Esketamine for Depression: From Therapeutic Characteristics to Efficacy and Safety

Depression affects over 280 million people worldwide. Conventional antidepressants like SSRIs can take weeks to work and fail for about 30% of patients, leaving urgent needs unmet, especially for those at risk of suicide. Esketamine, the S-enantiomer of ketamine, binds more strongly to NMDA receptors than its counterpart and rapidly relieves depressive symptoms and suicidal ideation. It has shown therapeutic potential across several depression subtypes, including major depressive disorder with suicidal behavior, postpartum depression, treatment-resistant depression, bipolar depression, and atypical depression. Combining esketamine with oral antidepressants may improve outcomes. Future research should assess long-term safety, dependence risks, and biomarkers for treatment response.

Study at a glance

Abstract

More than 280 million individuals worldwide suffer from depression, which is one of the main causes of mental disability. It has multiple subtypes, and conventional treatments have limitations such as slow onset of action, high non-response rate, and numerous side effects. For instance, it takes two to six weeks for selective serotonin reuptake inhibitors (SSRIs) to start working, and about 30% of patients experience treatment resistance. These limitations make conventional treatments unable to meet clinical needs, especially failing to address the urgent intervention needs of patients at risk of suicide. As the S-enantiomer of ketamine, esketamine exhibits a stronger binding affinity for NMDA receptors compared to its counterpart (the R-enantiomer of ketamine, or racemic ketamine). It relieves depressive symptoms rapidly through a unique mechanism of action and can also reduce suicidal ideation. Esketamine has shown therapeutic potential in various subtypes of depression, including Major Depressive Disorder (MDD) with acute suicidal ideation or behavior, Postpartum Depression (PPD), Treatment-Resistant Depression (TRD), Bipolar Depression (BD), and Atypical Depression (AD). Moreover, the combination of esketamine with oral antidepressants can improve therapeutic efficacy. Future efforts should focus on evaluating its long-term safety and dependence risks, expanding its therapeutic indications, conducting research on special populations, and developing biomarkers for predicting treatment response. This paper reviews the development and characteristics of esketamine, as well as its therapeutic applications in different types of depression, providing a new perspective for depression treatment.