Zuranolone for the Treatment of Postpartum Depression

Abstract

Objective

To review the safety, efficacy, and tolerability of zuranolone for the treatment of postpartum depression.

Data Sources:

A literature search was conducted through PubMed using the following terms: zuranolone, postpartum depression, perinatal depression, SAGE-217, and allopregnanolone analogue.

Study Selection and Data Extraction

Articles describing the pharmacology, pharmacokinetics, efficacy, safety, and/or tolerability of zuranolone were included in this review.

Data Synthesis

Zuranolone is an allopregnanolone analogue that works through modulation of the GABA_A receptor. Clinical trials have demonstrated that compared with placebo, zuranolone is effective in treating patients with postpartum depression. Common adverse events associated with zuranolone include fatigue, somnolence, headache, dizziness, diarrhea, sedation, upper respiratory tract infection, and nausea.

Conclusions:

Pharmacotherapeutic options to treat postpartum depression include selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors, with the medication brexanolone (the first allopregnanolone analogue) reserved for severe postpartum depression. Zuranolone, the newest medication in its class, is without the same limitations as brexanolone, thus affording providers an additional easy-to-use option for treating postpartum depression.

Introduction

Postpartum depression (PPD), also known as perinatal depression, involves the onset of a major depressive disorder (MDD) either during pregnancy or in the weeks/months following the birth of a child. Psychotic features involving hallucinations or delusions may be present in 1 in 500 women who experience episodes of postpartum depression. ¹ In the United States, ~20% of women develop a mental health condition either during or after pregnancy, with up to 20% of those women reporting suicidal ideation. ² Unfortunately, many of these women remain untreated or undertreated, which can have devastating consequences on the baby (e.g., infanticide), the partner, and other children in the household. ³

Prevention of PPD in high-risk patients is key. Risk factors for the development of PPD include personal or family history of depression or anxiety, difficult pregnancy, birth of multiples, relationship or financial difficulties, lack of social support, and unplanned pregnancy. ⁴ Psychotherapy, such as cognitive behavioral therapy, should be instituted first for patients with mild to moderate PPD. ³ Cognitive behavioral therapy helps patients identify triggers for depression and anxiety and coping strategies that can help them react to situations differently. ⁵ If pharmacotherapy is required, selective serotonin reuptake inhibitors (SSRIs) are recommended. Previous antidepressant use/response should be considered; if such information is not available, sertraline or escitalopram is the drug of choice. Serotonin-norepinephrine reuptake inhibitors (SNRIs), such as duloxetine or venlafaxine, are considered potential alternatives to SSRIs. ³ However, some data suggest that SNRIs may be associated with preeclampsia and spontaneous abortion. ⁶ Clinicians should be mindful of the delay in response associated with SSRIs and SNRIs (4–8 weeks), further emphasizing the importance of psychotherapy.

For moderate to severe postpartum depression presenting in the third trimester or within 4 weeks of delivery, brexanolone may be considered. ³ Brexanolone is the first medication with a U.S. Food and Drug Administration (FDA) indication for the treatment of postpartum depression. Cost (~$34,000) and restricted access via an FDA Risk Evaluation and Mitigation Strategies (REMS) program may inhibit the use of this agent. In addition, brexanolone must be given as an intravenous infusion over 2.5 days (60 hours) in the inpatient setting.^3,7,8

Zuranolone is an allopregnanolone analogue, similar to brexanolone, and is indicated for the treatment of postpartum depression. ⁹ The use of zuranolone does not have the same limitations as brexanolone. It is available as an oral medication to be taken on an outpatient basis and does not require an FDA REMS program for administration. With its unique mechanism of action and improved accessibility, zuranolone provides patients and clinicians with an additional treatment option for women suffering from postpartum depression.

Data Selection

A literature search was conducted using PubMed with an end search date of July 31, 2024, with the following keywords: zuranolone, postpartum depression, perinatal depression, SAGE-217, and allopregnanolone analogue. All relevant English-language studies assessing the pharmacology, pharmacokinetics, efficacy, safety, and tolerability of zuranolone were reviewed. In addition, product information was obtained from FDA labeling.

Pharmacology

Zuranolone is a neuroactive GABA_A receptor modulator mimicking allopregnanolone. Although its mechanism of action is not fully understood, it is thought to work via positive allosteric modulation of the GABA_A receptors, which leads to an upregulation of GABA_A expression and enhanced GABA_A signaling. ⁹ Benzodiazepines have long been recognized as GABA_A receptor modulators, but they only affect synaptic GABA_A receptors that primarily contain the ɣ subunit. Zuranolone differs from benzodiazepines in that it modulates both synaptic GABA_A receptors and extrasynaptic GABA_A receptors. The extrasynaptic GABA_A receptors primarily contain the δ subunit—thus, the activity of zuranolone is not completely dependent on the ɣ subunit containing GABA_A receptors.^10,11

Pharmacokinetics

A summary of the pharmacokinetic parameters of zuranolone can be found in Table 1. Zuranolone is recommended to be taken at bedtime with a high-fat food, which increases the maximum concentration by 1.8 and the area under the curve by 4.3 compared with fasting absorption. The prescribing information describes high-fat food as 400 to 1000 calories, 25% to 50% fat. Zuranolone is highly metabolized by cytochrome P450 3A4 (CYP3A4). ⁹

Table 1.

Pharmacokinetic Parameters of Zuranolone.

Absorption
T max	5−6 h
Bioavailability	Not studied
Distribution
Volume of distribution	>500 L
Plasma protein binding	>99.5%
Metabolism
Elimination half-life	19.7−24.6 h
Enzymes involved	Extensive via CYP 3A4
Excretion
Route	Via urine and feces as metabolites

Source: Sage Therapeutics Inc. ⁹

Clinical Trials

Zuranolone has been studied for the treatment of PPD in two phase 3 clinical trials.^12,13 Detailed results of these trials can be found in Table 2. The primary outcome in both trials reported results of the Hamilton Depression Rating Scale (HAMD-17). For study enrollment, the baseline HAMD-17 score had to be ≥26, indicating severe depression. Response to treatment was defined as a ≥50% reduction in the HAMD-17 score, and remission was defined as a score of ≤7. Common secondary outcomes reported in clinical trials with zuranolone included results from other scales, including the Montgomery–Asberg Depression Rating Scale (MADRS), the Clinical Global Impression Severity (CGI) Score, and the Hamilton Anxiety Rating Scale (HAM-A).

Table 2.

Phase 3 Clinical Trial Results.

Reference	Study Design	Duration	Population Size (n)	Comparator	Results
Deligiannidis et al. 12	R, DB, PC, PG, MC	45 d	150	ZUR 30 mg or PBO	Primary endpoint: CFB on HAMD-17 on day 15 ZUR 30 (–17.8) vs PBO (–13.6); LSM difference, –4.2 (95% CI, –6.9 to −1.5; P = .003; effect size .53) Secondary endpoints: CFB on HAMD-17 on day 3 ZUR 30 vs PBO; LSM difference, –2.7 (95% CI, –5.1 to −0.3; P = .025) CFB on HAMD-17 on day 8 ZUR 30 vs PBO; LSM difference, –3.4 (95% CI, –6 to −0.8; P = .011) CFB on HAMD-17 on day 21 ZUR 30 vs PBO; LSM difference, –3.1 (95% CI, –6 to −0.3; P = .032) CFB on HAMD-17 on day 45 ZUR 30 vs PBO; LSM difference, –4.1 (95% CI, –6.7 to −1.4; P = .003) Proportion of patients achieving response: ZUR 30 72% vs PBO 48%; odds ratio (OR), 2.6 (95% CI, 1.3–5.2; P = .005) Proportion of patients achieving remission: ZUR 30 45% vs PBO 23%; OR, 2.5 (95% CI, 1.2–5.2; P = .01) CFB on MADRS on day 15 ZUR 30 vs PBO; LSM difference, –4.6 (95% CI, –8.3 to −0.8; P = .02) CGI response rate on day 15 ZUR 30 72% vs PBO 52%; OR, 2.2 (95% CI, 1.1–4.3; P = .03) CFB on HAM-A on day 15 ZUR 30 vs PBO; LSM difference, –3.9 (95% CI, –6.7 to −1.1; P = .006)
Deligiannidis et al. 13	R, DB, PC, PG, MC	45 d	170	ZUR 50 mg or PBO	Primary endpoint: CFB on HAMD-17 on day 15 ZUR 50 (–15.6) vs PBO (–11.6); LSM difference, –4.0 (95% CI, –6.3 to −1.7; P = .001; Cohen’s d = 0.52) Secondary endpoints: CFB on HAMD-17 on day 3 ZUR 50 vs PBO; LSM difference, –3.4 (95% CI, –5.4 to −1.4; P = .001) CFB on HAMD-17 on day 28 ZUR 50 vs PBO; LSM difference, –2.9 (95% CI, –5.4 to −0.5; P = .02) CFB on HAMD-17 on day 45 ZUR 50 vs PBO; LSM difference, –3.5 (95% CI, –6 to −1; P = .007) Proportion of patients achieving response; ZUR 50 57% vs PBO 38.9%; OR, 2.02 (95% CI, 1.11–3.67; P = .02) Proportion of patients achieving remission: ZUR 50 26.9% vs PBO 16.7%; OR, 1.78 (95% CI, 0.88–3.62; P = .11) CFB on MADRS on day 15 ZUR 50 vs PBO; LSM difference, –5.1 (95% CI, –8.4 to −1.7; P = .003) CFB on CGI on day 15 ZUR 50 vs PBO; LSM difference, –0.6 (95% CI, –0.9 to −0.2; P = .005) CFB on HAM-A on day 15 ZUR 30 vs PBO; LSM difference, –2.2 (95% CI, –4.2 to −0.3; P = .02)

R, randomized; DB, double blind; PC, placebo controlled; PG, parallel group; MC, multicenter; ZUR, zuranolone; PBO, placebo; CFB, change from baseline; HAMD, Hamilton Depression Rating Scale; LSM, least squares mean; MADRS, Montgomery–Asberg Depression Rating Scale; CGI, Clinical Global Impression Severity Score; HAM-A, Hamilton Anxiety Rating Scale

The ROBIN study was conducted to determine the safety and efficacy of zuranolone in treating PPD. ¹² In this study, 153 patients were randomized to receive zuranolone 30 mg or placebo once daily for 14 days. Patients were eligible if they were between the ages of 18 and 45 years, ≤6 months postpartum, experiencing an MDD episode beginning in their third trimester or ≤4 weeks postdelivery, had an HAMD-17 score of ≥26, and had agreed to postpone or discontinue breastfeeding through day 21. Use of concomitant antidepressants was permitted as long as patients had been on a stable dose for ≥30 days prior to initiation of zuranolone. Patients were excluded if they had a prior history of bipolar disorder or schizophrenia, if they were currently psychotic or had attempted suicide with the current episode of PPD, and if they had a history of alcohol or substance use disorder. The primary endpoint in this study was the change in HAMD-17 score from baseline to day 15 between the zuranolone-treated patients and those receiving placebo. Secondary endpoints included the change from baseline in the HAMD-17 score on days 3, 8, 21, and 45 and the change from baseline in the MADRS, CGI, and HAM-A scores on day 15 as well as the proportion of patients meeting response and remission as determined by the change in HAMD-17 score. Baseline characteristics were similar between groups. The average age of patients was 29.3 years in the zuranolone group and 27.4 years in the placebo group. The onset of PPD occurred during the third trimester in 42% of patients in each group and occurred <4 weeks after delivery in 58% of patients in each group. The baseline HAMD-17 scores were 28.4 in the zuranolone group and 28.8 in the placebo group. Of the 153 patients randomized, 150 patients were included in the efficacy analysis.

Fewer patients in the placebo group were treated with concurrent antidepressant therapy at baseline (18% vs 21% in the placebo and zuranolone groups, respectively). Zuranolone treatment resulted in a significant reduction in HAMD-17 score on day 15 compared with placebo. Results of the secondary outcomes further supported the efficacy of zuranolone in the treatment of PPD. The most common (occurring in ≥5% in either group) treatment-emergent adverse events (TEAEs) were somnolence, headache, dizziness, upper respiratory tract infection, diarrhea, sedation, nausea, vomiting, abnormal dreams, and hyperhidrosis. Most patients reported their TEAEs as mild to moderate, but three patients in each group described their TEAEs as severe. Changes in electrocardiogram, laboratory tests, or vital signs were not clinically significant. The study investigators concluded that treatment with zuranolone 30 mg once daily was safe and effective in treating postpartum MDD.

A post hoc analysis of the ROBIN study reported on the rate of concurrent remission of depression and anxiety (defined as a HAM-A score of ≤7 plus a HAMD-17 score of ≤7 or a MADRS score of ≤10). ¹⁴ Improvements in symptoms of insomnia and the number needed to treat for HAMD-17 response and remission also were reported. Results of this analysis showed that 40.5% of patients taking zuranolone and 19.2% of patients taking placebo experienced concurrent remission of their depression and anxiety symptoms at day 15 (P = .007). In addition, changes in sleep-related items on the HAMD-17 and MADRS scales showed that patients taking zuranolone experienced improvements in insomnia symptoms at all time points (except day 21 on the MADRS scale). The number needed to treat was ~5 for HAMD-17 response and remission at day 15.

Another study, called the SKYLARK study, was conducted by Deligiannidis et al. ¹³ to evaluate the safety and efficacy of zuranolone in women with severe PPD. In this study, 196 patients were randomized to receive zuranolone 50 mg once daily or placebo for 14 days. Eligibility criteria were similar to the ROBIN study, but patients could be up to 12 months postpartum to enroll in this study. Concomitant use of antidepressants was permitted as long the patients had been on a stable dosage for ≥30 days prior to the first dose of zuranolone. The primary outcome was change from baseline in HAMD-17 score. Secondary outcomes included change from baseline in the HAMD-17 on days 3, 28, and 45 as well as changes from baseline in HAM-A, CGI, and MADRS scores on day 15 as well as rates of remission and response as defined on the HAMD-17. Baseline characteristics were similar between groups. The average age of patients was 30 and 31 years in the zuranolone and placebo groups, respectively. More patients in each group experienced an onset of their PPD <4 weeks after delivery (65.3% in the zuranolone group and 68.4% in the placebo group) than during the third trimester (34.7% in the zuranolone group and 31.6% in the placebo group). The average baseline HAMD-17 scores were 28.6 and 28.8 in the zuranolone and placebo groups, respectively.

Of the initial 196 patients randomized, 170 completed the study. In each group, 15.3% of patients used concomitant antidepressants at baseline. Compared with placebo, zuranolone use led to a significant decrease in HAMD-17 score at day 15. Results of the secondary outcomes further supported the efficacy of zuranolone. The most common TEAEs (occurring in ≥5% of patients in either group) were somnolence, dizziness, sedation, headache, diarrhea, nausea, upper respiratory tract infection, and COVID-19 infection. Three patients in each group rated their TEAEs as severe. There were no clinically significant changes in vital signs, laboratory tests, or electrocardiogram reported. Thus, the study investigators concluded that zuranolone use leads to a significant improvement in depressive symptoms and is well tolerated amongst patients suffering from PPD.

Safety

Safety data from clinical trials involving treatment with zuranolone in PPD are summarized in Table 3. A study by Cutler et al. ¹⁵ examining the long-term efficacy and safety of zuranolone for MDD is the first to shed light on the safety of zuranolone for an extended duration. Results of this study demonstrated a similar incidence of TEAEs through multiple courses of zuranolone compared with the first course of zuranolone. ¹⁵ Additionally, the study found that most treatment withdrawals occurred in the first treatment cycle compared with subsequent cycles.

Table 3.

Safety Data from Trials of Zuranolone for the Treatment of PPD.

Factor	Deligiannidis et al. 12		Deligiannidis et al. 13
Indication	PPD		PPD
Study arm	Z	P	Z	Z
TEAEs (%)	60	52	60.2	41.8
Serious AEs (%)	1	1	2	0
Dose reduction needed due to TEAE (n)	—	—	16.3	1.0
Discontinuation (n)	1	0	4.1	2.0

PPD, postpartum depression; Z, zuranolone; P, placebo; TEAEs, treatment-emergent adverse events; AEs, adverse events

The package insert contains a black box warning addressing CNS depression symptoms associated with zuranolone and suggests that patients refrain from driving within 12 hours of taking the medication. ⁹ Zuranolone is classified as a Schedule IV controlled substance and thus should be used cautiously in patients with a history of substance abuse disorder. ⁹

Drug Interactions

Zuranolone exhibits the potential for drug interactions, necessitating a comprehensive medication review before treatment initiation. Coadministration with CNS depressants or alcohol can exacerbate the sedative effects, potentially leading to impaired cognitive function, psychomotor coordination, and reaction time. ⁹ In such scenarios, a dose reduction of zuranolone may be warranted. Furthermore, CYP3A4 enzyme activity can significantly impact zuranolone pharmacokinetics. Strong CYP3A4 inhibitors elevate zuranolone exposure, potentially increasing the risk of adverse events and thus necessitating a reduction in zuranolone dose. Concomitant antidepressant use similar to that seen in clinical trials is common with zuranolone. SSRIs, specifically fluvoxamine and fluoxetine, should be used with caution or avoided due to the potential for CYP3A4 inhibition. Conversely, CYP3A4 inducers accelerate zuranolone metabolism, potentially diminishing its therapeutic efficacy. ⁹ Concomitant use of zuranolone with CYP3A4 inducers ideally should be avoided. A thorough evaluation of all medications, including prescription drugs, over-the-counter medications, and herbal supplements, is crucial for optimizing the safety and efficacy of zuranolone therapy.

Dosing and Administration

Zuranolone is available in 20-, 25-, and 30-mg capsules. The recommended dosage is 50 mg taken by mouth once daily in the evening for 14 consecutive days. ⁹ This medication can be used as monotherapy or as an adjunctive therapy with existing oral antidepressant therapy. It is important to note that studies have not established the safety or efficacy of zuranolone beyond this 2-week period. For optimal absorption, zuranolone should be taken with a meal containing fat, ideally between 400 and 1000 calories with 25% to 50% fat content. If a patient experiences CNS depressant effects during the 14-day treatment period, a dosage reduction to 40 mg once daily in the evening should be considered. ⁹ However, patients should not adjust their medication regimen on their own but rather consult with their healthcare provider for a proper evaluation and potential dosage modification. If a dose is missed, patients should take the next scheduled dose at the usual time the following evening and avoid doubling up on the medication. Dosage adjustments are necessary for patients with compromised liver or kidney function. Specifically, those with severe hepatic impairment (Child–Pugh C) should receive a reduced dose of 30 mg daily for 14 days. For patients with moderate or severe renal impairment (estimated glomerular filtration rate, <60 mL/min/1.73 m²), the recommended dosage is also 30 mg daily for 14 days. ⁹ No dosage adjustments are needed for individuals with mild to moderate hepatic or mild renal impairment.

Place in Therapy

Current guidelines recommend psychotherapy first for the treatment of mild to moderate postpartum depression. ³ If pharmacotherapy is deemed necessary, SSRIs are recommended, with SNRIs considered as potential alternatives. For moderate to severe postpartum depression, brexanolone may be considered. ³ However, the use of brexanolone is limited by cost, dosage form, and restricted access via an FDA REMS program.^3,7

With its similar mechanism of action, zuranolone is an alternative to brexanolone for treating moderate to severe PPD. Its oral dosage form and lack of FDA REMS program make it a more attractive alternative in treating such patients. Cost is a concern with this medication as well because it has a cash price of ~$16,000 for the 14-day treatment. Payment options include private insurance coverage in some cases as well as manufacturer discount programs. ¹⁶ In addition, although a REMS program is not required for obtaining zuranolone, it is only available at specialty pharmacies, somewhat limiting patient access.

Conclusion

Zuranolone is the second medication in its class approved by the FDA for the treatment of PPD. Results from clinical trials have demonstrated the efficacy of zuranolone in the treatment of PPD. Further, interim safety and efficacy results from a study evaluating the long-term use of zuranolone are promising. Because the use of zuranolone does not come with the same challenges as brexanolone, providers and patients may be more likely to use this agent. Data from postmarketing surveillance with zuranolone will shed additional light on the long-term safety and efficacy of this agent and help further define its role in the treatment of PPD.