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PND and PPD Pathophysiology
Expert Insights on Diagnosing and Managing Perinatal and Postpartum Depression

Released: April 08, 2024

Expiration: April 07, 2025

Anita H. Clayton
Anita H. Clayton, MD, DLFAPA, IF
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Key Takeaways
  • Between 10% and 16% of women experience episodes of depression that are triggered by hormonal changes associated with pregnancy and the postpartum period.
  • Major depressive episodes may be initiated by synaptic dysfunction mechanisms, such as reduced monoamine (serotonin, norepinephrine, dopamine) function, dysregulation of the GABA/glutamate balance, changes in endogenous neuroactive steroids, a hyperactive hypothalamic-pituitary-adrenal axis, and inflammatory mechanisms.
  • Neurosteroids like brexanolone and zuranolone are a new class of FDA-approved agents to treat postpartum depression, showing rapid and sustained symptom improvement in clinical studies.

Perinatal depression is a significant problem—affecting 10% to 16% of women during pregnancy and/or after delivery. The DSM-5-TR diagnosis of a major depressive episode includes more than 2 weeks of either a depressed mood/sadness and/or loss of interest or pleasure, as well as experiencing 5 total symptoms, such as sleep disturbance, fatigue/low energy, change in appetite/weight, agitation or physical slowing, concentration problems, feelings of worthlessness or inappropriate guilt, and thoughts of death or suicidal ideation with significant functional impairment. The onset of perinatal depression typically presents during pregnancy or within 4 weeks of delivery. It tends to stem from a genetic susceptibility to normal hormonal changes in combination with environmental triggers, resulting in hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and related inflammatory mechanisms. Further, it involves monoamine dysfunction (dopamine, norepinephrine, and serotonin), changes in neuroactive steroids, and/or dysregulation of the gamma-aminobutyric acid (GABA) and glutamate balance. Because some women are more sensitive to normal hormonal changes that occur during pregnancy and the postpartum period, they are at greater risk of developing perinatal depression.

The incidence of depression after the first trimester is more than twice that of the general population, and approximately 70% of women who discontinue their antidepressant therapy before or upon becoming pregnant will experience relapse. In the first 3 days after delivery, the high levels of estrogen, progesterone, and allopregnanolone that were present during pregnancy will drop dramatically and lead to the commonly experienced “baby blues” that are characterized by emotional lability, worry, unhappiness, crying, and/or fatigue. Up to 80% of new mothers experience the “baby blues,” and their symptoms will typically last 1 to 2 weeks, resolving without treatment. But women who are sensitive to hormonal changes may progress into postpartum depression. The 10-item Edinburgh Postnatal Depression Scale (EPDS) that includes an assessment of self-harm risk can be a very useful screening tool during and after pregnancy. In fact, in women experiencing depressive episodes 4 to 6 weeks postpartum, 40% will have begun postpartum, 33% during pregnancy, and 25% before pregnancy.

Treatment Options for Perinatal and Postpartum Depression
The goal in managing either perinatal or postpartum depression is to reduce the symptoms as effectively as possible and minimize exposure of the depression and medication to the baby. Oral antidepressants, most of which act as reuptake inhibitors for serotonin, dopamine, and norepinephrine, should be used during pregnancy. For women who have previously been treated for depression and develop symptoms during pregnancy, restarting a medication that has been effective and tolerable for them in the past is appropriate. In the absence of symptoms during pregnancy among those who have experienced postpartum depression in the past and want to avoid it, restarting a previously effective dose of antidepressant medication on the day of their delivery is likely to be effective in preventing onset. 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 events (AEs). Women who demonstrate increased metabolism and volume of distribution during pregnancy may require higher dosing as their pregnancy progresses to maintain therapeutic benefit. The EPDS is useful to monitor symptoms in response to treatment and inform the need for increasing dosages. Finally, antidepressant therapy exposure to the breastmilk can be a consideration in treatment choice for women wishing to breastfeed; for example, sertraline levels in breastmilk have shown to be low when compared with other antidepressants like fluoxetine.

Neurosteroids are a new class of agents, and the only antidepressants that are approved by the FDA to treat postpartum depression. Brexanolone and zuranolone are allopregnanolone analogs, which act as positive allosteric modulators of the GABA-A receptor that is composed of 5 subunits, forming a transmembrane ion channel. These medications increase chloride ion flow through synaptic GABA-A ion channels (benzodiazepines bind to different GABA-A synaptic receptors) to induce rapid effects, and they act at extrasynaptic receptors to induce sustained effects. Enhancement of GABAergic signaling is speculated to exert therapeutic effects on depressive symptomatology by inhibiting hyperactive neurotransmitter systems, like glutamate, and reducing HPA axis activity.

Brexanolone was approved in 2019 and is administered via intravenous infusion over 60 hours, with gradual titrations up to a maximum of 60 or 90 mcg/kg/hour followed by 12 hours of observation. Typical AEs during this time include headache, dizziness, and somnolence. Excessive sedation or loss of consciousness is a concern, so a risk evaluation and mitigation strategy (REMS) program is required. Patients are monitored with a pulse oximeter and assessed every 2 hours; an additional caregiver must be available if the baby is present. Breastfeeding is paused but may be resumed 36 hours post infusion. Studies have shown rapid responses to brexanolone infusion compared with placebo, starting at 24 hours with continued improvements into 60 hours. In phase III trials, 50% to 60% of patients achieved remission at the end of the 60-hour infusion period vs 15% to 40% of those treated with placebo. Studies have also documented improved symptoms that are maintained at 30 days and in clinical use for extended periods.

Zuranolone is an oral agent that targets GABA-A in the same manner as brexanolone (allopregnanolone analogue) that was FDA approved in 2023. It is taken once daily for 14 days, preferably in the evening as patients are advised not to drive for 12 hours following each dose. Studies have shown that patients tolerate this agent very well, with the most common AEs being somnolence, headache, dizziness, upper respiratory tract infection, diarrhea, sedation, and nausea. Two phase III trials, one studying a 30 mg/day dosage and the other 50 mg/day, found mean symptom improvement greater than placebo beginning at Day 3—which is rapid—and continuing through Day 45. Therefore, symptom improvement is sustained for 1 month after completing the 14-day treatment course (and remember, most antidepressant clinical trials last 6 weeks). Oral zuranolone has the advantage of convenience over brexanolone infusion, allowing mothers to continue caring for their babies at home during treatment. Further, any potential concerns about sedation due to zuranolone can be mitigated with evening dosing, and it is not restricted by requiring a REMS program. Insurance coverage for this agent is currently under consideration, but the lack of inpatient costs is a factor in its favor. Of note, women on oral antidepressants can continue their treatment throughout and following brexanolone or zuranolone treatment if desired. In a 1-year open label study of zuranolone 30 mg/day for major depressive disorder, 45% of participants required only the initial 14-day course of treatment vs 70% who required 1 to 2 14-day treatment courses over a year. Further, in patients taking zuranolone 50 mg/day, 50% needed only the 14-day course vs 80% who needed an additional treatment course in the year of follow-up.

Conclusion
The postpartum period, which the American College of Obstetricians and Gynecologists calls the “fourth trimester” (or the 12 months following delivery), can be a challenging time for women and should include routine monitoring for symptoms of postpartum depression that could be part of pediatric “well-child” visits. Some women are more sensitive to the hormonal changes surrounding pregnancy and childbirth, making them more vulnerable to depressive episodes during these risk periods. They may also be sensitive to other hormonal changes, such as with hormonal contraceptives, premenstrual dysphoric disorder, and perimenopause. For mild to moderate postpartum depression and general depression during pregnancy, standard of care oral antidepressants are effective and well-tolerated—although not FDA approved to treat postpartum depression—especially for patients who have previously responded to this therapy. For moderate to severe postpartum depression, neurosteroids are a treatment option. Both brexanolone and zuranolone have shown rapid and sustained symptom relief with a short course of therapy. Other interventions like lifestyle modifications, dietary changes, stress management, psychotherapy, and/or phototherapy can be combined with any of the previously discussed pharmacotherapies to provide the best outcomes for women.

Learn More
Please join us at CCO’s Psychiatry Summit 2024 to learn more about postpartum depression and other topics with CME/CE-certified live virtual presentations and downloadable slidesets from expert faculty.

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