Esketamine Nasal Spray Shows Rapid Antidepressant Effects in Treatment-Resistant Depression, suggests study

A new study published in The American Journal of Psychiatry showed that esketamine nasal spray monotherapy significantly improved depressive symptoms within 24 hours in patients with treatment-resistant depression. Common side effects like nausea, dissociation, and dizziness were generally resolved the same day. The study highlights esketamine's rapid and effective action across multiple doses.

In 2019, the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) authorized esketamine as the sole pharmacological drug with glutamatergic neuromodulatory capabilities to improve the effects of serotonin selective or serotonin and norepinephrine reuptake inhibitors. Apart from stimulating monoaminergic neurotransmission, several other modes of action for new pharmacological drugs are being investigated in light of the high rates of partial responsivity or non-response to currently known antidepressants.

For patients with treatment-resistant major depressive disorder who exhibit acute suicidal thoughts and actions, intranasal esketamine has been authorized as an adjuvant treatment. The existing information on its effectiveness against depression and suicidality, as well as its adverse effects, was systematically reviewed and meta-analyzed by this study.

For this study, on March 24, 2024, the PRISMA technique was used to scan MEDLINE using the term "esketamine." 87 of the 1,115 articles that were first found were included for debate and analysis. The meta-analysis found a weak but significant beneficial effect for depression (effect size range, 0.15–0.23 at weeks 2–4), comparable to augmentation strategies with atypical antipsychotics for treatment-resistant depression, despite the fact that randomized controlled trials were primarily negative or failed at weeks 2-4.

At no point in time was the impact size on suicidality meaningful. The findings of the sensitivity analysis were identical. Overall, the findings of this study show the effectiveness of esketamine as a supplement to antidepressants is negligible in treating treatment-resistant depression (much like augmentation techniques with atypical antipsychotics) and nonexistent when it comes to suicidality per se. Given the possibility of esketamine misuse and the incomplete understanding of its long-term consequences, these findings must be taken into account.

Reference:

Fountoulakis, K. N., Saitis, A., & Schatzberg, A. F. (2025). Esketamine treatment for depression in adults: A PRISMA systematic review and meta-analysis. The American Journal of Psychiatry, 182(3), 259–275. https://doi.org/10.1176/appi.ajp.20240515