Treatment-resistant depression (TRD) presents a complex clinical challenge, particularly when comorbid with substance use disorders (SUDs) or other compulsive behaviors. With up to a third of major depressive disorder (MDD) patients failing to respond to standard antidepressant therapies, there is growing interest in interventions such as esketamine, a glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonist approved for TRD in 2019, as an intranasal therapy. While esketamine has demonstrated efficacy in alleviating depressive symptoms of TRD, emerging data also point towards its potential in addressing compulsive and addictive behaviors, particularly in patients whose depression and SUDs are deeply intertwined. This review aims to evaluate and synthesize the current literature on the use of esketamine in treating not only TRD, but specifically its application in patients suffering from comorbid substance use and addiction-related behaviors. We aim to clarify the therapeutic mechanisms, examine both human and animal data, and identify whether esketamine offers a dual-modality treatment approach that concurrently reduces depressive symptoms and addictive tendencies. Across peer-reviewed studies, including randomized control trials, cohort analyses, systematic reviews, and preclinical investigations, findings suggest that esketamine may reduce drug-seeking behavior, attenuate cravings, and improve outcomes when combined with behavioral interventions (such as mindfulness-based therapy). In rodent models, esketamine significantly inhibited cocaine-seeking after various abstinence conditions, and clinical data point to its potential role in treating alcohol misuse. In conclusion, esketamine holds potential as a dual-action therapeutic in patients with TRD and comorbid addiction; however, further large-scale studies are needed to explore its therapeutic magnitude, duration of benefit, safety, and effects on substance use-related outcomes.
Shelke et al. (2026) studied this question.