Treatment-resistant depression (TRD) remains a relevant issue in psychiatric practice, driving the exploration of innovative therapeutic alternatives. Ketamine and its enantiomer, esketamine, are emerging as treatments known for their effectiveness as rapid-acting antidepressants. Although previous comparative studies have highlighted some differences in their effects, they did not concurrently evaluate these 2 therapies in the same patient. The goal of this case series is to extend this investigation by comparing the efficacy of ketamine and esketamine in the same patient. This study included 5 patients diagnosed with TRD who had previously received treatment with intravenous ketamine as inpatients on the Mood Disorder Unit at San Raffaele Hospital in Milan. The patients subsequently underwent intranasal esketamine treatment as outpatients due to relapse. All patients received routine oral antidepressant therapy during both episodes, including selective serotonin reuptake inhibitors or serotonin norepinephrine reuptake inhibitors. The depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) before the first administration of each treatment (T0) and after 6 infusions of ketamine (3 wk) or after 8 administrations of esketamine (4 wk), respectively (T1). Four of the 5 patients showed a clinical response to intravenous ketamine, but only 1 patient showed a clinical response to intranasal esketamine (with clinical response defined as a 50% reduction in MADRS score). In particular, a better response to ketamine did not predict a good response to esketamine. Conversely, the only patient who did not respond to ketamine showed a good response to esketamine. All of the patients showed a significant and rapid reduction in MADRS scores after both treatments, but none of the patients achieved remission with either treatment (defined as a MADRS score<10). Findings from this case series suggest that both ketamine and esketamine are associated with significant reductions in depressive symptoms in TRD. We observed a generally better response to ketamine than to esketamine. This difference may be due both to the pharmacological effects of the R-ketamine (arketamine) component of intravenous ketamine and to the different settings in which the 2 treatments were administered (inpatient vs. outpatient). A better response to ketamine was not predictive of a better response to esketamine in our case series. A deeper insight into the side effects of the treatments (eg, dissociation) and into the clinical history of the patients would be helpful in better understanding the relationship between the 2 treatments.
