Intranasal Ketamine for Depression in Adults: A Systematic Review and Meta-Analysis of Randomized, Double-Blind, Placebo-Controlled Trials

Major depressive disorder (MDD) is a prevalent and disabling condition with a substantial proportion of patients—approximately 30%—classified as treatment-resistant depression (TRD), typically defined as failure to respond to at least two adequate antidepressant trials. Earlier research established that sub‑anesthetic intravenous ketamine produces rapid, transient antidepressant effects, but the intravenous route poses practical limitations for long‑term treatment. Intranasal administration and the S‑enantiomer esketamine have therefore been investigated as more convenient alternatives. Steiger and colleagues set out to evaluate the efficacy, safety, and tolerability of intranasal ketamine formulations (predominantly esketamine) for unipolar major depressive episodes, with particular focus on TRD. The study is a systematic review and meta‑analysis of randomized, double‑blind, placebo‑controlled trials, aiming to synthesise effects on depressive symptoms (MADRS), clinical response and remission, dissociative symptoms, and common adverse events over short (hours to days) and longer (up to 28 days and beyond) timeframes.

The investigators searched Medline, EMBASE and the Cochrane Library through 1 April 2020 for double‑blind randomized controlled trials of intranasal ketamine or esketamine in adults with a primary unipolar major depressive episode. Search terms included combinations of depressive disorder, major depressive disorder, ketamine, and randomized controlled trial; unpublished items and abstracts without full text were excluded. The selection criteria required random allocation with allocation concealment, double‑blinding, placebo control, clinician‑rated primary outcome, total sample ≥10, adult participants (age ≥18), and intranasal delivery; trials limited to narrow or secondary depression, or ketamine used as an electroconvulsive therapy adjunct, were excluded. For cross‑over trials only first‑period data were used. Two independent reviewers extracted study characteristics (design, sample, age, gender), treatment details (ketamine vs esketamine formulation, dose, frequency, device), control condition, primary outcome measures (MADRS change), secondary outcomes (response defined as ≥50% MADRS reduction; remission using MADRS thresholds of ≤9/10/12), and safety data (Clinician Administered Dissociative States Scale, CADSS, and adverse events). Risk of bias was assessed by two authors using Cochrane domains; publication bias was not formally examined because fewer than seven studies were included. Meta‑analyses used a random‑effects model. Dichotomous outcomes were pooled as relative risks (RR) with 95% confidence intervals (CI) and continuous outcomes as weighted mean differences (WMD) with 95% CI. Heterogeneity was assessed with I2 and two‑tailed p values; the authors considered p < 0.05 and I2 > 50% indicative of notable heterogeneity and performed sensitivity analyses when appropriate. Analyses were conducted using a statistics package (MP‑parallel Edition 14.0).

The systematic search identified six eligible double‑blind RCTs including a total of 858 participants with MDD (792 classified as TRD). Five trials evaluated intranasal esketamine at varying doses and schedules; one trial tested racemic ketamine 50 mg once weekly. Most trials used a specially designed nasal spray device; three trials initiated a new oral antidepressant concomitantly from a prespecified list. Placebo formulations attempted to mimic taste in five studies with a bittering agent, while other controls included 0.9% saline or water for injection. One study enrolled patients older than 65; the remainder included participants under 65. The primary outcome was change in MADRS score at multiple time points; secondary outcomes included response and remission rates. Pooled continuous outcomes showed a significant improvement in MADRS score favouring intranasal ketamine/esketamine. Across timepoints the overall WMD was 6.74 (95% CI 5.17–8.32). By prespecified time windows the WMDs were: 6.16 (95% CI 4.44–7.88) at 2–4 hours, 9.96 (95% CI 8.97–10.95) at 24 hours, and 4.09 (95% CI 2.18–6.00) at 28 days, all p ≈ 0.00. Heterogeneity for the 2–4 hour subgroup was moderate (I2 = 64.7%, P = 0.037); sensitivity analyses using an article‑by‑article exclusion approach showed the findings remained statistically significant when various Daly 2018 dose arms or the Canuso 2018 study were removed (WMDs ranged approximately 5.47–6.99 with 95% CIs excluding 0). Dichotomous outcomes at 24 hours favoured ketamine with pooled RRs of 3.55 (95% CI 1.50–8.38) for clinical remission and 3.22 (95% CI 1.85–5.61) for clinical response, both p < 0.001. At 28 days pooled RRs were 1.70 (95% CI 1.28–2.24) for remission and 1.48 (95% CI 1.17–1.86) for response, both p < 0.001. Reported heterogeneity for these binary outcomes was low to moderate; for example remission at 28 days showed I2 = 0.0% (P = 0.587) while remission at 24 hours had I2 = 60% (P = 0.113). Safety data indicated transient increases in dissociative symptoms measured by CADSS: in one report (Lapidus) CADSS scores at +40 minutes increased by 1.75 ± 4.17 in ketamine responders versus 1.09 ± 1.76 in non‑responders, with resolution by +240 minutes. Across trials dissociative effects typically began shortly after dosing, peaked around 30–40 minutes, and resolved within 1.5–2 hours. Common adverse events more frequently observed with intranasal ketamine/esketamine included dizziness, dissociation, dysgeusia, vertigo and nausea; most events were mild to moderate and resolved within hours. No persistent psychoses, affective switches, interstitial cystitis, respiratory depression, or clinically significant liver enzyme elevations were reported in the included trials, and one long‑term trial cited cognitive performance that remained stable or improved over 52 weeks.

Steiger and colleagues interpret the pooled evidence as supporting a rapid‑onset antidepressant effect of intranasal ketamine/esketamine for unipolar depression, with the largest effect observed at 24 hours and a retained, though attenuated, benefit at 28 days. They note that the magnitude of MADRS improvement is comparable to that reported for intravenous ketamine in prior meta‑analyses, and suggest that the route of administration may not substantially alter antidepressant efficacy given intranasal bioavailability (reported up to 45%) and pharmacokinetic data indicating certain intranasal doses produce plasma concentrations similar to intravenous dosing. The authors discuss potential mechanisms, including ketamine metabolism to (2R,6R)‑hydroxynorketamine (HNK) and modulation of synaptic plasticity and prefrontal cortical circuits. They also consider differential glutamatergic profiles in unipolar versus bipolar depression and justify inclusion of unipolar cases only. In terms of safety, the discussion emphasises that most adverse events were transient and occurred on the day of dosing, but recommends monitoring for several hours post‑administration and cautions regarding potential harms with frequent long‑term use (neurocognitive effects, bladder, respiratory, and hepatic concerns), noting that available trial data did not demonstrate these serious outcomes. Key limitations acknowledged by the authors include the small number of eligible trials and limited data, which reduce statistical power and complicate heterogeneity assessment; the authors were unable to generate a funnel plot for publication bias because only six studies were included. They call for further research to define optimal dosing and frequency, to examine longer‑term safety, and to clarify whether efficacy differs by concomitant oral antidepressant choice. The authors also note regulatory context, citing the March 2019 FDA approval of intranasal esketamine combined with an oral antidepressant for adult TRD, and suggest that intranasal delivery may improve practicality for ongoing treatment.

The authors conclude that repeated intranasal ketamine administration produces a rapid antidepressant effect in adults with unipolar depression, with adverse effects that are generally mild, transient, and considered acceptable within the trial contexts. They advocate for further studies to optimise dosing regimens and to better characterise long‑term efficacy and safety.