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

This meta-analysis (s=6, n=858) found that (es)ketamine administrated intranasally (via the nose) led to quick antidepressant effects for those suffering from depression (MDD & TRD). Although the effect was most pronounced in the first 24 hours after administration (MADRS decreased by 9.96 points), the effects held up at 28 days (4.09).

Abstract

“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.”

Authors: Dongjiao An, Changwei Wei, Jing Wang & Anshi Wu

Summary

INTRODUCTION

Major depressive disorder (MDD) is a common psychiatric condition that has an increasing trend in prevalence. However, the effects of treatment for MDD are not satisfactory, and a rapid-onset antidepressive drug is necessary.

Ketamine is a traditional anesthetic drug that shows rapid anti-depressive effect. In 2014, Lapidus et al. explored a new route of intranasal administration of ketamine, which showed high efficacy in the amelioration of depressive symptoms and significantly reduced the Montgomery Asberg Depression Rating Scale (MADRS) score.

Search Strategy

We searched Medline, EMBASE, and the Cochrane Library for studies on ketamine and major depressive disorder and mailed study authors for literature without full-text or other useful information.

Study Selection

Studies involving ketamine or esketamine intranasally were included if they satisfied the following criteria: (1) study validity; (2) sample characteristics; (3) treatment characteristics; (4) publication in English.

Data Extraction

Data were extracted from studies meeting the criteria above and included study characteristics, ketamine dose, formulation, and frequency, control condition, primary outcome measure, clinical response, clinical remission, and safety assessments.

Quality Assessment

Two review authors independently assessed the risk of bias for each included study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions.

Data Synthesis and Analyses

Analyses were performed using the Statistics/Data Analysis MP-parallel Edition 14.0. A random-effects model was used to assess effect sizes, and heterogeneity was assessed using I 2 value and two-tailed p values.

Literature Search

We identified six double-blind RCTs that met the inclusion criteria through our systematic review. The study quality was assessed using the Cochrane Collaboration’s Tool for Assessing Risk of Bias.

Included RCTs: Main Characteristics

Six RCTs were included in the meta-analysis, including one crossover RCT. Esketamine was administered intranasally in five studies with racemic ketamine at 50 mg once a week, and duloxetine, escitalopram, sertraline, or venlafaxine extended release were used in three studies.

Five studies used bittering agents to simulate the taste of esketamine, one used 0.9% saline solution, and one used water for injection. The participants were younger than 65 years old.

Studies of the MADRS total score changed from baseline to different time points, and the proportion of individuals meeting the response and remission criteria were evaluated. No serious adverse reactions occurred.

Efficacy Results

The results showed that ketamine had a significant effect on depression severity scores over time, with a mean difference of 6.74 (95% CI 5.17 – 8.32, z = 8.38, and p = 0.00) favoring ketamine in 2 – 4 h, 9.96 in 24 h, and 4.09 in 28 day.

The sensitivity analysis revealed that the findings were relatively robust, with a WMD of 5.47 (95% CI, 3.87 to 7.08, and P = 0.00) when study Daly 2018 (84 mg) was excluded.

The pooled RR for clinical remission and response was 3.55 (95% CI 1.5 – 8.38, z = 2.89, and p 0.001) for 24 h and 1.7 (95% CI 1.28 – 2.24, z = 3.72, and p 0.001) for 28 day, suggesting that ketamine had a significant anti-depressive effect.

Safety Results

Dissociative symptoms increased in ketamine responders and resolved within 1.5 – 2 h, whereas non-responders experienced an increase in CADSS score at +40 min.

DISCUSSION

Ketamine’s anti-depressive effects were first observed in intravenous use, and later expanded to subcutaneous, oral, intranasal, and other methods. Its effectiveness was stronger than that of esketamine.

Our meta-analysis showed that ketamine had a comparable effect to placebo on the MADRS scale 24 h after a single dose of intravenous ketamine (0.5 mg/kg). However, the route of administration may affect the anti-depressive effect of ketamine.

Ketamine is a short-acting, fast-metabolizing antidepressant that increases -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-mediated excitatory post-synaptic potentials. It is thought to enhance synaptic plasticity and reverse the synaptic pathophysiology in brain regions associated with depression.

Ketamine might have different effects on people with unipolar and bipolar depression, and the inclusion criteria included unipolar depression only.

Intranasal esketamine was associated with undesirable adverse reactions including dizziness, dissociation, dysgeusia, vertigo, and nausea. Ketamine should be strictly regulated and used with caution because of the potential abuse and harmful consequences including neurocognitive impairment, interstitial cystitis, respiratory depression, and liver injury. Wajs et al. showed that long-term intranasal esketamine administration had a manageable safety profile, with no case of interstitial cystitis or respiratory depression.

Our meta-analysis had limitations, including a small number of trials and data included in the analyses. However, when multiple dimensions were considered, the ketamine favoring results were relatively robust.

Intranasal esketamine in conjunction with an oral antidepressant was approved by the Food and Drug Administration for treating TRD in adults. It may change the treatment pattern for people with MDD, especially those with TRD.