A review of the antidepressant effects of esketamine and arketamine in treatment-resistant depression

Aim.
This study aims to review the literature evaluating the effects of esketamine and arketamine in patients with Treatment-Resistant Depression within the context of Major Depressive Disorder. The mechanisms of action of both ketamine enantiomers, their clinical efficacy, and safety profiles are discussed.

Literature review.
Esketamine, the effectiveness of which has been extensively studied, acts primarily as an antagonist of the glutamatergic N-methyl-D-aspartate receptor, leading to increased neuroplasticity and improved cognitive function. When administered intranasally in combination with an oral antidepressant, esketamine has demonstrated a rapid antidepressant effect, most commonly assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS), which becomes evident within 24 hours of administration. The therapeutic benefit is sustained throughout the treatment period. Long-term studies involving large patient cohorts have confirmed the safety profile and sustained efficacy of esketamine. However, notable transient side effects, including dissociation and hypertension, have been observed, necessitating monitoring. Despite promising results in animal models, arketamine has been clinically tested only in small patient groups. Preliminary studies suggest its potential antidepressant benefits with a lower risk of dissociative symptoms compared to esketamine. However, these findings require further validation. Currently, no large, randomised clinical trials assess the efficacy and safety of arketamine, limiting its application in clinical practice and warranting further investigation.

Conclusions.
Esketamine appears to be an effective therapeutic option for treatment-resistant depression, particularly when administered intranasally, which enhances its clinical accessibility. Arketamine may offer an improved safety and tolerability profile, making it a potential alternative to esketamine. However, further clinical trials are required to confirm its efficacy and safety.