brexanolone: a new hope? updates on management of ... pgr 02262019.pdf · baby blues postpartum...

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Brexanolone: A New Hope? Updates on Management of Postpartum Depression Mikaela Hofer, PharmDPGY-1 Pharmacy Resident

Pharmacy Grand RoundsFebruary 26, 2019


Objectives• Identify risk factors associated with postpartum

depression • Review current options for treatment of

postpartum depression • Describe the potential place in therapy for

brexanolone in treating postpartum depression


Epidemiology

• Prevalence: 6.5 – 12.9% • Beyond 1st year after delivery: 20%• Beyond 2nd year after delivery: 13% • Approximately 40 – 80% of cases are

considered moderate to severe

Meltzer-Brody S. Lancet. 2018 Sep 22;392(10152):1058-1070Stewart DE. N Engl J Med. 2016 Dec 1;375(22):2177-2186Gavin NI. Obstet Gynecol. 2005 Nov;106(5 Pt 1):1071-83


Diagnosis

Major Depressive Disorder, with peripartum onset Five or more symptoms for 2 weeks (one of which must be either depressed mood or anhedonia)

1. Depressed mood most of the day nearly every day2. Anhedonia most of the day nearly every day 3. Significant weight loss or gain 4. Insomnia or hypersomnia 5. Psychomotor agitation or retardation 6. Fatigue or loss of energy7. Feelings of worthlessness or excessive guilt8. Diminished ability to think or concentrate;

indecisiveness9. Recurrent thoughts of death; suicidal ideation or

attempt Onset Symptom onset during pregnancy or the first four

weeks following delivery

American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing

Major Depressive Disorder, with peripartum onset Five or more symptoms for 2 weeks (one of which must be either depressed mood or anhedonia)

1. Depressed mood most of the day nearly every day2. Anhedonia most of the day nearly every day 3. Significant weight loss or gain 4. Insomnia or hypersomnia 5. Psychomotor agitation or retardation 6. Fatigue or loss of energy7. Feelings of worthlessness or excessive guilt8. Diminished ability to think or concentrate;

indecisiveness9. Recurrent thoughts of death; suicidal ideation or

attempt Onset Symptom onset during pregnancy or the first four

weeks following delivery


Baby blues Postpartum depression

Less than 10 days Duration More than two weeksWithin 2 – 3 days postpartum

Onset Often within 1st month; may be up to 1 year

• Brief crying spells • Irritability • Poor sleep • Nervousness • Emotional reactivity

Symptoms • Feelings of guilt or worthlessness

• Lack of enjoyment or interest in pleasurable activities

• Difficulty sleeping while infant sleeps

80% Prevalence ~13%Mild dysfunction Severity Moderate to severe

dysfunctionNot present Suicidal ideation May be present

Hirst KP, et al. Am Fam Physician. 2010 Oct 15;82(8):926-33


Payne JL, et al. Front Neuroendocrinol. 2019 Jan;52:165-180Stewart DE. N Engl J Med. 2016 Dec 1;375(22):2177-2186

History of depression

• Perinatal• Nonperinatal

Environmental • Financial stress• Marital stress• Lack of social support

• Adverse life events• Previous abuse

Other• Age <25 years• Single marital status• Multiparity

Risk Factors


Effects of postpartum depression

Mother

FamilyBaby

Meltzer-Brody S. Dialogues Clin Neurosci. 2011;13(1):89-100Yonkers KA. Obstet Gynecol. 2009 Sep;114(3):703-13Stewart DE. N Engl J Med. 2016 Dec 1;375(22):2177-2186

EconomicImpaired bonding

Poor adolescent outcomes

Lower Apgar scores

Decreased sensitivity

Poor self-care

Marital discord

Perinatal complications

Suicide

Loss of work days

Increased ICU admission


Screening

• Who to screen: • USPSTF recommends screening all

postpartum women • Why to screen:

• PPD is serious, prevalent, under-recognized, and treatable

• Standardized, valid screening tools are available

• Edinburgh Postnatal Depression Scale • Hamilton Depression Rating Scale

O'Connor E. JAMA. 2016 Jan 26;315(4):388-406


Postpartum Support International (PSI)

• In an emergency• Find local support and help• Chat with an expert for moms• Resources for fathers• Help for families

http://www.postpartum.net/


Barriers to treatment

Minimizing

Fear of losing child

Stigma

Diagnosis

Treatment

Jones I. BMJ. 2014 Aug 14;349:g4500


Question 1

• Which of the following is the strongest risk factor for developing PPD?

A. MultiparityB. Prenatal depression C. Age < 25 years at delivery D. Lack of social support


Pathophysiology

Genetics / Epigenetics Reproductive/ lactogenic hormones

Neurotransmitters Stress hormones / HPA axis dysfunction

Neurosteroids Neuro-inflammation

EstrogenProgesteroneOxytocin

GABAGlutamateSerotoninDopamine

CortisolAdrenocorticotropic hormone (ACTH)Corticotropin-releasing (CRH) Allopreganolone

Payne JL, et al. Front Neuroendocrinol. 2019 Jan;52:165-180

Circuit-level changes

IL-6TNF-αKynurenine pathway

Serotonin transporter (5-HTT)Catechol-O-methyl transferase (COMT)Monoamine oxidase (MAO)


Treatment targets

Genetics / Epigenetics Reproductive/ lactogenic hormones

Neurotransmitters Stress hormones / HPA axis dysfunction

Neurosteroids Neuro-inflammation


Circuit-level changes


Fluoxetine and cognitive-behavioral (CB) counseling, 1997Design Double blind, randomized, controlled trial Population Postnatal depression (6 – 8 weeks after childbirth), n = 87Intervention/Comparison

Fluoxetine + 1 session

Fluoxetine + 6 sessions

Placebo + 1 session

Placebo + 6 sessions

Outcomes Difference in revised clinical interview schedule (95% confidence interval)• 37.1% at 4 weeks (5.7% to 58.0%) • 40.7% at 12 weeks (10.9% to 60.6%);

Conclusions Fluoxetine & CB counseling were effective Combining treatments did not produce additional efficacy

Appleby et al. BMJ. 1997 Mar 29;314(7085):932-6


Sertraline vs nortriptyline, 2006Design Double-blind, randomized comparative trialPopulation Postpartum major depression + 17-item HRSD ≥ 18;

n = 109Intervention Sertraline (SERT) (50 to 200 mg/day) Comparison Nortriptyline (NTP) (25 to 150 mg/day)Outcomes Response at 8 weeks (50% reduction in HRSD)

• 80% vs 77%, p = 1.00 Remission at 8 weeks (HRSD <7)• 67% vs 55%, p = 1.00 Side effects• Similar burden, different effects

Comparisons are SERT vs NTP HRSD = Hamilton rating scale for depression

Wisner et al, J Clin Psychopharmacol. 2006 Aug;26(4):353-60


Cochrane review, 2014Design Review and meta-analysis Population Postpartum depression: 1 – 6 months postpartum;

n = 596 from 6 randomized controlled trials Intervention SERT

vs placebo

SERTvsplacebo

PAR vs placebo

FLX vs placebo

SERT vs NTP

ADP vs listening visits

Conclusion • SSRIs significantly more effective than placebo in response and remission (low quality of evidence)

• Insufficient evidence:• ADP vs psychological/psychosocial treatments • Comparing ADPs (efficacy, tolerability) • Duration of therapy • Safety of breastfeeding

Molyneaux et al. Cochrane Database Syst Rev. 2014 Sep 11;(9):CD002018

SERT = sertraline; PAR = paroxetine; FLX = fluoxetine; NTP = nortriptyline ADP = antidepressants


Treatment considerations:Antepartum

Teratogenic

• Septal defects (paroxetine)

• Persistent pulmonary hypertension (PPHN)

Obstetric

• Preterm delivery (<37 weeks)

• Small gestational age (SGA)

• Lower Apgar score

• Postpartum hemorrhage

Developmental

• Gross motor function

• Language development

Post-exposure

• Neonatal adaptation syndrome

Yonkers KA. Obstet Gynecol. 2009 Sep;114(3):703-13 Hanley GE, et al. Best Pract Res Clin Obstet Gynaecol. 2014 Jan;28(1):37-48Meltzer-Brody S. Dialogues Clin Neurosci. 2011;13(1):89-100 Becker M, et al. Curr Psychiatry Rep. 2016 Mar;18(3):32Stewart DE. N Engl J Med. 2016 Dec 1;375(22):2177-2186


Neonatal adaptation syndrome• Feeding difficulty• Jitteriness and tremors • Temperature instability• Sleep problems • Respiratory distress

Symptoms

• Abrupt antidepressant withdrawal• Antidepressant side effect/toxicity• Disruption of neonatal serotonergic system• Preterm birth• Genetic factors

Cause

• Monitor• Symptom management Treatment

Grigoriadis S, et al. J Clin Psychiatry. 2013 Apr;74(4):e309-20Hanley GE, et al. Best Pract Res Clin Obstet Gynaecol. 2014 Jan;28(1):37-48

• Shivering• Restlessness• Convulsions• Jaundice• Hypoglycemia


Treatment considerations

• Antepartum vs postpartum onset• Choose previously effective agent• 1st line: SSRI/SNRI • Consider side effect profile• Minimize number of exposures • If used during pregnancy, continue after delivery

Payne JL, et al. Clin Obstet Gynecol. 2009;52(3):469-482


Resources

• Micromedex (All Results Reproductive Risk) • Shepard’s• REPROTOX• TERIS

• Drugs and Lactation Database (LactMed)• MotherToBaby• Motherisk

https://www.micromedexsolutions.com/micromedex2/librarianhttps://toxnet.nlm.nih.gov/pda/lactmed.htmhttps://mothertobaby.org/ http://motherisk.org/


Treatment = time commitment

• Antidepressants • 4 to 6 weeks for efficacy

• Electroconvulsive therapy (ECT) • Three times weekly x 4 to 5 weeks

• Repetitive transcranial magnetic stimulation (rTMS)

• Daily x 4 to 6 weeks • Psychotherapy

• 8 to 20 weekly sessions

Brexanolone: FDA briefing document. November 2, 2018


Question 2

MC is a 31 year-old female recently diagnosed with postpartum depression. She was successfully treated during her previous pregnancy with citalopram. She would like to breastfeed. Which of the following would be the most appropriate treatment for MC?


Question 2

Which of the following would be the most appropriate treatment for MC? A. Fluoxetine 20 mg dailyB. Nortriptyline 50 mg dailyC. Sertraline 25 mg dailyD. Citalopram 20 mg daily


Future directions


Treatment targets

Neurotransmitters

Neurosteroids



Allopreganolone

GABAAGABAA

GABAA

Allopreganolone

Chloride

Meltzer-Brody S. Lancet. 2018 Sep 22;392(10152):1058-1070


Brexanolone, 2018Design Double-blind, randomized, placebo-controlled, phase 3 trialPopulation 18 – 45 years

≤ 6 months post partum Moderate – severe PPD

Exclusion History of schizophrenia, bipolar disorder, schizoaffective disorder, or alcohol/drug abuse, active psychosis, recent

suicide attemptIntervention Study 1

BRX90 x 60 hours (n = 45)BRX60 x 60 hours (n = 47)

Study 2BRX90 x 60 hours (n = 54)

Comparison Matching placebo x 60 hours (n = 46) (n = 45)

Outcome Change from baseline HAM-D at 60 hoursFollow-up 30 days BRX 90 = brexanolone 90 μg/kg per h; BRX 60 = brexanolone 60 μg/kg per h; HAM-D = Hamilton Rating Scale for Depression



Baseline characteristics Study 1Placebo BRX60 BRX90

Study 2Placebo BRX90

Onset of PPDThird trimester 14 (30%) 11 (23%) 10 (22%) 12 (22%) 12 (22%)

Within 4 weeks of delivery

31 (67%) 35 (74%) 35 (78%) 42 (78%) 42 (78%)

Antidepressant useBaseline 12 (26%) 12 (26%) 10 (22%) 10 (19%) 9 (17%)Previous 14 (30%) 15 (32%) 13 (29%) 10 (19%) 12 (22%)

Concomitant 14 (30%) 14 (30%) 13 (29%) 15 (28%) 12 (22%)



Primary outcomeStudy 1 (Severe PPD)

-25

-20

-15

-10

-5

0

LS m

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HA

M-D

Sco

re

Time

PlaceboBRX90BRX60

*


**

***

**

*

Day 30


Primary outcomeStudy 2 (Moderate PPD)

-18

-16

-14

-12

-10

-8

-6

-4

-2

0

LS m

ean

chan

ge fr

om b

asel

ine

HA

M-D

Sco

re

Time

PlaceboBRX90

*


***

Day 30


Safety

Study 1 Study 2Placebo BRX 60 BRX90 Placebo BRX90

Any AE 22 (51%) 19 (50%) 22 (54%) 24 (45%) 25 (49%)Serious AE 0 1 (3%) 0 1 (2%) 2 (4%)AE leading to discont.

1 (2%) 1 (3%) 0 0 2 (4%)


Most common adverse events (AEs): headache, dizziness, somnolence, infusion site pain, nausea, dry mouth, fatigue

REMSLoss of consciousness

(Decision March 19, 2019)


Place in therapy:Logistics • Location: Inpatient

• Obstetrics vs psychiatry • Monitoring by certified RN or higher • Space for mom and baby

• Administration• Each IV bag made separately


Question 3

• What is the place in therapy for brexanolone? Brexanolone should be…

A. administered to all patients for the prevention of PPD

B. used as treatment for all severities of PPD C. used solely for treatment of severe PPD D. should not be used for prevention nor

treatment of PPD


Summary• Due to stigma and difficulty of diagnosis, PPD is

an underdiagnosed but treatable disease • The largest risk factor is a history of depression • First-line treatment typically includes a selective

serotonin reuptake inhibitor or SNRI • Brexanolone is currently undergoing the

approval process to be the first medication indicated for the treatment of PPD

• A pharmacist can play a key role in guiding therapy plans


Thank [email protected]


Pregnancy pharmacokinetics

• Delayed gastric emptying• Decreased gastrointestinal motility• Increased volume of distribution, • Decreased drug binding capacity• Decreased plasma protein levels (albumin)• Increased hepatic metabolism due to liver

enzyme induction• Increased renal clearance

Ito S. Clin Pharmacol Ther. 2016 Jul;100(1):8-11Kalra S, et al. Expert Opin Drug Saf. 2005 Mar;4(2):273-84


Lactation considerations

• Volume of distribution (Vd)• Higher Vd = lower excretion in breast milk• Vd 1 – 20 L/kg = increased compatibility with breast-feeding

• Percentage of maternal protein binding (PB)• Higher PB = lower excretion into breast milk • PB > 90% = increased compatibility with breast-feeding

• Molecular weight (MW) • Higher MW = lower excretion into breast milk • MW > 800 Da = increased compatibility for breast-feeding

• Other: pH, logP, Tmax, t1/2, milk-to-plasma ratio, active transport, relative infant dose (RID)

• RID < 10% of maternal dose = safe for breast-feedingNice FJ, et al. J Am Pharm Assoc. 2012;52:86-94


Hamilton Depression Rating Scale (HAM-D)1. Depressed mood 2. Feelings of guilt3. Suicide4. Insomnia – initial (difficulty falling

asleep)5. Insomnia – middle (waking

during the night)6. Insomnia – delayed (waking in

early hours of the morning)7. Work and interests8. Retardation9. Agitation10. Anxiety – psychic 11. Anxiety – somatic12. Somatic symptoms –

gastrointestinal

11. Somatic symptoms – general12. Genital symptoms13. Hypochondriasis14. Weight gain 15. Insight

Total ______

18. Diurnal variation19. Depersonalization and

derealization20. Paranoid symptoms21. Obsessional symptoms

Depression severity: 0 – 7 = Normal 19 – 22 = Severe 8 – 13 = Mild ≥ 23 = Very severe 14 – 18 = Moderate

Hamilton M. J Neurol Neurosurg Psychiatry. 1960 Feb;23:56-62

brexanolone: a new hope? updates on management of ... pgr 02262019.pdf · baby blues postpartum...

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