Rapid Onset of Intranasal Esketamine in Patients with Treatment Resistance Depression and Major Depression with Suicide Ideation: A Meta-Analysis

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.