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

Front Psychol. 2021 Jun 1;12:648691. doi: 10.3389/fpsyg.2021.648691. eCollection 2021.


Background: There is growing interest in glutamatergic agents as a treatment for depression, especially intranasal ketamine, which has become a hot topic in recent years. We aim to assess the efficacy and safety of intranasal ketamine in the treatment of major depressive disorder (MDD), especially treatment-resistant depression (TRD).

Methods: We searched Medline, EMBASE, and the Cochrane Library until April 1, 2020 to identify double-blind, randomized controlled trials with allocation concealment evaluating intranasal ketamine in major depressive episodes. Clinical remission, response, and depressive symptoms were extracted by two independent raters. The outcome measures were Montgomery-Asberg Depression Rating Scale (MADRS) score improved from baseline, clinical response and remission, dissociative symptoms, and common adverse events. The analyses employed a random-effects model.

Results: Data were synthesized from five randomized controlled trials (RCTs) employing an intranasal esketamine and one RCT employing intranasal ketamine, representing 840 subjects in parallel arms, and 18 subjects in cross-over designs (n = 858 with MDD, n = 792 with TRD). The weighted mean difference of MADRS score was observed to decrease by 6.16 (95% CI 4.44-7.88) in 2-4 h, 9.96 (95% CI 8.97-10.95) in 24 h, and 4.09 (95% CI 2.18-6.00) in 28 day. The pooled relative risk (RR) was 3.55 (95% CI 1.5-8.38, z = 2.89, and p < 0.001) for clinical remission and 3.22 (95% CI 1.85-5.61, z = 4.14, and p < 0.001) for clinical response at 24 h, while the pooled RR was 1.7 (95% CI 1.28-2.24, z = 3.72, and p < 0.001) for clinical remission and 1.48 (95% CI 1.17-1.86, z = 3.28, and p < 0.001) for clinical response at 28 day. Intranasal ketamine was associated with the occurrence of transient dissociative symptoms and common adverse events, but no persistent psychoses or affective switches.

Conclusion: Our meta-analysis suggests that repeated intranasal ketamine conducted a fast-onset antidepression effect in unipolar depression, while the mild and transient adverse effects were acceptable.

Systematic review registration: PROSPERO, CRD42020196856.

Keywords: depression; intranasal; ketamine; meta-analysis; unipolar disorder.

Publication types

  • Review