Zuranolone for the Treatment of Postpartum Depression
Publication: American Journal of Psychiatry
Abstract
Objective:
Postpartum depression (PPD) is a common perinatal complication with adverse maternal and infant outcomes. This study investigated the efficacy and safety of zuranolone, a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors and neuroactive steroid, as an oral, once-daily, 14-day treatment course for patients with severe PPD.
Methods:
In this double-blind phase 3 trial, women with severe PPD were randomized in a 1:1 ratio to receive zuranolone 50 mg/day or placebo for 14 days. The primary endpoint was change from baseline in total score on the 17-item Hamilton Depression Rating Scale (HAM-D) at day 15; key secondary endpoints were change from baseline in HAM-D score at days 3, 28, and 45 and change from baseline in Clinical Global Impressions severity (CGI-S) score at day 15. Adverse events were monitored.
Results:
Among 196 patients randomized (zuranolone, N=98; placebo, N=98), 170 (86.7%) completed the 45-day study. Treatment with zuranolone compared with placebo resulted in statistically significant improvement in depressive symptoms at day 15 (least squares mean [LSM] change from baseline in HAM-D score, −15.6 vs. −11.6; LSM difference, −4.0, 95% CI=−6.3, −1.7); significant improvement in depressive symptoms was also reported at days 3, 28, and 45. CGI-S score at day 15 significantly improved with zuranolone compared with placebo. The most common adverse events (≥10%) with zuranolone were somnolence, dizziness, and sedation. No loss of consciousness, withdrawal symptoms, or increased suicidal ideation or behavior were observed.
Conclusions:
In this trial, zuranolone demonstrated significant improvements in depressive symptoms and was generally well tolerated, supporting the potential of zuranolone as a novel, rapid-acting oral treatment for PPD.
Postpartum depression (PPD) is a common perinatal condition affecting approximately 17.2% of women during pregnancy or following parturition globally (1). Major or minor depressive episodes in the postpartum period are frequently underdiagnosed and untreated (2–4), and many women experience PPD with elevated anxiety (5). Moreover, the risk of developing PPD is twofold in women with a family history of psychiatric disorders (6). Adverse maternal and infant outcomes associated with PPD include reduced breastfeeding initiation rates, poor maternal and infant bonding, and increased infant behavioral, emotional, and cognitive impairment (3, 7, 8). Women with severe PPD may experience suicidal ideation, and maternal death from suicide comprises approximately 20% of all postpartum deaths (3, 9). Current treatment options often include standard-of-care antidepressants; however, achieving response to treatment can take up to 12 weeks (10, 11). Given the deleterious effects of untreated PPD, identification of rapid and effective treatment options is critical.
Allopregnanolone, an endogenous, potent positive allosteric modulator of synaptic and extrasynaptic γ-aminobutyric acid type A (GABAA) receptors and neuroactive steroid, may play an important role in PPD (2, 3, 12). Maladaptation to peripartum fluctuations in reproductive hormone concentrations during the perinatal period may be associated with PPD (13, 14), with levels of allopregnanolone—a metabolite of progesterone—increasing during pregnancy, reaching peak concentrations in the third trimester, and then decreasing abruptly following childbirth (13, 14). In a functional MRI study investigating resting-state functional connectivity and allopregnanolone levels in women with or without PPD, those with PPD had greater resting-state functional connectivity between an area of the dorsomedial prefrontal cortex and the rest of the default mode network compared with healthy postpartum women (15). These alterations in functional connectivity in women with PPD were correlated positively with both allopregnanolone levels and with more severe depression scores compared with healthy postpartum women, suggesting a connection between neuroactive steroid levels, network connectivity, and symptom severity in PPD (15). In preclinical studies, mice deficient in the GABAA receptor delta subunit, a component of extrasynaptic GABAA receptors, demonstrated depression-like postpartum behavior, supporting dysregulated GABAA receptor function during the perinatal period as a potential mechanism of PPD (16).
Zuranolone, an investigational positive allosteric modulator of both synaptic and extrasynaptic GABAA receptors and neuroactive steroid, is in clinical development as an oral, once-daily, 14-day treatment for adults with PPD and major depressive disorder (MDD). A previous phase 3 study demonstrated the efficacy of zuranolone at 30 mg/day compared with placebo in patients with PPD and found zuranolone at this dosage to be generally well tolerated (17). Based on results in improving symptoms of depression in patients with MDD using a zuranolone dosage of 50 mg/day (18), further investigation of zuranolone at 50 mg/day in women with PPD was needed. Here we present results of a phase 3 study (NCT04442503) evaluating the efficacy and safety of zuranolone at 50 mg/day compared with placebo in adults with PPD.
Methods
Study Design and Patients
This randomized, double-blind, placebo-controlled, parallel-group study included a screening period of up to 28 days, a 14-day treatment course, and follow-up through day 45. The study received institutional review board approval and was conducted in accordance with the Declaration of Helsinki and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use and Good Clinical Practice guidelines. The 50-mg/day dosage used in the study was selected based on direct and modeled data assessing efficacy and safety outcomes of zuranolone at higher dosages. All patients provided written informed consent prior to enrollment. Eligible patients were 18- to 45-year-old women with a baseline score ≥26 on the 17-item Hamilton Depression Rating Scale (HAM-D) who had a major depressive episode with onset during the third trimester of pregnancy or ≤4 weeks postpartum and were ≤12 months postpartum. Antidepressant use was permitted, provided that patients were on a stable dosage for ≥30 days prior to first study treatment dose. All patients ceased lactating or agreed not to provide breast milk to their infant from first study drug dose through 7 days following last study drug dose. Patients with a history of bipolar disorder, psychotic disorders, attempted suicide, or risk of suicide in the current episode of PPD were excluded. Full eligibility criteria are listed in the online supplement .
Patients were randomized in a 1:1 ratio and in a stratified manner based on antidepressant use (current, stable use vs. not treated or withdrawn from antidepressants for ≥30 days or >5 half-lives) to receive zuranolone 50 mg/day or placebo. Patients, clinicians, and study personnel were blinded to treatment allocation during the study.
Procedures
Patients self-administered zuranolone 50 mg/day or placebo orally once daily in the evening with fat-containing food for 14 days. Study drug administration was monitored by a smartphone medical adherence monitoring platform to visually confirm ingestion. Patients unable to tolerate zuranolone at 50 mg/day were permitted a reduction to 40 mg/day for the remainder of the treatment course.
Outcome Measures
The primary efficacy endpoint was change from baseline in HAM-D total score at day 15. Key secondary endpoints were change from baseline in HAM-D score at days 3, 28, and 45 and change from baseline in Clinical Global Impressions severity (CGI-S) score at day 15. Additional secondary endpoints included HAM-D response (defined as a reduction ≥50% in HAM-D score from baseline) and remission (defined as a total score ≤7 on the HAM-D) at days 15 and 45, Clinical Global Impressions improvement (CGI-I) response (scores indicating “much improved” or “very much improved”) at day 15, change from baseline Hamilton Anxiety Rating Scale (HAM-A) total score at day 15, change from baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score at day 15, and change from baseline patient-reported outcome measures, as assessed by total score on the Edinburgh Postnatal Depression Scale (EPDS) and on the 9-item Patient Health Questionnaire (PHQ-9).
Safety and tolerability were assessed by treatment-emergent adverse events, vital signs, clinical laboratory measurements, and ECG. Suicidal ideation and behavior were evaluated using the Columbia–Suicide Severity Rating Scale (C-SSRS), and potential withdrawal symptoms were monitored with the 20-item Physician Withdrawal Checklist (PWC-20).
Statistical Analysis
A sample size of 86 evaluable patients per treatment would provide 90% power using a two-sided t test and an alpha level of 0.05 to detect a placebo-adjusted treatment difference on the primary endpoint, assuming a true difference of 4 points and a standard deviation of 8 points. Assuming a 10% dropout rate and 1:1 randomization, approximately 192 randomized patients were required in order to obtain 86 evaluable patients per treatment group. The safety set included all patients who received at least one dose of study drug. The full analysis set was defined as all randomized patients who received at least one dose of study drug with both a valid baseline and at least one postbaseline score on the HAM-D, HAM-A, MADRS, CGI-S, EPDS, and PHQ-9, or at least one postbaseline CGI-I score.
The primary endpoint was analyzed utilizing a mixed-effects model for repeated measures, which included treatment, baseline HAM-D score, baseline antidepressant use, assessment time point, and time point–by-treatment as explanatory variables (all explanatory variables were treated as fixed effects). Multiplicity adjustment for hypothesis testing of the key secondary endpoints was conducted using a fixed-sequence strategy. If the primary endpoint was statistically significant at a two-sided 0.05 level, hypothesis testing for the key secondary endpoints was performed at a 5% level of significance. If an endpoint was not significant at this level, the next endpoint in the sequence was to be interpreted with a nominal p value. Other secondary endpoints were not adjusted for multiplicity and are to be interpreted with nominal p values, and all comparisons are considered descriptive. Effect sizes were reported by Cohen’s d values, which were calculated for each study visit as the observed mean difference between measures in the zuranolone and placebo groups divided by the pooled standard deviation. Additional details of the statistical analysis of endpoints are provided in the online supplement . Statistical analyses were performed using SAS, version 9.4 (SAS Institute, Cary, N.C.).
Results
Patient Disposition and Baseline Characteristics
Among 200 patients enrolled and randomized, 196 received blinded study drug (zuranolone 50 mg/day, N=98; placebo, N=98) (Figure 1). Four patients were randomized but not treated because of patient withdrawal from the study (one patient in the zuranolone group and two in the placebo group) or loss to follow-up (one patient in the placebo group). Most patients completed the study treatment (zuranolone group, 90.8%; placebo group, 92.9%), and the proportion of patients who prematurely discontinued study treatment was similar between treatment groups (zuranolone group, 9.2%; placebo group, 7.1%). Similarly, most patients who received study drug completed the 45-day study (zuranolone group, 85.7%; placebo group, 87.8%).
Demographic and baseline clinical characteristics were generally balanced between treatment groups (Table 1). Overall, 21.9% of patients were Black/African American and 38.3% were Hispanic/Latina. The mean age was 30.0 years (SD=5.9) in the zuranolone group and 31.0 years (SD=6.0) in the placebo group. Most patients experienced onset of depression within 4 weeks postpartum (zuranolone group, 65.3%; placebo group, 68.4%). Most patients had a baseline HAM-A score ≥20 (zuranolone group, 75.5%; placebo group, 78.6%), indicating moderate to severe anxiety (19). Baseline stable antidepressant use was similar between the zuranolone and placebo groups (15.3% each). Among patients using concomitant psychotropic medications, most took selective serotonin reuptake inhibitors (zuranolone group, 68.2%; placebo group, 94.1%), including sertraline (zuranolone group, 40.9%; placebo group, 70.6%) and escitalopram (zuranolone group, 13.6%; placebo group, 11.8%).
| Characteristic | Zuranolone 50 mg/day (N=98) | Placebo (N=98) | ||
|---|---|---|---|---|
| N | % | N | % | |
| Ethnicity | ||||
| Hispanic/Latina | 33 | 33.7 | 42 | 42.9 |
| Race | ||||
| White | 68 | 69.4 | 69 | 70.4 |
| Black/African American | 25 | 25.5 | 18 | 18.4 |
| Otherb | 5 | 5.1 | 11 | 11.2 |
| Country | ||||
| United States | 95 | 96.9 | 96 | 98.0 |
| Outside United Statesc | 3 | 3.1 | 2 | 2.0 |
| Onset of postpartum depression | ||||
| Third trimester | 34 | 34.7 | 31 | 31.6 |
| ≤4 weeks postpartum | 64 | 65.3 | 67 | 68.4 |
| History of postpartum depression | ||||
| First episode | 81 | 82.7 | 87 | 88.8 |
| Recurrent episode | 17 | 17.3 | 11 | 11.2 |
| Antidepressant use | 15 | 15.3 | 15 | 15.3 |
| Mean | SD | Mean | SD | |
| Age (years) | 30.0 | 5.9 | 31.0 | 6.0 |
| Body mass index | 30.9 | 6.3 | 29.6 | 6.3 |
| Hamilton Depression Rating Scale (17-item) score | 28.6 | 2.5 | 28.8 | 2.3 |
| Hamilton Anxiety Rating Scale score | 24.4 | 6.0 | 24.7 | 6.0 |
| Montgomery-Åsberg Depression Rating Scale score | 35.5 | 5.4 | 35.0 | 4.8 |
| Patient Health Questionnaire–9 score | 19.1 | 4.4 | 19.0 | 4.6 |
| Edinburgh Postnatal Depression Scale score | 21.1 | 3.7 | 20.0 | 4.2 |
| Clinical Global Impressions severity scale score | 5.0 | 0.7 | 4.9 | 0.6 |
a
The safety set comprises patients who received at least one dose of the assigned blinded treatment (placebo or zuranolone).
b
Other included Asian, American Indian, Alaska Native, Native Hawaiian, Pacific Islander, multiple, other race, and/or not reported.
c
Consisted of the United Kingdom and Spain.
Efficacy Outcomes
The study demonstrated statistically significant improvement in depressive symptoms on the primary endpoint, as assessed by change from baseline in HAM-D score at day 15, in the zuranolone group compared with the placebo group (least squares mean [LSM]=−15.6, SE=0.82, vs. LSM=−11.6, SE=0.82; LSM difference=−4.0, 95% CI=−6.3, −1.7; p=0.001; Cohen’s d=0.52) (Figure 2; see also Tables S1 and S2 in the online supplement ). The study also demonstrated statistically significant improvements on the key secondary endpoints in the zuranolone group compared with the placebo group. The zuranolone group demonstrated a significantly greater change from baseline in HAM-D score compared with the placebo group at day 3 (LSM=−9.5, SE=0.70, vs. LSM=−6.1, SE=0.71; LSM difference=−3.4, 95% CI=−5.4, −1.4; p=0.001; Cohen’s d=0.45), day 28 (LSM=−16.3, SE=0.88, vs. LSM=−13.4, SE=0.88; LSM difference=−2.9, 95% CI=−5.4, −0.5; p=0.02; Cohen’s d=0.33), and day 45 (LSM=−17.9, SE=0.90, vs. LSM=−14.4, SE=0.90; LSM difference=−3.5, 95% CI=−6.0, −1.0; p=0.007; Cohen’s d=0.33) (see Tables S1 and S2 in the online supplement ). Similarly, change from baseline in CGI-S score at day 15 was also significantly greater in the zuranolone group compared with the placebo group (LSM=−2.2, SE=0.14, vs. LSM=−1.6, SE=0.14; LSM difference=−0.6, 95% CI=−0.9, −0.2; p=0.005) (see Table S1 in the online supplement ).
FIGURE 2. Change from baseline in HAM-D score in a placebo-controlled trial of zuranolone 50 mg/day for postpartum depression (full analysis set)a
aThe primary endpoint was change from baseline in score on the 17-item Hamilton Depression Rating Scale (HAM-D) at day 15, and the key secondary endpoints included change from baseline in HAM-D score at days 3, 28, and 45. Multiplicity was accounted for when analyzing primary and key secondary endpoints. All other secondary endpoints were not adjusted for multiplicity and are to be interpreted with nominal p values. Error bars indicate standard error. *p<0.05. **p<0.01. ***p<0.001.
Other secondary endpoint results supported the primary and key secondary endpoints. Response to zuranolone treatment was rapid, with a median time to first HAM-D response of 9 days in the zuranolone group and 43 days in the placebo group. The proportion of patients achieving HAM-D response favored zuranolone compared with placebo starting at day 3, and this trend was observed at every subsequent study visit (see Table S3 in the online supplement ). The proportion of patients achieving HAM-D response at day 15 was significantly higher in the zuranolone group compared with the placebo group (57.0% [N=53] vs. 38.9% [N=35]; odds ratio=2.02, 95% CI=1.11, 3.67; p=0.02) (Figure 3). The HAM-D remission rate was numerically greater for zuranolone compared with placebo treatment at day 15 (26.9% [N=25] vs. 16.7% [N=15]; odds ratio=1.78, 95% CI=0.88, 3.62; p=0.11) and significantly greater at day 45 (44.0% [N=37] vs. 29.4% [N=25]; odds ratio=2.08, 95% CI=1.11, 3.92; p=0.02) (see Table S3 in the online supplement ). Consistent with the primary and key secondary endpoints showing overall improvements in total score on the HAM-D at day 15, the majority of change from baseline in individual HAM-D item scores (15 of 17 items) and all HAM-D subscale scores favored zuranolone compared with placebo (see Figures S1 and S2 in the online supplement ). Improvements in depressive symptoms with zuranolone as assessed by change from baseline in HAM-D total score were observed irrespective of concomitant antidepressant use from baseline (see Table S4 in the online supplement ). The day-15 CGI-I response rate was significantly greater in the zuranolone group compared with the placebo group (66.7% [N=62] vs. 46.7% [N=42]; odds ratio=2.23, 95% CI=1.22, 4.07; p=0.009). Improvement in depressive symptoms as assessed by change from baseline MADRS score was also significantly greater in the zuranolone group (LSM=−19.7, SE=1.20) compared with the placebo group (LSM=−14.6, SE=1.21) at day 15 (LSM difference=−5.1, SE=1.71, 95% CI=−8.4, −1.7; p=0.003) and at days 8 (p=0.004) and 45 (p=0.01) (see Figure S3 in the online supplement ). Improvements in anxiety as assessed by change from baseline HAM-A score at day 15 were also significantly greater in the zuranolone group compared with the placebo group (LSM=−12.8, SE=0.69, vs. LSM=−10.6, SE=0.70; LSM difference=−2.2, SE=0.98, 95% CI=−4.2, −0.3; p=0.02) (see Figure S4 in the online supplement ).
FIGURE 3. HAM-D response and remission (full analysis set) in a trial of zuranolone 50 mg/day for postpartum depressiona
aResponse was defined as a reduction ≥50% from baseline in score on the 17-item Hamilton Depression Rating Scale (HAM-D), and remission was defined as a HAM-D score ≤7. Secondary endpoints were not adjusted for multiplicity and are to be interpreted with nominal p values. *p<0.05. **p<0.01. ***p<0.001.
Consistent with investigator-reported outcome measures, patient-reported change from baseline EPDS scores was significantly greater in the zuranolone group compared with the placebo group at day 3 (LSM=−3.8, SE=0.49, vs. LSM=−2.3, SE=0.49; LSM difference=−1.5, 95% CI=−2.9, −0.1; p=0.03), day 8 (LSM=−8.4, SE=0.60, vs. LSM=−6.2, SE=0.59; LSM difference=−2.2, 95% CI=−3.8, −0.5; p=0.01), day 15 (LSM=−10.3, SE=0.66, vs. LSM=−8.4, SE=0.66; LSM difference=−2.0, 95% CI=−3.8, −0.1; p=0.04), and day 45 (LSM=−12.2, SE=0.76, vs. LSM=−9.8, SE=0.76; LSM difference=−2.4, 95% CI=−4.5, −0.3; p=0.03) (see Figure S5 in the online supplement ). Significant improvements in patient-reported PHQ-9 scores in the zuranolone group compared with the placebo group were reported at days 8 and 15, with numerically lower scores at all other time points except at day 3 (see Figure S6 in the online supplement ).
Safety and Tolerability
Zuranolone was generally well tolerated; most patients who experienced treatment-emergent adverse events reported mild or moderate events (Table 2). During the 14-day treatment course, treatment-emergent adverse events were reported by 60.2% (N=59) and 41.8% (N=41) of patients receiving zuranolone and placebo, respectively. In the zuranolone group, 16.3% (N=16) experienced treatment-emergent adverse events leading to dosage reduction, compared with 1.0% (N=1) in the placebo group; 15 of these patients (zuranolone, N=14; placebo, N=1) completed the study. Treatment-emergent adverse events leading to dosage reduction in more than one patient receiving zuranolone included somnolence (7.1%, N=7), dizziness (6.1%, N=6), and sedation (3.1%, N=3); the treatment-emergent adverse event leading to dosage reduction in the placebo group was anxiety. Among patients who experienced treatment-emergent adverse events leading to discontinuation of study drug, 4.1% (N=4) were in the zuranolone group and 2.0% (N=2) were in the placebo group.
| Zuranolone 50 mg/day (N=98) | Placebo (N=98) | |||
|---|---|---|---|---|
| Safety Parameter | N | % | N | % |
| TEAEs | 65 | 66.3 | 52 | 53.1 |
| During treatment | 59 | 60.2 | 41 | 41.8 |
| Posttreatment | 21 | 21.4 | 27 | 27.6 |
| Mild | 33 | 33.7 | 39 | 39.8 |
| Moderate | 29 | 29.6 | 12 | 12.2 |
| Severe AE | 3 | 3.1 | 1 | 1.0 |
| Serious AEb | 2 | 2.0 | 0 | 0.0 |
| AE leading to dosage reductionc | 16 | 16.3 | 1 | 1.0 |
| AE leading to treatment discontinuationd | 4 | 4.1 | 2 | 2.0 |
| AE leading to withdrawal from studye | 1 | 1.0 | 1 | 1.0 |
| Death | 0 | 0.0 | 0 | 0.0 |
| TEAEs with ≥5% in any group, through day 45 | ||||
| Somnolence | 26 | 26.5 | 5 | 5.1 |
| Dizziness | 13 | 13.3 | 10 | 10.2 |
| Sedation | 11 | 11.2 | 1 | 1.0 |
| Headache | 9 | 9.2 | 13 | 13.3 |
| Diarrhea | 6 | 6.1 | 2 | 2.0 |
| Nausea | 5 | 5.1 | 6 | 6.1 |
| Urinary tract infection | 5 | 5.1 | 4 | 4.1 |
| COVID-19 | 5 | 5.1 | 0 | 0.0 |
a
AE=adverse event; TEAE=treatment-emergent adverse event.
b
One patient (age 36 years) experienced three serious adverse events (SAEs) on treatment: severe upper abdominal pain on day 8, which resulted in hospitalization and resolved on day 38, and moderate hypertension and peripheral edema on day 14, which resolved on day 15; the patient remained on treatment throughout and the dosage was not reduced; all three SAEs were reported as not related to zuranolone by the investigator. A different patient (also age 36 years) experienced an SAE of perinatal depression secondary to methamphetamine use on day 22 during the posttreatment follow-up; the event was assessed as not related to study drug by the investigator and resolved on day 25.
c
The most common adverse events leading to dosage reduction in the zuranolone group included somnolence, dizziness, and sedation.
d
Discontinuation of blinded treatment occurred during the 14-day treatment course. Patients who discontinued treatment early could complete the remaining study visits through day 45, unless the patient withdrew consent.
e
Withdrawal from the study could occur at any time from day 1 through day 45 for any reason. AEs leading to withdrawal from the study also resulted in treatment discontinuation.
The most common treatment-emergent adverse events (≥5%) reported by patients were somnolence (zuranolone, 26.5%; placebo, 5.1%), dizziness (zuranolone, 13.3%; placebo, 10.2%), sedation (zuranolone, 11.2%; placebo, 1.0%), headache (zuranolone, 9.2%; placebo, 13.3%), diarrhea (zuranolone, 6.1%; placebo, 2.0%), nausea (zuranolone, 5.1%; placebo, 6.1%), urinary tract infection (zuranolone, 5.1%; placebo, 4.1%), and COVID-19 (zuranolone, 5.1%; placebo, 0%). Two serious adverse events were reported, both of them in patients in the zuranolone group—one during the treatment course and one during the posttreatment period—and were considered unrelated to study drug. No loss of consciousness and no clinically significant changes in vital signs, ECG, or clinical laboratory parameters were reported. Most patients had maintenance or improvement from baseline in maximum severity score on the C-SSRS at all postbaseline time points. The change from baseline in PWC-20 scores was similar between treatment groups, with no evidence of withdrawal symptoms. During the follow-up period, two patients in the zuranolone group and one in the placebo group started new antidepressant treatments. No patient deaths occurred in the study.
Discussion
In this phase 3 trial of oral zuranolone 50 mg/day for PPD, women with PPD receiving zuranolone demonstrated statistically significant and clinically meaningful improvements in depressive symptoms at day 15 compared with the placebo group. Demographic characteristics were well balanced between treatment groups, and the groups were ethnically and racially diverse, with 38.3% Hispanic/Latina and 21.9% Black/African American patients included. The effects of zuranolone were rapid (by day 3), were sustained at all measured time points through day 45, and were observed across 15 of the 17 HAM-D items and all reported subscales, reflecting a broad overall improvement in depressive symptoms. The improvements observed in the primary endpoint assessed by the investigator-reported HAM-D were mirrored by patients’ self-reported assessment of their depressive symptoms by the EPDS. Consistent with previous studies (17, 18, 20), zuranolone was generally well tolerated, with most treatment-emergent adverse events being mild or moderate in severity. Notably, 14 of 16 patients receiving zuranolone who experienced treatment-emergent adverse events resulting in dosage reduction completed the study. No increase in suicidal ideation from baseline, loss of consciousness, withdrawal symptoms, or deaths were observed during the study.
Brain network dysregulation and excitation-inhibition imbalance is postulated to be a core component of the pathophysiology of PPD and may be addressed with positive allosteric modulators of GABAA receptors and neuroactive steroids that enhance inhibitory GABAergic signaling and are hypothesized to restore dysregulated brain networks. Clinical studies of intravenous brexanolone, the first treatment specifically approved by the U.S. Food and Drug Administration for PPD in patients ≥15 years of age, have established the clinical utility of neuroactive steroid positive allosteric modulators of GABAA receptors for the treatment of PPD (12, 21). In the clinical development program for brexanolone, this agent demonstrated rapid, significant, and clinically meaningful improvements in depressive symptoms, as measured by change from baseline HAM-D score at hour 60 compared with placebo (2, 12, 21–23).
In a previous phase 3 study, patients with PPD treated with zuranolone 30 mg/day had a sustained improvement in depressive symptoms through the 45-day study period (17). The present study further supports these results with a zuranolone dosage of 50 mg/day. Patients receiving zuranolone demonstrated robust, clinically meaningful, and rapid improvements in depressive symptoms, as assessed by change from baseline HAM-D score, which were evident as early as day 3 and were maintained through day 45. All key secondary endpoints were also achieved. Patient-reported outcome results (on the EPDS and the PHQ-9) correlated well with the overall depression HAM-D score, indicating stability over time, and may allow for comparison of treatment effects between studies; clinically important symptoms of anxiety and insomnia broadly favored zuranolone. Together, these two randomized placebo-controlled clinical trials provide some of the most substantial results to date for improving depressive symptoms in women with PPD.
Limitations of this study include a lack of adjustment for multiplicity in the testing of non-key secondary endpoints. There was low representation from outside the United States, women with PPD who have a history of bipolar disorder and/or psychotic disorders were excluded, and only patients with severe PPD (a baseline HAM-D score ≥26) were assessed. Another limitation was the potential for population homogeneity. A statistical analysis of clinical data collected from women with PPD across seven international sites identified five distinct subtypes of PPD that varied by timing of onset of depressive symptoms (during pregnancy, within 4 weeks postpartum, 4 to <8 weeks postpartum, and ≥8 weeks postpartum) and symptom severity, suggesting that the population of women with PPD is heterogeneous (24). Given that the study limited enrollment to women diagnosed with onset of the depressive episode between the third trimester and 4 weeks postpartum, the population may have been less heterogeneous than if women with a later postpartum onset were included. Patients in the zuranolone group reported treatment-emergent adverse events of sedation, somnolence, or dizziness more often than patients in the placebo group, which may have affected blinding in the study. An additional limitation may be the high placebo response observed in the study. The placebo response may have been influenced by the frequency of study visits (eight visits in 45 days), which is higher than that observed in real-world settings and is consistent with studies of standard-of-care antidepressants demonstrating an increase in placebo response with increasing study visits (25, 26). Furthermore, because patients were followed only through day 45, the long-term efficacy and safety of zuranolone in women with PPD are unknown. Lastly, because patients were not permitted to breastfeed, the effect of zuranolone on lactation and its relative infant dose were not evaluated in this study and will be published separately based on assessments from other studies.
Given the prevalence and substantial adverse maternal and infant outcomes associated with PPD, its appropriate management is essential. While the distinction between PPD and depression generally is an area of open investigation, there is evidence suggesting that depressive episodes occurring during pregnancy or the early postpartum period are distinct from those that occur outside this window, in part as a result of hormonal fluctuations (27). Selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors are commonly prescribed for women with PPD; however, evidence for their use is primarily based on empirical data and limited randomized clinical trials providing low-certainty evidence of efficacy (12, 28–30). Additionally, standard-of-care antidepressants often must be taken chronically and generally require weeks to months to take effect, leading to substantial morbidity (31–34). Therefore, if approved, zuranolone would be the first short-course, rapid-acting, oral treatment for patients with PPD.
Footnote
ClinicalTrials.gov identifier: NCT04442503.
Supplementary Material
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Information & Authors
Information
Published In
History
Received: 15 September 2022
Revision received: 27 February 2023
Revision received: 20 April 2023
Accepted: 4 May 2023
Published online: 26 July 2023
Published in print: September 01, 2023
Keywords
Authors
Competing Interests
Dr. Deligiannidis has served as a consultant for Brii Biosciences, Gerbera Therapeutics, GH Research, Neuroscience Software, Reunion Neuroscience, and Sage Therapeutics; she has received grants from Sage Therapeutics, awarded to Zucker Hillside Hospital/Feinstein Institutes for Medical Research (related to clinical trials of brexanolone and zuranolone), and grants from NIH and Vorso Corporation; and she has received royalties from an NIH employee invention. Dr. Meltzer-Brody has received grant funding from Janssen, awarded to the University of North Carolina Chapel Hill, grants from NIH and the Patient-Centered Outcomes Research Institute, and grants and other research funding from Sage Therapeutics, awarded to the University of North Carolina at Chapel Hill; and she has received personal fees from WebMD/Medscape. Dr. Maximos has received grants from Sage Therapeutics related to the zuranolone clinical trial; he has served as a consultant for Evofem Biosciences; and he may hold stock in Sage Therapeutics. Dr. Peeper holds stock in Sage Therapeutics. Dr. Freeman conducts research with the Massachusetts General Hospital (MGH) National Pregnancy Registry and, as an employee of MGH, works with the MGH Clinical Trials Network and Institute, which received research funding from multiple pharmaceutical companies and NIMH; current sponsors of the MGH National Pregnancy Registry include Alkermes, Eisai, Johnson & Johnson/Janssen Pharmaceuticals, Otsuka America Pharmaceutical, Sage Therapeutics, Sunovion Pharmaceuticals, Supernus Pharmaceuticals, and Teva Pharmaceutical Industries; she is a research investigator for Sage Therapeutics; she serves on advisory boards for independent data safety and monitoring committees for Beckley Psytech, Brainify, Eliem, Everly Health, Janssen (Johnson & Johnson), Neurocrine, Novartis, Relmada, Sage Therapeutics, and Tibi Health; she has participated in Everly Health Educational activities (speaking, planning): WebMD, Medscape, Pri-Med, and Postpartum Support International; and she has received royalties from the MGH Scale and the Massachusetts General Hospital Female Reproductive Lifecycle and Hormones Questionnaire. Dr. Lasser, Dr. Bullock, Ms. Li, and Dr. Doherty are employees of Sage Therapeutics, and may hold stock and/or stock options. Dr. Rana and Dr. Garcia were employees of Sage Therapeutics at the time of the study and development of the manuscript, and may hold stock and/or stock options. Dr. Kotecha, Ms. Forrestal, and Dr. Leclair are employees of Biogen, and may hold stock.
Funding Information
This study was funded by Sage Therapeutics and Biogen. Medical writing and editorial support were provided by Zehra Gundogan, V.M.D., and Ryan Coleman, Ph.D., of AlphaBioCom, and funded by Sage Therapeutics and Biogen.
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