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. 2024 May 28;241(7):1299–1317. doi: 10.1007/s00213-024-06611-y

The efficacy and safety of Zuranolone for treatment of depression: A systematic review and meta-analysis

Aya M Fayoud 1,2,✉, Hisham Ahmed Orebi 2,3, Iman Abdelhady Elshnoudy 2,3, Mai Alaaeldin Temraz Elsebaie 2,4, Mariam Mahmoud Mohamed Elewidi 2,3, Hamdy Khaled Sabra 2,3
PMCID: PMC11199213  PMID: 38802705

Abstract

Rationale

Zuranolone, a newly FDA-approved synthetic neurosteroid, shows promise in treating depression.

Objectives

Our aim is to evaluate Zuranolone's efficacy and safety in treating depression.

Methods

Five databases were searched until September 2023 for relevant randomized clinical trials evaluating the efficacy and safety of zuranolone. The potential risk of bias in the included trials was evaluated by the Cochrane Risk of Bias II guideline Data were extracted and pooled using Review Manager Software (RevMan 5.3).

Results

An analysis of eight studies highlights Zuranolone's efficacy in treating depression compared to placebo across most of the outcomes. Notably, the 30mg and 50mg doses demonstrated significant improvements in reducing HAM-D scores by over 50% within a 15-day follow-up (RR) of 1.46 (95% CI [1.27, 1.68], p < 0.0001) and 1.14 (95% CI [1.01, 1.3], p = 0.04). Additionally, the HAM-D ≤ 7% score analysis revealed significant enhancements with the 30mg dose over both 15-day (RR = 1.82, 95% CI [1.44, 2.31], p < 0.0001) and 45-day (RR = 1.43, 95% CI [1.16, 1.77], p = 0.0008) durations. Adverse Events Drug Discontinuation demonstrated no overall significant difference (OR = 1.33, 95% CI: [0.79, 2.23], p = 0.282). Further, specific adverse events, such as headache, showed no significant overall difference between Zuranolone and placebo (OR = 1.11, 95% CI: [0.84, 1.47], p = 0.47), with dose-dependent analysis revealing less headache in the 30 mg group.

Conclusion

Zuranolone demonstrates favorable tolerability and safety, particularly at 30mg and 50mg doses after 15 days, suggesting its potential and effective treatment for depression.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00213-024-06611-y.

Keywords: Zuranolone, Major depressive disorder, Postpartum depression, Synthetic neurosteroid

Introduction

Major Depressive Disorder (MDD) stands as a global mental health challenge, causing widespread disability (GBD 2017 Disease and Injury Incidence and Prevalence Collaborators 2018). Its manifestations involve alterations in affect, as well as cognitive, social, and occupational functions (Otte et al. 2016). The global prevalence of depression has surged, with over 19 million individuals in the United States having experiencing multiple depressive episodes, more than half of whom struggle with severe functional impairment (2019 NSDUH Detailed Tables n.d; Kessler et al. 2003). Unfortunately, approximately 788,000 individuals, burdened by depression, commit suicide (World Health Organization [Internet] 2017). Postpartum Depression (PPD), a form of major depressive disorder that emerges within four weeks after childbirth, leads to a decline in overall well-being and mental functioning (Bauman et al. 2020; Da Costa et al. 2006). The profound impact of PPD is evident through the loss of maternal-infant bonding and an increased susceptibility to suicide (Kerstis et al. 2016).

Treatment typically involves Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs), and Tricyclic Antidepressants (TCAs) (Hockenberry et al. 2019). However, the effectiveness of these interventions is not guaranteed, with remission rate of over a 30% and at least 50% resistance to treatment with combined antidepressants(Kulkarni & Dhir 2009). After initial treatment, a significant number of patients struggle to maintain remission, contending with persistent symptoms that affect their quality of life and increase the risk of relapse (Trivedi 2009; Trivedi et al. 2006). Factors such as discontinuation of treatment and poor compliance, often due to delayed improvement or intolerance to side effects like weight gain and sexual dysfunction, contribute to this challenge (Bull et al. 2002; Geddes et al. 2003; Kulkarni & Dhir 2009).

The pathophysiology of depression is multifaceted, involving genetic, epigenetic, and environmental risk factors (Batterham et al. 2009). Disruption in the excitatory-inhibitory balance, regulated by glutamatergic and GABAergic signaling, is posited to play a role in depression development (Lener et al. 2017). This hypothesis gains support by observed alterations in GABA levels in the plasma, cerebrospinal fluid (CSF), and brain tissue of depressed patients, along with downstream changes in the expression of GABA-synthesizing enzymes and mRNA of GABA type A in individuals who died by suicide (Cutler et al. 2023; Gerner & Hare 1981; Luscher et al. 2011; Luykx et al. 2012; Merali et al. 2004; Sanacora et al. 2004).

Preclinical studies have identified allopregnanolone levels as a risk factor influencing GABAergic signaling (Osborne et al. 2017). Allopregnanolone, a neuroactive steroid and positive allosteric modulator of GABAA receptors, shows promise as an antidepressant, as evidenced by its normalization in CSF following SSRI treatment for depression (Paul & Purdy 1992; Uzunova et al. 1998).

Recently, Zuranolone, a synthetic neurosteroid and positive allosteric modulator of GABAA receptors, has gained approval from the U.S. Food and Drug Administration (FDA) for use in postpartum depression, based on two phase 3 randomized controlled trials (FDA NEWS RELEASE 2023; Heo 2023). Our goal is to systematically assess the efficacy and safety of Zuranolone for major depressive disorder and postpartum depression based on available clinical trials.

Methodology

We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines (Page et al. 2021) and the Cochrane Handbook of Systematic Reviews and Meta-analysis (Higgins, et al. 2019). PRISMA checklist is illustrated in (See supplementary Tables S1 and S2, online resource).

Data sources & search strategy

We searched PubMed, Web of Science, SCOPUS, clinicaltrials.gov and Cochrane Central through September 2023, using the following keywords ((Zuranolone OR SAGE$217) AND (Depress* OR dysphoria OR Melancholia OR dysthymi* OR "adjustment disorder*" OR "mood disorder*" OR "affective disorder*" OR "affective symptoms")).

Eligibility criteria

We included clinical trials with the following PICO criteria: population (P): human patients with depression (e.g. MMD) or postpartum depression; intervention (I): Zuranolone; control (C): placebo. On the other hand, we excluded studies not fulfilling the previous criteria such as observational studies (cohort, case–control, cross-sectional, case series, and case reports), unpublished study protocols, letters to the editor, non-human studies, or those published in languages other than English.

Selection process

Two authors independently carried out a two-step selection process, screening titles and abstracts of retrieved records. Subsequently, full texts of potentially eligible records were retrieved and assessed for inclusion in the meta-analysis. Any conflicts were resolved through discussion to reach a consensus.

Data extraction

Four authors, using a pre-formed data extraction sheet, extracted the following data: study design characteristics (last authors' name, year of publication, NCT number, study design, country, inclusion criteria, exclusion criteria, intervention, control, outcomes, and Duration of treatment); Baseline sheet of the enrolled participants included study arms, number of participants in each arm, age in years, weight (kg), BMI (kg/m2), sex (%), ethnicity (%), race (%), Baseline antidepressant use No. (%) and baseline Hamilton Depression Rating Scale (HAMD) total score, mean (SD). All sheets were independently reviewed by the first author.

Risk of bias

Two authors independently evaluated the potential risk of bias in the included trials following the Cochrane Risk of Bias II guideline (Sterne et al. 2019). We accordingly considered the following: randomization process, deviation from intended intervention, bias in the measurement of outcomes, selection of reported results, missing outcome data, and overall bias. Conflicts were resolved by reaching a consensus through discussion.

Endpoints

Efficacy outcomes

HAMD-17 score improvement, Reduction of > 50% from baseline in HAM-D score, HAM-D ≤ 7% score, Clinical Global Impression Improvement (CGI-I) total score, Bech-6 total score, Montgomery-Åsberg Depression Rating Scale (MADRS) total score and Hamilton Rating Scale for Anxiety (HAM-A) total score.

Safety outcomes

Any treatment-emergent adverse event (TEAE), patients with a serious adverse event (any adverse event occurring while the patient was receiving the trial medication or placebo, that resulted in death, was immediately life-threatening, led to inpatient hospitalization or prolongation of hospitalization, caused persistent or clinically significant disability or incapacity, or resulted in a congenital abnormality or birth defect), patients with a severe adverse event (any event that was incapacitating or caused an inability to perform normal activities of daily living), adverse events drug discontinuation, and most common TEAEs.

Statistical analysis

This meta-analysis was conducted by using two programs; Review Manager Software (RevMan version 5.3 n.d; Cochrane Collaboration, Copenhagen, Denmark, 2014) and Open Meta Analyst (OMA n.d) (Computer program) (Version 5.4. Copenhagen: The Nordic Cochrane Centre, the Cochrane Collaboration, 2014). We presented all data as either (1) mean difference (MD) in pooling continuous outcomes, or (2) odds/risk ratio (OR) in pooling dichotomous outcomes with 95% confidence intervals (CIs). We tested the heterogeneity between pooled studies using chi-square and I-square tests. When the heterogeneity between studies at chi-square of I2 > 50% P-value < 0.05, we used a random-effect model for analysis. We performed subgroup analysis to test whether the effect estimate of zuranolone differs significantly according to the dose and duration.

Results

Literature search results

Our systematic search identified 222 potential studies; Among these, 56 were excluded as duplicates. Following title and abstract screening, an additional 107 studies were excluded. Subsequently, full-text screening led to the exclusion of 51 studies. Finally, eight eligible studies were included for quantitative and qualitative synthesis in this systematic review. An extra 107 studies were excluded after title/abstract screening and then 51 studies were excluded after the full-text screening. In the end, we got eight eligible studies to be included in the quantitative and qualitative synthesis of this systematic review (Fig. 1; PRISMA).

Fig. 1.

Fig. 1

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PRISMA flow diagram of the systematic review

Characteristics of included studies

All the included studies were RCTs with a total number of 2,176 patients. The eight included RCTs were controlled with a placebo, with two of them incorporating two intervention arms featuring different doses of Zuranolone. Additionally, one study compared Zuranolone in combination with antidepressant therapy (ADT) to placebo with ADT. The number of patients in these included studies ranged from 89 to 537 patients with mean age varying between 27.4 and 49.1 years, and The Hamilton Depression Rating Scale ranged between 24.5 to 28.8. Zuranolone was administered orally once daily, with doses ranging from 20 to 50 mg over 2 weeks. Seven trials were conducted in the United States, and one study was conducted in Japan (Tables 1 and 2).

Table 1.

Summary of included studies

Study ID Protocol registration (NCT) Study Design Setting (country) Total number of patients Intervention Comparison Duration of treatment Outcomes Participants (inclusion criteria) Exclusion criteria
Deligiannidis et al. 2021 NCT02978326 RCT USA 150 Zuranolone (30-mg/day) Placebo 14 days Zuranolone was effective in improving symptoms of PPD indicated by HAMD-17 score, and generally well-tolerated Female aged 18 to 45 years old, with PPD without psychosis (not more than 6 months postpartum) Patients with known medical problems that prevent them from taking zuranolone
Gunduz-Bruce et al. 2019 NCT03000530 RCT USA 89 SAGE 217 (30-mg/day) Placebo 14 days SAGE-217 was effective in reducing depressive symptoms, but the safety and tolerability is still questionable Males and females aged 18 to 65 years old with MDD Patients with history of suicide, resistant to antidepressant, or known medical problems that prevent them from taking the intervention
Clayton et al. 2023 NCT03672175 RCT USA 482 Zuranolone (20-mg/day or 30-mg/day) Placebo 14 days Significant rapid improvements in depressive symptoms were observed with zuranolone 30 mg, and it was generally well-tolerated Males and females aged 18 to 65 years old with MDD Patients with history of suicide, resistant to antidepressant, or known medical problems that prevent them from taking the intervention
Deligiannidis et al. 2023 NCT02978326 RCT USA 150 Zuranolone (30-mg/day) Placebo 14 days Zuranolone was effective in improving depressive, anxiety, and associated insomnia symptoms Female aged 18 to 45 years old, with PPD without psychosis (not more than 6 months postpartum) Patients with known medical problems that prevent them from taking zuranolone
Suthoff et al. 2022 NCT03000530 RCT USA 89 SAGE 217 (30-mg/day) Placebo 14 days Zuranolone-treated patients reported rapid and significant improvements in HRQoL Males and females aged 18 to 65 years old with MDD Patients with history of suicide, resistant to antidepressant, or known medical problems that prevent them from taking the intervention
Kato et al. 2023a JapicCTI-205276 RCT Japan 249 Zuranolone (20-mg/day or 30-mg/day) Placebo 14 days Zuranolone was safe and demonstrated significant improvements in depressive symptoms Males and females aged 18 to 75 years old with MDD Patients with antidepressant resistance or known medical problems that prevent them from taking the intervention
Clayton et al. 2023 NCT04442490 RCT USA 537 Zuranolone (50-mg/day) Placebo 14 days Zuranolone demonstrated significant improvements in depressive symptoms Males and females aged 18 to 64 years old with MDD Patients with history of suicide, resistant to antidepressant, or known medical problems that prevent them from taking the intervention
Parikh et al. 2024 NCT04476030 RCT USA 430 Zuranolone (50-mg/day) + ADT Placebo + ADT 14 days Zuranolone demonstrated significant improvements in depressive symptoms Males and females aged 18 to 64 years old with MDD Patients with history of suicide, resistant to antidepressant, or known medical problems that prevent them from taking the intervention
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ADT Antidepressant Therapy, HAMD-17 17-item Hamilton Rating Scale for Depression, HRQoL Health-related Quality of Life, MMD Major Depressive Disorder, PPD Postpartum Depression, RCT Randomized Controlled Trial, USA United States of America

Table 2.

Baseline characteristics of the included studies

Study ID Study Arm No. of participants Age, mean (SD), y Sex No. (%) Weight, mean (SD), kg BMI, mean (SD), kg/m2 Ethnicity, No. (%) Race, No. (%) Baseline antidepressants use No. (%) Baseline Hamilton Depression Rating Scale (HAMD) total score, mean (SD)
Male Female Hispanic or Latino Not Hispanic or Latino African American White Asian Other
Deligiannidis et al. 2021 zuranolone 30 mg 76 29.3 (5.4) 0 100% 85.1(19) 31.1(6) 16 (21) 60 (79) 31(41) 44(58) 1(1) 16(21) 28.4(2)
placebo 74 27.4(5.3) 0 100% 80.2(24) 30.3(8) 18(24) 56(76) 31(42) 40(54) 3(4) 13(18) 28.8(2)
Gunduz-Bruce et al. 2019

Zuranolone

30 mg

 45 49.1(13.6) 20 (44) 25(56) _ 30.0(6.3) _ _ 36(80) 7(16) 1(2) 1(2) 12(27) 25.2(2.6)
placebo 44 38.3(12.2) 14 (32) 30 (68) _ 29.9(5.2) _ _ 28(64) 16(36) 0 0 10(23) 25.7(2.4)
Clayton et al. 2023 zuranolone 30 mg 166 42.3 (11.8) 45 (27.1) 121 (72.9) 89.7 (22.4) _ 27 (16.3) 139(83.7) 64 (38.6) 94 (56.6) 2 (1.2) 6 (3.6) 47 (28.3) 25.9 (2.9)
zuranolone 20 mg 159 41.9 (12.2) 47 (29.6) 112 (70.4) 87.3 (20.2) _ 31 (19.5) 128(80.5) 56 (35.2) 99 (62.3) 3 (1.9) 1 (0.6) 46 (28.9) 25.8 (2.8)
placebo 157 41.4 (12.2) 51(32.5) 106 (67.5) 89.5 (22.9) _ 26 (16.6) 131(83.4) 54 (34.4) 96 (61.1) 3 (1.9) 4 (2.5) 49 (31.2) 25.8 (3.1)
Deligiannidis et al. 2023 zuranolone 30 mg 76 29.3 (5.4) 0 100% 85.1(19) 31.1(6) 16 (21) 60 (79) 31(41) 44(58) 1(1) 16(21) 28.4(2)
placebo 74 27.4(5.3) 0 100% 80.2(24) 30.3(8) 18(24) 56(76) 31(42) 40(54) 3(4) 13(18) 28.8(2)
Suthoff et al. 2022 zuranolone 30 mg 45 49.1(13.6) 20 (44) 25(56) _

30.0

(6.3)

 _ _ 36(80) 7(16) 1(2) 1(2) 12(27) 25.2(2.6)
placebo 44 38.3(12.2) 14 (32) 30 (68) _ 29.9(5.2) _ _ 28(64) 16(36) 0 0 10(23) 25.7(2.4)
Kato et al. 2023a placebo 82 40.8 (10.6) 35 (42.7) 47 (57.3) 63.4 (16.5) 23.6 (5.3) 0 82 (100) 0 0 82(100) 0 _ 24.5 (2.1)
zuranolone 20 mg 85 39.3 (12.6) 36 (42.4) 49 (57.6) 64.6 (13.8) 23.9 (4.4) 0 85 (100) 0 0 85(100) 0 _ 24.8 (2.4)
zuranolone 30 mg 82 38.8 (12.0) 35 (42.7) 47 (57.3) 61.0 (12.9) 22.7 (4.0) 0 82(100) 0 0 82(100) 0 _ 24.6 (2.2)
Clayton et al. 2023 zuranolone 50 mg 268 39.4 (12.3) 82(30.6) 186 (69.4) _ 29.6 (6.3) 58 (21.6) 210 (78.4) 75(28.0) 169 (63.1) 13 (4.9) 11(4.1) 79 (29.5) 26.8 (2.6)
placebo 269 40.1 (12.6) 103(38.3) 166 (61.7) _ 30.3 (6.2) 54 (20.1) 215 (79.9) 46 (17.1) 206 (76.6) 4 (1.5) 13(4.8) 81 (30.1) 26.9 (2.7)
Parikh et al. 2024 Zuranolone 50 mg + ADT 212 38.6 (12.72) 83 (39.2) 129 (60.8) _ 29.1 (6.26) 41 (19.3) 171 (80.7) 46 (21.7 153 (72.2) 6 (2.8) 3 (1.4) 115 (54.2)

26.8

(2.51)
Placebo + ADT 218 37.7 (12.28) 78 (35.8) 140 (64.2) _

29.9

(6.44)

 52 (23.9) 166 (76.1) 31 (14.2 168 (77.1) 12 (5.5) 3 (1.4) 120 (55.0) 26.6 (2.58)
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Quality assessment

According to the Cochrane Risk of Bias Assessment Tool for Randomized Clinical Trials II (ROB-II), the quality of the included studies ranges from low to some concerned risk of bias. One study showed a potentially high risk of bias in the randomization process domain. While four studies showed some concerned risk of bias regarding the measurement of the outcomes domain, and one study in the missing data domain (Fig. 2 and Table 3).

Fig. 2.

Fig. 2

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Risk of bias assessment of the included studies

Table 3.

Risk of bias assessment of the included studies

Domains Risk of bias Judgment of the authors
Deligiannidis et al. (2021)
Randomization Process Low The randomization scheme was performed using an interactive response technology system vendor using SAS statistical software version 9.4 (SAS Institute). There were no baseline differences between intervention groups
Deviation from the intended intervention Low Participants and personnel were blinded
Missing outcome data Low Intention to treat analysis
Bias in the measurement of outcome Low All other site personnel except site–designated pharmacy staff were blinded to treatment assignments during the study
Selection of reported results Low The protocol was available, and data were analyzed in accordance with pre-specified plan
Overall bias Low The study is judged to be at low risk of bias for all domains
Gunduz-Bruce et al. (2019)
Randomization Process Low Randomization was performed using interactive response technology created by 4G Clinical (Wellesley, MA). In a 1:1 ratio, patients were assigned to receive either SAGE-217 (30 mg) or placebo
Deviation from the intended intervention Low Participants and personnel were blinded, and analysis was appropriate
Missing outcome data Low Analyses were performed according to the intention-to-treat principle and included all patients who underwent randomization
Bias in the measurement of outcome Some concerns No information whether outcome assessors were aware of intervention or not and assessment can be influenced by knowledge of intervention
Selection of reported results Low The protocol was available, and data were analyzed in accordance with pre-specified plan
Overall bias Some concerns The study is judged to raise some concerns in one domain
Clayton et al. (2023)
Randomization Process Some concern No information about the allocation concealment
Deviation from the intended intervention Low Participants and personnel were blinded
Missing outcome data Some concerns There is large number of follow up loss, but proportions of missing outcome data were balanced between intervention groups
Bias in the measurement of outcome Some concerns No information whether outcome assessors were aware of intervention or not and assessment can be influenced by knowledge of intervention
Selection of reported results Low The protocol was available, and data were analyzed in accordance with pre-specified plan
Overall bias Some concerns The study is judged to raise some concerns in three domains
Deligiannidis et al. (2023)
Randomization Process Low The randomization scheme was performed using an interactive response technology system vendor using SAS statistical software version 9.4 (SAS Institute). There were no baseline differences between intervention groups
Deviation from the intended intervention Low Participants and personnel were blinded
Missing outcome data Low Intention to treat analysis
Bias in the measurement of outcome Low All other site personnel except site–designated pharmacy staff were blinded to treatment assignments during the study
Selection of reported results Low The protocol was available, and data were analyzed in accordance with pre-specified plan
Overall bias Low The study is judged to be at low risk of bias for all domains
Suthoff et al. 2022
Randomization Process Low Randomization was performed using interactive response technology created by 4G Clinical (Wellesley, MA). In a 1:1 ratio, patients were assigned to receive either SAGE-217 (30 mg) or placebo
Deviation from the intended intervention Low Participants and personnel were blinded, and analysis was appropriate
Missing outcome data Low Analyses were performed according to the intention-to-treat principle and included all patients who underwent randomization
Bias in the measurement of outcome Some concerns No information whether outcome assessors were aware of intervention or not and assessment can be influenced by knowledge of intervention
Selection of reported results Low The protocol was available, and data were analyzed in accordance with pre-specified plan
Overall bias Some concerns The study is judged to raise some concerns in one domain
Kato et al. (2023a)
Randomization Process Low Patients were randomized (1:1:1) at baseline (visit 1), with stratification based on the 17-item Hamilton Depression Rating Scale (HAMD-17) total score at baseline (< 25 vs ≥ 25) and sex, to receive zuranolone 20 mg, zuranolone 30 mg, or matching placebo once daily for 14 days (double-blind treatment period)
Deviation from the intended intervention Low Study was double blinded, and analysis was appropriate
Missing outcome data Low "Full analysis set (FAS) comprised all patients randomly assigned to the study drug and administered at least one dose of the study drug”; Analysis was intention to treat
Bias in the measurement of outcome Some concerns No information whether outcome assessors were aware of intervention, however; the assessment tools were reliable
Selection of reported results Low The protocol was available, and data were analyzed in accordance with pre-specified plan
Overall bias Some concerns The study is judged to raise some concerns in one domain
Clayton et al. (2023)
Randomization Process Low Randomization, in a 1:1 ratio, was performed centrally via an interactive response technology system
Deviation from the intended intervention Low participants and personnel were blinded, and analysis was appropriate
Missing outcome data Low "543 were randomized, 537 were included in the safety set and 534 were included in the full analysis set", Nearly all randomized participants were involved in the analysis with missing outcome data is sufficiently small that their outcomes could have made no important difference to the estimated effect of intervention
Bias in the measurement of outcome Low Patients, clinicians, site personnel, the study sponsor, and the study team were blinded to treatment allocation. Blinding was maintained until database lock after all patients completed the study visit at day 42
Selection of reported results Low The protocol was available, and data were analyzed in accordance with pre-specified plan
Overall bias Low The study is judged to be at low risk of bias for all domains
Parikh et al. (2024)
Randomization Process High Randomization was performed by stratification according to the co-initiated antidepressant and the administration of the antidepressants was open labelled
Deviation from the intended intervention Low Participants and personnel were blinded
Missing outcome data Low "Full analysis set (FAS) comprised all patients randomly assigned to the study drug and administered at least one dose of the study drug", Analysis was intention to treat
Bias in the measurement of outcome Low Outcome assessors were blinded
Selection of reported results Low The protocol was available, and data were analyzed in accordance with pre-specified plan
Overall bias High The study is judged to raise high risk of bias in one domain
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Outcomes

Efficacy outcomes

HAMD-17 score improvement

The overall effect estimates of 15-day follow-up duration showed a significant difference between Zuranolone and placebo groups favoring Zuranolone (SMD = -0.3, 95% CI: [-0.43, -0.17], p < 0.00001). The pooled results were heterogeneous (p = 0.03, I2 = 53%) which could not be solved. After introducing subgroup analysis based on Zuranolone dose, the effect estimates showed significant improvement in both Zuranolone 30-mg and Zuranolone 50-mg groups when compared to placebo group [(SMD = -0.44, 95% CI [-0.63, -0.24], p < 0.0001); p = 0.1, I2 = 49%] and [(SMD = -0.18, 95% CI [-0.31, -0.05], p = 0.008); p = 0.4, I2 = 0%], respectively. However, the effect estimate showed no significant difference in the Zuranolone group 20-mg when compared to the placebo group [SMD = -0.18, 95% CI [-0.45, 0.08], p = 0.18); p = 0.16, I2 = 49%] (Table 4). Also, see supplementary Fig. S1 (online resource).

Table 4.

Mean difference OR standardized mean difference of the efficacy outcomes

Variables Duration Doses Effect estimates No. of participants Heterogeneity
MD/SMD 95% CI P Zurnaonlone Placebo I2 P
HAMD-17 15 days 20-mg -0.18 [-0.45, 0.08] 0.18 233 223 49 0.16
30-mg -0.44 [-0.63, -0.24]  < 0.0001 424 414 49 0.1
50-mg -0.18 [-0.31, -0.05] 0.008 437 466 0 0.4
Total -0.3 [-0.43, -0.17]  < 0.00001 1098 1103 53 0.03
42–45 days 20-mg -0.12 [-0.47, 0.022] 0.48 215 209 66 0.08
30-mg -0.26 [-0.45, -0.08] 0.004 401 396 38 0.17
50-mg -0.06 [-0.19, 0.08] 0.42 417 409 0 0.49
Total -0.16 [-0.28, -0.04] 0.008 1033 1014 42 0.09
Bech-6 score NA NA -7.75 [-20.66, 5.15] 0.24 125 126 84 0.01
MADRS score 15 days 20-mg -0.06 [-0.29, 0.17] 0.59 152 141 NA NA
30-mg -0.31 [-0.46, -0.16]  < 0.0001 348 332 15 0.31
50-mg -0.2 [-0.38, -0.02] 0.03 247 250 NA NA
Total -0.22 [-0.32, -0.12]  < 0.001 747 723 26 0.24
42–45 days 20-mg 0.05 [-0.19, 0.28] 0.69 140 135 NA NA
30-mg -0.24 [-0.4, -0.09] 0.002 331 322 39 0.18
Total -0.16 [-0.28, -0.03] 0.02 471 457 56 0.06
HAM-A score 15 days 20-mg -1.03 [-2.99, 0.93] 0.3 232 223 28 0.24
30-mg -2.34 [-3.83, -0.85] 0.002 354 341 40 0.17
50-mg -1.29 [-2.41, -0.17] 0.02 247 250 NA NA
Total -1.56 [-2.37, -0.74] 0.0002 833 814 25 0.24
42–45 days 20-mg -0.05 [-1.44, 1.34] 0.94 140 135 NA NA
30-mg -2.42 [-5.63, 0.8] 0.14 258 253 76 0.01
50-mg -0.81 [-2.16, 0.54] 0.24 240 232 NA NA
Total -1.33 [-2.83, 0.18] 0.08 638 620 66 0.02
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CI: Confidence interval; HAM-A: Hamilton Rating Scale for Anxiety; HAMD-17: Hamilton Rating Scale for Depression-17; MADRS: Montgomery–Åsberg Depression Rating Scale; MD: Mean difference; SMD: Standardized mean difference

The overall effect estimates of 42 to 45-day follow-up duration showed a significant difference between Zuranolone and placebo groups favoring Zuranolone (SMD = -0.16, 95% CI: [-0.28, -0.04], p = 0.008). The pooled results were homogenous (p = 0.09, I2 = 42%). After introducing subgroup analysis based on Zuranolone dose, the effect estimates showed significant improvement in Zuranolone 30-mg when compared to the placebo group [SMD = -0.26, 95% CI [-0.45, -0.08], p = 0.004); p = 0.17, I2 = 38%]. However, the effect estimates showed no significant difference in both Zuranolone 20-mg and Zuranolone 50-mg groups when compared to the placebo group [SMD = -0.12, 95% CI [-0.47, 0.22], p = 0.48); p = 0.08, I2 = 66%] and [SMD = -0.06, 95% CI [-0.19, 0.08], p = 0.42); p = 0.49, I2 = 0%], respectively (Table 4). Also, see supplementary Fig. S2 (online resource).

Reduction of > 50% from baseline in HAM-D score

The overall effect estimates of 15-day follow-up duration showed a significant difference between Zuranolone and placebo groups favoring Zuranolone (RR = 1.25, 95% CI: [1.14, 1.36], p < 0.00001). The pooled results were homogenous (p = 0.05, I2 = 49%. After introducing subgroup analysis based on Zuranolone dose, the effect estimates showed significant improvement in both Zuranolone 30-mg and Zuranolone 50-mg groups when compared to the placebo group [(RR = 1.46, 95% CI [1.27, 1.68], p < 0.0001); p = 0.2, I2 = 33%] and [(RR = 1.14, 95% CI [1.01, 1.3], p = 0.04); p = 0.48, I2 = 0%], respectively. However, the effect estimate showed no significant difference between Zuranolone 20-mg when compared to the placebo groups [RR = 1.07, 95% CI [0.84, 1.37], p = 0.58); p = 0.34, I2 = 0%] (Table 5). Also, see supplementary Fig. S3 (online resource).

Table 5.

Risk ratio of the efficacy outcomes

Variables Duration Doses Effect estimates No. of participants Heterogeneity
RR 95% CI P Zurnaonlone Placebo I2 P
Reduction of > 50% from baseline in HAM-D score 15 days 20-mg 1.07 [0.84, 1.37] 0.58 233 223 0 0.34
30-mg 1.46 [1.27, 1.68]  < 0.00001 426 413 33 0.2
50-mg 1.14 [1.01, 1.3] 0.04 437 448 0 0.48
Total 1.25 [1.14, 1.36]  < 0.00001 1096 1084 49 0.05
42–45 days 20-mg 1.26 [0.76, 2.1] 0.36 215 209 77 0.04
30-mg 1.24 [1.08, 1.43] 0.003 398 391 9 0.35
50-mg 1.02 [0.82, 1.28] 0.84 417 409 71 0.06
Total 1.16 [1.02, 1.33] 0.02 1030 1009 53 0.03
HAM-D score ≤ 7 15 days 20-mg 1.15 [0.78, 1.72] 0.48 233 223 51 0.15
30-mg 1.82 [1.44, 2.31]  < 0.00001 426 413 6 0.37
50-mg 1.19 [0.96, 1.48] 0.11 437 448 0 0.4
Total 1.41 [1.21, 1.63]  < 0.00001 1096 1084 48 0.05
42–45 days 20-mg 1.11 [0.79, 1.56] 0.54 215 209 0 0.75
30-mg 1.43 [1.16, 1.77] 0.0008 398 391 53 0.07
50-mg 1 [0.83, 1.21] 0.97 417 409 0 0.7
Total 1.17 [1.03, 1.33] 0.02 1030 1009 47 0.06
CGI score of 1 or 2 15 days 20-mg 1.02 [0.8, 1.3] 0.16 151 141 NA NA
30-mg 1.34 [1.15, 1.57] 0.0002 273 259 38 0.2
50-mg 1.59 [1.16, 2.16] 0.004 263 264 NA NA
Total 1.3 [1.15, 1.47]  < 0.0001 687 664 54 0.07
42–45 days 20-mg 1.06 [0.83, 1.35] 0.66 140 135 NA NA
30-mg 1.22 [1.05, 1.42] 0.01 258 253 0 0.93
Total 1.17 [1.03, 1.33] 0.02 398 388 0 0.77
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CI Confidence interval, CGI Clinical Global Impression, HAM-D Hamilton Rating Scale for Depression, RR Risk ratio

The overall effect estimates of 42 to 45-day follow-up duration showed a significant difference between Zuranolone and placebo groups favoring Zuranolone (RR = 1.16, 95% CI: [1.02, 1.33], p = 0.02). The pooled results were heterogeneous (p = 0.03, I2 = 53%) which can’t be resolved. After introducing subgroup analysis based on Zuranolone dose, the effect estimates showed significant improvement in Zuranolone 30-mg when compared to the placebo group [RR = 1.24, 95% CI [1.08, 1.43], p = 0.003); p = 0.35, I2 = 9%]. However, the effect estimates showed no significant difference in both Zuranolone 20-mg and Zuranolone 50-mg groups when compared to the placebo group [RR = 1.26, 95% CI [0.76, 2.1], p = 0.36); p = 0.04, I2 = 77%] and [RR = 1.02, 95% CI [0.82, 1.28], p = 0.84); p = 0.06, I2 = 71%], respectively (Table 5). Also, see supplementary Fig. S4 (online resource).

HAM-D ≤ 7% score

The overall effect estimates of 15-day follow-up duration showed a significant difference between Zuranolone and placebo groups favoring Zuranolone (RR = 1.41, 95% CI: [1.21, 1.63], p < 0.00001). The pooled results were homogenous (p = 0.05, I2 = 48%. After introducing subgroup analysis based on Zuranolone dose, the effect estimates showed significant improvement in the Zuranolone 30-mg group when compared to the placebo group [RR = 1.82, 95% CI [1.44, 2.31], p < 0.0001); p = 0.37, I2 = 6%]. However, the effect estimates showed no significant difference in both Zuranolone 20-mg and Zuranolone 50-mg groups when compared to the placebo group [RR = 1.15, 95% CI [0.78, 1.72], p = 0.48); p = 0.115, I2 = 51%] and [RR = 1.19, 95% CI [0.96, 1.48], p = 0.11); p = 0.4, I2 = 0%], respectively (Table 5). Also, see supplementary Fig. S5 (online resource).

The overall effect estimates of 42 to 45-day follow-up duration showed a significant difference between Zuranolone and placebo groups favoring Zuranolone (RR = 1.17, 95% CI: [1.03, 1.33], p = 0.02). The pooled results were homogenous (p = 0.06, I2 = 47%). After introducing subgroup analysis based on Zuranolone dose, the effect estimates showed significant improvement in Zuranolone 30-mg when compared to the placebo group [RR = 1.43, 95% CI [1.16, 1.77], p = 0.0008); p = 0.07, I2 = 53%]. However, the effect estimates showed no significant difference in both Zuranolone 20-mg and Zuranolone 50-mg groups when compared to the placebo group [RR = 1.11, 95% CI [0.79, 1.56], p = 0.54); p = 0.75, I2 = 0%] and [RR = 1, 95% CI [0.83, 1.21], p = 0.97); p = 0.7, I2 = 0%], respectively (Table 5). Also, see supplementary Fig. S6 (online resource).

CGI-I total score

The overall effect estimates of 15-day follow-up duration showed a significant difference between Zuranolone and placebo groups favoring Zuranolone (RR = 1.3, 95% CI: [1.15, 1.47], p < 0.0001). The pooled results were homogenous (p = 0.07, I2 = 54%). After introducing subgroup analysis based on Zuranolone dose, the effect estimates showed significant improvement in both Zuranolone 30-mg and 50-mg Zuranolone groups when compared to the placebo group [RR = 1.34, 95% CI [1.15, 1.57], p = 0.0002); p = 0.2, I2 = 38%] and [RR = 1.59, 95% CI [1.16, 2.16], p = 0.004)], respectively. However, the effect estimates showed no significant difference in the Zuranolone 20-mg group when compared to the placebo group [RR = 1.02, 95% CI [0.8, 1.3], p = 0.87)] (Table 5). Also, see supplementary Fig. S7 (online resource).

The overall effect estimates of 42 to 45-day follow-up duration showed a significant difference between Zuranolone and placebo groups favoring Zuranolone (RR = 1.17, 95% CI: [1.03, 1.33], p = 0.02). The pooled results were homogenous (p = 0.77, I2 = 0%). After introducing subgroup analysis based on Zuranolone dose, the effect estimates showed significant improvement in Zuranolone 30-mg when compared to the placebo group [RR = 1.22, 95% CI [1.05, 1.42], p = 0.01); p = 0.93, I2 = 0%]. However, the effect estimates showed no significant difference in the Zuranolone 20-mg group when compared to the placebo group [RR = 1.06, 95% CI [0.83, 1.35], p = 0.66] (Table 5). Also, see supplementary Fig. S8 (online resource).

Bech-6 total score

The overall effect estimates showed no significant difference between Zuranolone and placebo groups (MD = -7.75, 95% CI: [-20.66, 5.15], p = 0.24). The pooled results were heterogenous (p = 0.01, I2 = 84%) which can’t be resolved (Table 4). Also, see supplementary Fig. S9 (online resource)

MADRS total score

The overall effect estimates of 15-day follow-up duration showed a significant difference between Zuranolone and placebo groups favoring Zuranolone (SMD = -0.22, 95% CI: [-0.32, -0.12], p < 0.0001). The pooled results were homogenous (p = 0.24, I2 = 26%). After introducing subgroup analysis based on Zuranolone dose, the effect estimates showed significant improvement in both Zuranolone 30-mg and Zuranolone 50-mg groups when compared to placebo group [(SMD = -0.31, 95% CI [-0.46, -0.16], p < 0.0001); p = 0.31, I2 = 15%] and [(SMD = -0.2, 95% CI [-0.38, -0.02], p = 0.03)], respectively. However, the effect estimate showed no significant difference in the Zuranolone 20-mg group when compared to the placebo group [SMD = -0.06, 95% CI [-0.29, 0.17], p = 0.59] (Table 4). Also, see supplementary Fig. S10 (online resource).

The overall effect estimates of 42 to 45-day follow-up duration showed a significant difference between Zuranolone and placebo groups favoring Zuranolone (SMD = -0.16, 95% CI: [-0.28, -0.03], p = 0.02). The pooled results were homogenous (p = 0.06, I2 = 56%). After introducing subgroup analysis based on Zuranolone dose, the effect estimates showed significant improvement in Zuranolone 30-mg when compared to the placebo group [SMD = -0.24, 95% CI [-0.4, -0.09], p = 0.002); p = 0.18, I2 = 39%]. However, the effect estimates showed no significant difference in the Zuranolone 20-mg group when compared to the placebo group [SMD = 0.05, 95% CI [-0.19, 0.28], p = 0.69] (Table 4). Also, see supplementary Fig. S11 (online resource).

HAM-A total score

The overall effect estimates of 15-day follow-up duration showed a significant difference between Zuranolone and placebo groups favoring Zuranolone (MD = -1.56, 95% CI: [-2.37, -0.74], p = 0.0002). The pooled results were homogenous (p = 0.24, I2 = 25%). After introducing subgroup analysis based on Zuranolone dose, the effect estimates showed significant improvement in both Zuranolone 30-mg and Zuranolone 50-mg groups when compared to placebo group [(MD = -2.34, 95% CI [-3.83, -0.85], p = 0.002); p = 0.17, I2 = 40%] and [(MD = -1.29, 95% CI [-2.41, -0.17], p = 0.02], respectively. However, the effect estimate showed no significant difference in the Zuranolone group 20-mg when compared to the placebo group [SMD = -1.03, 95% CI [-2.99, 0.93], p = 0.3); p = 0.24, I2 = 28%] (Table 4). Also, see supplementary Fig. S12 (online resource).

The overall effect estimates of 42 to 45-day follow-up duration showed no significant difference between Zuranolone and placebo groups (MD = -1.33, 95% CI: [-2.83, 0.18], p = 0.08). The pooled results were heterogeneous (p = 0.02, I2 = 66%). After introducing subgroup analysis based on Zuranolone dose, the effect estimates also showed no significant improvement in Zuranolone 20-mg, Zuranolone 30-mg, and Zuranolone 50-mg groups when compared to the placebo group [MD = -0.05, 95% CI [-1.44, 1.34], p = 0.94], [MD = -2.42, 95% CI [-5.63, 0.8], p = 0.14); p = 0.01, I2 = 76%] and [MD = -0.81, 95% CI [-2.16, 0.54], p = 0.24], respectively (Table 4). Also, see supplementary Fig. S13 (online resource).

Safety outcomes

TEAEs

For this outcome the higher the odd ratio (OR) the worse the outcome. Meaning more events occurred with the intervention. Looking at zuranolone, regardless of the dose, the intervention showed more TEAEs compared with the placebo (OR = 1.46, 95% CI: [1.15, 1.84], p = 0.002).). The pooled results were homogenous (p = 0.06, I2 = 46%). After introducing subgroup analysis based on Zuranolone dose, the higher the dose the more TEAEs reported, as for 50 mg, 30 mg vs 20 mg (OR = 1.71, 95% CI: [1.31, 2.22], p > 0.0001), (OR = 1.49, 95% CI: [0.93, 2.38], p = 0.09).), (OR = 1.19, 95% CI: [0.85, 1.66], p = 0.32), respectively. A dose of 50 mg showed a significant difference compared to the placebo. However, doses 30 mg and 20 mg showed non-significant differences (Table 6). Also, see supplementary Fig. S14 (online resource).

Table 6.

Odds ratio of the safety outcomes

Variables Doses Effect estimates No. of participants Heterogeneity
OR 95% CI P Zurnaonlone Placebo I2 P
TEAEs 20-mg 1.19 [0.85, 1.66] 0.32 273 272 0 0.69
30-mg 1.49 [0.93, 2.38] 0.09 275 462 64 0.02
50-mg 1.71 [1.31, 2.22]  < 0.0001 480 487 0 0.42
Total 1.46 [1.15, 1.84] 0.002 1228 1221 45 0.06
SAEs 20-mg 1.4 [0.274, 7.23] 0.682 273 272 0 0.836
30-mg 1.46 [0.42, 5.313] 0.565 397 389 0 0.959
50-mg 1.63 [0.31, 8.5] 0.562 480 487 0 0.374
Total 1.49 [0.63, 3.54] 0.366 1150 1148 0 0.992
Severe AEs 30-mg 0.94 [0.21, 4.25] 0.936 123 117 0 0.983
50-mg 2.05 [0.86, 4.87] 0.104 480 487 0 0.584
Total 1.69 [0.8, 3.58] 0.17 603 604 0 0.783
AEs- related drug discontinuation 20-mg 0.66 [0.183, 2.38] 0.526 273 272 0 0.322
30-mg 0.94 [0.36, 2.43] 0.906 475 462 0 0.874
50-mg 2.01 [0.983, 4.09] 0.056 480 487 0 0.776
Total 1.33 [0.79, 2.23] 0.282 1228 1221 0 0.735
Deaths 20-mg 1.93 [0.16, 23.1] 0.605 273 272 0 0.657
30-mg 0.976 [0.14, 6.97] 0.98 397 389 0 1
Total 1.27 [0.27, 5.92] 0.763 670 661 0 0.996
Headache 20-mg 1.66 [0.88, 3.13] 0.12 273 272 0 0.77
30-mg 0.94 [0.56, 1.57] 0.81 379 389 0 0.77
50-mg 1.04 [0.7, 1.56] 0.85 480 487 54 0.14
Total 1.11 [0.84, 1.47] 0.47 1150 1148 0 0.61
Dizziness 20-mg 2.18 [1.04, 4.56] 0.04 273 272 0 0.91
30-mg 1.76 [1, 3.11] 0.05 475 462 0 0.86
50-mg 3.55 [0.98, 12.78] 0.05 480 487 82 0.02
Total 2.33 [1.62, 3.35]  < 0.00001 1228 1221 9 0.36
Nausea 20-mg 1.13 [0.45, 2.85] 0.8 188 190 NA NA
30-mg 0.93 [0.3, 2.87] 0.9 315 307 44 0.17
50-mg 0.32 [0.18, 0.57]  < 0.0001 212 218 NA NA
Total 0.71 [0.33, 1.52] 0.38 715 715 62 0.03
Somnolence 20-mg 1.65 [0.81, 3.38] 0.17 273 272 0 0.62
30-mg 1.97 [1.24, 3.13] 0.004 475 462 0 0.6
50-mg 3.58 [2.25, 5.7]  < 0.00001 480 487 66 0.09
Total 2.48 [1.84, 3.33]  < 0.00001 1228 1221 21 0.26
Dry mouth 30-mg 2.16 [0.47, 9.92] 0.32 123 117 15 0.28
50-mg 1.09 [0.56, 2.11] 0.8 212 218 NA NA
Total 1.23 [0.67, 2.23] 0.51 335 335 0 0.49
Sedation 20-mg 1.98 [0.75, 5.22] 0.166 273 272 0 0.803
30-mg 1.83 [0.8, 4.19] 0.156 475 462 0 0.589
50-mg 5.7 [0.6, 54.1] 0.13 480 487 75.56 0.043
Total 2.29 [1.36, 3.84] 0.002 1228 1221 0.44 0.43
Decreased appetite 30-mg 0.48 [0.04, 5.46] 0.55 45 44 NA NA
50-mg 1.81 [0.7, 4.69] 0.22 212 218 NA NA
Total 1.5 [0.63, 3.56] 0.36 257 262 0 0.32
Insomnia 30-mg 0.48 [0.04, 5.46] 0.55 45 44 NA NA
50-mg 1.3 [0.67, 2.54] 0.44 212 218 NA NA
Total 1.2 [0.63, 2.29] 0.57 257 262 0 0.44
Diarrhea 20-mg 1.12 [0.46, 2.7] 0.8 188 190 NA NA
30-mg 1.26 [0.66, 2.39] 0.48 393 380 12 0.33
50-mg 0.59 [0.34, 1.03] 0.07 480 487 0 0.88
Total 0.86 [0.59, 1.26] 0.45 1061 1057 16 0.31
Upper respiratory tract infection 20-mg 1.48 [0.4, 5.45] 0.55 85 82 NA NA
30-mg 3.25 [1.27, 8.34] 0.01 238 228 0 0.49
Total 2.54 [1.19, 5.38] 0.02 323 310 0 0.54
Fatigue 20-mg 0.6 [0.14, 2.55] 0.49 188 190 NA NA
30-mg 2.72 [1.05, 7.07] 0.04 270 263 0 0.96
50-mg 1.75 [0.8, 3.79] 0.04 212 218 NA NA
Total 1.74 [1.01, 2.99] 0.04 670 671 0 0.4
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AEs Adverse events, CI Confidence interval, OR Odds ratio, SAEs Serious adverse events, TEAEs Treatment emergent adverse events

Serious adverse events

The overall effect estimates showed a non-significant difference between Zuranolone and placebo groups (OR = 1.49, 95% CI: [0.62, 3.53], p = 0.366). After introducing subgroup analysis based on Zuranolone dose, the higher the dose the more serious adverse events reported, as for 50 mg, 30 mg vs 20 mg (OR = 1.62, 95% CI: [0.31, 8.5], p = 0.562), (OR = 1.46, 95% CI: [0.40, 5.313], p = 0.565), (OR = 1.40, 95% CI: [0.27, 7.23], p = 0.682), respectively. (Table 6). Also, see supplementary Fig. S15 (online resource).

Severe adverse events

Only two interventions (zuranolone 30, 50 mg) were included in this analysis. the overall effect estimates showed a non-significant difference between Zuranolone and placebo groups (OR = 1.69, 95% CI: [0.79, 3.58], p = 0.17). It is observed that the severe adverse events were more in dose 50 mg compared to dose 30mg (OR = 2.05, 95% CI: [0.86, 4.87], p = 0.104), (OR = 0.94, 95% CI: [0.20, 4.24], p = 0.936), respectively. (Table 6). Also, see supplementary Fig. S16 (online resource).

AEs-related drug discontinuation

The overall effect estimates showed a non-significant difference between Zuranolone and placebo groups (OR = 1.33, 95% CI: [0.79, 2.23], p = 0.282). After introducing subgroup analysis based on Zuranolone dose, the higher the dose the more adverse events drug discontinuation reported, as for 50 mg, 30 mg vs 20 mg (OR = 2.00, 95% CI: [0.98, 4.09], p = 0.056), (OR = 0.94, 95% CI: [0.36, 2.43], p = 0.906), (OR = 0.66, 95% CI: [0.18, 2.38], p = 0.526), respectively. (Table 6). Also, see supplementary Fig. S17 (online resource).

Most common TEAEs

Somnolence, dizziness, and headache were the most reported TEAEs in the zuranolone dose groups. However, the overall effect estimates showed a non-significant difference between Zuranolone and placebo groups (OR = 1.11, 95% CI: [0.84, 1.47], p = 0.47) for headache. In contrast, the zuranolone showed more dizziness compared with the placebo (OR = 2.33, 95% CI: [1.62, 3.35], p > 0.00001).) and Somnolence (OR = 2.48, 95% CI: [1.84, 3.33], p > 0.00001).). (Table 6). Also, see supplementary Fig. S18 (online resource).

Regardless of the dose, zuranolone showed more sedation (OR = 2.28, 95% CI: [1.36, 3.84], p = 0.002), fatigue (OR = 1.74, 95% CI: [1.01, 2.99], p = 0.04).), and upper respiratory tract infection (OR = 2.54, 95% CI: [1.19, 5.38], p = 0.02) compared to the placebo. In contrast, the overall effect estimate showed a non-significant difference between zuranolone and placebo in terms of insomnia, dry mouth, decreased appetite, nausea, diarrhea, and death [(OR = 1.20, 95% CI: [0.63, 2.29], p = 0.57), (OR = 1.23, 95% CI: [0.67, 2.23], p = 0.51), (OR = 1.50, 95% CI: [0.63, 3.56], p = 0.36), (OR = 0.71, 95% CI: [0.33, 1.52], p = 0.38), (OR = 0.86, 95% CI: [0.59, 1.26], p = 0.45), and (OR = 1.26, 95% CI: [0.27, 5.92], p = 0.763)], respectively. (Table 6). Also, see supplementary Fig. S18 (online resource).

Discussion

Depression, a pervasive mental health challenge affecting millions globally, prompts a continuous search for more effective and safer treatment options (Reddy 2010) Zuranolone, a novel selective neuroactive steroid GABAA receptor-positive allosteric modulator, exhibits promise in preclinical and early clinical trials for depression treatment (Althaus et al. 2020) This meta-analysis consolidates the latest data from 8 randomized controlled trials (RCTs) exploring zuranolone's efficacy and safety in major depressive disorder (MDD) and postpartum depression (PPD).

Our study evaluates zuranolone's impact compared to placebo across varied follow-up durations, employing common outcome measures in depression research (Rabin et al. 2022). The primary goal is to determine zuranolone's overall efficacy while scrutinizing its safety profile based on reported adverse events (AEs). Noteworthy findings reveal significant benefits favoring zuranolone in terms of efficacy outcomes. Specifically, both the 30-mg and 50-mg zuranolone groups exhibit substantial improvement at the 15-day follow-up, reflected in a reduction of over 50% from baseline in the Hamilton Depression Rating Scale (HAM-D) score. A similar trend is observed at the 42 to 45-day follow-up.

Efficacy outcomes

Unlike other common GABAA positive allosteric modulators like benzodiazepines, zuranolone can modulate both synaptic and extrasynaptic GABAA conductance due to binding to a non-benzodiazepine site on the receptor (Clayton et al. 2023; Stahl et al. 2023). Furthermore, it may restore the balance of GABAA receptor function that is disrupted by the rapid decline of allopregnanolone after childbirth (Stahl et al. 2023).

The overall effect estimates demonstrated a statistically significant improvement in HAMD-17 following 15 days after zuranolone administration and with a 42 to 45-day follow-up duration. Subgroup analysis based on zuranolone dose revealed that both the zuranolone 30-mg and 50-mg groups showed significant improvement in HAMD-17 scores compared to the placebo group. This is consistent with the study conducted on women with PPD which reported that rates of concurrent remission of depressive and anxiety symptoms were higher with zuranolone versus placebo (Deligiannidis et al. 2023) also a study conducted in the United States among adults with MDD reported significant improvement at days 3, 8, and 12 (Clayton et al. 2023).

On the other hand, the effect estimate for the zuranolone 20-mg group did not show a significant difference compared to the placebo group. However, a study conducted on Japanese patients aged between ≥ 18 years and ≤ 75 years with a diagnosis of MDD to test the efficacy and safety of zuranolone (Kato et al. 2023a) reported improvement in HAMD-17 scores and insomnia symptom score showed nominally significant differences in the zuranolone 20 mg groups when compared with the placebo group at Day 15. This suggests that the efficacy of zuranolone may vary depending on the specific dose used, and the 20-mg dose may not be as effective in improving HAMD-17 scores.

Regarding the Bech-6 scale (a shortened version of the HAMD-17 scale), our pooled analysis showed a great numerical improvement in zuranolone compared to placebo, but this numerical improvement didn’t reach statistical significance. Our finding was consistent with Kato et al. and Gunduz-Bruce et al. (Gunduz-Bruce et al. 2019; Kato et al. 2023a). However, Gunduz-Bruce et al. showed statistical significance. Unfortunately, the Bech-6 scale was reported by two studies, however; it’s more sensitive than the HAMD-17 scale in detecting treatment effects. The small sample size and high heterogeneity in our pooled analysis may mask the statistical significance of the treatment effects (Dunlop et al. 2019).

Regarding the reduction of > 50% from baseline in HAM-D score, this meta-analysis demonstrates that zuranolone, particularly at the 30-mg dose, is associated with a higher likelihood of achieving a reduction of > 50% from baseline in HAM-D score at both the 15-day and 42 to 45-day follow-up durations. However, there was no significant difference between Zuranolone 20-mg when compared to the placebo groups at 15 days and 42 to 45-day follow-ups as reported by a study conducted among Japanese adults (Kato et al. 2023a) and a study conducted in the United States among adults with MDD (Clayton et al. 2023). The negative results with these doses suggest the antidepressant effects of zuranolone may be threshold-dependent, requiring a minimum effective concentration to be reached. The 20 mg dose appears to be below this threshold level to consistently achieve clinically important reductions in depression severity (Walkery et al. 2021).

Additionally, zuranolone at 50 mg dosage showed no significant difference regarding the reduction of > 50% from baseline in HAM-D score between the treatment and placebo groups at 42 to 45-day follow-up duration. The lack of a significant difference seen with 50 mg dose versus placebo at 6 weeks also aligns with potential non-linear pharmacokinetics. Higher concentrations do not necessarily confer additional benefits and may come with an increased risk of adverse effects (Deligiannidis et al. 2021; Lin et al. 2023a, b). The lack of effect of 50 mg zuranolone compared to 30 mg may be attributed to a lack of compliance to 50 mg due to increased incidence of side effects (Lin et al. 2023a, b).

The ability to demonstrate a sustained response to antidepressant drugs was limited with the duration of follow-up of included trials. Nevertheless, it's important to evaluate the benefit of maintenance of medications over time to determine how long patients with MDD should take antidepressants. Kato et al. (Kato et al. 2021)recommended at least 6 months of maintenance therapy of antidepressants to prevent relapse and treatment failure as they found that the antidepressant maintenance group has a lower relapse rate than the antidepressant discontinuation group in both 6 months and 1 year maintenance periods. Another meta-analysis conducted by Kishi et al. (Kishi et al. 2023)recommended that maintenance treatment with antidepressants should be continued for at least 18 months or at least one year as the sustained response to antidepressants was more in 15 and 18 months than in 1 year or less. In contrast, the included studies, investigating the efficacy of zuranolone, only gave it for two weeks and the follow-up duration was relatively short; about 45 days. Furthermore, the overall effect achieved at 45 days of follow-ups was less than the effect achieved at 15 days of follow-ups in terms of HAMD-17 score, reduction of > 50% in HAM-D score, HAM-D score ≤ 7, CGI-I score of 1 or 2, MADRS score, and HAM-A score. Further long-term clinical trials are needed to evaluate the efficacy of a longer period of zuranolone maintenance in preventing relapse.

Safety outcomes

This analysis indicates a higher occurrence of treatment-emergent adverse events (TEAEs) in comparison to the placebo. Significantly, the relative risk of TEAEs rises with escalating zuranolone doses, particularly with the 50-mg dose posing the greatest risk compared to the placebo (Kato et al. 2023a) This dose-dependent safety profile aligns with zuranolone's pharmacokinetic properties, underscoring the need to consider dosage levels when assessing safety (Parikh et al. 2024). These findings are consistent with a study assessing the efficacy and safety of zuranolone among adults with major depressive disorder (MDD), reporting that 74.1% of patients who received zuranolone experienced at least one TEAE. While the 30-mg dose showed a nominally higher TEAE risk than the 20-mg dose, this difference did not reach statistical significance. This suggests that the safety risks associated with the 30-mg dose are comparable to those of the 20-mg dose, acknowledging the limitations of the included studies and sample sizes.

Concerning severe adverse events and adverse events related to drug discontinuation, the comparison between zuranolone and placebo groups yielded non-significant differences, indicating a similarity in the occurrence of severe adverse events between the two groups. This finding aligns with a study assessing the tolerability of zuranolone among U.S. patients (Hoffmann et al. 2020) This is supported by studies conducted by Sage Therapeutics and Biogen, where no notable difference was found in adverse events related to discontinuation of the drug between the zuranolone and placebo groups, and a separate study involving women with PPD (Deligiannidis et al. 2021; Sage Therapeutics and Biogen Announce Positive Pivotal, n.d.).

The most frequent adverse events include somnolence, dizziness, and fatigue, with no alarming safety concerns. This agrees with a study conducted among adults with MDD to assess the efficacy and safety of zuranolone (Parikh et al. 2024).

Strengths and limitations

This study was conducted based on PRISMA guidelines and pooled the results according to the available clinical trials to assess the efficacy and safety of zuranolone in depression. However, our review suffers from some limitations, including the limited number of randomized trials, and subsequently small sample size. Additionally, some of the measured outcomes were heterogeneous due to variations between the included studies. Our meta-analysis didn’t separate patients with postpartum depression and major depressive disorder. Although we acknowledge the importance of meticulously separate studies of zuranolone in postpartum patients from those involving MDD to better elucidate any nuanced effects and implications within each population, Lin et al. reported that the subgroup analysis didn’t show significant differences in outcomes between these two categories(Lin et al. 2023a, b). Also, most of the included studies were conducted in the US, making the generalizability of these results questionable.

Conclusion

In conclusion, these findings suggest zuranolone's potential as an effective treatment for depression, emphasizing the crucial need for cautious consideration regarding its safety. Notably, there is no significant difference in discontinuation rates between the zuranolone and placebo groups.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 831 KB) (830.7KB, docx)

Acknowledgements

we would like to express our gratitude to Mohamed Elsaid who guided us throughout this project. your useful advice and suggestions were really helpful to us during the project's completion. we would also like to thank Gehad S. Remeih who offered deep support to us.

Authors’ contributions

AMF: generating the research idea, writing the manuscript, data analysis, and solving any conflict; HAO: two-phase screening, quality assessment, and writing the manuscript; IAE: two-phase screening, and quality assessment; MATE: data extraction (summary and baseline); MMME: data extraction (outcomes); HKS: writing the manuscript, and data analysis.

Funding

Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB). No funding was received to this study.

Data availability

All data are available upon reasonable request from the corresponding author.

Declarations

Ethics approval

Not applicable.

Consent for publication

Not applicable.

Ethical considerations

Not applicable.

Conflict of interests

No conflict or competing interests between the manuscripts’ authors.

Footnotes

The original version of this article was revised: This article was originally published with a mispelled author name. It should be Elewidi.

Publisher's Note

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Change history

6/22/2024

A Correction to this paper has been published: 10.1007/s00213-024-06642-5

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