Back Back
Expert Tips for PPD
Expert Tips for Identification and Clinical Management of Postpartum Depression

Released: December 22, 2023

Anita H. Clayton
Anita H. Clayton, MD, DLFAPA, IF
Activity Information

Activity

Progress
1
Course Completed
Continue
Key Takeaways
  • 10% to 16% of pregnant women experience episodes of depression triggered by normal hormonal changes associated with the perinatal and postpartum periods.
  • The Edinburgh Postnatal Depression Scale is a brief assessment that can be used to screen patients for depressive symptoms at routine clinical visits.
  • Neuroactive steroid GABA-A receptor–positive allosteric modulators are a new class of agents with the potential for rapid and sustained symptom improvement in women with postpartum depression after a short course of therapy.

Etiology and Risk Factors for Postpartum Depression
Postpartum depression (PPD) is a significant problem affecting 10% to 16% of pregnant women. This condition tends to stem from a genetic susceptibility in combination with environmental triggers, resulting in hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis and related inflammatory mechanisms, and also involves monoamines (dopamine, norepinephrine, and serotonin), neuroactive steroids, particularly γ-aminobutyric acid (GABA), and glutamate. Some women are more sensitive to normal hormonal changes occurring during the perinatal and postpartum periods, putting them at greater risk of developing depressive symptoms and the clinical phenotype of PPD.

The incidence of depression during pregnancy is twice that of the general population after the first trimester, including relapse in 70% of women who discontinue previous antidepressant therapy before or upon pregnancy. In the first 3 days after delivery, high levels of estrogen and progesterone/allopregnanolone experienced during pregnancy drop dramatically, leading to normal “baby blues” characterized by worry, unhappiness, emotional lability, crying, and/or fatigue in approximately 80% of new mothers. These symptoms typically last 1-2 weeks, but women sensitive to hormonal changes may progress into PPD, which is defined by the Diagnostic and Statistical Manual of Mental Disorders as an episode developing within 4 weeks of childbirth and lasting at least 2 weeks. The Edinburgh Postnatal Depression Scale (EPDS), consisting of 10 items including assessment of self-harm risk, can be a very useful screening tool during pregnancy as well as postpartum. In fact, among women experiencing depressive episodes 4-6 weeks postpartum, one third of these episodes began during pregnancy and one fourth began before pregnancy.

Treatment Options for PPD
The goal in managing either perinatal or postpartum depression is to reduce symptoms as effectively as possible and minimize exposure of the baby to both depression and medication. Oral antidepressants, most of which act as reuptake inhibitors for the neurotransmitters serotonin, dopamine, and norepinephrine, are available as standard of care. I let patients’ history drive treatment in women who have previously been treated for depression, meaning that if they develop symptoms, I first restart a medication that has been effective and tolerable for them in the past. For women who have experienced PPD with past pregnancies, I even recommend restarting medication soon after delivery in the absence of any current symptoms because of their high risk in that time period. It is preferable to maximize the dose of a single medication rather than giving lower doses of multiple agents, both for increased efficacy and to minimize potential adverse effects. Women demonstrate increased metabolism and increased volume of distribution during pregnancy, which may necessitate higher dosing as the pregnancy progresses to maintain therapeutic benefits. The EPDS is useful in monitoring of symptoms in response to treatment and for the need for dose increases. Finally, breastmilk exposure can be a consideration in treatment choice for women wishing to breastfeed; for example, sertraline levels in breast milk are low vs other antidepressants such as fluoxetine.  

Neuroactive steroids are a new class of agents available for the treatment of PPD. Brexanolone and zuranolone are allopregnanolone analogs that act as positive allosteric modulators of the GABA-A receptor, comprising 5 subunits forming a transmembrane ion channel. These increase chloride ion flow through synaptic GABA-A ion channels (benzodiazepines bind to different GABA-A synaptic receptors) for rapid effects, and act at extrasynaptic receptors for sustained efficacy. Enhancement of GABergic signaling is proposed to exert therapeutic effects on depressive symptomatology by inhibiting hyperactive neurotransmitter systems such as glutamate and reducing HPA axis activity.

Brexanolone, approved in 2019, is administered via IV infusion over 60 hours with gradual titrations up to and down from a maximum of 60 or 90 µg/kg/hour, followed by 12 hours of observation. Typical adverse effects during this time include headache, dizziness, and somnolence. Excessive sedation or loss of consciousness is a concern, and a Risk Evaluation and Mitigation Strategy (REMS) program is required. Patients are monitored with a pulse oximeter and assessed every 2 hours, and an additional caregiver must be available if the baby is present. Breastfeeding is paused but may be resumed 36 hours post infusion. We see very rapid responses to brexanolone infusion at 24 hours with continued improvements up to 60 hours. In phase III trials, approximately 50% to 60% of patients achieved remission at the end of the 60-hour infusion period compared with approximately 15% to 40% for placebo. Studies documented that symptom improvement was maintained at 30 days and, in clinical use, for extended periods.

Zuranolone, approved by the FDA just this year, is an oral agent targeting GABA-A in the same manner as brexanolone. It is taken once daily during a brief 14-day course, with recommended dosing in the evening as patients are advised not to drive for 12 hours following each dose. Patients tolerate it very well, with the most common adverse effects being somnolence, headache, dizziness, upper respiratory tract infection, diarrhea, sedation, and nausea. Two phase III trials, one using a 30-mg/day dose and one using 50 mg/day, found mean symptom improvement greater than placebo beginning at Day 3 (rapid) and continuing through Day 45 (sustained for 1 month after completing the 14-day course of treatment). Oral zuranolone has the advantage of convenience over brexanolone infusion, allowing mothers to continue caring for their babies at home during treatment, and potential concerns about sedation can be mitigated with evening dosing. Zuranolone is also not restricted by a REMS, so it may be more accessible to patients. Insurance coverage is uncertain at this time, but the lack of inpatient cost is a factor in its favor. Of note, women receiving oral antidepressants can continue to take them throughout and after brexanolone or zuranolone treatment, if desired. In addition, a 1-year open-label study of zuranolone for major depressive disorder has shown that 45% of patients receiving 30 mg/day and 50% of patients receiving 50 mg/day required only the initial 14-day course, with 70% and 80%, respectively, requiring 1-2 treatment courses in the year of follow-up.

Conclusion
The postpartum period, which the American College of Obstetricians and Gynecologists calls the “fourth trimester,” is a challenging time for women and should include routine monitoring for symptoms of PPD, potentially as part of pediatric “well baby” visits. Some women seem to be more sensitive to normal hormonal changes during pregnancy and childbirth, giving them greater vulnerability for depressive episodes during these risk periods. For mild to moderate PPD, standard-of-care oral antidepressants are effective and well tolerated, especially for patients who have responded to one previously. For moderate to severe PPD, neuroactive steroid GABA-A receptor–positive allosteric modulators are a treatment option. In this class, both brexanolone and zuranolone have shown rapid and sustained relief of PPD symptoms with a short course of therapy, likely by enhancing inhibition of the hyperactive hypothalamic–pituitary axis to restore neural network functioning. Other interventions such as lifestyle modifications, dietary changes, stress management, psychotherapy, and/or phototherapy can be combined with any of the pharmacotherapies and may provide the best outcomes in most women.

Your Thoughts
How do you discuss and monitor for PPD with your patients? Join the conversation by answering the polling question or providing a comment below.

Continue

Poll

1.

How comfortable are you managing PPD in your patients?

Submit