DIAGNOSIS AND TREATMENT OF POSTPARTUM DEPRESSION

Learning Objectives

•Improve the recognition of postpartum depression

•Optimize treatment for patients with postpartum depression

Epidemiology of Postpartum Depression (PPD)

Gelaye B et al. Lancet Psychiatry 2016;3(10):973-82;Shorey S et al. J Psychiatr Res 2018;104:235-48;

Stewart DE, Vigod SN. Annu Rev Med 2019;70:183-96.

•Worldwide incidence and prevalence of PPD is approximately 12% and 17%, respectively

•Prevalence is 6.9–12.9% in high-income countries and >20% in low-income countries

•Highest prevalence in Middle Eastern countries (26%)

•Lowest prevalence in European countries (8%)

Suicide in the Postpartum

•Suicide deaths and attempts are lower during postpartum than in the general population of women

•Suicide is the second leading cause of mortality in postpartum women

•Postpartum suicide is characterized by violent and lethal means

Lindahl V et al. Arch Womens Ment Health 2005;8(2):77-87.

PPD in Adolescence

•Higher prevalence of PPD among adolescents (~25%) than adults (~17%)

•Suicidal behavior in postpartum adolescents is higher than the general population of adolescent girls and women

•Adolescent mothers face more psychosocial challenges (e.g., lower social support and socioeconomic status) that increase risk for PPD

Dinwiddie KJ et al. J Psychosom Obstet Gynaecol 2018;39(3):168-75;Lindahl V et al. Arch Womens Ment Health 2005;8(2):77-87.

“Major Depressive Disorder, With Peripartum Onset” DSM-5 Diagnostic Criteria

• Diagnostic criteria are the same as major depression

• Peripartum specifier stipulates symptom onset within 4 weeks of delivery

• In clinical practice and research, symptom onset within 12 months of delivery may be considered PPD

Five or more symptoms present ≥2 weeks; change from previous functioning; causing clinically significant distress

• Depressed mood• Anhedonia• Sleep and appetite disturbance• Impaired concentration• Psychomotor disturbance• Fatigue• Feelings of guilt or worthlessness• Suicidal thoughts

Major Depression Diagnostic Criteria

Stewart DE, Vigod SN. Annu Rev Med 2019;70:183-96.

Additional Symptoms Common to PPD

Obsessional worries or preoccupations with baby

Feeling overwhelmed

Irritability

Thoughts of harming child

Mood lability Anxiety

Stewart DE, Vigod SN. Annu Rev Med 2019;70:183-96.

PPD Detection

Score indicating PPD in a screening tool

Clinical interview to confirm diagnosis

If positive answer to either question:Administer Edinburgh Postnatal Depression Scale (EPDS) or

other screening questionnaire

Ask all postpartum women about feelings in past month:Feeling down, depressed, or

hopeless?Bothered by little interest or pleasure in doing things?

Stewart DE, Vigod SN. Annu Rev Med 2019;70:183-96; ACOG Committee Opinion No. 736. Obstet Gynecol 2018;131(5):e140-50.

The American College of Obstetrics and

Gynecology (ACOG) recommends all

mothers be screened for PPD within 3

weeks of giving birth

Edinburgh Postnatal Depression Scale (EPDS)

•Easy to administer, 10-item questionnaire about feelings in the past 7 days

•Items scored 0–3 depending on severity of symptoms

•Total score is sum of all 10 items (max score 30)

•A score ≥10 or a positive response to item 10 (i.e., self-harm ideation) indicate possible depression and require clinical evaluation

Cox JL et al. Br J Psychiatry 1987;150:782-6;Wisner KL et al. JAMA Psychiatry 2013;70(5):490-8.

Differential Diagnosis

Depressive symptoms secondary to untreated medical conditions (e.g., thyroid dysfunction, anemia) or alcohol or other substance abuse must also be ruled out

Condition Distinguishing Features From PPD

Postpartum blues• Less severe and persistent symptoms• Onset of symptoms always during postpartum• Typically no severe obsessional preoccupations or suicidality

Adjustment disorders • Fewer and less severe symptoms• Improvement after mitigating stressorsPosttraumatic stress disorder (PTSD)

• Remote or recent traumatic events associated with nightmares, flashbacks, or other symptoms of PTSD

Bipolar disorder • Manic or hypomanic symptomsPostpartum psychosis (PPP)

• Delusions, grandiosity, hallucinations, confusion, bizarre behavior, or disorganized thoughts, accompanied by depression or mania

Stewart DE, Vigod SN. Annu Rev Med 2019;70:183-96.

Strongest Risk Factors for PPD

Domestic violence,

previous abuse

Negative life events, low

social support

Low partner support, marital

difficultiesMigration status*

Depression or unhappiness in

pregnancyAnxiety in

pregnancy*History of

depression

*Only in high-income countries

Howard LM et al. Lancet 2014;384(9956):1775-88; Wisner KL et al. JAMA Psychiatry 2013;70(5):490-8;

English S et al. Sci Rep 2018;8(1):12799.

The strongest risk factor is a history of mood or anxiety disorder, especially if symptomatic during pregnancy

Postpartum Anxiety Is More Common Than You Think

• An estimated 8.5% of postpartum women are diagnosed with one or more anxiety disorders

• Approximately two-thirds of women with PPD have a comorbid anxiety disorder or symptoms

• Women with postpartum depression and anxiety diagnoses display poorer quality of life and their illness is slower to remit than women with postpartum depression only

• DSM-5 specifies no diagnosis of postpartum anxiety disorder and no standardized diagnostic criteria exist

Goodman JH et al. J Affect Disord 2016;203:292-331; Farr SL et al. J Womens Health (Larchmt) 2014;23(2):120-8; Wisner KL et al. JAMA Psychiatry 2013;70(5):490-8; Misri S, Swift E. J Obstet

Gynecol Can 2015;37(9):798-803; Jordan V, Minikel M. J Fam Pract 2019;68(3):165-74.

Course of PPD Illness

•33% of women experience depression during pregnancy (i.e., antepartum depression)

•With treatment, most cases resolve within a few months

• 24% are depressed 1 year after giving birth despite receiving treatment

• 13% are depressed 2 years after giving birth despite receiving treatment

•40% will relapse during subsequent pregnancy or unrelated to pregnancy

Stewart DE, Vigod SN. Annu Rev Med 2019;70:183-96.

PPD Outcomes

↓ Physical health↓ Psychological health↓ Quality of life

↑ Relationship problems↑ Risky behavior

Mother

↓ Quality of sleep↓ Cognitive development↓ Language

development

↑ Health concerns↑ Behavioral problems

Infant

↓ Bonding and attachment

↓ Maternal care

↑ Breastfeeding problems

Mother-Infant Interactions

Slomian J et al. Womens Health (Lond) 2019;15:1745506519844044.

Reduction in Rate of Subsequent Live Births Following Postpartum Psychiatric Illness • Women with postpartum psychiatric illness after their first birth

demonstrate a decline in subsequent live births

• The reduction in subsequent live births is

• 33% for women with any postpartum psychiatric illness;

• 39% for women with postpartum depression; and

• 47% for women with any postpartum psychiatric illness with hospitalization (indicating greater severity)

• In women with postpartum psychiatric illness whose first child died, there is no reduction in subsequent births, suggesting that the reduction in subsequent live births in this population is at least, in part, voluntary

Liu X et al. Hum Reprod 2020;35(4):958-67.

Pathophysiological Mechanisms Implicated in PPD

Postpartum Depression

Neurotransmitter Alterations

(GABA, glutamate, serotonin, dopamine)

Neuroendocrine Changes

(allopregnanolone, progesterone,

estrogen, oxytocin, prolactin, cortisol,

ACTH, CRH)

Neuroinflammation(IL-6, IL-1ꞵ, IL-8, TNF-

α, IFN-γ)Neurocircuit Dysfunction

(amygdala, prefrontal cortex, cingulate cortex, insula)

Genetics/ Epigenetics(ESR1, 5-HTT, MOAO, COMT,

TPH2, OXT/OXTR, HMNC1, HPA

pathways)

Payne LJ, Maguire J. Front Neuroendocrinol 2019;52:165-80.

5-HTT:serotonin transporterACTH:adrenocorticotropic hormoneCOMT:catechol-O-methyltransferase

CRH:corticotropin releasing hormoneESR1:estrogen receptor alpha geneGABA:gamma aminobutyric acid

HMNC1:Hemicentin 1 geneHPA:hypothalamic-pituitary-adrenalIFN:interferon

IL:interleukinMOAO:monoamine oxidase A

OXT:oxytocinOXTR:oxytocin receptor

TNF:tumor necrosis factorTPH2:tryptophan hydroxylase 2

Evidence-Based Treatment Recommendations

All PPDSelf-careSleep protectionExercisePsychosocial support strategies

Investigate and manage social stressors, medical and psychiatric comorbidities

Moderate PPDPsychological treatments, including cognitive behavioral therapy and interpersonal therapyAdd selective serotonin reuptake inhibitor (SSRI) if insufficient response Brexanolone

Severe PPDSSRI alone or with psychological interventionConsider antidepressant switch and augmentation strategies if no response to SSRI aloneBrexanoloneConsider electroconvulsive therapy with severe suicidality or treatment resistance

Stewart DE, Vigod SN. Annu Rev Med 2019;70:183-96; Zheng W et al. Psychiatry Res 2019;279:83-9.

Psychological Interventions Reduce Depression Symptoms in Women With PPD

Stephens S et al. Ann Fam Med 2016;14(5):463-72.

Data from meta-analysis of 10 studies with randomized controlled design (N=1,324) examining change in depressive symptoms following psychological interventions for PPD in primary care

InterventionChange in Depression Symptoms

Immediately Post-intervention, SMD (95% CI)

Cognitive behavioral therapy -0.36 (-0.52 to -0.21) *

Interpersonal therapy -0.93 (-1.27 to -0.59) *Counseling -0.29 (-0.53 to -0.05) *Other psychological interventions -0.23 (-0.46 to 0.01)

#

Total -0.38 (-0.49 to -0.27) *SMD=standardized mean difference; CI=confidence interval. *p

Efficacy of SSRIs for the Treatment of PPD

Meta-analysis of 3 randomized controlled trials with parallel group design (N=146, PPD onset up to 6 months after giving birth) comparing effects of SSRIs (sertraline [2 studies] and paroxetine [1 study]) and placebo.

Post-TreatmentResponse Rate

Post-TreatmentRemission

Molyneaux E et al. Cochrane Database Syst Rev 2014;9:CD002018

Sertraline

•Sertraline is the SSRI with the most evidence in the treatment of PPD

•Effects of sertraline treatment may be more pronounced in women who have an onset of PPD within 4 weeks of childbirth

•There is evidence of sertraline efficacy in combination with CBT for treating PPD

Frieder A et al. CNS Drugs 2019;33(3):265-82;Hantsoo L et al. Psychopharmacology (Berl) 2014;231(5):939-48;

Milgrom J et al. Aust N Z J Psychiatry 2015;49(3):236-45.

Brexanolone

• The only FDA-approved (2019) treatment for postpartum depression

• Neuroactive steroid chemically similar to allopregnanolone, a positive allosteric modulator of GABAA receptor

• Administered intravenously over 60 hours in a single dose

• Most common adverse events:

• Sedation/somnolence, dry mouth, loss of consciousness, and flushing/hot flush

• Use with antidepressants may increase sedation

• Ongoing clinical trial to test safety, tolerability, and pharmacokinetics in adolescents with PPD (NCT03665038)

Meltzer-Brody S, Kanes SJ. Neurobiol Stress 2020;12:100212.

Efficacy of Brexanolone for the Treatment of PPD

65.0

50.744.7

24.0

PEAK RESPONSE (36 H) PEAK REMISSION (60 H)

PER

CEN

T

Brexanolone Placebo

Meta-analysis of randomized control trials (3 studies; n=267) comparing brexanolone vs. placebo effects on depression response (≥50% reduction of Hamilton Depression Rating Scale [HAMD] total score) and

remission (HAMD total score ≤7) in women with moderate-to-severe PPD.

Zheng W et al. Psychiatry Res 2019;279:83-9.

*

*p≤0.02 compared to placebo

*

Brexanolone: Barriers to Access

• Very expensive: ~$34,000 per treatment alone and additional indirect costs for infusion, continuous monitoring, health care providers, and required hospital stay

• Available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS)

• No published data to support its use for mild PPD

• Concerns remain about sustained efficacy

• Interruption in normal mother-child interactions due to patients being isolated from or supervised in the presence of their children during infusions

• May be advantageous for patients requiring rapid response due to disease severity

Burval J, Reed K. Nursing 2020;50(5):48-53;Hutcherson TC et al. Am J Health Syst Pharm 2020;77(5):336-45.

Efficacy and Safety of Zuranolone for Severe PPD (ROBIN Study)

Results from a phase 3, randomized, double-blind study of women with severe PPD (N=151) treated with daily oral zuranolone (30 mg) or placebo for 2 weeks

• Decrease in Hamilton Depression Rating Scale (HAMD-17)• Day 3: zuranolone -12.5 vs placebo -9.8 (p=0.0255)• Day 14 (primary endpoint): zuranolone -17.8 vs placebo -13.6 (p=0.0029)• Difference was maintained to the end of the 4-week follow-up period (p=0.0027)• Response at Day 14: zuranolone 72% vs placebo 48% (p=0.0050)• Remission at Day 14: zuranolone 45% vs placebo 23% (p=0.0122)

• The most common adverse events (≥ 5%) were somnolence/sedation, headache, dizziness, upper respiratory infections, and diarrhea

https://investor.sagerx.com/news-releases/news-release-details/sage-therapeutics-announces-sage-217-meets-primary-and-secondary

https://investor.sagerx.com/news-releases/news-release-details/sage-therapeutics-announces-sage-217-meets-primary-and-secondary

Other Treatments With Limited Research Evidence of Efficacy in PPD

• Venlafaxine

• Desvenlafaxine

• Bupropion

• Nefazodone

• Nortriptyline

• Transdermal estradiol patches

• Repetitive transcranial magnetic stimulation

• Transcranial direct-current stimulation

• Omega-3 fatty acids

• Vitamin D

• Yoga

Frieder A et al. CNS Drugs 2019;33(3):265-82; Reza N et al. Obstet Gynecol Clin North Am 2018;45(3):441-54.

Considerations for Breastfeeding: Antidepressants

Berle JO, Spigset O. Curr Womens Health Rev 2011;7(1):28-34; Chad L et al. Can Fam Physician 2013;59(6):633-34; McDonagh MS et al. Obstet Gynecol 2014;124(3):526-34.

Relative Infant Doses of Commonly Used AntidepressantsAntidepressant Relative Infant Dose, %a

Bupropion 2Citalopram 3 – 10Desvenlafaxine 5.5 – 8.1Duloxetine < 1Escitalopram 3 – 6Fluoxetine < 12Fluvoxamine < 2Mirtazapine 0.5 – 3Paroxetine 0.5 – 3Sertraline 0.5 – 3Venlafaxine 6 – 9a Relative infant dose ≤10% is associated with decreased risk to infant.

• Infant exposure through lactation should be considered when recommending pharmacological treatment

• Most antidepressants are not contraindicated during breastfeeding

• No direct evidence that antidepressants are unsafe in pregnancy

Considerations for Breastfeeding: Brexanolone

•Relative infant dose in breast milk 36 hours after brexanolone infusion is 1-2%

•Oral bioavailability is low (

Considerations for Breastfeeding: Pump and Dump

• Infant daily dose in breastfeeding with SSRI use can be reduced by “pump and dump” at 8 to 9 hours after maternal medication

•Drug concentrations tend to be higher in hindmilk because of its lipophilic nature

Newport DJ et al. J Clin Psychiatry 2002;63(Suppl 7):31-44; Lattimore KA et al. J Perinatol 2005;25(9):595-604;

Sie SD et al. Arch Dis Child Fetal Neonatal Ed 2012;97(6):F472-76.

PPD Prevention in Pregnant and Postpartum Women

•Counseling services (i.e., cognitive behavioral therapy and interpersonal therapy) are recommended for high-risk women

US Preventive Services Task Force et al. JAMA 2019;321(6):580-7.

History of depression

Current depressive symptoms

Low income

Young or single parenthoodHigh Risk

Summary

•PPD has a prevalence of 17% and is the second leading cause of death among postpartum women

•Screening for PPD should occur regularly beginning within 3 weeks of giving birth

•Severity of PPD symptoms and patient preferences should guide treatment selection• Mild: psychosocial support strategies

• Moderate: CBT/IPT alone or with SSRI; brexanolone

• Severe: SSRI alone or with CBT/IPT; brexanolone; ECT (with severe suicidality, treatment resistance)

Posttest Question 1

Monica is a first-time, single mother who gave birth to a healthy son 4 weeks prior. She lives alone with her child and has been receiving help from her mother a few times a week since her son was born. During a postpartum visit she reports feeling overwhelmed, fatigued and irritable since the birth of her son. She is having trouble concentrating and reports feeling like a “terrible mother.” She denies suicidal thoughts or behavior. Screening with the Edinburgh Postnatal Depression Scale results in a score of 11.

Based on this information, what intervention would be most appropriate for Monica at this time?

A. Psychosocial support strategiesB. Cognitive behavioral therapyC. Treatment with sertralineD. Treatment with brexanolone

Posttest Question 2

A 31-year-old woman is diagnosed with severe postpartum depression 3 weeks after giving birth. The patient is hesitant about starting pharmacological treatment because she would like to continue breastfeeding her child.

Which statement is the most accurate regarding pharmacological treatments for postpartum depression?

A. Serotonin-norepinephrine reuptake inhibitors have the best lactation safety profileB. Brexanolone has minimal effects on breast milk productionC. Most antidepressants are not contraindicated during breastfeeding

Diagnosis and Treatment of Postpartum DepressionLearning ObjectivesEpidemiology of Postpartum Depression (PPD)Suicide in the PostpartumPPD in Adolescence“Major Depressive Disorder, With Peripartum Onset” DSM-5 Diagnostic CriteriaAdditional Symptoms Common to PPDPPD DetectionEdinburgh Postnatal Depression Scale (EPDS) Differential DiagnosisStrongest Risk Factors for PPDPostpartum Anxiety Is More Common Than You ThinkCourse of PPD IllnessPPD OutcomesReduction in Rate of Subsequent Live Births Following Postpartum Psychiatric Illness Pathophysiological Mechanisms Implicated in PPDEvidence-Based Treatment RecommendationsPsychological Interventions Reduce Depression Symptoms in Women With PPDEfficacy of SSRIs for the Treatment of PPDSertralineBrexanoloneEfficacy of Brexanolone for the Treatment of PPDBrexanolone: Barriers to AccessEfficacy and Safety of Zuranolone for Severe PPD (ROBIN Study)Other Treatments With Limited Research Evidence of Efficacy in PPDConsiderations for Breastfeeding: AntidepressantsConsiderations for Breastfeeding: BrexanoloneConsiderations for Breastfeeding: �Pump and DumpPPD Prevention in Pregnant and Postpartum WomenSummaryPosttest Question 1Posttest Question 2