The study enrolled patients diagnosed with treatment-resistant depression who had not responded to at least two prior antidepressant therapies. Participants received esketamine nasal spray alongside standard-of-care treatment in a structured clinical setting. Anhedonia was assessed through validated self-report measures and clinician-administered scales over the course of treatment. Results showed that esketamine led to significant and sustained reductions in anhedonia scores compared to baseline, even in cases where overall depression severity showed slower or less dramatic improvement. This suggests that esketamine may have a direct effect on the neural pathways underlying reward processing, which are often impaired in treatment-resistant depression. Anhedonia—defined as the inability to feel pleasure—is recognized as a core symptom of major depressive disorder and bipolar depression. It is strongly linked to poorer prognosis, higher suicide risk, and functional impairment. Traditional antidepressants, while effective for mood symptoms, often fail to adequately address anhedonia. Esketamine, a glutamate receptor modulator derived from ketamine, has already been approved for treatment-resistant depression due to its rapid antidepressant effects. The current findings expand on this by suggesting that esketamine could offer a novel therapeutic option specifically for patients whose primary challenge is persistent anhedonia. The authors cautioned that while the results are promising, further research is needed to determine the long-term durability of these effects, the optimal dosing strategy, and whether esketamine’s benefits extend to broader patient populations. Still, this study provides encouraging evidence that targeting glutamatergic pathways could represent a major advance in managing difficult-to-treat depression symptoms.