar Disorder During Pregnancy

Presented at NCDEU, Viguera et al, June 2006Viguera, et al , Am J Psychiatry, 2008

RISKS OF UNTREATED DEPRESSION DURING RISKS OF UNTREATED DEPRESSION DURING PREGNANCYPREGNANCY

• 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

GUIDELINES FOR TREATMENT OF DEPRESSION GUIDELINES FOR TREATMENT OF DEPRESSION DURING PREGNANCYDURING 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

• 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

• 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

Regardless of circumstances, a woman with suicidal or psychotic symptoms should

immediately see a mental health specialist for treatment.

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).

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

SSRI Use during PregnancySSRI 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; 3 Einarson 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; 6 Hallberg P, Sjoblom V. J Clin Psychopharmacol 2005; 7Wogelius P, et al. Epidemiology 2006; 8 www.gsk.ca/english/docs-pdf/PAXIL_PregnancyDHCPL_E-V4.pdf Dear Healthcare Professional (3/17/08); 9 www.fda.gov/medwatch/safety/2005/Paxil_dearhcp_letter.pdf Dear Healthcare Professional (3/17/08)

17

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

Non-SSRI’s During PregnancyNon-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 200619

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].

“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

““Poor Neonatal Adaptation” and SSRI Use Poor Neonatal Adaptation” and SSRI Use During PregnancyDuring 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 communicationWarburton et al, Acta Psychiatr Scand 2010; 121(6): 471-9.

Risk for PPHN Associated With Late Risk for PPHN Associated With Late Trimester Exposure to SSRITrimester 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

23

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

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

LONGTERM NEUROBEHAVIORAL EFFECTSLONGTERM NEUROBEHAVIORAL EFFECTS

• 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 (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 Pediatr Adolesc Med. 2007;161:22-29. Misri S, et al. Am J Psychiatry. 2006;163

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: 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

27

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

• 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

28

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.

Summary of Findings Across Pregnancy RegistriesSummary 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.

30

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.

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

Lamotrigine (Lamictal) Monotherapy Lamotrigine (Lamictal) Monotherapy Exposure: Increased Risk for Oral CleftsExposure: 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) 2152-8Dolk, H et . ;Neurology 2008, 71 (10) 714-22

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;42:38-44Newham, JJ et Br J Psych; 2008, 192(5) 333-7McKenna et al, J. Clin. Psychiatry 2005;66:444-9

Antipsychotic Use During PregnancyTypical 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;42:38-44Newham, JJ et Br J Psych; 2008, 192(5) 333-7McKenna et al, J. Clin. Psychiatry 2005;66:444-9

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

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

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 effectsBalance the benefits and risks , especially that of relapse of a

psychotic illness

Benzodiazepine Use during PregnancyBenzodiazepine 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

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).

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

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.

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.

Epidemiology of Postpartum Episodes

Kendell RE et al. Br J Psychiatry. 1987;150:662-673.

0

10

20

30

40

50

60

70

Adm

issi

ons/

Mon

th

Pregnancy

–2 Years – 1 Year Childbirth +1 Year +2 Years

Spectrum of Postpartum Mood DisordersSpectrum of Postpartum Mood DisordersPostpartum Psychosis(0.1-Postpartum Psychosis(0.1-0.2%)0.2%)

PostpartumSymptomSeverity

Postpartum Depression(10-15%)Postpartum Depression(10-15%)

NoneNone

Postpartum BluesPostpartum Blues(50-85%)(50-85%)

Risks of Untreated PPDTo 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

Risks of Untreated PPDTo 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

PRESENTATION OF PPDPRESENTATION 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.

POST PARTUM PSYCHOSISPOST 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

POST PARTUM PSYCHOSISPOST 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 %.

TREATMENT OF PPDTREATMENT OF PPDSelection 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.

Postpartum Depression: Pharmacologic Postpartum Depression: Pharmacologic StrategiesStrategies

• Data to support use of serotonergic agents (sertraline, fluoxetine, venlafaxine, fluvoxamine) and TCAs (nortriptyline)

• Other antidepressants can also be effective

• Adequate dosage need to be given

• Adequate duration of treatment (>6 months)

• TREAT ANXIETY: Adjunctive anxiolytic agents (lorazepam, clonazepam) are often needed

Colombo, et al. 1999

Which Antidepressant is the Best ?Which Antidepressant is the Best ?

The one that is most likely to be effective• Continue antidepressant used during pregnancy

• Use agent to which patient has responded to in the past

• All SSRIs are secreted into breast milk, but no serious adverse effects have been reported in association with this. There have been some anecdotal reports of mild adverse effects possibly associated with exposure to the drugs through breast milk

• Caution may be needed with exposure in premature infants with hepatic immaturity

Use of SSRI’s During LactationUse of SSRI’s During Lactation

• Exposure for the infant is lowest for sertraline (Zoloft) and fluvoxamine (Luvox), somewhat higher for paroxetine (Paxil), highest with citalopram (Celexa) and fluoxetine (Prozac)

• SSRI’s are present in the infant’s blood stream at very low levels, not detectable by usual methods. ACOG does not recommend checking infant serum levels.

• With the current knowledge there is no strong evidence to recommend one drug over another or rationale to switch from one SSRI to another to promote safety during breastfeeding

Use of BZN’s/Hypnotics During LactationUse of BZN’s/Hypnotics During Lactation

• Data is somewhat limited• When measured, exposure through breast milk is

extremely low• Some anecdotal reports of sedation, poor feeding,

respiratory distress; pooled data show low incidence of adverse effects

• Diazepam more likely to accumulate in breast feeding baby

• Less likely to accumulate—lorazepam (Ativan) clonazepam (Klonopin)

Birnbaum et al; Pediatrics, 1999, July 104 (1)e11

Treatment of Postpartum Bipolar Disorder

• PROTECT SLEEP! Sleep deprivation – similar to antidepressants regarding risk of induction of mania/hypomania (10%)

• Despite the theoretical risk of Stevens-Johnsons Syndrome with Lamictal, this has not been reported, Lamictal levels are significant in infant serum

• Lithium is not generally recommended• Depakote and tegretol are approved for use during

lactation by the AAP, but should be used with much caution

TREATMENT OF POSTPARTUM PSYCHOSISTREATMENT OF POSTPARTUM PSYCHOSIS

• Psychiatric/obstetrical emergency• Treat as affective psychosis—i.e. as Bipolar

disorder• Requires inpatient hospitalization • Medication treatment is necessary beginning

with an antipsychotic/mood stabilizer such as Zyprexa, a traditional mood stabilizer like lithium or Lamictal, adjunctive bezodiazepines

TREATMENT OF POSTPARTUM PSYCHOSISTREATMENT OF POSTPARTUM PSYCHOSIS

• ECT is very effective and rapid treatment• Then consider adding a mood stabilizer such

as Lamictal or Lithium• As 70-90% of women with a prior history of

post partum psychosis relapse with subsequent pregnancies, prophylactic treatment either before delivery at 36 weeks or no later than 48 hours after delivery is recommended. Lithium has been best studied

Mood Stabilizers and Lactation• Lamictal present in breast milk at variable levels; infant

serum levels 20-50 % of maternal . Only one adverse event reported with daily maternal Lamictal dose of 850 mg.

• Tegretol and Depakote are approved by the AAP for use in lactating infants. Need very close monitoring for drug levels and liver function

• Lithium is excreted into breast milk at high levels– Breastfeeding generally avoided– Possible as monotherapy with close supervision at lowest possible

dose with close clinical monitoring for signs of toxicity and checking Li levels, TSH, BUN, Cr

Newport DJ, Pennell PB, Calamaras MR, et al. Pediatrics. 2008. 122(1):e223-e231Viguera AC, Newport DJ, Ritchie J et al. Am J Psychiatry. 2007: 164(2): 342-345Yonkers KA, Wisner KL, Stowe Z, et al.Am J Psychiatry. 2004: 161(4): 608-620.

Antipsychotics and Lactation

• Medium to high potency typical antipsychotics rarely have adverse effects

• Thorazine associated with sedation and developmental delay

• Clozapine may be concentrated in breast milk– requires infant blood monitoring

• Atypicals: olanzapine, risperidone, and quetiapine-– excretion into breast milk is low– adverse effects appear to be rare.

Effective treatment of maternal postpartum

illness is an early intervention for a child

WEB RESOURCES•www.mainepsych.org MAPP’s website for the PPD Project

•www.womensmentalhealth.org MGH Center for Women’s Mental Health

•www.postpartum.net Postpartum Support International•www.mededppd.org NIMH supported website•Excellent resource, regularly updated•9 educational modules aimed at different provider categories offering CME’s•www.motherisk.org Motherisk Program of Canada , clinical research and teaching program on drug and other exposure during pregnancy and lactation•www.marce

For more information or resources, or to get involved with the PPD project:Please contact me:P. Lynn [email protected]

Subject line: MAPP PPD Project

ReferencesReferences• Altshuler LL, Hendrich V, Cohen LS. Course of mood and anxiety disorders during pregnancy

and the postpartum period. J Clin Psychiatry 1998; 59:29-33.• Appleby L, Warner R, Whitton A, Faragher B. A controlled study of fluoxetine and cognitive-

behavioural counselling in the treatment of postnatal depression. Br Med J 1997; 314:932-939.• Birnbaum et al; Serum concentrations of antidepressants and benzodiazepines in nursing infants: A

case series; Pediatrics, 1999, July 104 (1)e11• Burt VK, Suri R, Altshuler L, Stowe Z, Hendrick VC, Muntean E. The use of psychotropic

medications during breast-feeding. Am J Psychiatry. 2001; 158(7):1001-9.• Chambers CD, Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Jones KL, Mitchell AA.

Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med. 2006; 354(6):579-87.

• Cohen LS, Altshuler LL, Harlow BL, Nonacs R, Newport DJ, Viguera AC, Suri R, Burt VK, Hendrick V, Remnick AM, Loughead A, Vitonis AF, Stowe ZN. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006; 295(5):499-507.

• Cohen LS, Sichel DA, Robertson LM, Heckscher E, Rosenbaum JF. Postpartum prophylaxis for women with bipolar disorder. Am J Psychiatry 1995;152, 1641-1645.

• Cunnington M, et al. Neurology. Lamotrigine and the risk of malformations in pregnancy Neurology March 22, 2005 64:955-960.

• Dennis CL. Psychosocial and psychological interventions for prevention of postnatal depression: systematic review. BMJ 2005; 331(7507):15.

• Dolk, h et . Does lamotrigine use in pregnancy increase orofacial cleft risk relative to other malformations?;Neurology 2008, 71 (10) 714-22

• Hemels ME, Einarson A, Koren G, Lanctôt KL, Einarson TR. Antidepressant use during pregnancy and the rates of spontaneous abortions: A meta-analysis. Ann Pharmacother. 2005;39:803–809.

• Einarson A, Pistelli A, DeSantis M, Malm H, Paulus WD, Panchaud A, et al. Evaluation of the risk of congenital cardiovascular defects associated with use of paroxetine during pregnancy. Am J Psychiatry. 2008;165:749–752.

• Evans J, Heron J, Francomb H, Oke S, Golding J. Cohort study of depressed mood during pregnancy and after childbirth. BMJ 2001; 323:257-60.

References (cont.)References (cont.)• Frank E, Kupfer DJ, Thase ME, Mallinger AG, Swartz HA, Fagiolini AM, Grochocinski V,

Houck P, Scott J, Thompson W, Monk T. Two-year outcomes for interpersonal and social rhythm therapy in individuals with bipolar I disorder. Arch Gen Psychiatry. 2005;62(9):996-1004.

• Freeman MP, Smith KW, Freeman SA et al. The impact of reproductive events on the course of bipolar disorder in women. J Clin Psychiatry; 2002 63(4), 284-287.

• Gavin NL, Gaynes BN, Lohr KN, Meltzer-Brody S, Gartlehner G, Swinson T. Perinatal Depression: A Systematic Review of Prevalence and Incidence. Obstet Gynecol. 2005; 106(5):1071-1083.

• Gavin AR, Chae DH, Mustillo S, Kiefe CI. Prepregnancy depressive mood and preterm birth in black and white women: Findings from the CARDIA study. J Womens Health (Larchmt). 2009;18:803–811.

• Holmes LB, et al. Increased frequency of isolated cleft palate in infants exposed to lamotrigine during pregnancy.; Neurology 2008 70 (22 part2) 2152-8

• Jentink, J. Valproic acid monotherapy in pregnancy and major congenital malformationNew England Journal of Medicine, 2010; vol 362: pp 2185-2193.

• Kimford, JM et al, Cognitive function at 3 years of age after fetal exposure to antepileptic drugs, NEJM; 2009 , 360 (16) 1597-1605

• Lund N, Pedersen LH, Henriksen TB. Selective serotonin reuptake inhibitor exposure in utero and pregnancy outcomes. Arch Pediatr Adolesc Med. 2009;163:949–954.

• Marcus SM, Flynn HA, Blow FC, Barry KL. Depressive symptoms among pregnant women screened in obstetrics settings. J Womens Health. 2003; 12(4):373-80.

• McKenna et al. Pregnancy outcome of women using atypical antipsychotics: A prospective comparison(J. Clin. Psychiatry 2005;66:444-9

• Miller LJ. Use of electroconvulsive therapy during pregnancy. Hosp Community Psychiatry. 1994; 45(5):444-50.

• Misri S, Reebye P, Corral M, Milis L. The use of paroxetine and cognitive-behavioral therapy in postpartum depression and anxiety: a randomized controlled trial. J Clin Psychiatry. 2004; 65(9):1236-41.

References References (Cont.)(Cont.)

• Moses-Kolko EL, Bogen D, Perel J, Bregar A, Uhl K, Levin B, Wisner KL. Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: literature review and implications for clinical applications. JAMA. 2005; 293(19):2372-83.

• Munk-Olsen T, Laursen TM, Mendelson T, Pedersen CB, Mors O, Mortensen PB. Risks and predictors of readmission for a mental disorder during the postpartum period.Arch Gen Psychiatry. 2009;66(2):189-95.

• Murray L, Fiori-Cowley A, Hooper R, Cooper P. The impact of postnatal depression and associated adversity on early mother-infant interactions and later infant outcome. Child Dev 1996; 67:2512-252.

• Newport DJ, Hostetter A, Arnold A, Stowe ZN. The treatment of postpartum depression: minimizing infant exposures.J Clin Psychiatry. 2002;63 Suppl 7:31-44.

• Newport DJ, Pennell PB, Calamaras MR, et al. Lamotrigine in breast milk and nursing infants: Determination of exposure . Pediatrics. 2008. 122(1):e223-e231

• Newport DJ, Wilcox MM, Stowe ZN. Maternal depression: a child's first adverse life event. Semin Clin Neuropsychiatry. 2002; 7(2):113-9.

• Newham, JJ et al;Birth weights of infants after maternal exposure to typical and atypical antipsychotics: prospective comparison study Br J Psych; 2008, 192(5) 333-7

• O'Hara MW, Neunaber DJ, & Zekoski EM. Prospective study of postpartum depression: prevalence, course, and predictive factors. J Abnormal Psychol. 1984;93:158-171.

• O’Hara MW, Schlechte JA, Lewis DA, Varner MW. Controlled prospective study of postpartum mood disorders: psychological, environmental, and hormonal variables.J Abnorm Psychol. 1991; 100(1):63-73.

References References (Cont.)(Cont.)• O’Hara MW, Stuart S, Gorman LL, Wenzel A. Efficacy of interpersonal psychotherapy for

postpartum depression. Arch Gen Psychiatry 2000; 57:1039-1045.• Oberlander TF, Warburton W, Misri S, Aghajanian J, Hertzman C. Neonatal outcomes after

prenatal exposure to selective serotonin reuptake inhibitor antidepressants and maternal depression using population-based linked health data. Arch Gen Psychiatry. 2006; 63(8):898-906.

• Perinatal Depression: Prevalence, Screening Accuracy, and Screening Outcomes, 2005. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/tp/perideptp.htm

• Rahimi R, Nikfar S, Abdollah M. Pregnancy outcomes following exposure to serotonin reuptake inhibitors: A meta-analysis of clinical trials. Reprod Toxicol. 2006;22:571–575.

• Robertson E, Grace S, Wallington T, Stewart DE. Antenatal risk factors for postpartum depression: a synthesis of recent literature. Gen Hosp Psychiatry. 2004; 26(4):289-95.

• Sichel DA, Cohen LS, Robertson LM, Ruttenberg A, Rosenbaum JF. Prophylactic estrogen in recurrent postpartum affective disorder.Biol Psychiatry. 1995; 38(12):814-8.

• Sit D, Rothschild A, Wisner KL. A review of postpartum psychosis. Journal of Women’s Health 2006:15:352-68.

• Spinelli MG, Endicott J. Controlled clinical trial of interpersonal psychotherapy versus parenting education program for depressed pregnant women. Am J Psychiatry 2003;160(3):555-62.

• Steiner M. Postnatal depression: a few simple questions. Fam Pract. 2002; 19(5):469-70.

References References (Cont.)(Cont.)• Stowe ZN, Hostetter AL, Newport DJ. The onset of postpartum depression: Implications

for clinical screening in obstetrical and primary care. Am J Obstet Gynecol. 2005; 192(2):522-6.

• Stuart S, O'Hara MW, Gorman LL. The prevention and psychotherapeutic treatment of postpartum depression. Arch Women Ment Health 2003; 6 Suppl 2:S57-69.

• Wadhwa PD, Sandman CA, Porto M, Dunkel-Schetter C, Garite TJ. The association between prenatal stress and infant birth weight and gestational age at birth: a prospective investigation. Am J Obstet Gynecol 1993; 169:858-865.

• Wisner KL, Perel JM, Peindl KS, Hanusa BH, Piontek CM, Findling RL. Prevention of postpartum depression: a pilot randomized clinical trial. Am J Psychiatry. 2004; 161(7):1290-2.

• Wisner KL, Perel JM, Peindl KS, Hansusa BH, Findling RL, Rapport D. Prevention of recurrent postpartum depression: a randomized clinical trial. J Clin Psychiatry. 2001; 62(2):82-6.

• Wisner KL, Zarin DA, Holmboe ES, Appelbaum PS, Gelenberg AJ, Leonard HL, Frank E. Risk-benefit decision making for treatment of depression during pregnancy. Am J Psychiatry 2000; 157:1933-1940.

• Wisner KL, Sit DKY, Hanusa BH, Moses-Kolko EL, Bogen DL, Hunker DF, et al. Major depression and antidepressant treatment: Impact on pregnancy and neonatal outcomes. Am J Psychiatry. 2009;166:557–566.

References References (Cont.)(Cont.)

• www.fda.gov/medwatch/safety/2005/Paxil_dearhcp_letter.pdf, September, 2005.

• Viguera AC, Nonacs R, Cohen LS, Tondo L, Murray A, Baldessarini RJ. Risk of recurrence of bipolar disorder in pregnant and nonpregnant women after discontinuing lithium maintenance. Am J Psychiatry. 2000;157(2):179-84.

• Viguera AC, Newport DJ, Ritchie J et al. Lithium in Breastmilk and Nursing Infants: Clinical Implications. Am J Psychiatry. 2007: 164(2): 342-345

• Wang et al, Increased Risk of Adverse Pregnancy Outcomes in Women Receiving Zolpidem During Pregnancy, 2010Clinical Pharmacology and Therapeutics, Vol 88, No 3, 369-374

• Warburton et al, A Register Studyof the Impact of Stopping Third Trimester Selective Serotonin Reuptake Inhibitor on Neonatal Health, Acta Psychiatr Scand 2010; 121(6): 471-9.

• Yonkers KA, Wisner KL, Stowe Z, et al. Management of Bipolar Disorder During Pregnancy and the Postpartum Period, Am J Psychiatry. 2004: 161(4): 608-620.

• Zlotnick C, Johnson SL, Miller IW, Pearlstein T, Howard M. Postpartum depression in women receiving public assistance: pilot study of an interpersonal-therapy-oriented group intervention. Am J Psychiatry. 2001; 158(4):638.

• Zlotnick C, Miller IW, Pearlstein T, Howard M, Sweeney P. A preventive intervention for pregnant women on public assistance at risk for postpartum depression.

• Am J Psychiatry. 2006;163(8):1443-5.