This meta-analysis (s=7; n=1488) of double-blind placebo-controlled studies with those suffering from depression (MDD; TRD) and suicidal ideation (SI) found that esketamine (24-84mg) significantly improved scores on a measure of depression (MADRS) over the placebo up to 28 days alter, the SI scores were only significant within the first 24 hours.
Objective
We performed a meta-analysis of randomized double-blinded placebo controlled trials (DB-RCTs) to investigate efficacy and safety of intranasal esketamine in treating major depressive disorder (MDD) including treatment resistant depression (TRD) and major depression with suicide ideation (MDSI).
Methods
Mean change in total scores on Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to different time-points were our primary outcome measure. Secondary efficacy measures included rate of remission of depression and resolution of suicidality.
Results
Eight DB-RCTs (seven published and one un-published) covering 1,488 patients with MDD were included. Esketamine more significantly improved MADRS total scores than placebo starting from 2-4 hours after the first administration (standardized mean difference, -0.41 [95% CI, -0.58 to -0.25], p < 0.00001), and this superiority maintained until end of double-blinded period (28 days). Sub-group analysis showed that superior antidepressant effects of esketamine over placebo in TRD and MDSI was observed from 2-4 hours, which was maintained until 28 days. Resolution of suicide in MDSI was also greater for esketamine than for placebo at 2-4 hours (OR of 2.04, 95% CIs, 1.37 to 3.05, p = 0.0005), but two groups did not statistically differ at 24 hours and day 28. Total adverse events (AEs), and other common AEs including dissociation, blood pressure increment, nausea, vertigo, dysgeusia, dizziness, and somnolence were more frequent in esketamine than in placebo group.
Conclusion
Esketamine showed rapid antidepressant effects in patients with MDD, including TRD and MDSI. The study also suggested that esketamine might be associated with rapid anti-suicidal effects for patients with MDSI.
Papers cited by this study that are also in Blossom
Zanos, P., Gould, T. D. · Molecular Psychiatry (2018)
Ionescu, D. F., Lane, R., Lim, P. et al. · Journal of Clinical Psychiatry (2020)
Ionescu, D. F., Qiu, X., Lane, R. et al. · International Journal of Neuropsychopharmacology (2020)
Major depressive disorder (MDD) is common and disabling, with substantial proportions of patients failing to respond to standard antidepressants and therefore classified as treatment-resistant depression (TRD). Conventional antidepressants also suffer from a delayed onset of action, leaving patients with acute suicidal ideation at continued risk for days to weeks. Earlier research has suggested that drugs acting on glutamatergic systems, notably esketamine — the S‑enantiomer of ketamine and an N‑methyl‑D‑aspartate (NMDA) receptor antagonist — have rapid antidepressant and potential anti‑suicidal effects; intranasal esketamine received FDA approvals in 2019 for TRD and for depressive symptoms with suicidal ideation or behaviour when used as an adjunct to oral antidepressants. However, randomized double‑blind placebo‑controlled trials (DB‑RCTs) of intranasal esketamine have given mixed signals about the rapidity and durability of benefit, and prior meta‑analyses were limited by small numbers of trials and inconsistent timing of outcome measurement. Bahk and colleagues set out to synthesise available DB‑RCT evidence on intranasal esketamine as augmentation to oral antidepressants in adults with MDD, with particular attention to rapid antidepressant and anti‑suicidal effects. The meta‑analysis aimed to quantify change in Montgomery‑Åsberg Depression Rating Scale (MADRS) scores at multiple time points after the first dose, to assess remission and resolution of suicidality, and to summarise safety and tolerability across trials, including analyses focused on TRD and major depression with suicidal ideation (MDSI).
The investigators performed a systematic search from 1 December 2020 to 10 January 2021 across PubMed, Embase, PsycINFO, CINAHL, Web of Science, ClinicalTrials.gov and the Cochrane Central Register of Controlled Trials, complemented by hand‑searching reference lists. Three investigators conducted the initial search and data extraction, two additional authors re‑evaluated potentially eligible papers, and final disagreements were resolved by consensus. Inclusion criteria required randomized double‑blind placebo‑controlled trials comparing adjunctive intranasal esketamine versus placebo in adults with MDD, with clearly reported inclusion/exclusion criteria; no restrictions were placed on severity, setting, dose range, or geography. When a trial included multiple double‑blind phases, only data from the first double‑blind period were extracted. Primary efficacy outcome was change from baseline in MADRS total score at multiple time points through the end of each trial’s double‑blind phase. Secondary efficacy outcomes included study‑defined remission rates and resolution of suicidality at the same time points. Safety outcomes comprised total adverse events (AEs) and common specific AEs (dissociation, blood pressure increment, nausea, vertigo, dysgeusia, dizziness, somnolence, headache). Statistical analyses used Review Manager 5.4. For continuous outcomes the standardised mean difference (SMD; Hedges’ g) with 95% confidence intervals (CIs) was computed; dichotomous outcomes were pooled as odds ratios (ORs) with 95% CIs using the Mantel‑Haenszel method. The authors interpreted effect sizes with Cohen’s conventions (small ≈ 0.2, medium ≈ 0.5, large ≈ 0.8). Heterogeneity was assessed with I2 and significance threshold for heterogeneity set at p < 0.10 with I2 ≥ 50% taken as substantial; fixed‑effect models were used when heterogeneity was low and random‑effects models when heterogeneity was significant. Trial quality was appraised according to Cochrane recommendations.
The search identified eight DB‑RCTs (seven published, one unpublished) enrolling 1,488 participants with MDD; 827 received intranasal esketamine plus an oral antidepressant and 661 received placebo plus an oral antidepressant. Five trials enrolled patients with TRD and three enrolled patients with major depression and suicidal ideation (MDSI). Four trials used flexible esketamine dosing and four used fixed doses; reported doses ranged from 28 mg to 84 mg. Risk‑of‑bias assessment rated the included trials as generally good, and publication bias could not be formally tested because only one trial was unpublished. Primary efficacy: across all trials intranasal esketamine produced significantly greater improvement in MADRS total scores beginning at 2–4 hours after the first administration (SMD = −0.41, 95% CI −0.58 to −0.25, p < 0.00001) versus placebo. The superiority persisted at 24 hours (SMD = −0.36, 95% CI −0.47 to −0.24, p < 0.00001), at week 1 (SMD = −0.25, 95% CI −0.36 to −0.13, p < 0.0001) and at the end of the double‑blind period (week 3–4; SMD = −0.25, 95% CI −0.35 to −0.14, p < 0.00001). Heterogeneity was low for these pooled estimates (I2 = 0% for 2–4 hours and week 3–4; I2 = 42% at 24 hours; I2 = 13% at week 1), and fixed‑effect models were applied for most analyses. Subgroup analyses: in TRD patients intranasal esketamine exceeded placebo from 2–4 hours (SMD = −0.67, 95% CI −1.16 to −0.17, p = 0.008) through 24 hours (SMD = −0.48, 95% CI −0.82 to −0.13, p = 0.007), week 1 (SMD = −0.27, 95% CI −0.42 to −0.12, p = 0.0003) and week 3–4 (SMD = −0.23, 95% CI −0.37 to −0.10, p = 0.0007); the authors note only one TRD study contributed a 2–4 hour assessment. For the MDSI subgroup similar rapid antidepressant effects were observed at 2–4 hours (SMD = −0.38, 95% CI −0.56 to −0.21, p < 0.0001) and were maintained at subsequent time points through week 3–4. Resolution of suicidality: among patients with MDSI esketamine was associated with greater resolution of suicidality at 2–4 hours (OR = 2.04, 95% CI 1.37 to 3.05, p = 0.0005), but differences were not statistically significant at 24 hours (OR = 1.15, 95% CI 0.80 to 1.65, p = 0.46) or at week 3–4 (OR = 1.32, 95% CI 0.91 to 1.90, p = 0.44). Remission rates: pooled remission at week 3–4 favoured esketamine (OR = 1.64, 95% CI 1.30 to 2.07, p < 0.0001). Remission was also more likely at 2–4 hours (OR = 2.43, 95% CI 1.27 to 4.67, p = 0.007) and at 24 hours (OR = 2.47, 95% CI 1.58 to 3.85, p < 0.0001), but there was no statistically significant difference at day 8 (OR = 1.46, 95% CI 0.96 to 2.23, p = 0.08). Safety and tolerability: intranasal esketamine was associated with higher odds of total adverse events (OR = 4.23, 95% CI 2.85 to 6.27, p < 0.00001; I2 = 55%), and increased rates of several specific AEs: dissociation (OR = 7.93, 95% CI 5.36 to 11.72, p < 0.00001), blood pressure increment (OR = 7.18, 95% CI 4.82 to 10.69, p < 0.00001), nausea (OR = 3.28, 95% CI 2.40 to 4.48, p < 0.00001), vertigo (OR = 6.22, 95% CI 3.97 to 9.73, p < 0.00001), dysgeusia (OR = 1.67, 95% CI 1.21 to 2.31, p = 0.002), dizziness (OR = 4.47, 95% CI 3.27 to 6.11, p < 0.00001) and somnolence (OR = 2.08, 95% CI 1.49 to 2.89, p < 0.0001). Headache was numerically more common but did not reach statistical significance (OR = 1.33, 95% CI 1.00 to 1.77, p = 0.05).
Bahk and colleagues interpret their results as confirming that adjunctive intranasal esketamine produces rapid antidepressant effects in adults with MDD, with measurable separation from placebo as early as 2–4 hours after the first dose and sustained superiority through the end of the double‑blind periods (week 3–4). The meta‑analysis is presented as the largest pooled DB‑RCT evidence to date (eight trials, 1,488 participants), and the authors highlight that their subgroup analyses are the first to show a similarly rapid antidepressant signal specifically in TRD and in MDSI populations. In addition, a rapid anti‑suicidal effect was observed at 2–4 hours in MDSI, although the advantage over placebo was not maintained at 24 hours or at week 3–4. The authors note that the pooled standardised mean differences (SMDs) correspond to small‑to‑medium effect sizes (SMDs ≈ 0.25–0.41 by Cohen’s classification). They propose that part of the apparent attenuation of group differences over time may reflect concomitant oral antidepressants given in all trials, which begin to take effect and thereby reduce between‑group separation. Regarding safety, the pooled analysis confirms higher overall adverse events with esketamine and markedly increased odds of dissociation and transient blood pressure increases; prior trial data indicate these effects peak shortly after dosing and generally resolve within hours and with repeated dosing. The authors caution, however, that long‑term safety and tolerability data remain sparse and require further study. Limitations acknowledged by the study team include pooling across a range of esketamine doses (28–84 mg) which precluded dose–response analysis, the presence of at least one unpublished negative trial (raising the possibility of additional unpublished negative studies and publication bias), and lack of time‑resolved analyses of the onset and duration of specific adverse events. The authors call for additional DB‑RCTs—particularly in MDSI—to better define rapid anti‑suicidal effects and for longer‑term safety evaluations.
Major depressive disorder (MDD) is a common debilitating disease with a lifetime prevalence of 15-20%, and it is known to cause severe functional impairment. Multiple antidepressants are available, but approximately one-third of patients with MDD fail to achieve adequate response or remission and become treatment-resistant depression (TRD). Besides low remission and response rate, delayed onset of efficacy is another important limitation of conventional antidepressants. Moreover, around 10-20% of patients with MDD attempt suicide over their lifetimee, and 3.4% of patients with MDD actually commit or complete suicide. However, due to therapeutic lag between administration of antidepressant and onset of clinical improvement, patients having major depression with suicide ideation (MDSI) remain symptomatic and at risk of suicidal behavior and self-harm for more than two weeks. The monoamine hypothesis of depression received criticisms for more than a decade, and studies suggested that patients with TRD may need novel antidepressants with different mechanisms of action. Thus, additional antidepressant having novel mechanism of action, higher potency, faster onset of ac-tion, and anti-suicidal effect are urgently needed. Esketamine is a nonselective, noncompetitive antagonist at the N -methyl-D-aspartate (NMDA) receptor which modulates glutamatergic transmission. It is an S-enantiomer of ketamine, which is known to have a higher affinity for the NMDA receptor than the R-enantiomer. The US Food and Drug Administration (FDA) approved intranasal esketamine in conjunction (augmentation) with an oral antidepressant first for the treatment of TRD in 2019. Three double-blinded randomized placebo controlled trials (DB-RCTs) have shown its anti-suicidal effect, so the US FDA further approved intranasal esketamine augmentation to treatment depressive symptoms in adults with MDD having suicidal ideation or behavior. An earlier study of intranasal esketamine showed its rapid onset of action in TRD. However, findings from subsequent DB-RCTs of intranasal esketamine have been mixed in terms of its rapid antidepressant effect. Although studies confirmed its anti-suicidal effects in patients with MDSI, but whether or not the anti-suicidal effects are rapid is still obscure. In terms of understanding efficacy and safety of a new drug, meta-analysis is important because it can overcome limitation of small sample sizes, increase statistical power of group comparisons, enhance generalizability of DB-RCTs, and quantify inconsistencies of DB-RCTs. An initial meta-analysis for intranasal esketamine showed that significant superiority of intranasal esketamine over placebo with regard to response and remission in patients with MDD were noted as early as two hours. However, the study included only four DB-RCTs which precluded more detailed elucidation of publication bias for outcome measures. In addition, due to small sample size, the study was unable to confirm its effects in MDSI. A more recent study by Papakostas et al.also showed that adjunctive intranasal esketamine was significantly more effective than placebo for Montgomery-Åsberg Depression Rating Scale (MADRS) score change, response, and remission. However, besides having small study numbers (5 DB-RCTs), the timing of primary outcome or end-point measurements differed depending on the studies, but the meta-analysis did not specify their efficacies according to different time after esketamine administration. The study also failed to address whether or not esketamine have rapid antidepressant effect. We performed a meta-analysis and studied efficacy and safety of intranasal esketamine in treatment of patients with MDD. We also aimed to investigate its rapid antidepressive actions in patients with TRD and MDSI.
Three investigators (SMW, NKK, and YSW) independently searched from December 1st, 2020 to January 10th, 2021 using following terms: "esketamine," and "depression" (Mesh) at PubMed, Embase, PubMed, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Web of Science for published articles. No restrictions were utilized for publication date. In terms of clinical trials, Cochrane Central Register of Controlled Trials Library and ClinicalTrials.gov (www.clinicaltrials.gov) was explored. We also manually searched reference lists from identified articles and reviews to find additional studies. Two other authors (HRN and HKL) re-evaluated potentially eligible papers to determine whether they truly met the selection criteria. The last two authors (CUP and WMB) discussed and reached a consensus for disagreements.
Primary inclusion criteria were all DB-RCTs comparing adjunctive treatment of intranasal esketamine with standard antidepressants for MDD. To be included in our meta-analysis, studies were required to: 1) have placebo as a comparator, regardless of having an active comparator, 2) exclusively focused on patients with MDD 3) have clearly described all inclusion and exclusion criteria. No restrictions were utilized for severity of MDD, gender, treatment basis (i.e., inpatient or outpatient), dose range, or study location. Three investigators (SMW, NKK, and YSW) who conducted initial data search also extracted the data. In addition, if a DB-RCT contained multiple double-blinded phases (i.e., Daly et al.), only data from the first period were extracted and analyzed. We also assessed quality of DB-RCTs based on recommendations of Cochrane Review.
The primary outcome measures were change of MADRS total score from baseline to different time points until the end of double blinded phase. The secondary efficacy measures were rate of study-defined remission and reso- lution of suicidality at different time points during the double blinded phase. In terms of safety and tolerability, total number of adverse events (AEs) and common AEs including dissociation, blood pressure increment, nausea, vertigo, dysgeusia, dizziness, somnolence, and headache were included in the meta-analysis.
Review Manager version 5.4 software (Cochrane Collaboration, Oxford, UK) was used to undertake statistical analysis. Standardized mean difference (SMD) using method developed by Hedges (Hedges g) with 95% confidence intervals (95% CIs) and odds ratio (OR) with 95% CIs using Mantel-Haenszel method were used for continuous and dichotomous outcome measures respec-tively. Cohen's classification can be used to assess effect size: small = SMD ＜ 0.2, medium = SMD of 0.5, and large = SMD ＞ 0.8. In terms of heterogeneity, we used I 2 statistic and evaluated what degree of variance between studies can be attributed to actual differences between the studies rather than to chance. Studies suggested that I 2 of 75-100% indicate considerable heterogeneity, and the heterogeneity threshold was defined as 50% or more in I 2 value and p ＜ 0.10.
Initially 804 abstracts were identified with use of Embase, PubMed, Psychinfo, and Web of Science. After a preliminary review, 754 papers were excluded because they were either duplicates, irrelevant, or non-full articles. The remaining 50 full-text articles were retrieved for a more detailed evaluation. Among them seven published DB-RCTs were included in the meta-analysis. Of the 35 records obtained from ClinicalTrials.gov and 132 studies from Cochrane Central Register of Controlled Trials, we found one DB-RCT having full reports which were not published. Thus, a total of eight DB-RCTs (seven published and one un-published) were finally selected for our meta-analysis (Fig.). Tablepresents main characteristics of these eight DB-RCTs. All studies were multi-centered, and six studieswere multi-national while two were conducted either in Japanor USonly. Five trialsinvolved TRD while other threeinvolved patients with MDSI. A total of 1,488 participants were included, and number of patients included in placebo and intranasal esketamine groups were 661 and 827 respectively. Fourstudies used flexible doses while other fourused fixed doses of intranasal esketamine. Risk of bias assessment showed that all studies included were good in quality in terms of their methodologies (Supplementary Fig.; available online). Publication bias could not be tested because only one trial was un-published.
Primary endpoint: mean change of MADRS Mean change of MADRS total score from baseline to 2-4 hours, 24 hours, week 1, and week 3-4 are presented as forest plots (Fig.). Intranasal esketamine more significantly improved MADRS total scores than placebo for treating MDD starting from 2-4 hours after the first injection (SMD, -0.41 [95% CI, -0.58 to -0.25], p ＜ 0.00001), and the significant superiority maintained at 24 hours (SMD, -0.36 [95% CI, -0.47 to -0.24], p ＜ 0.00001), week 1 (SMD, -0.25 [95% CI, -0.36 to -0.13], p ＜ 0.0001), and end of double-blinded period (week 3-4) (SMD, -0.25 [95% CI, -0.35 to -0.14], p ＜ 0.00001). Significant heterogeneities were not reported for 2-4 hours (I 2 = 0%, p = 0.40), 24 hours (I 2 = 42%, p = 0.13), week 1 (I 2 = 13%, p = 0.33), and week 3-4 (I 2 = 0%, p = 0.68), so we used fixed effect model for all analyses. We conducted sub-group analysis for patients with TRD and MDSI. In terms of patients with TRD, MADRS improvement was significantly more superior in intranasal esketamine group than in placebo group from 2-4 hours (SMD, -0.67 [95% CI, -1.16 to -0.17], p = 0.008) to 24 hours (SMD, -0.48 [95% CI, -0.82 to -0.13], p = 0.007), week 1 (SMD, -0.27 [95% CI, -0.42 to -0.12], p = 0.0003), and week 3-4 (SMD, -0.23 [95% CI, -0.37 to -0.10], p = 0.0007). However, only one study assessed MADRS at 2-4 hours after the first injection (Fig.). Significant heterogeneity was noted for 24 hours (I 2 = 73%, p = 0.02), so random effect model was used. For 2-4 hours, week 1, and week 3-4 fixed effect model was utilized because no significant heterogeneity was observed. Similar trends of rapid antidepressive effects were noted for subgroup analysis involving patients with MDSI at 2-4 hours (SMD, -0.38 [95% CI, -0.56 to -0.21], p ＜ 0.0001), 24 hours (SMD, -0.34 [95%CI, -0.52 to -0.17], p = 0.0001), week 1 (SMD, -0.21 [95% CI, -0.39 to -0.02], p = 0.03), and week 3-4 (SMD, -0.27 [95% CI, -0.44 to -0.10], p = 0.002) (for all heterogeneity = 0), which is illustrated in Figure.
Esketamine showed superior efficacy over placebo in resolution of suicide at 2-4 hours after initial nasal infusion with OR of 2.04 (95% CIs, 1.37 to 3.05, p = 0.0005; heterogeneity = 0%), but the two groups did not statistically differ at 24 hours (OR = 1.15, 95% CIs, 0.80 to 1.65, p = 0.46; heterogeneity = 0%) and week 3-4 (OR = 1.32, 95% CIs, 0.91 to 1.90, p = 0.44; heterogeneity = 0%) (Supplementary Fig.; available online).
A total of seven studies were included for comparing rate of remission between intranasal esketamine and placebo groups at week 3-4. Intranasal esketamine group showed superior remission rate than placebo with OR of 1.64 (95% CIs, 1.30 to 2.07, p ＜ 0.0001; heterogeneity = 0%) at week 3-4. In addition, superior efficacy was noted at 2-4 hours (OR = 2.43, 95% CIs, 1.27 to 4.67, p = 0.007; heterogeneity = 41%, p = 0.18) and 24 hours (OR = 2.47, 95% CIs, 1.58 to 3.85, p ＜ 0.0001; heterogeneity = 0%) after initial nasal esketamine infusion, but the two groups did not differ at day 8 (OR = 1.46, 95% CIs, 0.96 to 2.23, p = 0.08; heterogeneity = 0%) (Supplementary Fig.
In terms of commonly observed side effects, esketamine showed higher incidence of total AEs (OR = 4.23, 95% CIs, 2.85 to 6.27, p ＜ 0.00001; heterogeneity = 55%, p = 0.04), dissociation (OR = 7.93, 95% CIs, 5.36 to 11.72, p ＜ 0.00001; heterogeneity = 0%), blood pressure increment (OR = 7.18, 95% CIs, 4.82 to 10.69, p ＜ 0.00001; heterogeneity = 0%), nausea (OR = 3.28, 95% CIs, 2.40 to 4.48, p ＜ 0.00001; heterogeneity = 30%, p = 0.20), vertigo (OR = 6.22, 95% CIs, 3.97 to 9.73, p ＜ 0.00001; heterogeneity = 43%, p = 0.10), dysgeusia (OR = 1.67, 95% CIs, 1.21 to 2.31, p = 0.002; heterogeneity = 0%), dizziness (OR = 4.47, 95% CIs, 3.27 to 6.11, p ＜ 0.00001; heterogeneity = 0%), and somnolence (OR = 2.08, 95% CIs, 1.49 to 2.89, p ＜ 0.0001; heterogeneity = 0%) compared with placebo (Fig.). Although headache was numerically more common in esketamine group than in placebo group, the two groups did not differ statistically (OR = 1.33, 95% CIs, 1.00 to 1.77, p = 0.05; heterogeneity = 5%, p = 0.39).
To the best of our knowledge, this is the largest metaanalysis (eight DB-RCTs with 1,488 subjects) comparing efficacy and safety of intranasal esketamine and placebo in patients with MDD. Our study confirmed previous research by showing that augmentation of antidepressants with intranasal esketamine was significantly more effective than with placebo for MADRS score change and depression remission. In addition, the superior treat- ment response and remission of intranasal esketamine were noticeable as early as 2-4 hours after the first intranasal esketamine, and this superior efficacy lasted until end of double blinded phase, which is week 3-4. By conducting subgroup analysis, we are the first one to show that the rapid improvement of depressive symptoms was evident in patients with TRD and MDSI. Our results also extended previous studies and showed rapid anti-sui-cidal effect of intranasal esketamine (resolution of suicidality 2-4 hours after the 1st injection) in MDSI. However, although intranasal esketamine showed trend of superior efficacy over placebo, the statistical significance was not maintained at 24 hours and week 3-4. Only three studies were conducted in MDSI, so small number of clinical trials might have been the main cause. More DB-RCTS are needed to define rapid anti-suicidal effects of intra-nasal
The SMD in MADRS across different time ranged from 0.25-0.41, which equal to small~medium effect size according to Cohen's classification. More importantly, all efficacies including MADRS score change, remission of depression, and resolution of suicidality were greatest either at 2-4 hours or 24 hours after the 1st administration of intranasal esketamine. All patients in the eight DB-RCTS were taking oral antidepressants in addition to intranasal esketamine or placebo, so the efficacy difference between the two groups might have decreased or attenuated as the onset of actions for oral antidepressants started to show effects. In line with our hypothesis, the mean change of MADRS from baseline to week 3-4 was less than four points difference in all eight DB-RCTs. Thus, as Canuso et al. has suggested, intranasal esketamine could be used to overcome the efficacy gap observed between drug administration and onset of action for the conventional antidepressants. This therapeutic role could be particularly important in patients having MDSI. In terms of safety and tolerability, intranasal esketamine showed higher total AEs than the placebo group. Since esketamine was initially introduced medically as an anesthetic in Germany in 1997, its higher risk of causing somnolence, dizziness, and vertigo are not surprising. The intranasal esketamine also had significantly higher rate of nausea and dysgeusia. The risk of intranasal esketamine causing dissociationand blood pressure incrementhave been well documented. Likewise, the rate of dissociation and blood pressure increment was higher in intranasal esketamine than in placebo with particularly higher odd ratios (7.18-7.93) compared with AEs. Previous studies showed that dissociation and perceptual change symptoms peaked shortly after esketamine administration, which generally resolved by 2 hours after dosing. Evidence also showed that rate and intensity of dissociation lowered with repeated administrations of intranasal esketamine. Similarly, studies consistently illustrated that blood pressure increment following intranasal esketamine were transient, asymptomatic, and not associated with serious cardiovascular complications. However, number of studies investing long-term safety and tolerability of intranasal esketamine are scarce. Therefore, whether or not intranasal esketamine result in long-terms adverse events needs further varication. Our study contained several limitations. First, we combined all doses of intranasal esketamine (28-84 mg/day) so were not able to conduct meta-regression and investigate its dose related efficacy, tolerability, and safety. Second, we found one unpublished DB-RCT whish showed negative results. There could have been more unpublished negative trials and possibility of publication bias. Third, we did not investigate rate and severity of diverse side effects across different time. As a result, we were not able to confirm that important side effects such as dissociation and blood pressure increment resolved shortly after and attenuated as the administration of intranasal esketamine repeated. In conclusion, the present meta-analysis confirmed that intranasal esketamine was effective in patients with MDD including TRD and MDSI. Our meta-analysis further showed that intranasal esketamine was associated with rapid antidepressant effect for patients with TRD and MDSI. The study also suggested that esketamine might have rapid anti-suicidal effects for patients with MDSI. No potential conflict of interest relevant to this article was reported.
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