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10/1/2021 1 PSYCHIATRIC MEDICATION IN PREGNANT AND BREASTFEEDING WOMEN Madison Holbrook, Pharm.D. PGY-2 Psychiatric Pharmacy Resident Laureate Psychiatric Clinic and Hospital Oklahoma Society of Health System Pharmacists Meeting October 22, 2021 FINANCIAL DISCLOSURE AND RESOLUTION Under guidelines established under the Standards for Integrity and Independence in Accredited Continuing Education, disclosure must be made regarding relevant financial relationships with ineligible companies within the last 24 months. I have no relevant financial relationships with ineligible companies to disclose.

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Page 1: PSYCHIATRIC MEDICATION IN PREGNANT AND …

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PSYCHIATRIC MEDICATION IN PREGNANT AND BREASTFEEDING WOMEN

Madison Holbrook, Pharm.D.

PGY-2 Psychiatric Pharmacy Resident

Laureate Psychiatric Clinic and Hospital

Oklahoma Society of Health System Pharmacists Meeting

October 22, 2021

FINANCIAL DISCLOSURE AND RESOLUTION

Under guidelines established under the Standards for Integrity and Independence in Accredited Continuing Education, disclosure must be made regarding relevant financial relationships with ineligible companies within the last 24 months.

I have no relevant financial relationships with ineligible companies to disclose.

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PROFESSIONAL PRACTICE GAP

• There is a lack of significant evidence in the setting of psychiatric medication use in pregnant and breastfeeding women as it is unethical. It is imperative to apply the data we do have to make clinical decisions in favor of both the mother and the fetus or infant at risk.

• It is important to have evidential and reliable resources on hand.

• As pharmacist, it is our responsibility to share and communicate our knowledge and educate patients and colleagues about the risk vs benefit in psychiatric medications use in pregnant or breast feeding women.

LEARNING OBJECTIVES

At the completion of this activity, pharmacists will be able to:

• Identify psychiatric medications appropriate for utilization in pregnant patients

• Identify psychiatric medications appropriate for utilization in breastfeeding patients

• Recognize potential psychiatric medication adverse effects or fetal harm

At the completion of this activity, pharmacy technicians will be able to:

• Identify psychiatric medications appropriate for utilization in pregnant patients

• Identify psychiatric medications appropriate for utilization in breastfeeding patients

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PRE-ASSESSMENT QUESTION 1

JN is a pregnant patient on ziprasidone and escitalopram who has struggled with conception for years. Due to this difficulty, she is worried about the impact of medications on her baby. In research studies, which impact on infants has been found to be most associated with in utero antidepressant exposure?

• Spontaneous abortion with 3rd trimester antidepressant use• Reduced gestational time with 2nd trimester antidepressant use • Persistent pulmonary hypertension with any antidepressant use • Postnatal adaption syndrome with 1st trimester antidepressant use

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PRE-ASSESSMENT QUESTION 2

After discussing the risks of untreated depression with JN, you begin to consider the role of pharmacotherapy in JN’s perinatal depression. Considering what is known about JN, and any known risk factors, which statement describes the most likely impact of antidepressant therapy in JN?

• Conversion to manic episode• Risk of psychosis or infanticide • Possible postpartum hemorrhage • Development of gestational hypertension

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PRE-ASSESSMENT QUESTION 3

Based on the adverse effects of ziprasidone, what side effect could have added to JN’s struggle in conceiving? Which of the following would be most important to monitor for a patient taking this medication?

• Weight loss • Hyperprolactemia• Akathisia• QTc prolongation

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ABBREVIATIONS

ABBREVIATION WORD

PTSD Post-traumatic stress disorder

PO Oral

TID Three times daily

BID Twice daily

PRN As needed

SSRI Selective serotonin reuptake inhibitor

SNRI Serotonin norepinephrine reuptake inhibitor

TCA Tricyclic antidepressant

MAOI Monoamine oxidase inhibitor

EPS Extrapyramidal symptoms

OR Odds ratio

AE Adverse effect

EKG Electrocardiogram

FGA First generation antipsychotic

SGA Second generation antipsychotic

SCr Serum creatinine

BUN Blood urea nitrogen

MOA Mechanism of action

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THE DEBATE

Exposure to psychiatric medication

Consequences of mother’s poor mental health

• Spontaneous abortion • Birth defects• Abnormal brain development • Behavioral abnormalities • Withdrawal • Unknown

• Low birth weight• Preterm Labor• Preeclampsia • Maternal Suicide • Compliance to fetus/infant care • Use of substances

Risk to infant or fetus from

Controversial evidence for psychiatric medications inducing birth defects

Committee Opinion Number 757. American College of Obstetrician and Gynecologists. Obstet Gynecol. 2018;132:e208-12. Massachusetts General Hospital. Center for Women’s Mental Health.

BACKGROUND

• Facts • 500,000 pregnancies per year involve women with psychiatric illness • Pregnant women who discontinue antidepressants are 5 times more

likely to relapse • Suicide is the leading cause of maternal death • Risk of postpartum psychosis 3-fold higher with perinatal discontinuation

of mood stabilizers • 4.5% rate of infanticide with postpartum depression psychosis

• Pharmacist • 60% of pregnant women take >1 medications • 70% of women who breastfeed and/or pump their milk take medication• 90% of clinically approved medications do not have appropriate drug

labeling information for pregnant and lactating women

Am Fam Physician. 2008 Sep 15;78(6):772-778.MGH Center for Women’s Mental Health.

Cohen L, et al. JAMA. 2006;295(5):499-507.

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PATIENT CASE

• Kara is a 29 year old female with a PMH including bipolar disorder, anxiety, PTSD, alcohol use disorder, and type II diabetes.

• Her medications include: • Lithium 300 mg PO TID • Sertraline 50 mg PO daily• Quetiapine 400 mg PO HS • Hydroxyzine 10 mg PO TID prn • Trazodone 50 mg PO HS • Metformin 500 mg PO BID

• Kara has been sober for 2 years and is now 6 weeks pregnant. She presents today asking about her medications in relation to her pregnancy.

ADVERSE EFFECTS

PREGNANCY

BREASTFEEDING

POSTPARTUM THERAPY

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ADVERSE EFFECTS

Structural Teratogeneis

Behavioral Teratogensis

Perinatal Syndrome

Postnatal Syndrome

STRUCTURAL TERATOGENESIS

• Physical malformations

• Risk is highest week 2-8 post fertilization

• Occurs in 6% of all pregnancies with 3% induced by drug or environment

• Examples: • Oral cleft • Spinal bifida• Atrial septal defect

Ward R, et al. Am Fam Physician. 2002 .66(4):629-637.

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BEHAVIORAL TERATOGENESIS

• Occurrence of behavior or neuropsychiatric symptoms in offspring after in utero exposure to a drug or toxin

• Inherited mental illness vs. drug effects

• Highest risk during the third trimester

• Examples: • Autism • Attention Deficit Hyperactivity Disorder• Feeding issues

Grote N, et al. Arch Gen Psychiatry. 2010;67(10):1012-1024. Ward R, et al. Am Fam Physician. 2002 .66(4):629-637.

PERINATAL SYNDROME

• Drug intoxication or withdrawal

• Examples: • Agitation • Tachycardia • Hypo tonicity • Tremor or restlessness • Respiratory distress or cyanosis • Poor temperature control • Seizures

American College of Obstetricians and Gynecologists: Yonkers K, et al. Obstet Gynecol. 2009;114(3)703-713.Ward R, et al. Am Fam Physician. 2002 .66(4):629-637.

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POSTNATAL SYNDROME

• Hormonal changes peak in the third trimester of pregnancy

• After labor and birth of baby, hormones drop dramatically

Ward R, et al. Am Fam Physician. 2002 .66(4):629-637.

ADVERSE EFFECTS

PREGNANCY

BREASTFEEDING

POSTPARTUM THERAPY

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PREGNANCY

FIRST TRIMESTER

• Major organ development

SECOND TRIMESTER

• Baby bump • Movement

THIRD TRIMESTER

• Hormonal peak

PREGNANCY

American College of Obstetricians and Gynecologists. Obstet Gynecol. 2018;132:e208-212.

PREGNANCY

• Psychiatric medications are recommended in patients with moderate depression or those with recurrent history of severe depression or psychiatric disorder

• Medication Selection• History • Contraindications • Lowest effective dose • Fewer metabolites • Higher protein binding • Fewer drug interactions

• Alternatives: • Psychotherapy

American College of Obstetricians and Gynecologists. Obstet Gynecol. 2018;132:e208-212.

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PHARMACOKINETIC DIFFERENCES IN PREGNANCY

• Pregnancy: • Increased volume of distribution for lipophilic medications (antipsychotics) • Increased hepatic blood flow • Increased renal blood flow and glomerular filtration rate

• CYP enzyme changes • Inhibited during pregnancy

– CYP1A2– CYP2B6– CYP2C19– CYP3A4

• Induced during pregnancy – CYP2A6– CYP1A4– CYP2B7

Deligiannidis K, et al. J Clin Psychopharmacol. 2014;34(2):244-255.

PREGNANCY + DEPRESSION

Medication Adverse Effects Considerations

SSRI Perinatal Syndrome Pulmonary Hypertension (0.3%)Autism Congenital heart defects

Most well-studied class in pregnancy Paroxetine: septal and atrial heart defects Sertraline preferred ACCEPTABLE

SNRI Perinatal Syndrome Venlafaxine increases BPACCEPTABLE

Bupropion Congenital heart defects Non-conclusive data RISK VS BENEFIT

Trazodone Congenital malformations Low risk Little evidenceRISK VS BENEFIT

Mirtazapine Congenital malformations Low risk Little evidenceRISK VS BENEFIT

Tricyclic Preterm birthNeonatal withdrawal

No clear association during pregnancyRISK VS BENEFIT

Monoamine Inhibitors

Structural teratogenisis Evidence of major malformationRequires dietary restrictions Multiple drug interactions NOT RECOMMENDED

Bar-Oz B, et al. Clin Ther. 2007;29:918-926. Wisner KL, et al. Pharmacological treatment of depression during pregnancy. JAMA. 1999;282:1264-9.

CDC Treating for Two: Safer Medication Use in Pregnancy.

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ANTIDEPRESSANTS

• Miscarriage • Miscarriage events occur at 10 weeks • Discontinuation of SSRI use 3 months prior to conception is associated

with 24% increase in miscarriage

• Spontaneous abortion • Risk is 7-11% with general population • Risk is 11-15% in patients on SSRIs, SNRIs, or TCAs• Higher with paroxetine and venlafaxine

• Conflicting data around congenital malformations • Recall and surveillance biases • Increased provider vigilance during examinations

• Most SSRIs have mixed results • Both positive and negative association studies • Highly confounded

Yonkers K, et al. Annu Rev Clin Psychol. 2014;10:369-392.Byatt N, et al. Acta Psychiatr Scand. 2013:127:94-114.

Anderson J, et al. Obstet Gynecol.2014;124:655-661.

ANTIDEPRESSANTS AND CARDIAC DEFECTS

• Study with 949,504 pregnant women found NO increase risk for any cardiac malformation when exposed to multiple types of antidepressants

• No significant associations between paroxetine and Right Ventricular Outflow Tract Obstruction (1.07, 95% CI 0.59 -1.93), or between sertraline and Ventral Septal Defects (1.04, 95% CI 0.76-1.41)

Adjusted Risk Ratio Cardiac Malformations

95% CI

SSRIs 1.06 0.93-1.22

TCAs 0.77 0.52-1.14

SNRIs 1.20 0.91-1.57

Other antidepressants 1.22 0.91-1.60

Bupropion 0.92 0.69-1.22

Huybrechts K, et al. N Engl J Med. 2014;370(25):2397-2407.

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ANTIDEPRESSANTS AND PRETERM BIRTH

• Antidepressant use typically shortens pregnancy 3-7 days

• 1% preterm deliveries are attributable to consistent use during 2nd trimester

• Risk factors: • Higher dose• Longer treatment periods • Choice of antidepressant • 2nd trimester use

Antidepressant Class Odds Ratio of Preterm Birth

TCA 2.36

SNRI 1.98

SSRI 1.46

Yonkers K, et al. Annu Rev Clin Psychol. 2014;10:369-392.Hayes R, et al. Am I Obstet Gynecol. 2012;207(1):49;e1-9.

ANTIDEPRESSANT DELAYED USE

• Postnatal adaption syndrome • Occurs in up to 30% of those with late pregnancy use of SSRIs • Common in third trimester • More evidence with paroxetine, fluoxetine, and venlafaxine

• Persistent pulmonary hypertension • Mixed data but longer or later exposure may increase risk and severity • Use SSRI after 20th week vs use SSRI before 20 weeks (OR 6.1)

• Neurodevelopment • SSRIs have no impact on global IQ, language, behavioral development• Maternal mental illness in utero is most important factor in development

of Autism Spectrum Disorder (OR 1.49 for depression)

Yonkers K, et al. Annu Rev Clin Psychol. 2014;10:369-392.Byatt N, et al. Acta Psychiatr Scand. 2013:127:94-114.

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PREGNANCY + ANXIETY

Medication Adverse Effects Considerations

Benzodiazepines Perinatal Syndrome Floppy infant syndrome Cleft lip Seizures Impaired temperature regulationHypotonicityFeeding difficulties Apnea

2.5-3.0 times more likely:• Require caesarian delivery • Ventilator support for baby

Diazepam: oral cleftAlprazolam, chlordiazepoxide: withdrawal NOT RECOMMENDED

Hydroxyzine Withdrawal Contraindicated NOT RECOMMENDED

Marijuana Low birth weight Same smoke consequences as tobacco on fetusNOT RECOMMENDED

Relcher C, et al. Obstet Med. 2015;8(4):168-171.Briggs GG, et al. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. 5th ed. Baltimore: Williams Wilkins, 1998.

Center for Disease Control and Prevention. Marijuana use in pregnancy.2021.

PREGNANCY + BIPOLAR DISORDER

Medication Adverse Effects Considerations

Lithium 1st Trimester: • Ebstein’s anomaly 3rd Trimester: • Perinatal syndrome• Hypoglycemia• Cardiac arrhythmias• Thyroid disorders• Floppy infant syndrome • Premature delivery • Neonatal lithium toxicity

Teratogenic Suspend 24-48 hours prior to delivery Therapeutic drug monitoring needed RISK VS BENEFIT

Valproic Acid 1st Trimester: • Fetal malformation (4%)Autism Decreased IQ

Teratogenic Contraindicated Clotting factor abnormalities in mother Last line medication in pregnancy NOT RECOMMENDED

Carbamazepine Malformations Malformation dose dependent Therapeutic drug monitoring needed NOT RECOMMENDED for bipolar

Lamotrigine Malformations not observed Therapeutic drug monitoring needed RISK VS BENEFIT

Grover s, et al. Indian J Psychiatry. 2015. 57(2):S308-S323.

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LITHIUM

• Lithium clearance changes during pregnancy and postpartum

• Dose Changes: • 2nd trimester: increased 30-50% and administered twice daily • Postpartum: Reduced in the days to weeks following delivery

• Recommendations • Monthly or twice monthly level recommended in pregnancy until week 34 • From week 34, weekly level monitoring recommended until delivery • Twice weekly level monitoring recommended for first 2 weeks postpartum • Levels desired at 0.5-1.2 mmol/L

Westin A, et al. BMJ Open.2017;7(3):e015738.Viguera A, et al. Am J Psychiatry. 2007;164(2):342-345.

PREGNANCY + SCHIZOPHRENIA

Medication Adverse Effect Recommendations

First Generation Antipsychotics:

Haloperidol Limb malformation Increase risk in 1st trimesterMonitoring every 3 months

ACCEPTABLE

Fluphenazine EPS Withdrawal

Increase risk during 3rd trimesterRISK VS BENEFIT

Chlorpromazine Jaundice Withdrawal

Increased risk in 3rd trimester ACCEPTABLE

Second Generation Antipsychotics: NOT RECOMMENDED Adverse Effects: - Increased risk during third trimester of withdrawal and EPS - Increased respiratory depression

Olanzapine Miscarriage Birth defects

Gestational diabetes NOT RECOMMENDED

Quetiapine Withdrawal Most commonACCEPTABLE

Risperidone Agenesis of corpus callosm More risk than others NOT RECOMMENDED

Kulkarni J, et al. Antipsychotic use in pregnancy. Expert Opin Pharmacother. 2015 Jun;16(9):1335-45.

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PATIENT CASE

• Kara is a 29 year old female with a PMH including bipolar disorder, anxiety, PTSD, alcohol use disorder, and type II diabetes.

• Her medications include: • Lithium 300 mg PO TID • Sertraline 50 mg PO daily• Quetiapine 400 mg PO HS • Hydroxyzine 10 mg PO TID prn • Trazodone 50 mg PO HS • Metformin 500 mg PO BID

Response:

• Discuss with Kara

• Risk vs Benefit • Lithium • Hydroxyzine • Trazodone • Metformin

• Continue• Sertraline • Quetiapine

Labs

Lithium level 0.9 mmol/L

Poels E, et al. Lithium during pregnancy and after delivery: a review. Int J Bipolar Disord 6, 26 (2018).

BACKGROUND

ADVERSE EFFECTS

PREGNANCY

BREASTFEEDING

ALTERNATIVE THERAPY

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PATIENT CASE

• Kara returns for advice, as she is now breastfeeding. She also complains that she has been feeling more depressed than usual. She has not restarted hydroxyzine or trazodone.

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• Her medications include: • Lithium 300 mg BID • Sertraline 50 mg PO daily • Quetiapine 400 mg PO HS • Metformin 500 mg PO BID

Kara would like to know which medications will her baby be

exposed to and if her medications are still working.

BREASTFEEDING

• Psychiatric medications are indicated only when mental disorder left untreated outweighs risk of infant exposure in breast milk

• Relative infant dose (%) = dose received via breast milk (mg/kg/day) relative to mother’s dose (mg/kg/day), with >10% considered unsafe

• Considerations: • Timing of breastfeeding • Risk vs benefit of exposure• Percentage of exposure • Pumping

• Alternatives: • Formula • Psychotherapy • Change in dose and/or frequency

American College of Obstetricians and Gynecologists. Obstet Gynecol. 2018;132:e208-212.

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PHARMACOKINETIC DIFFERENCES POSTPARTUM

• Postpartum: • Rapid decline in sex steroid levels and renal filtration

– Allopregnalone specifically • Risk of adverse effects or toxicity due to dose adjustments

Orsolini L, et al. Hum Psychopharmacol.2015:30(1)4-20.Deligiannidis K, et al. J Clin Psychopharmacol. 2014;34(2):244-255.

Factors Impacting Excretion into Breast Milk

Medication Factors Maternal Factors

Degree of ionization pH gradient of maternal breast milk

Molecular weight CYP2D6 polymorphisms

Time to peak plasma + milk concentrations vs breastfeeding time

Concomitant medications

Blood protein binding Composition of fore and hind milk

Metabolites Cigarette smoking

BREASTFEEDING + DEPRESSION

Medication Class Excreted Considerations

SSRI Excreted Overall infant exposure low or negligibleParoxetine and sertraline: preferred at lowest dose Fluoxetine and citalopram: higher infant serum concentrations ACCEPTABLE

SNRI Excreted Overall infant exposure low or negligibleVenlafaxine: higher infant serum concentrations ACCEPTABLE

Bupropion Excreted Little evidence RISK VS BENEFIT

Trazodone Excreted Little evidence RISK VS BENEFIT

Mirtazapine Excreted Little evidence RISK VS BENEFIT

TCA Excreted Infant exposure low Imipramine or nortriptyline: First lineDoxepin: Avoid due to high infant concentration and sedationRISK VS BENEFIT

MAO inhibitors Uncertain Based on molecular size, most likely excreted RISK VS BENEFIT

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BREASTFEEDING + ANXIETY

Medication Excreted Considerations

Benzodiazepines Excreted Infant serum level low ACCEPTABLE Closely monitor baby if utilized • Sleepiness • Low energy • Weight loss • Poor suckling

Hydroxyzine Unknown May decrease prolactin production NOT RECOMMENDED Closely monitor baby if utilized• Drowsiness • Irritability

Cannabis Excreted THC stored in fat and slowly released over timeBaby still exposed even after marijuana cessation Conflicting evidence NOT RECOMMENDED

Colorado Department of Public Health and Environment. Monitoring Health Concerns Related to Marijuana in Colorado: 2014. (2015).

SAFETY SCORE

• Breastfed infant antidepressant safety index • (# infant AE) / (# healthy outcomes + # AEs) x 100 • < 2 = relatively safe during breastfeeding • 2.1-10 = use with great caution • >10 = contraindicated

• Psychotropic Medications:

Uguz F. J Clin Psychopharmcol. 2016;36(3):244-252.

BI-ASI

Sertraline = 0.68

Paroxetine = 0.95

Fluoxetine = 3.5

Citalopram = 5.3

Higher = safer Very low(<3)

Low(3.1-5)

Moderate(5.1-7)

Good (7.1-8.5)

Very good(8.6-10)

Aripiprazole Clozapine Doxepin Zolpidem

Haloperidol Risperidone Paliperidone Ziprasidone Bupropion Duloxetine Trazodone Lithium Diazepam Clonazepam oxazepam

Quetiapine Fluoxetine Escitalopram Venlafaxine Mirtazapine Amitriptyline Nortriptyline Valproic acid Lamotrigine Lorazepam Alprazolam

Olanzapine Citalopram Midazolam

Sertraline Paroxetine

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BREASTFEEDING + BIPOLAR DISORDER

Medication Excreted Adverse Effects Considerations

Lithium Excreted Hypotonia Hypothermia CyanosisEKG changes Lethargy

Infant serum level (10-50%) RISK VS BENEFIT

Depakote Excreted Hepatotoxicity Thrombocytopenia Anemia Jaundice

Infant serum levels do not correlate with motherNOT RECOMMENDED

Carbamazepine Excreted Respiratory depression Seizures Nausea/vomiting/diarrhea Decreased feeding Perinatal syndrome

Infant serum level (20-50%) Active metabolite Per guidelines, ACCEPTABLE for bipolar

Lamotrigine Excreted Apnea Drowsiness Poor sucking Thrombocytopenia Rash

Infant serum level (9%) ACCEPTABLE when infant serum level <10%

BREASTFEEDING + SCHIZOPHRENIA

Medication Excreted Adverse Effect Considerations

First Generation Antipsychotics

Haloperidol Excreted Galactorrhea Gynecomastia

RISK VS BENEFITUnless FGA is needed

Fluophenazine Excreted Increase prolactin Galactorrhea

Gynecomastia

NOT RECOMMENDED

Chlorpromazine Excreted Drowsiness Lethargy

NOT RECOMMENDED

Second Generation Antipsychotics - Lurasidone , asenapine, ziprasidone, risperidone (1.5-5% infant serum) - Monitor weekly for 1st month - Consider breastfeeding when concentration is lowest

Aripiprazole Excreted Lactation failure Appetite change

Insomnia

Infant serum level (8.3%) ACCEPTABLE

Clozapine Excreted AgranulocytosisSeizures

NOT RECOMMENDED

Olanzapine Excreted Metabolic side effects CYP1A2 metabolismInfant serum level (0.3-4%)

ACCEPTABLE

Quetiapine Excreted QTc prolongation Infant serum level (0.43%) ACCEPTABLE

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UPDATED EVIDENCE

• Lithium: • No longer absolute contraindication • No serious adverse effects observed:

– One infant dehydrated found with toxicity (level = 1.4 mEq/L) – One infant (10%) developed elevated TSH – Three infants (30%) developed elevations in SCr and BUN

• Antipsychotics• Limited data available • 37 reports in n = 206 infants exposed to SGAs

– Most exposure was olanzapine – Only 30 relative infant doses (RID) or milk/plasma ratios were

reported – Results:

• Low RID values for olanzapine, quetiapine, and ziprasidone • Moderate RID values for risperidone, paliperidone, and aripiprazole • All RID estimated < 5%

Poels EMP,et al. Int J Bipolar Disord. 2018;6-26. Uguz F. J Clin Psychopharmcol. 2016;36(3):244-252.

PATIENT EDUCATION

• Limit breast milk exposure with• Lowest effective dose • Use as few drugs as possible • Divided daily doses to avoid high peak serum levels

• Observe for signs and symptoms of toxicity • Behavioral changes • Poor hydration • Sedation • Hypotonia • Poor feeding and slow weight gain • Signs of hepatic impairment • Signs of hematological impairment

Bergink V, et al. Am K Psychiatry.2016;173(12):1179-1188.

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BACKGROUND

ADVERSE EFFECTS

PREGNANCY

BREASTFEEDING

POSTPARUM TREATMENT

POSTPARTUM DEPRESSION

• 70-80% of women experience “baby blues”

• Postpartum depression is experienced by 20% of new mothers

• 50% of women begin postpartum depression during pregnancy

• Facts • 10% postpartum cases result in suicide or infanticide • Treatment is 80% effective

• Risks• History of depression or anxiety • Family history of mental illness • Lower socioeconomic status• Diagnosis of Bipolar Disorder• Teen pregnancy • Difficulty becoming pregnant • Preterm baby or hospitalized baby • Twins or triplets

Kanes S, et al. Lancet. 2017;390:480-489.

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POSTPARTUM DEPRESSION TREATMENT

Lifestyle

Therapy

Medication

Lifestyle

Therapy

Medications

POSTPARTUM DEPRESSION MEDICATIONS

• Off-label Medication Options: • Sertraline • Fluoxetine

• FDA Approved Medications: • Brexanolone (Zulresso)

– MOA: Positive allosteric modulation of GABA-A receptors – Dose: 4200 mcg/kg IV over 60 minutes– Only available through specialty pharmacy + REMS program – Efficacy trials indicate decrease in HAMD-17 score at 24-84 hours

• Considerations: • Restart medications within first 24 hours after birth • Utilization of non-pharmacotherapy treatments

Meltzer-Brody S, et al. Lancet 2018:392; 1058-70.Kanes S, et al. Lancet. 2017;390:480-489.

Powell JG, et al. Brexanolone (Zulresso). Ann Pharmacother. 2020 Feb;54(2):157-163.

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PATIENT CASE

• Kara returns for advice, as she is now breastfeeding. She also complains that she has been feeling more depressed than usual. She has not restarted her previous medications.

• Her current medications include: • Lithium 300 mg PO BID• Sertraline 50 mg PO daily • Quetiapine 400 mg PO daily • Metformin 500 mg PO BID

Kara would like to know which medications will her baby be

exposed to and if her medications are still working.

Response:Counsel Kara on baby blues and discuss risk vs benefit for each medication.

• Exposed to: • Lithium • Sertraline • Quetiapine• Metformin

SUMMARY

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SUMMARY

First Trimester Second Trimester

Third Trimester Breastfeeding Postpartum

SSRI ✔Paroxetine

✔Paroxetine

✔Paroxetine

✔Fluoxetine Paroxetine

SNRI ✔Venlafaxine

✔Venlafaxine

✔Venlafaxine

✔Venlafaxine

TCA X X X ✔Doxepin

MAOI X X X X

Benzodiazepines X X X ✔Antipsychotics

Quetiapine

XHaloperidolQuetiapine

XHaloperidolQuetiapine

XOlanzapineQuetiapineAripiprazole

Mood StabilizersLamotrigine Valproic acid

CONCLUSION AND CLINICAL PEARLS

• Pregnant • Fetus risk to medication exposure vs mother with poor mental health• SSRIs require a second or third trimester dose increase • Close clinical and pharmacokinetic monitoring recommended

• Depression: • AVOID: paroxetine, fluoxetine, venlafaxine, and MAOI • Preferred: sertraline

– Anxiety: • AVOID: benzodiazepines, marijuana, hydroxyzine

– Bipolar Disorder: • AVOID: valproic acid, carbamazepine

– Schizophrenia: • AVOID: Most • Preferred: quetiapine

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CONCLUSION AND CLINICAL PEARLS

• Breastfeeding • All psychiatric medications are excreted into the breastmilk • Recommended use if infant serum level <5-10% attainable

– Depression: • AVOID: citalopram, fluoxetine, venlafaxine, and MAOI • Preferred: paroxetine, sertraline

– Anxiety: • AVOID: marijuana, hydroxyzine

– Bipolar Disorder: • AVOID: valproic acid

– Schizophrenia: • AVOID: first generation antipsychotics

POST-ASSESSMENT QUESTION 1

JN is a pregnant patient on ziprasidone and escitalopram who has struggled with conception for years. Due to this difficulty, she is worried about the impact of medications on her baby. In research studies, which impact on infants has been found to be most associated with in utero antidepressant exposure?

• Spontaneous abortion with 3rd trimester antidepressant use• Reduced gestational time with 2nd trimester antidepressant use • Persistent pulmonary hypertension with any antidepressant use • Postnatal adaption syndrome with 1st trimester antidepressant use

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POST-ASSESSMENT QUESTION 2

After discussing the risks of untreated depression with JN, you begin to consider the role of pharmacotherapy in JN’s perinatal depression. Considering what is known about JN, and any known risk factors, which statement describes the most likely impact of antidepressant therapy in JN?

• Conversion to manic episode• Risk of psychosis or infanticide • Possible postpartum hemorrhage • Development of gestational hypertension

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POST-ASSESSMENT QUESTION 3

Based on the adverse effects of ziprasidone, what side effect could have added to JN’s struggle in conceiving? Which of the following would be most important to monitor for a patient taking this medication?

• Weight loss • Hyperprolactemia• Akathisia• QTc prolongation

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ADDITIONAL RESOURCES

• https://www.cdc.gov/pregnancy /meds/treatingforwo/facts.html

• https://womensmentalhealth.org/specialty-clinics/psychiatric -disorders-during-pregnancy/

• http://www.motherrisk.org/

REFERENCES

• Committee Opinion Number 757. American College of Obstetrician and Gynecologists. Obstet Gynecol. 2018;132:e208‐12. • Massachusetts General Hospital. Center for Women’s Mental Health• Am Fam Physician. 2008 Sep 15;78(6):772‐778.• Cohen L, et al. JAMA. 2006;295(5):499‐507• Ward R, et al. Am Fam Physician. 2002 .66(4):629‐637.• Grote N, et al. Arch Gen Psychiatry. 2010;67(10):1012‐1024. • American College of Obstetricians and Gynecologists: Yonkers K, et al. Obstet Gynecol. 2009;114(3)703‐713.• Deligiannidis K, et al. J Clin Psychopharmacol. 2014;34(2):244‐255.• Bar‐Oz B, et al. Clin Ther. 2007;29:918‐926. • Wisner KL, et al. Pharmacological treatment of depression during pregnancy. JAMA. 1999;282:1264‐9.• CDC Treating for Two: Safer Medication Use in Pregnancy. • Yonkers K, et al. Annu Rev Clin Psychol. 2014;10:369‐392.• Anderson J, et al. Obstet Gynecol.2014;124:655‐661.• Huybrechts K, et al. N Engl J Med. 2014;370(25):2397‐2407.• Relcher C, et al. Obstet Med. 2015;8(4):168‐171.• Briggs GG, et al. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. 5th ed. Baltimore: Williams Wilkins, 1998.• Grover s, et al. Indian J Psychiatry. 2015. 57(2):S308‐S323. • Westin A, et al. BMJ Open.2017;7(3):e015738.• Viguera A, et al. Am J Psychiatry. 2007;164(2):342‐345.• Kulkarni J, et al. Antipsychotic use in pregnancy. Expert Opin Pharmacother. 2015 Jun;16(9):1335‐45. • Poels E, et al. Lithium during pregnancy and after delivery: a review. Int J Bipolar Disord 6, 26 (2018).• Orsolini L, et al. Hum Psychopharmacol.2015:30(1)4‐20.• Uguz E. Am J Ther. 2019. • Colorado Department of Public Health and Environment. Monitoring Health Concerns Related to Marijuana in Colorado: 2014. (2015).• Kanes S, et al. Lancet. 2017;390:480‐489.• Meltzer‐Brody S, et al. Lancet 2018:392; 1058‐70.• Powell JG, et al. Brexanolone (Zulresso). Ann Pharmacother. 2020 Feb;54(2):157‐163.

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PSYCHIATRIC MEDICATION IN PREGNANT AND BREASTFEEDING WOMEN

Madison Holbrook, Pharm.D.

PGY-2 Psychiatry Pharmacy Resident

Laureate Psychiatric Clinic and Hospital

Oklahoma Society of Health System Pharmacist Meeting

October 22, 2021