ARTICLE

Zuranolone for the Treatment of Adults With Major

Depressive Disorder: A Randomized, Placebo‐Controlled
Phase 3 Trial
Anita H. Clayton, M.D., Robert Lasser, M.D., M.B.A., Sagar V. Parikh, M.D., Dan V. Iosifescu, M.D., JungAh Jung, Ph.D.,
Mona Kotecha, M.D., Fiona Forrestal, M.Sc., Jeffrey Jonas, M.D., Stephen J. Kanes, M.D., Ph.D., James Doherty, Ph.D.

Objective: This study assessed the efficacy and safety of a score, 214.1 vs. 212.3). Numerically greater improvements
14-day treatment course of once-daily zuranolone 50 mg, in depressive symptoms for zuranolone versus placebo
an investigational oral positive allosteric modulator of the were observed by day 3 (least squares mean change from
g-aminobutyric acid type A (GABAA) receptor, for the treat- baseline HAM-D score, 29.8 vs. 26.8), which were sus-
ment of major depressive disorder. tained at all visits throughout the treatment and follow-up
periods of the study (through day 42, with the difference
Methods: Patients 18–64 years of age with severe major remaining nominally significant through day 12). Two pa-
depressive disorder were enrolled in this randomized, double- tients in each group experienced a serious adverse event;
blind, placebo-controlled trial. Patients self-administered zur- nine patients in the zuranolone group and four in the
anolone 50 mg or placebo once daily for 14 days. The primary placebo group discontinued treatment due to adverse
endpoint was change from baseline in total score on the events.
17-item Hamilton Depression Rating Scale (HAM-D) at
day 15. Safety and tolerability were assessed by incidence Conclusions: Zuranolone at 50 mg/day elicited a significantly
of adverse events. greater improvement in depressive symptoms at day 15, with
a rapid time to effect (day 3). Zuranolone was generally well
Results: Of 543 randomized patients, 534 (266 in the zur- tolerated, with no new safety findings compared with pre-
anolone group, 268 in the placebo group) constituted the full viously studied lower dosages. These findings support the
analysis set. Compared with patients in the placebo group, potential of zuranolone in treating adults with major de-
patients in the zuranolone group demonstrated a statistically pressive disorder.
significant improvement in depressive symptoms at day
15 (least squares mean change from baseline HAM-D AJP in Advance (doi: 10.1176/appi.ajp.20220459)

Major depressive disorder (MDD) is a leading cause of dis- options that have a rapid onset of action, high response and
ability in the United States and worldwide (1–3). A limitation remission rates, and minimal safety concerns commonly
of standard-of-care antidepressant therapies for MDD (e.g., associated with standard-of-care antidepressant therapies.
selective serotonin reuptake inhibitors) is that they typically To address this unmet need, therapies with novel
require weeks or months to improve depressive symptoms (4, mechanisms of action are being investigated, including
5). Furthermore, they are associated with several adverse therapies targeting g-aminobutyric acid (GABA) signaling.
effects, including weight gain, sexual dysfunction, and cog- GABA is the primary inhibitory neurotransmitter in the
nitive impairment, which may result in treatment discon- brain and is thought to serve an important role in network
tinuation (6–9). signaling by balancing excitatory and inhibitory neuro-
As demonstrated in the Sequenced Treatment Alterna- transmission (10–12). Patients with depression may have
tives to Relieve Depression (STAR*D) study, delay in treat- impaired network balance and low or reduced plasma and
ment response may be a barrier for some antidepressant cerebrospinal fluid GABA levels (13–16). However, the
therapies and may fuel an extended duration of disability and therapeutic potential of modulating GABA signaling for the
delay in functional recovery (4). These therapies may also treatment of MDD is underexplored.
require daily use for months to years to prevent relapse, Inhibitory GABA receptor signaling is modulated by en-
potentially resulting in a long-term burden of treatment (4, 5). dogenous neuroactive steroids such as allopregnanolone,
Accordingly, some patients with MDD need new treatment which acts as a positive allosteric modulator of both synaptic

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ZURANOLONE FOR THE TREATMENT OF MAJOR DEPRESSIVE DISORDER

and extrasynaptic GABA type A receptors (GABAARs) (17). a HAM-D score $24 at screening and prior to dosing on day 1.
Supporting the potential of modulating GABAAR signaling for The study excluded patients with active psychosis, those who
the treatment of depression, brexanolone, a proprietary in- attempted suicide or were at risk of suicide in their current
travenous formulation of allopregnanolone, is currently the MDD episode, and those with treatment-resistant depres-
only drug approved by the U.S. Food and Drug Adminis- sion, defined in this study as persistent depressive symptoms
tration (FDA) specifically for the treatment of postpartum despite treatment within the current major depressive episode
depression in patients age 15 or older (18–21). Phase 3 studies with antidepressants (excluding antipsychotics) from two
of brexanolone demonstrated a rapid onset of effect in pa- different classes at adequate dosages for $4 weeks. A full list of
tients with postpartum depression, with significant placebo- eligibility criteria is provided in the Supplemental Methods
adjusted improvements in depressive symptoms observed section of the online supplement. After screening, eligible
at 60 hours following a single intravenous infusion of patients were randomized to treatment with zuranolone
brexanolone (19). Zuranolone, a positive allosteric mod- 50 mg/day or placebo and underwent a 14-day treatment
ulator of synaptic and extrasynaptic GABAARs, is thought to period and 28-day follow-up period (see Figure S1 in the online
upregulate GABAAR expression and enhance inhibitory supplement). The use of antidepressants in both groups was
GABAergic signaling. As a neuroactive steroid, zuranolone is permitted, provided that patients were on a stable dosage
hypothesized to rapidly restore network balance in brain for $60 days prior to day 1 and agreed to continue on the stable
areas dysregulated in depression (17, 22, 23). In a preclinical dosage through day 42. All patients provided written informed
study using the beta EEG band (b band) as a robust biomarker consent after receiving a complete description of the study.
of GABAAR positive allosteric modulator activity, oral ad-
ministration of zuranolone in mice led to a rapid (,1 hour) Randomization and Blinding
increase in b band power, suggesting a potential rapid onset of Randomization, in a 1:1 ratio, was performed centrally via an
activity in the brain (23). interactive response technology system. Patients, clinicians,
The LANDSCAPE and NEST clinical development pro- site personnel, the study sponsor, and the study team were
grams include a series of randomized clinical trials assessing blinded to treatment allocation. Blinding was maintained
the efficacy and safety of zuranolone as an oral, once-daily, until database lock after all patients completed the study visit
14-day therapy for MDD and postpartum depression, re- at day 42.
spectively. Previous studies in adult patients with MDD
(phase 2) and postpartum depression (phase 3) met their Procedures
primary endpoint of a statistically significant improvement in Patients self-administered oral zuranolone 50 mg or placebo
depressive symptoms with zuranolone 30 mg/day compared once daily in the evening with fat-containing food. Study
with placebo at day 15, as assessed by total score on the visits occurred at days 1, 3, 8, 12, 15, 18, 21, 28, 35, and 42. All
17-item Hamilton Depression Rating Scale (HAM-D) (24, 25). reported assessments were administered by the investigators.
Here, we report the results of a phase 3 study (Clinical- The Columbia–Suicide Severity Rating Scale (C-SSRS) was
Trials.gov identifier: NCT04442490) evaluating the efficacy, used to evaluate suicidal ideation or behavior. HAM-D
safety, and tolerability of zuranolone 50 mg/day for the score, Clinical Global Impressions severity (CGI-S) score,
treatment of MDD in adults. Montgomery-Åsberg Depression Rating Scale (MADRS)
score, and CGI improvement (CGI-I) score were used to
evaluate depressive symptoms. The Hamilton Anxiety Rating
METHODS
Scale (HAM-A) score was used to evaluate symptoms of
Study Design and Participants anxiety, and the 20-item Physician’s Withdrawal Checklist
This was a multicenter, randomized, double-blind, placebo- (PWC-20) score was used to assess symptoms of withdrawal.
controlled phase 3 clinical trial conducted between May Further details on study procedures and visits are provided in
2020 and April 2021 at 39 sites in the United States. All pa- the Supplemental Methods section of the online supplement.
tients were screened #28 days prior to day 1 of the study. The
study received institutional review board approval at each Outcome Measures
site, was conducted in accordance with the ethical guidelines The primary endpoint was change from baseline in HAM-D
of the Declaration of Helsinki, and was consistent with the score at day 15. Key secondary endpoints were change from
International Council for Harmonisation of Technical Re- baseline in CGI-S score at day 15 and change from baseline in
quirements for Pharmaceuticals for Human Use and Good HAM-D score at days 3, 8, and 42. Other secondary endpoints
Clinical Practice. The 50-mg/day dosage used in the study included the proportion of patients who achieved HAM-D
was selected based on direct and modeled data to assess response (a reduction $50% in HAM-D score from baseline)
efficacy and safety outcomes of zuranolone at higher dosages and remission (a HAM-D score #7) at days 15 and 42, a CGI-I
(further details are provided in the Supplemental Methods response of “much improved” or “very much improved” at
section of the online supplement). Patients were 18–64 years day 15, change from baseline in MADRS score at day 15, and
old with a diagnosis of MDD (per Structured Clinical In- change from baseline in HAM-A score at day 15. Subgroup
terview for DSM-5 criteria) with symptoms for $4 weeks and analyses included change from baseline in HAM-D score by

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baseline patient characteristics and HAM-D response and RESULTS

remission rates by antidepressant use at baseline.
Of 1,087 patients screened, 543 were randomized, 537 were
Safety was evaluated from the incidence and severity of
included in the safety set (268 in the zuranolone group, 269 in
treatment-emergent adverse events and serious adverse
the placebo group), and 534 were included in the full analysis
events. Additional safety assessments included suicidal ide-
set (266 in the zuranolone group, 268 in the placebo group)
ation and behavior (per the C-SSRS), potential withdrawal
(Figure 1). Baseline characteristics were generally balanced
symptoms after zuranolone discontinuation (per the PWC-
between the zuranolone and placebo groups (Table 1). Pa-
20), and changes in laboratory values, ECG, and vital signs.
tients in both groups had a diagnosis of MDD for a mean of
approximately 11 years, with a mean duration of .1 year for
Statistical Analysis
the current depressive episode, and approximately 30% were
Based on a two-sided alpha level of 0.05 and an assumed
on antidepressant therapies (Table 1; see Table S1 in the
10% dropout rate, a sample size of 240 patients was required
online supplement for concomitant antidepressant thera-
to have 90% power if the true placebo-adjusted treatment
pies). Most patients were White (zuranolone group, 63.1%;
difference in the primary endpoint of HAM-D score was
placebo group, 76.6%) and female (zuranolone group, 69.4%;
4 points (assuming a standard deviation of 9 points). To in-
placebo group, 61.7%). Patients had similar severity of de-
crease power for analyses of key secondary endpoints, the
pressive symptoms as assessed by the HAM-D (mean scores:
sample size was adjusted to permit enrollment of approxi-
zuranolone group, 26.8; placebo group, 26.9).
mately 575 patients (randomized set). The safety set included
all patients who received at least one dose of zuranolone or
placebo. The full analysis set, used for efficacy analyses, in- Efficacy
cluded all patients in the safety set who had a valid baseline Treatment with zuranolone demonstrated a significantly
HAM-D score and at least one postbaseline HAM-D score. greater improvement in depressive symptoms compared
Primary and secondary change from baseline endpoints with placebo at day 15, as assessed by change from baseline in
were analyzed in the full analysis set with mixed models for HAM-D score (LSM change, 214.1 [SE50.5] vs. 212.3
repeated measures (MMRM) comparing the change from [SE50.5], p50.01; Cohen’s d50.23) (Figure 2, Figure 3A; see
baseline least squares mean (LSM) differences in outcome effect size data in Table S2 in the online supplement). The
measures between the zuranolone and placebo groups. For LSM change from baseline in CGI-S score at day 15 was
each outcome measure (e.g., change from baseline in HAM-D numerically greater for zuranolone compared with placebo,
score and in CGI-S score), one MMRM model was used to but the difference was not statistically significant (21.8
estimate all time points. The models included terms for [SE50.1] vs. 21.6 [SE50.1], p50.12), so formal testing of the
treatment, time point, baseline outcome measure, antide- following key secondary endpoints in the fixed sequence
pressant use at baseline (yes or no), and the treatment-by- stopped, and all subsequent key secondary endpoints were
time point interaction. All explanatory variables were treated interpreted with nominal p values (Figure 2B; see also Figure
as fixed effects, and random effects were included as part of S2 in the online supplement). In addition to improvements
the marginal covariance matrix (26). Each model used an in depressive symptoms demonstrated at day 15, the LSM
unstructured covariance matrix to model the within-patient change from baseline in HAM-D score was numerically
errors. A generalized estimating equation (GEE) method was greater for zuranolone compared with placebo at all other
used to analyze HAM-D response, HAM-D remission, and study visits, including day 3 (29.8 [SE50.4] vs. 26.8
CGI-I response. An unstructured covariance matrix was used [SE50.4], p,0.001; Cohen’s d50.49), day 8 (212.0 [SE50.5]
for each GEE model to account for the within-patient error. vs. 29.5 [SE50.5], p,0.001; Cohen’s d50.38), day 12 (213.7
Multiplicity adjustment for statistical hypothesis testing of [SE50.5] vs. 211.2 [SE50.5], p,0.001; Cohen’s d50.32),
the key secondary endpoints was conducted using a pre- day 21 (213.3 [SE50.5] vs. 212.1 [SE50.5], p50.09), day 28
specified fixed sequence reviewed by the FDA prior to da- (212.6 [SE50.5] vs. 211.6 [SE50.5], p50.18), day 35 (213.0
tabase lock and final analysis. Key secondary endpoints were [SE50.6] vs. 212.3 [SE50.6], p50.37), and day 42 (213.5
tested only if the primary endpoint demonstrated a statisti- [SE50.6] vs. 212.6 [SE50.6], p50.23) (Figure 3A; see effect
cally significant difference at the 0.05 level. The sequence of size data in Table S2 in the online supplement).
key secondary endpoint testing began with the change from The subgroup analyses (based on baseline characteristics)
baseline in CGI-S score at day 15, followed by the change from were generally consistent with the results of the primary
baseline in HAM-D score at days 8, 3, and 42, in that order. endpoint, showing favorable results for zuranolone com-
Formal testing stopped if the p value for the previous endpoint pared with placebo (see Figure S3 in the online supplement).
in the sequence was .0.05, and subsequent endpoints were As seen with the primary endpoint, greater improvement in
interpreted only with nominal p values. All other secondary depressive symptoms was observed for zuranolone at day
endpoints and additional analyses were not adjusted for mul- 15 compared with placebo as measured by change from
tiplicity and hence were interpreted with a nominal p value. baseline in MADRS score (LSM change, 217.5 [SE50.8]
The effect size was measured using Cohen’s d estimates for vs. 215.1 [SE50.8], p50.02) (Figure 2B), which was main-
change from baseline in HAM-D score at days 3, 8, 12, and 15. tained at all posttreatment visits (see Figure S4 in the online

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ZURANOLONE FOR THE TREATMENT OF MAJOR DEPRESSIVE DISORDER

FIGURE 1. CONSORT flow diagram for a placebo-controlled trial of zuranolone for major depressive disorder

Screened (N=1,087)

Did not meet study criteria

(N=544)

Randomized (N=543)

Zuranolone 50 mg/day (N=271) Placebo (N=272)

• Dosed (N=268) • Dosed (N=269)
• Lost to follow-up (N=2) • Lost to follow-up (N=1)
• Withdrawal by patient (N=1) • Withdrawal by patient (N=1)
• Not dosed due to physician decision • Not dosed due to physician decision
(N=0) (N=1)

Premature Premature
discontinuation discontinuation
(N=22) (N=19)

Premature withdrawal from study (N=26) Premature withdrawal from study (N=34)
• Adverse events (N=6) • Adverse events (N=2)
Completed Completed
treatment (N=246) • Withdrawal by patient (N=10) • Withdrawal by patient (N=18) treatment (N=250)
• Nonadherence with study drug (N=1) • Nonadherence with study drug (N=3)
• Lost to follow-up (N=7) • Lost to follow-up (N=7)
• Physician decision (N=1) • Physician decision (N=2)
• Other (N=1) • Other (N=2)

• Safety set (N=268) • Safety set (N=269)

• Full analysis set (N=266) • Full analysis set (N=268)
• Completed study (N=242) • Completed study (N=235)

supplement). Greater improvements in anxiety symptoms at zuranolone or placebo who were assessed for HAM-D re-
day 15 were observed for zuranolone compared with placebo, sponse at both days 15 and 42 had a HAM-D response at day
as assessed by change from baseline in HAM-A score 15 but not at day 42 (15.2% and 12.9%, respectively). Rates of
(LSM change, 210.4 [SE50.4] vs. 29.1 [SE50.4], p50.02) HAM-D remission were observed in a greater proportion of
(Figure 2B). Numerical but nonsignificant improvements in patients receiving zuranolone at day 3 compared with pa-
HAM-A score were maintained with zuranolone compared tients who received placebo (7.6% [20/263] vs. 2.3% [6/264];
with placebo at day 28 (LSM change, 29.8 [SE50.5] vs. 29.2 odds ratio53.6, 95% CI51.4–9.1; p50.01) (see Figure S7A in
[SE50.5], p50.31) and day 42 (LSM change, 210.7 [SE50.5] the online supplement). Remission rates were numerically
vs. 29.9 [SE50.5], p50.21) (Figure 3B). A greater proportion but not significantly greater in the zuranolone group at day
of patients receiving zuranolone achieved CGI-I response 15 (29.8% [74/248] vs. 27.1% [68/251]; odds ratio51.1, 95%
(ratings of “much improved” or “very much improved”) com- CI50.8–1.7; p50.55) and at day 42 (30.8% [74/240] vs.
pared with patients receiving placebo at day 3 (30.0% [79/263] 29.6% [69/233]; odds ratio51.1, 95% CI50.7–1.6; p50.68)
vs. 18.9% [50/264]; odds ratio51.9, 95% CI51.2–2.8; p50.003), (see Figure S7A in the online supplement). Greater
at day 15, and at all study visits throughout the posttreatment HAM-D response and remission rates were observed
follow-up period (see Figure S5 in the online supplement). among patients receiving zuranolone compared with
A greater proportion of patients receiving zuranolone than placebo irrespective of concomitant antidepressant use
patients receiving placebo achieved HAM-D response at day from baseline (see Figures S6B,C and S7B,C in the online
3 (29.3% [77/263] vs. 16.3% [43/264]; odds ratio52.1, 95% supplement).
CI51.4–3.3; p,0.001), at day 15 (56.0% [139/248] vs. 47.0%
[118/251]; odds ratio51.4, 95% CI51.0–2.0; p50.06), and at Safety
day 42 (52.9% [127/240] vs. 45.9% [107/233]; odds ratio51.4, The overall incidence of treatment-emergent adverse events
95% CI51.0–1.9; p50.09) (see Figure S6A in the online with zuranolone was 60.1% (161/268), compared with 44.6%
supplement). A small proportion of patients receiving either (120/269) with placebo (Table 2). Most patients who

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TABLE 1. Baseline demographic and clinical characteristics of participants in a experienced serious adverse events. Two pa-
placebo-controlled trial of zuranolone for major depressive disorder (safety set)a tients, one in each group, experienced serious
Zuranolone adverse events during the treatment period; the
50 mg/day Placebo remaining serious adverse events occurred
Characteristic (N5268) (N5269)
during the posttreatment follow-up period.
N % N % Details of serious adverse events are provided
Female 186 69.4 166 61.7 in the Supplemental Results section of the
Race online supplement.
White 169 63.1 206 76.6 There were no changes in laboratory
Black/African American 75 28.0 46 17.1
Asian 13 4.9 4 1.5
values, ECG results, or vital signs leading to
Multiracial 7 2.6 5 1.9 treatment interruption or discontinuation in
American Indian or Alaska Native 1 0.4 3 1.1 either group. No evidence of increased suicidal
Native Hawaiian or other Pacific 1 0.4 1 0.4 ideation or behavior relative to the baseline
Islander assessment was observed in either the zur-
Other 2 0.7 4 1.5
anolone or the placebo group, as measured by
Ethnicity
the C-SSRS (see Table S4 in the online sup-
Hispanic or Latino 58 21.6 54 20.1
Not Hispanic or Latino 210 78.4 215 79.9 plement). There was no indication of increased
History of any antidepressant useb 183 68.3 190 70.6
withdrawal symptoms after zuranolone treat-
Antidepressant use at baseline (any 79 29.5 81 30.1 ment (see the online supplement).
stable dosage)c
Mean SD Mean SD
DISCUSSION
Age (years) 39.4 12.3 40.1 12.6
Years since initial MDD diagnosis 10.6 10.1 11.2 10.8 In this study, patients receiving zuranolone
Days since start of current episode 468.2 1,117.4 481.0 702.3 50 mg/day demonstrated significantly greater
Number of depressive episodes 5.3 5.5 5.3 6.7 improvements in depressive symptoms at day
experiencedd
HAM-D score 26.8 2.6 26.9 2.7
15 compared with those receiving placebo, and
Body mass index 29.6 6.3 30.3 6.2 the observed onset of effect was rapid, with
a greater improvement in HAM-D and CGI-S
HAM-D517-item Hamilton Depression Rating Scale; MDD5major depressive disorder.
b
Defined as antidepressant therapy taken within 6 months prior to screening. scores observed for zuranolone compared
c
Defined as stable for .60 days; based on list of medications provided by World Health Orga- with placebo at the earliest assessment, on day
nization Drug Dictionary Anatomical Therapeutic Chemical classification system level 3, N06A.
3. The effect sizes for change from baseline in
See Table S1 in the online supplement for the list of antidepressants used.
d
Inclusive of current episode. HAM-D score at visits from day 3 to day
15 ranged from 0.49 to 0.23, which are com-
experienced treatment-emergent adverse events had events parable to effect sizes seen at the primary assessment time
that were at most mild or moderate (zuranolone, 95.0% [153/ point in clinical studies of approved antidepressant therapies
161]; placebo, 97.5% [117/120]). The most common treatment- (a mean effect size of 0.29 from 34 registration studies
emergent adverse events (.5% frequency in any group) were conducted after 2000) (27). The differences in HAM-D score
somnolence, dizziness, headache, sedation, and diarrhea between the zuranolone and placebo groups at study visits
(Table 2). A total of 23 patients in the zuranolone group and from day 3 (23.0) through day 15 (21.7) also surpassed the
one in the placebo group had their dosage reduced due to estimated minimal important difference (21.67), suggesting
treatment-emergent adverse events (Table 2), the most that the improvements in depressive symptoms were clini-
common being dizziness and somnolence with zuranolone cally meaningful (28). Greater improvements in depressive
and fatigue with placebo. Nine patients in the zuranolone and anxiety symptoms with zuranolone were sustained in the
group and four in the placebo group discontinued treatment follow-up period, as evidenced by the generally stable
due to treatment-emergent adverse events (Table 2). The HAM-D, MADRS, and HAM-A scores across all study visits
most common treatment-emergent adverse events that led to through day 42. Furthermore, while the sample sizes were
treatment discontinuation were nervous system disorders, relatively small, the efficacy results favored zuranolone re-
including dizziness and sedation in the zuranolone group and gardless of the use of antidepressant therapies at baseline.
sedation and somnolence in the placebo group. The incidence The rapid onset of action and potential for benefit of zur-
of treatment-emergent adverse events was not notably dif- anolone with an antidepressant therapy is further reinforced
ferent among patients receiving zuranolone with or without a by a recently completed phase 3 study of patients with MDD
concomitant antidepressant therapy at baseline (see Table S3 (ClinicalTrials.gov identifier: NCT04476030), which showed
in the online supplement). No deaths, loss of consciousness, improvements in patients co-initiated with zuranolone and a
weight gain, sexual dysfunction, or euphoria were reported in standard-of-care antidepressant therapy compared with
either treatment arm. Four patients (0.7%), two in each group, patients co-initiated with placebo and a standard-of-care

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ZURANOLONE FOR THE TREATMENT OF MAJOR DEPRESSIVE DISORDER

FIGURE 2. Efficacy of zuranolone 50 mg/day compared with placebo in the primary endpoint and across multiple endpoints
(full analysis set)a
A B

Zuranolone Placebo Zuranolone Placebo

N=248 N=251 Endpoint LSM Treatment Difference N LSM (SE) LSM (SE)
0
CFB in HAM-D score, day 15 499 −14.1 (0.51) −12.3 (0.50)

CFB in CGI-S score, day 15 499 −1.8 (0.08) −1.6 (0.08)

CFB in HAM-D score, day 8 517 −12.0 (0.45) −9.5 (0.45)

–5
LSM CFB in HAM-D Score

CFB in HAM-D score, day 3 527 −9.8 (0.38) −6.8 (0.38)

CFB in HAM-D score, day 42 473 −13.5 (0.55) −12.6 (0.55)

CFB in MADRS score, day 15 498 −17.5 (0.77) −15.1 (0.76)

–10
CFB HAM-A score, day 15 497 −10.4 (0.43) −9.1 (0.43)

−6 −5 −4 −3 −2 −1 0 1 2

–15
Favors zuranolone Favors placebo

p=0.01 Primary endpoint Key secondary endpoints Other secondary endpoints

–20
a
Panel A shows change from baseline in total score on the HAM-D at day 15, the primary study endpoint. Error bars indicate standard error. In panel B,
the order of the key secondary endpoints (CGI-S score at day 15 and HAM-D score at days 8, 3, and 42) was prespecified to test the difference
between treatments with multiplicity adjustment in the statistical analysis plan. Error bars indicate 95% confidence interval. CFB5change from baseline;
CGI-S5Clinical Global Impressions severity scale; HAM-A5Hamilton Anxiety Rating Scale; HAM-D517-item Hamilton Depression Rating Scale;
LSM5least squares mean; MADRS5Montgomery-Åsberg Depression Rating Scale.

antidepressant therapy at day 3 and over the treatment period network function in the brain (24, 25). The difference be-
through day 15. tween the hypothesized mechanism of action of neuroactive
Consistent with previous studies of zuranolone at 30 mg/ steroids, such as zuranolone, and that of benzodiazepines
day, no weight gain, sexual dysfunction, withdrawal symp- may also explain the observation that while benzodiazepines
toms, or increased suicidal ideation or behavior was observed promote receptor desensitization, downregulation, and tol-
in this study. Additionally, no new safety findings emerged erance, neuroactive steroids in preclinical studies upregu-
with zuranolone 50 mg/day compared with previous studies lated receptor expression (32, 33).
of zuranolone 30 mg/day (24, 25). Zuranolone 50 mg/day was Patients with MDD frequently have symptoms of anxiety
generally well tolerated, with most treatment-emergent stemming from their depression and may receive treatment
adverse events being mild or moderate in severity and low with a standard-of-care antidepressant therapy plus a ben-
rates of dosage reduction or study discontinuation due to zodiazepine (34, 35). This is because benzodiazepines elicit a
treatment-emergent adverse events. In the present study and rapid onset of effect and may work with an antidepressant
the published studies of zuranolone to date, the most common therapy to quickly alleviate symptoms of anxiety and de-
adverse events included somnolence and headache and were pression and prevent discontinuation of antidepressant
generally not clinically serious (24, 25). As efficacy and safety therapy (36). However, the results supporting this strategy
outcomes in this study were not notably different between are mixed, and evidence suggests that the potential additive
patients receiving zuranolone with or without an antide- effects may not persist with long-term treatment (37). Fur-
pressant therapy, these data support zuranolone as a viable thermore, benzodiazepine monotherapy is associated with
option as a monotherapy or concomitant with an antide- limited antidepressant effects, and the potential benefits of the
pressant therapy in patients with MDD, if approved. antidepressant-benzodiazepine combination may be offset by
The approach of targeting GABAARs, although emergent the risk of tolerance, dependence, and abuse associated with
for the treatment of depression, is well characterized for the benzodiazepines, and an increased likelihood of experiencing
treatment of anxiety-related disorders. Benzodiazepines are adverse events (37–40). The improvements observed in both
commonly used to treat anxiety and act on synaptic GABAARs HAM-D and HAM-A scores in the present study suggest that
to promote phasic inhibition. By contrast, zuranolone has a patients with MDD with elevated anxiety who received zur-
different binding site and acts on both synaptic and extra- anolone experienced improvements in anxiety symptoms
synaptic GABAARs, leading to potentiation of both phasic and compared with placebo. Long-term outcomes of using zur-
tonic inhibition, respectively (10, 11, 22, 23, 29–31). This anolone monotherapy for management of MDD with elevated
mechanistic difference of promoting both transient phasic anxiety are not yet known and will be further elucidated with
and sustained tonic inhibition may help restore normal real-world use of zuranolone, if approved.

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 CLAYTON ET AL.

FIGURE 3. Change from baseline in HAM-D and HAM-A scores over time with proportion of African American and Asian
zuranolone 50 mg/day compared with placebo (full analysis set)a patients in the zuranolone group compared
A End of with the placebo group, which may limit the
treatment
(day 14) generalizability of the results. Additionally,
0 this study showed a robust placebo response,
LSM CFB in HAM-D Score

and its magnitude was similar to that ob-

–5 * served previously for zuranolone or antide-
* pressant therapies. The observed placebo
–10 *
* response may be due in part to the high
frequency of study visits (10 visits in 42 days),
–15
which is both higher than the typical fre-
–20
quency of real-world visits and consistent
Base- 3 8 12 15 21 28 35 42 with previous evaluations in other
line
Days standard-of-care antidepressant therapy tri-
Zuranolone, N 266 263 255 250 248 237 239 237 240
als, which showed a positive correlation be-
Placebo, N 268 264 262 248 251 239 234 231 233 tween the number of study visits and placebo
Zuranolone 50 mg/day
response (42, 43). Another factor that pos-
B End of
treatment Placebo sibly had an influence on the results was that
(day 14) the study was conducted entirely during
0
the COVID-19 pandemic. A U.S. population-
LSM CFB in HAM-A Score

based survey conducted at the beginning

–5 of the COVID-19 pandemic demonstrated a
*
threefold increase in depressive symptoms
*
as measured by the Patient Health
–10
Questionnaire–9 compared with prepan-
demic levels (44). The frequent in-person
–15 visits in this study may have contributed to
Base- 8 15 28 42
line alleviating feelings of isolation and predis-
Days posed patients to experience improvements in
Zuranolone, N 266 255 247 237 240 symptoms even if they were receiving placebo.
Placebo, N 268 260 250 231 232
a
An important observation in this study
All indicated p values except change from baseline in HAM-D at day 15 (primary endpoint)
are nominal; p values were calculated by a mixed-effects model for repeated measures. Error was that a small proportion of patients who
bars indicate standard error. CFB5change from baseline; HAM-A5Hamilton Anxiety Rating had a HAM-D response at day 15 did not
Scale; HAM-D517-item Hamilton Depression Rating Scale; LSM5least squares mean. maintain the HAM-D response at day 42,
*p,0.05.
after cessation of treatment. Accordingly,
clinicians may continue to monitor patients
A limitation of this study is that it was a short-term one after response to the initial treatment to determine whether
designed to assess the outcomes of patients after one 14-day the major depressive episode was successfully treated and
treatment course of zuranolone. The long-term safety and continue to intervene if appropriate.
efficacy of zuranolone and the potential need for repeated
treatment courses over a 1-year period are being addressed in
CONCLUSIONS
an ongoing open-label study (ClinicalTrials.gov identifier:
NCT03864614). The present study’s patient population was This randomized, placebo-controlled phase 3 trial demon-
also severely depressed at study entry (mean baseline strated significantly greater improvements in depressive
HAM-D scores of 26.8 and 26.9 for patients receiving zur- symptoms favoring zuranolone based on the primary end-
anolone and placebo, respectively), which may limit the point and supports the potential role for a 14-day therapy with
degree to which the results generalize to patients with mild or oral zuranolone 50 mg/day in adults with MDD, with rapid
moderate depressive symptoms. However, the mean baseline improvements in depressive symptoms observed at the day
HAM-D score in this study is consistent with a meta-analysis 3 visit that were sustained through day 42, relatively high
of several clinical trials of standard-of-care antidepressant response and remission rates, and a favorable safety profile.
therapies, which reported mean baseline HAM-D scores Furthermore, efficacy and safety results with zuranolone
ranging from 17.0 to 30.5, and other studies in the LAND- were similar regardless of whether patients were receiving a
SCAPE program included patients with moderate to severe concomitant antidepressant therapy, suggesting that com-
depressive symptoms (41). While the patient population was bination therapy may be a viable option for patients who are
racially and ethnically diverse in both groups, there was a currently on an antidepressant therapy but would benefit
slightly lower proportion of White patients and a higher from a therapy that may improve depressive symptoms with

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ZURANOLONE FOR THE TREATMENT OF MAJOR DEPRESSIVE DISORDER

TABLE 2. Summary of treatment-emergent adverse events over Axsome, Biogen, Boehringer Ingelheim, the Centers for Psychiatric Ex-
the 42-day study (safety set)a cellence, Clexio, Jazz, Lundbeck, Neumora, Otsuka, Precision Neuro-
science, Relmada, Sage Therapeutics, and Sunovion, and he has received
Zuranolone
50 mg/day Placebo grant support (paid to his institutions) from Alkermes, AstraZeneca,
(N5268) (N5269) BrainsWay, LiteCure, NeoSync, Otsuka, Roche, and Shire. Ms. Forrestal
and Dr. Kotecha are employees of Biogen and may hold stock. Drs.
Safety Parameter N % N % Lasser, Doherty, Jonas, and Jung are employees of Sage Therapeutics
TEAEs 161 60.1 120 44.6 and may hold stock and/or stock options. Dr. Jonas serves as a board
Mild 86 32.1 76 28.3 member for Sage Therapeutics. Dr. Kanes is currently an employee of
Moderate 67 25.0 41 15.2 Ancora Bio and was an employee of Sage Therapeutics at the time this
Severe 8 3.0 3 1.1 trial was conducted and is a shareholder of Sage Therapeutics.
SAEs 2 0.7 2 0.7 Received May 20, 2022; revisions received December 14, 2022, and
Death 0 0.0 0 0.0 February 3, 2023; accepted February 14, 2023.
Dosage reduction 23 8.6 1 0.4
due to TEAE
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