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

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 studiesTable 2 Baseline characteristics of the included studiesQuality 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

Risk of bias assessment of the included studies

Table 3 Risk of bias assessment of the included studiesOutcomesEfficacy 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

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

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 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).