ABSTRACT
The 2023 American College of Obstetricians and Gynecologists (ACOG) guideline on perinatal mental health conditions recommends prescribing and titrating pharmacotherapy for perinatal depression, with the selective serotonin reuptake inhibitors sertraline and escitalopram as first-line medications for patients who have not previously taken any medications for mood disorders. A subsequent ACOG Clinical Practice Update addresses zuranolone for postpartum depression. The authors present an overview of the guideline’s recommendations on pharmacotherapy for treating perinatal depression and summarize actionable recommendations for nonpsychiatric clinicians.
Selective serotonin reuptake inhibitors are recommended as first-line pharmacotherapy for perinatal depression; serotonin norepinephrine reuptake inhibitors are reasonable alternatives.
Continue or represcribe previously effective pharmacotherapy. If newly initiating pharmacotherapy, sertraline or escitalopram is recommended.
When prescribing and titrating pharmacotherapy, use a validated screening tool to monitor treatment response with the goal of symptom remission.
Zuranolone, a synthetic allopregnanolone analogue, can be considered for postpartum patients with depression who may benefit from rapid medication onset.
Perinatal depression is defined as a major depressive disorder that occurs during pregnancy or within 4 weeks after delivery,1 though most clinical experts suggest extending the time period to 12 months postpartum.2 Due to abrupt declines in progesterone levels after delivery, perinatal depression can differ physiologically from depression not related to pregnancy. An estimated 10% of pregnant and 21.9% of postpartum patients experience depression,3 yet only 20% receive adequate treatment.4 Patients who discontinue antidepressants during pregnancy have a higher risk of depression than those who continue pharmacotherapy.5 The Edinburgh Postnatal Depression Scale is effective at identifying patients with postpartum depression.3
See related editorial, page 207
This article summarizes recommendations pertaining to pharmacotherapy for perinatal depression from the 2023 American College of Obstetricians and Gynecologists (ACOG) clinical practice guideline.2 Other psychiatric conditions that can develop during the perinatal period, including bipolar disorder, anxiety disorders, and postpartum psychosis, are discussed in the guideline but not reviewed here.
While the 2023 ACOG guideline recommended consideration of intravenous brexanolone, a synthetic progesterone metabolite and the first medication approved by the US Food and Drug Administration (FDA) specifically for postpartum depression, it was removed from the commercial market in January 2025.6 A similar oral agent, zuranolone, was approved by the FDA in August 2023 to treat depression in postpartum patients. ACOG recently published a Clinical Practice Update7 on zuranolone because it was approved after the 2023 guideline was released. Evidence on zuranolone and its utility in clinical practice is also discussed here in the context of the guideline recommendations.
WHO IS THE INTENDED AUDIENCE?
The updated 2023 guideline primarily addresses obstetricians and physicians caring for pregnant and postpartum patients, but the recommendations are relevant for any clinician caring for a patient in the preconception, pregnancy, or postpartum periods. As primary care clinicians play a key role in supporting mental health during the perinatal period, including prescribing medications such as selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) and facilitating referrals to psychotherapy, this guideline is applicable to many nonpsychiatric clinicians.
WHO WROTE THE GUIDELINES?
The original 2007 ACOG guideline on the use of psychiatric medications during pregnancy and lactation was updated in 2008.8 The 2023 guideline2 provides updated evidence-based recommendations from a guideline committee that was composed of obstetricians, with consultation from 2 psychiatrists. The guideline includes recommendations for pregnant or postpartum individuals with depression; anxiety and anxiety-related disorders; bipolar disorder; and acute psychosis with onset predating pregnancy, onset or exacerbation during pregnancy, or 1 year post partum.
WHAT ARE THE MAIN RECOMMENDATIONS?
A validated screening tool should be used to monitor treatment response and titrate medications to achieve the goal of symptom remission when using pharmacotherapy. In a sequential case series of 10,000 mothers, 1,396 had a positive screening result on the Edinburgh Postnatal Depression Scale (score ≥ 10), and 68.5% were subsequently diagnosed with unipolar depressive disorder.3 Most (66%) had a comorbid condition, of which 82.9% were anxiety disorders.
Pharmacotherapy, psychotherapy, or both are recommended as first-line treatment for perinatal depression. Many perinatal depression treatment recommendations are extrapolated from those for the general population.9,10
SSRIs are recommended as first-line pharmacotherapy, and SNRIs are reasonable alternatives during pregnancy and post partum.
A randomized controlled trial of 254 women in England with postpartum depression (defined as Edinburgh Postnatal Depression Scale score ≥ 13) compared pharmacotherapy using 1 of 5 first-line SSRIs with “listening visits.” Participants initially randomized to pharmacotherapy were more likely to have improved Edinburgh Postnatal Depression Scale scores (< 13) after 4 weeks vs those receiving listening visits (45% vs 20%, odds ratio 3.4, 95% confidence interval 1.8–6.5, P < .001).11
Sertraline and escitalopram are the recommended first-line medications for patients with no previous pharmacotherapy use. Sertraline is preferred because of its well-established safety profile and high remission rates. In a randomized controlled trial of 36 participants with postpartum depression, 59% of those receiving sertraline 50 to 200 mg for 6 weeks demonstrated clinical response (defined as Hamilton Depression Rating Scale score ≤ 10, 50% reduction in baseline score, and improvement in Clinical Global Impression score) compared with 26% of the placebo group (P = .05).12 Increased remission rates (Hamilton Depression Rating Scale score ≤ 7) were seen in 53% of the sertraline group vs 21% of the placebo group (P = .05).
The guideline also recommends escitalopram as an alternative because it is safe, effective, and well tolerated.
Reinitiation of a previously effective medication should be considered as first-line treatment during pregnancy or post partum.
Withholding or discontinuing antidepressant medications during pregnancy or due to lactation status alone is not recommended, as discontinuation is associated with an increased risk of depression and destabilization.5 Additional risks of discontinuation include preterm birth, impaired infant attachment, and suicide, and these risks must be balanced against the low risk of persistent pulmonary hypertension of the newborn and transient neonatal adaptation syndrome.2
Evidence suggests that the benefits of pharmacotherapy outweigh the risks. Studies have shown small, inconsistent associations between SSRIs and SNRIs and neonatal risks.2 While some studies evaluate specific antidepressant medications separately, many combine several SSRIs and SNRIs and study their effects compared with no antidepressant use. This makes it difficult to compare them directly. Exposure to SNRIs in the first trimester may carry a small increased risk of preeclampsia and spontaneous abortion. First-trimester paroxetine exposure may be associated with an increased risk of birth defects compared with other SSRIs.8
A cohort study of 949,504 women enrolled in Medicaid evaluated first-trimester antidepressant medication exposures and found no increased risk of infant cardiac malformations in those taking SSRIs (odds ratio 1.06, 95% confidence interval 0.93–1.22) or SNRIs (odds ratio 1.20, 95% confidence interval 0.91–1.57).13 There is also little evidence that suggests SSRIs or SNRIs increase the risk of postpartum hemorrhage.2
Overall, the benefits of treatment are clear, whereas the risks of first-line medications are small and inconsistently described.
Zuranolone, a daily oral synthetic allopregnanolone, should be considered for treating depression in postpartum patients with moderate to severe depression now that brexanolone, which was included in the 2023 guideline, is no longer commercially available.
Postpartum depression is influenced by many physiologic and environmental factors, including hormones.14,15 Progesterone levels rapidly decline after childbirth. Reduction of allopregnanolone, a progesterone metabolite, is associated with postpartum depression via reduced modulation of gammaaminobutyric acid A receptors.16,17 Given this understanding of unique hormonal contributions to the pathophysiology of postpartum depression, novel neurosteroid treatments have been of great interest. FDA approval of the first oral medication for postpartum depression is an advancement in treatment.
Phase 3 randomized controlled trials have compared zuranolone with placebo for severe postpartum depression.16,17 In 150 patients who were 6 months or less post partum and had depression onset between the third trimester and 4 weeks after delivery, zuranolone 30 mg for 14 days improved Hamilton Depression Rating Scale scores compared with placebo at day 15 (least squares mean difference −4.2, 95% confidence interval −6.9 to −1.5, P= .003).16 Significant improvement was observed from days 3 through the end of the 45-day follow-up period.
A separate study evaluating zuranolone’s efficacy on symptom improvement in patients with major depressive disorder outside of the perinatal period found improvement with a once-daily 50-mg dose.18 This prompted evaluation of zuranolone 50 mg for postpartum depression.17 In 196 patients with postpartum depression receiving zuranolone 50 mg for 14 days, Hamilton Depression Rating Scale scores similarly improved at day 15 compared with placebo (least squares mean difference −4.0, 95% confidence interval −6.3 to −1.7, P = .001), with improved remission rates from days 3 through 45.17
Treatment-emergent adverse events were reported by 60.2% of participants receiving zuranolone 50 mg compared with 41.8% for placebo; dizziness and somnolence were the most common.17 Fifteen percent of patients in both the zuranolone 50-mg and placebo groups took concomitant antidepressants, which were mostly SSRIs (68.2% and 94.1%, respectively). Lower adverse event rates were reported in those taking lower doses (30 mg and 40 mg).16,19
WHAT DIFFERS FROM PREVIOUS GUIDELINES?
The most impactful change from previous guidelines is the recommendation to use pharmacotherapy for perinatal mood disorders. The 2008 guideline8 reviewed the safety data of SSRIs, SNRIs, benzodiazepines, tricyclic antidepressants, and mood stabilizers to treat perinatal mood disorders but did not recommend pharmacotherapy. The 2023 guideline2 updated the recommendation to initiate and titrate medications for perinatal depression based on data from several trials.
DO OTHER SOCIETIES AGREE OR DISAGREE?
The third edition (2010) of the practice guideline for the treatment of patients with major depressive disorder from the American Psychiatric Association20 includes a section on pregnancy and postpartum. Similar to the 2023 ACOG guideline, the American Psychiatric Association recommends pharmacotherapy for treating depression with onset before pregnancy, favoring a particular antidepressant that has worked for the patient in the past and using a single agent whenever possible. For patients with new-onset perinatal depression, the American Psychiatric Association describes, but does not explicitly recommend, prescribing antidepressants according to the same principles for other types of major depressive disorders.
HOW WILL THIS CHANGE DAILY PRACTICE?
Mental health conditions are a leading cause of perinatal mortality,7 yet few clinical trials have been conducted on effective treatments during pregnancy. Identifying and treating perinatal depression decreases the risk of substance use, disengagement in care, low birth weight, preeclampsia, relationship disruption, self-harm, and suicide.2
Universal screening for perinatal depression
Clinicians should screen all perinatal patients for depression by using a validated instrument. The Edinburgh Postnatal Depression Scale and Patient Health Questionnaire-9 are easily administered and effective at identifying patients with perinatal depression.2,3
Patients who have a positive screening result, or those who report depression symptoms, should be assessed with a careful history of past diagnoses and treatment trials, including medications (dosages, effectiveness, side effects) and psychotherapy. Patients with perinatal depression symptoms who are already taking an SSRI or SNRI should continue treatment, and the dose should be titrated up. Those who were previously treated with an effective SSRI or SNRI should be restarted on the lowest dose and titrated up until symptom remission. For medication-naive patients, the guideline recommends starting first-line treatment with sertraline or escitalopram, reevaluating within 4 weeks, and titrating up to symptom remission (Table 1).2
First-line pharmacotherapy options for perinatal depression
Patients should be referred to a psychiatrist if they develop significant side effects or treatment resistance to an SSRI or SNRI, or have a history of or active bipolar disorder, postpartum psychosis (a psychiatric emergency), or postpartum obsessive-compulsive disorder.
Selecting the right medication
SSRIs and SNRIs remain affordable, accessible, and safe for the duration of perinatal depression. Given the high prevalence and low treatment rates of perinatal depression, implementing these recommendations has the potential to benefit patients, neonates, and families, with minimal risk.
Strategies to optimize medication response and minimize side effects include the following:
Select a single agent
Start with the lowest dose and titrate up
Monitor response with validated instruments such as the Edinburgh Postnatal Depression Scale
Minimize medication transitions
Avoid discontinuing effective medications due to pregnancy alone
Provide psychotherapy and social support.
Zuranolone should be considered for postpartum patients who experience significant SSRI or SNRI side effects, those already on a high-dose SSRI or SNRI, or those who would benefit from rapid medication onset. Although few patients in zuranolone trials took concomitant SSRIs, limiting interpretation of its efficacy in SSRI-refractory postpartum depression, a 2024 indirect treatment comparison estimated that postpartum depression treatment with zuranolone resulted in larger decreases in Edinburgh Postnatal Depression Scale scores compared with SSRIs.21
The recommended starting dose is 50 mg, which can be titrated down to 40 mg if a patient experiences significant side effects such as dizziness or somnolence.19 The dose should be reduced to 30 mg for patients with severe hepatic impairment (Child-Pugh class C liver cirrhosis), estimated glomerular filtration rate less than 60 mL/min/1.73 m2, or concurrent use of a strong cytochrome P450 3A4 inhibitor.19 Similar improvements were seen at 15 days in patients taking 30-mg and 50-mg doses,16,17 though the doses were not directly compared with each other or against first-line SSRIs.
Of note, zuranolone may require insurance prior authorization and is only available from specialty pharmacies, necessitating prescriber familiarity or assistance from an experienced pharmacist.
Further studies are needed to better understand the safety and efficacy of pharmacotherapy, including SSRIs and SNRIs, for perinatal depression. Additional zuranolone studies are also warranted, especially comparing its effectiveness with SSRIs or SNRIs, effectiveness between doses, administration during pregnancy, safety and efficacy with adjunctive therapies, benefits beyond 45 days, and effects on lactation.
WHEN WOULD THE GUIDELINES NOT APPLY?
The transient depressive condition immediately after childbirth that lasts 10 days or less, colloquially referred to as postpartum blues, does not meet the criteria for perinatal depression and does not require medication.20 Patients who develop depression symptoms in the perinatal period and have a history of mania or other prior psychiatric diagnosis should be treated according to standard guidelines for either bipolar disorder or the preceding psychiatric diagnosis.
DISCLOSURES
The authors report no relevant financial relationships which, in the context of their contributions, could be perceived as a potential conflict of interest.
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