Efficacy of esketamine nasal spray for treatment-resistant depression: A meta-analysis of randomized controlled studies

Abstract

Background:

The efficacy of esketamine nasal spray for treatment-resistant depression remains controversial. This systematic review and meta-analysis was conducted to explore the influence of esketamine nasal spray on treatment efficacy for treatment-resistant depression.

Methods:

We conducted a comprehensive search across multiple databases, including PubMed, EMbase, Web of Science, EBSCO, and Cochrane library through March 2024 for randomized controlled trials (RCTs) assessing the effect of esketamine nasal spray on the treatment efficacy of depression. This meta-analysis was performed using the random-effect model.

Results:

Five RCTs are included in the meta-analysis. Overall, compared with control group treatment-resistant depression, esketamine nasal spray is associated with significantly reduced MADRS scores (SMD = −3.88; 95% confidence interval [CI] = −5.71 to −2.05; P < .0001), increased response rates (RR = 1.99; 95% CI = 1.28–3.10; P = .002), decreased Sheehan Disability Scale (SMD = −3.01; 95% CI = −4.39 to −1.64; P < .0001) and PHQ-9 scores (SMD = −2.32; 95% CI = −3.51 to −1.13; P = .0001), but leads to the increase in dizziness (RR = 3.55; 95% CI = 2.37–5.32; P < .00001) and nausea (RR = 3.88; 95% CI = 2.10–7.18; P < .0001).

Conclusion:

Esketamine nasal spray is beneficial to improve the efficacy of treatment-resistant depression.

1. Introduction

Major depressive disorder significantly disrupts patients’ lives, causing substantial impairment in cognitive function, daily activities, and overall quality of life. The condition often leads to disability and may require hospitalization, placing considerable emotional and practical burdens on caregivers and support networks.^[1–4] Older patients face unique challenges, with lower response rates to standard antidepressant treatments and a higher likelihood of receiving electroconvulsive therapy. Moreover, these patients are more vulnerable to potential cognitive side effects and tolerability issues associated with treatment.^[5–10]

In a pilot double-blind crossover study, ketamine demonstrated greater efficacy compared to midazolam (used as an active control) in treating depression in older adults who had not responded to prior treatments.^[11] Esketamine, a more potent component of the ketamine molecule, binds to N-methyl-D-aspartate receptors 3 to 4 times more strongly than its R-enantiomer counterpart.^[12] Two phase 2 clinical trials evaluated esketamine, administered both intravenously and as a nasal spray, in patients under 65 with treatment-resistant depression. These studies revealed that esketamine produced rapid antidepressant effects, with higher doses yielding greater efficacy.^[13,14]

Recent studies investigating the efficacy of esketamine nasal spray as an adjunctive treatment for treatment-resistant depression have shown mixed outcomes.^[15–17] The frequency and dosage of esketamine nasal spray vary significantly across treatments, ranging from 3 to 8 sprays per day, with varying drug concentrations in each spray.^[14,15] This systematic review and meta-analysis of randomized controlled trials aims to evaluate the overall impact of esketamine nasal spray on the efficacy and safety of treatment-resistant depression.

2. Materials and methods

This systematic review and meta-analysis was conducted in accordance with the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and the Cochrane Handbook for Systematic Reviews of Interventions.^[18,19] Ethical approval and patient consent were not required, as all analyses were based on data extracted from previously published studies.

2.1. Literature search and selection criteria

We conducted a comprehensive search across multiple databases, including PubMed, EMBASE, Web of Science, EBSCO, and the Cochrane Library, to identify all relevant publications up to March 2024. The search strategy utilized the keywords “esketamine” and “depression.” Additionally, we manually examined the reference lists of included studies and pertinent review articles to identify any additional eligible research.

The inclusion criteria were as follows: the study design was a randomized controlled trial (RCT), participants were diagnosed with treatment-resistant depression, and the intervention compared esketamine nasal spray with a placebo.

2.2. Data extraction and outcome measures

Key baseline data extracted from each study included the first author’s name, total number of patients, participants’ age and gender, age at initial diagnosis, total Montgomery–Asberg Depression Rating Scale (MADRS) scores, and detailed methodology of the intervention and control groups. Two independent researchers conducted the data extraction, resolving any disagreements through discussion. When necessary, we contacted corresponding authors to obtain additional data.

The primary outcome measure was the change in MADRS scores. Secondary outcomes included the percentage of patients achieving a clinical response and remission, scores on the Sheehan Disability Scale and Patient Health Questionnaire 9-Item (PHQ-9), as well as the incidence of side effects such as dizziness and nausea.

2.3. Quality assessment in individual studies

The methodological quality of each RCT was assessed using the Jadad Scale, which evaluates 3 key elements: randomization (0–2 points), blinding (0–2 points), and dropouts/withdrawals (0–1 point).^[20] Each element is assigned one point if adequately described and conducted in the original study, and additional points are awarded for specific methodological rigor. The total score ranges from 0 to 5 points.

RCTs with a Jadad score of ≤2 are considered low-quality studies, while those scoring ≥3 are classified as high-quality studies.^[21] This scale provides a structured and standardized way to evaluate the robustness of clinical trial methodologies.

2.4. Statistical analysis

We evaluated the standard mean difference (SMD) with a 95% confidence interval (CI) for continuous outcomes such as Montgomery–Asberg Depression Rating Scale (MADRS) scores, Sheehan Disability Scale scores, and Patient Health Questionnaire-9 (PHQ-9) scores. For dichotomous outcomes, including response rates, remission rates, and the occurrence of side effects (e.g., dizziness and nausea), we assessed the risk ratio (RR) with a 95% CI.

Heterogeneity across studies was evaluated using the I² statistic, where an I² value > 50% indicated significant heterogeneity.^[22] A random-effects model was applied for all meta-analyses to account for variations across studies. When significant heterogeneity was identified, we investigated potential sources using subgroup analysis or by systematically omitting 1 study at a time (sensitivity analysis).

Due to the limited number of included studies (<10), publication bias was not assessed. Statistical significance was determined at P < .05. All statistical analyses were performed using Review Manager Version 5.3 (The Cochrane Collaboration, Oxford, UK).

3. Results

3.1. Literature search, study characteristics and quality assessment

Figure 1 provides a detailed flowchart of the article search and selection process. A total of 396 potentially relevant articles were identified through the initial search. After screening for eligibility, 5 RCTs were ultimately included in the meta-analysis.^[14–17,23]

Figure 1.

Flow diagram of study searching and selection process.

3.1.1. Baseline characteristics of the included studies

The characteristics of the 5 included RCTs are summarized in Table 1. These studies were published between 2018 and 2020, with a combined sample size of 1315 participants. The dose of esketamine nasal spray administered in these trials ranged from 28 to 84 mg daily.

Table 1.

Characteristics of included studies.

No	Author	Esketamine group						Control group						Jada scores
		Number	Age (yr)	Female (n)	Age at diagnosis	MADRS total score	Methods	Number	Age (yr)	Female (n)	Age at diagnosis	MADRS total score	Methods
1	Ochs-Ross et al[15]	72	70.6 ± 4.79	45	42.6 ± 16.18	35.5 ± 5.91	Esketamine nasal spray twice-weekly	65	69.4 ± 4.15	40	43.7 ± 16.28	34.8 ± 6.44	Placebo	4
2	Popova et al[16]	114	44.9 ± 12.58	75	32.1 ± 12.53	37.0 ± 5.69	Esketamine sprays for total dose of 28 mg per device	109	46.4 ± 11.14	63	35.3 ± 13.04	37.3 ± 5.66	Placebo	5
3	Fedgchin et al[17]	115	46.4 ± 11.18	81	30.3 ± 12.34	37.4 ± 4.76	Esketamine sprays for total dose of 56 mg per device	113	46.8 ± 11.36	81	31.8 ± 12.44	37.5 ± 6.16	Placebo	4
4	Daly et al[14]	90	45.4 ± 12.12	58	32.5 ± 11.42	37.4 ± 5.20	Esketamine nasal spray (56 or 84 mg, flexibly dosed) twice weekly for stable remission	86	46.2 ± 11.16	59	33.4 ± 11.41	37.6 ± 4.66	Placebo	4
		62	47.2 ± 11.00	38	36.2 ± 13.25	40.1 ± 5.56	Esketamine nasal spray (56 or 84 mg, flexibly dosed) twice weekly for stable response	59	46.7 ± 9.76	42	34.0 ± 10.54	38.9 ± 4.92
5	Daly et al[23]	11	44.7 ± 10.0	–	–	33.2 ± 6.26	Esketamine sprays for total dose of 56 mg per device	33	44.7 ± 10.0	–	–	35.0 ± 5.18	Placebo	4

MADRS = Montgomery–Asberg Depression Rating Scale.

Among the 5 included RCTs:

• Four trials reported MADRS scores and response rates.^[15–17,23]

• Two trials reported remission rates.^[15,16]

• Three trials provided data on Sheehan Disability Scale and PHQ-9 scores.^[15–17]

• Four trials reported data on side effects, including dizziness and nausea.^[14–17]

3.1.2. Quality assessment

The Jadad scores of the 5 studies ranged from 3 to 5, indicating high methodological quality across all included RCTs.

3.2. Primary outcome: MADRS scores

The random-effect model is used for the analysis of primary outcome. The results find that compared to control group in treatment-resistant depression, esketamine nasal spray is associated with significantly reduced MADRS scores (SMD = −3.88; 95% CI = −5.71 to −2.05; P < .0001) with no heterogeneity among the studies (I² = 0%, heterogeneity P = .99, Fig. 2).

Figure 2.

Forest plot for the meta-analysis of MADRS scores. MADRS = Montgomery–Asberg Depression Rating Scale.

3.3. Sensitivity analysis

There is no heterogeneity for the primary outcome, and thus we do not perform the meta-analysis via omitting 1 study or subgroup analysis to detect the heterogeneity.

3.4. Secondary outcomes

In treatment-resistant depression, esketamine nasal spray demonstrates notable benefits compared to control interventions: Increased response rates: esketamine nearly doubles the likelihood of achieving a response (RR = 1.99; 95% CI = 1.28–3.10; P = .002; Fig. 3); No significant effect on remission rates: despite increased response rates, the effect on remission is not statistically significant (RR = 1.50; 95% CI = 0.91–2.49; P = .11; Fig. 4). Additionally, esketamine improves depression-related quality of life as reflected by: Reduced Sheehan Disability Scale scores (SMD = −3.01; 95% CI = −4.39 to −1.64; P < .0001; Fig. 5); Lower PHQ-9 scores (SMD = −2.32; 95% CI = −3.51 to −1.13; P = .0001; Fig. 6). However, esketamine is associated with increased adverse effects: Dizziness: significant rise (RR = 3.55; 95% CI = 2.37–5.32; P < .00001; Fig. 7). Nausea: markedly higher incidence (RR = 3.88; 95% CI = 2.10–7.18; P < .0001; Fig. 8). These findings highlight esketamine’s potential to enhance response and functional outcomes while emphasizing the need to manage its side effects.

Figure 3.

Forest plot for the meta-analysis of response rates.

Figure 4.

Forest plot for the meta-analysis of remission rates.

Figure 5.

Forest plot for the meta-analysis of Sheehan Disability Scale.

Figure 6.

Forest plot for the meta-analysis of PHQ-9 scores. PHQ-9 = Patient Health Questionnaire 9-Item.

Figure 7.

Forest plot for the meta-analysis of dizziness.

Figure 8.

Forest plot for the meta-analysis of nausea.

4. Discussion

Esketamine nasal spray offers a more accessible option for patients compared to intravenous administration. In Phase 3 studies involving patients aged 18 to 64 with treatment-resistant depression, the nasal spray demonstrated a rapid onset of action, with its effects maintained over the long term through intermittent dosing.^[16,17] In a phase 3 double-blind study involving patients aged 65 and older with treatment-resistant depression, the combination of flexibly dosed esketamine nasal spray and a new oral antidepressant (esketamine/antidepressant) resulted in a 3.6-point mean reduction in the MADRS total score compared to the antidepressant/placebo group. However, this difference was not statistically significant is consistent with the typical 2-to-3-point difference observed between previously approved antidepressants and placebo groups.^[24,25]

The response rate in the antidepressant/placebo group (13.8%) was relatively lower than those reported in studies of younger patients (38.9% and 52.0% in the 2 phase 3 short-term studies).^[16,17] Our meta-analysis confirms that the addition of esketamine nasal spray significantly reduces MADRS scores and improves response rates in patients with treatment-resistant depression. However, it did not show a significant impact on remission rates. This aligns with previous findings from clinical trials that reported improvements in depressive symptoms and response rates with esketamine nasal spray, but the effect on remission remains less conclusive.

The changes in Sheehan Disability Scale and PHQ-9 scores are important for evaluating both mood and functional outcomes in patients with treatment-resistant depression. Our meta-analysis indicates that, similar to the findings in patients aged 18 to 64 years, there were significant reductions in both the Sheehan Disability Scale and PHQ-9 scores following esketamine treatment compared to placebo. These results suggest that esketamine can not only alleviate depressive symptoms but also improve patients’ overall functioning. The magnitude of change observed is consistent with the positive impact seen in younger patients, reinforcing the potential benefits of esketamine nasal spray in improving both mood and daily functioning for individuals suffering from treatment-resistant depression.

The analysis of age at study entry indicates a greater reduction in MADRS total scores among 65 to 74-year-old patients treated with esketamine compared to those receiving a placebo. This effect was not observed in patients aged 75 years or older. Furthermore, separation in the curves for the change in MADRS total score occurred earlier in the 65 to 74 age group. These findings suggest that the age of patients may influence the response to esketamine treatment, with younger elderly patients (65–74 years) showing more significant improvements compared to older patients (≥75 years). This highlights the importance of age as a factor in the treatment outcomes of esketamine for treatment-resistant depression.^[15] Late-onset depression was associated with greater treatment resistance in some studies.^[26] Additionally, dosing may have impacted efficacy.^[16,17] The 28 mg dose was considered subtherapeutic in a phase 2 trial in younger adults, but was included in the elderly study to improve tolerability.^[23] Esketamine at the dose of 56 mg may be sufficient for improve the efficacy (mean difference = −4.1; 95% CI = −7.67 to −0.49; P = .027).^[16] This meta-analysis found that adverse events, such as dizziness and nausea, were more common following esketamine treatment. However, these side effects were generally well-tolerated by patients, indicating that they were not severe enough to significantly impact the overall treatment outcomes. While these adverse events should be monitored, they did not appear to outweigh the therapeutic benefits of esketamine for treatment-resistant depression.^[15–17]

There are several limitations in this meta-analysis that should be considered. First, the analysis is based on only 5 randomized controlled trials (RCTs), and further studies with larger sample sizes are necessary to confirm these findings. Second, while no significant heterogeneity was detected, the variation in doses and administration methods of esketamine across studies could introduce some bias. Finally, the potential for unpublished or missing data may affect the pooled effect, leading to further biases in the overall conclusions. More comprehensive data from larger, more diverse trials are needed to provide more robust evidence on the efficacy and safety of esketamine nasal spray in treatment-resistant depression.

5. Conclusion

Esketamine provides some benefits to improve the efficacy for treatment-resistant depression.

Author contributions

Conceptualization: Yannan Ouyang.

Investigation: Yannan Ouyang.

Methodology: Yannan Ouyang.

Supervision: Juan Li.

Writing – review & editing: Yannan Ouyang, Juan Li.

Writing – original draft: Juan Li.