DIAGNOSIS AND TREATMENT OF Learning Objectives

•Improve the recognition of postpartum depression •Optimize treatment for patients with postpartum depression Epidemiology of Postpartum Depression (PPD)

•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%)

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. 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

Major Depression Diagnostic Criteria • Diagnostic criteria are the same Five or more symptoms present ≥2 as major depression weeks; change from previous functioning; causing clinically significant distress • Peripartum specifier stipulates symptom onset within 4 weeks • Depressed mood of delivery • Anhedonia • Sleep and appetite disturbance • In clinical practice and research, • Impaired concentration symptom onset within 12 • Psychomotor disturbance months of delivery may be • Fatigue considered PPD • Feelings of guilt or worthlessness • Suicidal thoughts

Stewart DE, Vigod SN. Annu Rev Med 2019;70:183-96. Additional Symptoms Common to PPD

Irritability Mood lability Anxiety

Feeling Thoughts of harming child overwhelmed

Obsessional worries or preoccupations with baby

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

Ask all postpartum women about feelings in past month: Feeling down, depressed, or Bothered by little interest or hopeless? pleasure in doing things? The American College of Obstetrics and If positive answer to either question: Gynecology (ACOG) Administer Edinburgh Postnatal Depression Scale (EPDS) or recommends all other screening questionnaire mothers be screened for PPD within 3 weeks of giving birth Score indicating PPD in a screening tool

Clinical interview to confirm diagnosis

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

Condition Distinguishing Features From PPD • Less severe and persistent symptoms Postpartum blues • Onset of symptoms always during postpartum • Typically no severe obsessional preoccupations or suicidality • Fewer and less severe symptoms Adjustment disorders • Improvement after mitigating stressors Posttraumatic stress • Remote or recent traumatic events associated with nightmares, disorder (PTSD) flashbacks, or other symptoms of PTSD • Manic or hypomanic symptoms Postpartum psychosis • Delusions, grandiosity, hallucinations, confusion, bizarre behavior, (PPP) or disorganized thoughts, accompanied by depression or mania Depressive symptoms secondary to untreated medical conditions (e.g., thyroid dysfunction, anemia) or or other substance abuse must also be ruled out

Stewart DE, Vigod SN. Annu Rev Med 2019;70:183-96. Strongest Risk Factors for PPD

Domestic Negative life Low partner Migration violence, events, low support, marital status* previous abuse social support difficulties

Depression or Anxiety in History of unhappiness in pregnancy* depression pregnancy

*Only in high-income countries The strongest risk factor is a history of mood or anxiety disorder, especially if symptomatic during pregnancy

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. 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 ↓ Quality of sleep ↓ Bonding and ↓ Psychological health ↓ Cognitive development attachment ↓ Quality of life ↓ Language ↓ Maternal care development ↑ Relationship problems ↑ Breastfeeding ↑ Risky behavior ↑ Health concerns problems ↑ Behavioral problems Mother-Infant 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

Neuroinflammation (IL-6, IL-1ꞵ, IL-8, TNF- Neuroendocrine α, IFN-γ) Changes Neurocircuit (, Dysfunction , (amygdala, prefrontal 5-HTT:serotonin transporter estrogen, oxytocin, cortex, cingulate ACTH:adrenocorticotropic hormone prolactin, cortisol, cortex, insula) ACTH, CRH) COMT:catechol-O-methyltransferase CRH:corticotropin releasing hormone ESR1:estrogen receptor alpha gene GABA:gamma aminobutyric acid HMNC1:Hemicentin 1 gene Genetics/ HPA:hypothalamic-pituitary-adrenal Neurotransmitter Epigenetics IFN:interferon Alterations Postpartum (ESR1, 5-HTT, IL:interleukin MOAO, COMT, MOAO:monoamine oxidase A (GABA, glutamate, Depression TPH2, OXT/OXTR, serotonin, dopamine) OXT:oxytocin HMNC1, HPA OXTR:oxytocin receptor pathways) TNF:tumor necrosis factor TPH2:tryptophan hydroxylase 2

Payne LJ, Maguire J. Front Neuroendocrinol 2019;52:165-80. Evidence-Based Treatment Recommendations

All PPD

Self-care Moderate PPD Sleep protection Psychological treatments, Severe PPD Exercise including cognitive Psychosocial support behavioral therapy and SSRI alone or with strategies interpersonal therapy psychological intervention Add selective serotonin Consider antidepressant switch and augmentation Investigate and manage reuptake inhibitor (SSRI) if insufficient response strategies if no response to social stressors, medical and SSRI alone psychiatric comorbidities Brexanolone Brexanolone Consider 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

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 Change in Depression Symptoms Intervention Immediately Post-intervention, Psychological SMD (95% CI) interventions also Cognitive behavioral significantly reduced -0.36 (-0.52 to -0.21) * therapy depressive symptoms 6 months post-intervention Interpersonal therapy -0.93 (-1.27 to -0.59) * (SMD = -0.21) and were Counseling -0.29 (-0.53 to -0.05) * significantly better than Other psychological control conditions for -0.23 (-0.46 to 0.01) # interventions reducing symptoms Total -0.38 (-0.49 to -0.27) * below threshold (odds ratio [OR] = 2.24) SMD=standardized mean difference; CI=confidence interval. *p<0.05, #p=0.06 test for overall effect.

Stephens S et al. Ann Fam Med 2016;14(5):463-72. Efficacy of SSRIs for the Treatment of PPD

Post-Treatment Response Rate

Post-Treatment Remission

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.

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 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

Brexanolone Placebo 65.0

* 50.7 44.7 *

24.0 PERCENT

*p≤0.02 compared to placebo PEAK RESPONSE (36 H) PEAK REMISSION (60 H)

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. 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 Other Treatments With Limited Research Evidence of Efficacy in PPD

• Venlafaxine • Repetitive transcranial magnetic stimulation • Desvenlafaxine • Transcranial direct-current • Bupropion stimulation • Nefazodone • Omega-3 fatty acids • Nortriptyline • Vitamin D • Transdermal estradiol patches • 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

• Infant exposure through Relative Infant Doses of Commonly Used Antidepressants lactation should be Antidepressant Relative Infant Dose, %a considered when Bupropion 2 recommending Citalopram 3 – 10 pharmacological treatment Desvenlafaxine 5.5 – 8.1 Duloxetine < 1 • Most antidepressants are Escitalopram 3 – 6 not contraindicated during < 12 breastfeeding Fluvoxamine < 2 Mirtazapine 0.5 – 3 • No direct evidence that Paroxetine 0.5 – 3 antidepressants are unsafe Sertraline 0.5 – 3 in pregnancy Venlafaxine 6 – 9 a Relative infant dose ≤10% is associated with decreased risk to infant.

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. Considerations for Breastfeeding: Brexanolone

•Relative infant dose in breast milk 36 hours after brexanolone infusion is 1-2% •Oral bioavailability is low (<5%) •No data on effects of milk production or effects on breastfed infants

Hutcherson TC et al. Am J Health Syst Pharm 2020;77(5):336-45. 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

History of depression

Current depressive symptoms

Low income High Risk Young or single parenthood

US Preventive Services Task Force et al. JAMA 2019;321(6):580-7. 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 strategies B. Cognitive behavioral therapy C. Treatment with sertraline D. 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 profile B. Brexanolone has minimal effects on breast milk production C. Most antidepressants are not contraindicated during breastfeeding