Espresso: Zuranolone for Postpartum Depression

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We’re back! While we’ll operate for a bit on a reduced schedule (new episodes every-other-week), we are so excited to get back to podcasting and covering the need-to-know in OB/GYN. Thanks for all the love and support over the last few months! <3 Nick & Fei

Reading: Zuranolone for the Treatment of Postpartum Depression (ACOG Practice Advisory)

What is zuranolone and why is it important? 

    • We know that postpartum/perinatal mental health conditions and some of the leading causes of preventable maternal mortality 

      • PPD affects approximately 14% of women 

      • Understanding/discussing/recommending medication and treatment can potentially decrease maternal morbidity and mortality 

  • Medication type

    • Neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive modulator 

    • Oral medication  

    • Recent FDA approval for use in PPD 

Why is zuranolone recommended, and what else is out there? 

  • Why is it recommended? 

    • Two phase 3 randomized double-blind, placebo-controlled multicenter studies 

    • Primary endpoint in both: change in depressive symptoms in the Hamilton depression rating scale (HAMD-17) 

      • 17 point scale 

      • Assesses somatic (physical ie. loss of appetite), affective (mood ie. sadness), cognitive (thinking, ie. difficulty concentrating), and behavioral (ie. social withdrawal) symptoms of depression 

      • Reliable and valid method of assessing and measuring depression 

    • In both studies, those on Zuranolone showed significantly more improvement in their symptoms compared those in placebo 

      • Treatment effect maintained at day 42 (4 weeks after last dose of zuranolone) 

  • Why the HAMD-17? 

    • More used in research settings, but anticipated that other validated tools (like EPDS or PHQ9) will be used in clinical settings 

  • What else is out there? 

    • Brexanolone - first FDA approved medication specifically for postpartum depression

      • However, unlike zuranolone which is oral, brexanolone consists of a 60 hour in-hospital IV infusion, which may not be readily accessible 

        • May be difficult to arrange inpatient admission 

        • May also be difficult for patients to leave their newborns for 60 hours to get infusion 

    • SSRIs 

      • Not specific for postpartum/perinatal depression 

      • Can be effective, but also may be difficult to find the correct SSRI

      • Many SSRIs also require uptitration of dosage 

  • What to consider when prescribing zuranolone 

    • Consideration of zuranolone in the postpartum period (within 12 months postpartum) for depression that has onset in the third trimester or within 4 weeks postpartum

    • Benefits: 

      • Significantly improved and rapid resolution of symptoms 

    • Risks: 

      • Potential suicidal thoughts or behavior 

      • Sedation - can make it so you can’t drive 

      • Lack of efficacy data beyond 42 days 

  • How to prescribe and take zuranolone 

    • Daily recommended dose is 50 mg 

      • Take in evening with fatty meal (400-1000 calories, 25-50% fat) for 14 days 

      • Can reduce dose to 40 mg if CNS depression effects occur 

      • If hepatic or renal impairment, start dose at 30 mg 

    • Can be used alone or as an adjunct to other oral antidepressant therapy like SSRIs 

    • Recommendation is to have effective contraception during treatment and for 1 week after final dose. There is a registry if pregnancy occurs 

    • Warn patients about adverse reactions 

      • Impaired ability to drive 

      • CNS depressant effects 

      • Increased suicidal thoughts and behaviors 

    • Zuranolone does pass into breastmilk, but relative infant dose is smaller than that of SSRIs 

Premenstrual Dysphoric Disorder (PMDD)

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Great Pearls of Exxcellence article about this from Society for Academic Specialists in General Ob/Gyn (SASGOG).If you haven’t heard of the Pearls of Exxcellence, go and check it out! Great review for CREOGs and boards.

Background

  • What is PMDD? 

    • You have probably heard of premenstrual syndrome (PMS) 

      • PMS: wide variety of signs and symptoms that occur in a predictable pattern usually before or during menses 

        • Symptoms/signs: mood swings, tender breasts, food cravings, fatigue, irritability, depression 

        • Can affect up to 3 out of 4 menstruating people 

        • Estimated that 15-20% of patients who have PMS will have PMS that significantly impairs functioning 

    • PMDD is a more severe form of premenstrual syndrome, according to the DSM-V 

      • Usually appears the week before menstruation and end within a few days of menses starting 

      • Will involve at least one severe affective symptom such as depression, hopelessness, anxiety, affective lability, or persistent anger that resolves around time of menses onset 

      • But not just mood, it can involve multiple systems (don’t have to list all of them, just some) 

        • Psychological symptoms 

          • Irritability, nervousness, feeling of lack of control, anger, insomnia, difficulty concentrating, severe fatigue, depression, anxiety, confusion, forgetfulness, paranoia, emotional sensitivity

        • Respiratory problems 

          • Allergies, infections 

        • Eye problems 

          • Vision changes 

        • GI symptoms 

          • Abdominal cramping, bloating, constipation, nausea/vomiting, pelvic heaviness or pressure, backache 

        • Skin symptoms 

          • Acne, itching, aggravation of other skin disorders (ie. coldsores) 

        • Neurologic/vascular symptoms 

          • Headache, dizziness, fainting, numbness, tingling, heart palpitations, muscle spasms 

        • Other 

          • Painful menstruation, diminished sex drive, appetite changes, food cravings, hot flashes, weight gain/swelling, breast tenderness/pain 

      • Approximately 3-8% of patients who menstruate will have PMDD 

  • Differential diagnosis 

    • Diagnosis of PMDD 

      • As discussed above, can be any of those symptoms + one severe affective symptom 

      • Be coordinated with timing of menses (onset prior to menses and resolves within a few days of menses) 

      • Demonstrates a history of two consecutive menstrual cycles in exclusion of other medical conditions 

    • Should rule out primary mood or anxiety disorders, thyroid function, substance abuse, and menopausal transition

      • This means that we need to take an extensive history and do a physical exam to rule out these other possibilities 

      • Other tests that you may want to order depend on patient symptoms 

        • Ie. excessive fatigue/insomnia/temperature dysregulation, weight gain, etc: rule out thyroid disorders 

        • If concerns for premenopausal transition, can order FSH/estrogen

        • If concerns for heavy bleeding, irregular bleeding, depending on situation may need to do endometrial biopsy, etc

        • We won’t go into everything here, as we have other episodes that discuss how to manage AUB 

        • If you think the patient has a mood disorder that is not due to menstrual cycle, can be a reason to start treatment, refer to psychiatry/psychology 

What are some conservative ways to manage PMDD? 

  • A word on management 

    • As with many chronic conditions in medicine, the goal of treatment is to improve patient function and symptoms, with the understanding that we may not be able to make symptoms go away 100% 

    • Often, it may not be a single management method that helps but a combination 

  • Lifestyle modifications 

    • Diet 

      • Some evidence that diet can affect severity of PMS and PMDD - doesn’t mean that eating certain foods will cause PMDD, but there is a possibility that certain dietary modifications can reduce severity 

      • Reduction of sugar, salt, red meat, caffeine, and alcohol may reduce PMDD symptoms 

      • Some evidence that calcium and vitamin B6 supplementation can benefit 

    • Exercise 

      • Aerobic exercise can improve PMDD symptoms 

      • One study showed that women that did 60 minute aerobic exercise 3x/week for 8 weeks felt much improved physically, mentally, and emotionally 

      • A systematic review and meta-analysis shows that there is likely some improvement in symptoms, but some uncertainty remains: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465566/

    • Adjunct/alternative treatments 

      • Some studies, but no enough evidence at this time to recommend routinely the following: 

        • Massage, biofeedback, yoga, chiropractic manipulation, evening primrose oil and Chinese herbal medicines 

        • If patients find these work for them, they can continue 

      • Things that have some limited evidence that they may work: bright light therapy, stress reduction, and adequate sleep 

      • Low quality evidence suggests that acupuncture may reduce symptoms of PMDD 

  • Cognitive behavioral therapy

    • Can be effective 

    • Group psychoeducation and relaxation therapy may benefit patients with significant stress or anxiety component 

  • Pharmacologic Therapy/Medication 

    • Psychoactive therapy 

      • Selective serotonin reuptake inhibitors (SSRIs) have been shown to be very effective and are first line treatment for PMDD 

      • Results in response in 60-70% of patients 

      • You can try both continuous or just luteal phase SSRIs 

      • No single agent has been shown to be better than the other 

      • First line therapy include sertraline, paroxetine, citalopram, escitalopram, and fluoxetine 

      • Second line: venlafaxine, alprazolam 

    • Hormonal therapies 

      • Combined oral contraceptives have shown mixed effects in RCTs 

        • Both cyclic and extended regimens inhibit ovulation and may reduce physical symptoms 

      • For patients who desire contraception, COC is reasonable first line therapy with addition of SSRI if needed 

      • Drospirenone-containing COC formulations are specifically FDA approved for treating PMDD, with 48-60% of patients reporting significant improvement 

    • NSAIDs 

      • May be useful to manage physical symptoms 

More advanced therapies 

  • GnRH agonists 

    • Example: leuprolide 

    • Has been shown to be effective for ovulation suppression and physical symptoms of PMDD 

    • Long term use should be approached with caution, and only after informed consent 

    • Reasoning: side effects (ie. hot flashes), and irreversible bone loss 

  • Surgery 

    • If patient has disabling symptoms refractory to other medical therapies, oophorectomy can be considered 

    • A 3-6 month trial of GnRH agonist demonstrating efficacy is a prerequisite to surgical treatment 

    • Must discuss risks and benefits, given oophorectomy in younger women can be associated with multiple morbidities such as cardiovascular events and osteoporosis

Perinatal Mental Health, feat. Dr. Tiffany Moore-Simas and Dr. Nancy Byatt

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Today on the podcast, we’re addressing perinatal mental health. While we’ve talked about depression on the show before, there’s so much more in this sphere as we’ll discuss today.

 

Joining us are two experts in this field who share their passion for this work with us. Dr. Tiffany Moore Simas is Chair and Professor of OB/GYN at UMass Memorial Health and UMass Chan Medical School as well as co-Chair of the ACOG Maternal Mental Health Expert Work Group. And Dr. Nancy Byatt is a tenured Professor of Psychiatry and OB/GYN at UMass Memorial Health and UMass Chan Medical School. Both serve as senior leaders with the Massachusetts Perinatal Psychiatry Access Program, MCPAP for Moms, and Lifeline For Moms.

 

Importance of Perinatal Mental Health

  • Mental health conditions are the most common complications of pregnancy – 1 in 5!

    • More common in adolescents, veterans, marginalized populations (BIPOC, poverty).

  • Untreated mental health conditions carry both short- and long-term consequences that can affect whole family:

    • o   Less engagement in medical care

    • o   Smoking, substance use

    • o   Preterm delivery, low birth weight, NICU admission

    • o   Lactation challenges, bonding issues

      • Parent with untreated mental health disorder is considered an Adverse Childhood Experience (ACE) for the infant.

    • o   Adverse partner relationships

  • Mortality: leading cause of preventable maternal mortality.

    • 100% of maternal deaths due to mental health, including suicide, overdose, are preventable!

  • Underdetected and undertreated

  • OB/GYNs can screen and help manage mental health conditions. The majority (80%) of depression, for example, is managed by primary care providers, not psychiatrists. As obstetric care clinicians, we are the primary care providers to pregnant and postpartum individuals and thus, we should be providing mental health care!

Screening for Perinatal Mood and Anxiety Disorders

  • In this context, perinatal refers to during pregnancy and the first year after pregnancy ends

  • Perinatal Mood and Anxiety Disorders primarily include depression, bipolar disorder, and anxiety or anxiety-related conditions (generalized anxiety disorder, PTSD, OCD).

  • Screens should be performed with validated tools that query the last 7-14 days of symptoms for anxiety and depression.

    • o   Validated tools:

      • PHQ-9, EPDS (depression)

      • GAD-7 (generalized anxiety)

    • o   ACOG recommends screening patients at least once during the perinatal period for depression and anxiety symptoms. If a patient is screened during pregnancy, additional screening should occur during the comprehensive postpartum visit.

      • We recommend screening: new OB visit, later in pregnancy (i.e., 3rd trimester) and postpartum given the almost even distribution of onset predating pregnancy, onset in pregnancy, and onset postpartum.

    • o   Data suggests that early detection and treatment improves outcomes.

  • Bipolar disorder screening:

    • o   In one study, 1 in 5 patients screening positive for postpartum depression actually had bipolar disorder.

      • Recall: bipolar disorder can worsen with antidepressant treatment (unopposed SSRIs) – thus, need to screen for bipolar before initiating pharmacotherapy and ideally universally to prevent harm!

    • o   Patients with bipolar disorder have higher risk of postpartum psychosis

      • Rare: 1-2/1000 perinatal individuals; but 70% have bipolar disorder!

      • 4% risk of infanticide with postpartum psychosis

      • This is a psychiatric emergency.

        • Often occurs within the first days of delivery and most cases occur within the first 3 weeks.

    • o   Screening options:

      • Mood Disorder Question (MDQ) – self administered

      • CIDI – clinician administered with branching logic

    • o   Appropriate to refer to psychiatry if bipolar disorder is suspected – more on resources to help later!

Positive Screening   General Principles of Treatment

  • Just like a glucola, our questionnaires for mental health concerns are screening tests. Subsequent assessment is critical to confirm diagnosis.

    • o   See resources collection at the end of these notes for help!

  • For depression and anxiety, there are three pillars of treatment:

    • o   Psychotherapy

    • o   Pharmacotherapy or medication

      • o   Adjunctive interventions

  • Treat based on level of severity. For information on assessing and treating perinatal mental health conditions, visit the ACOG website.

  • If pharmacotherapy is indicated/started, patients may have some concerns:

    • o   Provide reassurance

    • o   Frame risk/benefit discussion in treated disease vs. untreated disease as not treating is associated with risks - just like any other disease!

    • o   Use lowest effective dose and monotherapy when able

  • Find more information on educating patients about treatment on ACOG’s website.

Concerns for Suicidality or Harm To Baby

  • These can represent urgent clinical scenarios and further assessment and response is critical:

    • o   Thoughts of harming self or baby are common yet not all are necessarily a psychiatric emergency.

    • o   When assessing for risk of harm to self or others it is important to assess:

      • Ideation – Do they have thoughts of harming themselves or someone else?  Are the thoughts fleeting or do they persist?

      • Intent – Are they intending to act on it? Have they thought of how they could do harm themselves or someone else or die by suicide?

      • Plan - Are they planning to act on it?  Have they developed a plan for how to die by suicide or to harm someone else?

    • o   If you are concerned that the patient is at risk of harm to self or others, then it is important to obtain further assessment which includes an evaluation for whether the patient may need psychiatric hospitalization

    • o   Regardless of whether these are a psychiatric emergency, the presence of thoughts of harming self or baby are indicative of higher illness severity.

  • More information on ACOG’s website.

 Resources for Integrating Perinatal Mental Health Care into Your Practice

 

Perinatal Depression

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Depression is a major health disorder affecting around 10% of women, particularly in the perinatal and postpartum periods. Depression is twice as common in women as in men, and OB/GYNs should be familiar with its diagnosis and management, particularly in the perinatal period. You can read more with ACOG CO 757.

There are many different types of depression diagnoses, including: major depressive disorder, persistent depressive disorder, seasonal affective disorder, perinatal (postpartum) depression, premenstrual dysphoric disorder (PMDD), etc. According to the DSM-V, a major depressive episode is diagnosed when one has: 

  • Five (or more) of the following symptoms have been present for a 2-week period and represent a change from previous functioning; at least one of the symptoms is either depressed mood or loss of interest/pleasure. 

  • Symptoms cannot be explained by medications or another medical illness (i.e., hypothyroidism).

  • The remaining (need 4+ from this list):

    • Depressed most of the day, nearly every day as indicated by subjective report or observation made by others;

    • Diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day;

    • Significant weight loss when not dieting or weight gain, or increase/decrease in appetite nearly every day;

    • Insomnia or hypersomnia;

    • Psychomotor agitation or retardation; 

    • Fatigue or loss of energy;

    • Feelings of worthlessness or inappropriate guilt;

    • Decreased ability to think/concentrate;

    • Recurrent thoughts of death/suicidal ideation.

Perinatal depression is defined separately as major and minor depressive episodes that occur during pregnancy or in the first 12 months after delivery. This is one of the most common medical complications during pregnancy and the postpartum period, affecting 1/7 women. 

Depression and other mood disorders can have devastating effects on women and their families: maternal suicide exceeds hemorrhage and hypertensive disorders as a cause of maternal mortality 

SO how do we screen for perinatal depression? ACOG recommends that obstetric care providers screen patients at least once during the perinatal period for depression and anxiety symptoms using a standardized tool, and again in the postpartum period during a comprehensive postpartum visit. There is evidence that screening alone can have clinical benefits for patients suffering with depression.

One of the most commonly used is the Edinburgh Postnatal Depression Screen, which is a 10 item survey that takes less than 5 minutes to complete. The sensitivity is estimated between: 59-100%, and specificity: 49-100%. A Spanish version is available.

The Patient Health Questionnaire 9 (PHQ-9) is another acceptable tool. Other items like the Postpartum Depression Screening Scale (PDSS) is more sensitive (91-94%) and specific (72-98%), but it is a 35 item survey and thus more time intensive.

Management of perinatal depression is a team sport, requiring multiple additional support members and medical team members. Medication prescription will vary for OB/GYNs and their comfort with this. In brief:

  • Women with current depression/anxiety or a history of perinatal mood disorder should have close monitoring, evaluation, and assessment.

  • Some OB/GYNs are comfortable starting antidepressant medication and following their patients, most commonly an SSRI. Psychiatry referral is also acceptable.

  • Referral to social work and behavioral health - possibly for psychotherapy, which alone is a reasonable alternative to antidepressants if needed.

  • For those with severe postpartum depression, another possibility is brexanolone.

    • Limited clinical experience and restricted availability 

    • Usually restricted to patients who do not improve with antidepressants