Esketamine in depression: putative biomarkers from clinical research.

Esketamine, the (S)-enantiomer of racemic ketamine, is an FDA-approved rapid-acting antidepressant for treatment-resistant depression (TRD) that outperforms traditional oral antidepressants. Research on biomarkers predicting response to esketamine remains limited and mostly extrapolated from racemic ketamine studies. Genetic, proteomic, and metabolomic profiles suggest inflammation and mitochondrial function may contribute to its effects, but these findings require verification. Neuroimaging consistently implicates the prefrontal cortex, striatum, and anterior cingulate cortex. In perioperative settings, esketamine reduces depression and anxiety, correlating with increased brain-derived neurotrophic factor and serotonin. Better-designed biomarker-focused clinical trials are needed to clarify mechanisms and identify patients most likely to benefit.

Study at a glance

Abstract

The discovery of racemic (R, S)-ketamine as a rapid-acting antidepressant and the subsequent FDA approval of its (S)-enantiomer, esketamine, for treatment-resistant depression (TRD) are significant advances in the development of novel neuropsychiatric therapeutics. Esketamine is now recognized as a powerful tool for addressing persistent symptoms of TRD compared to traditional oral antidepressants. However, research on biomarkers associated with antidepressant response to esketamine has remained sparse and, to date, has been largely extrapolated from racemic ketamine studies. Genetic, proteomic, and metabolomic profiles suggest that inflammation and mitochondrial function may play a role in esketamine's antidepressant effects, though these preliminary results require verification. In addition, neuroimaging research has consistently implicated the prefrontal cortex, striatum, and anterior cingulate cortex in esketamine's effects. Esketamine also shows promise in perioperative settings for reducing depression and anxiety, and these effects appear to correlate with increased peripheral biomarkers such as brain-derived neurotrophic factor and serotonin. Further indications are likely to be identified with the continued repurposing of racemic ketamine, providing further opportunity for biomarker study and mechanistic understanding of therapeutic effects. Novel methodologies and well-designed biomarker-focused clinical research trials are needed to more clearly elucidate esketamine's therapeutic actions as well as biologically identify those most likely to benefit from this agent, allowing for the improved personalization of antidepressant treatment.