This study represents the first real-world single-center cohort to include a significant number of patients with a history of ECT non-response in the current depressive episode. Overall, our study revealed significant alleviation of depression severity as well as reduction in suicidal ideations following esketamine nasal spray treatment in highly affected individuals, who had been hospitalized due to treatment-resistant depression. Our data confirm the efficacy of esketamine intranasal spray in a real-world setting. The seen improvement in depression severity occurred in both the investigator rated as well as the patient rated depression measures.

Our data indicate that patients with a history of electroconvulsive therapy non-response in the current major depressive episode are more severely affected. Although, the observed effects on the change in depression severity following esketamine treatment tended to be less pronounced in previous ECT non-responders, the differences were not statistically significant. Overall, there was no statistically significant negative impact of ECT non-response in the current episode on the change in depression severity nor on response and remission rates following esketamine treatment.

To the best of our knowledge, this is the largest report on the outcome of esketamine in ECT non-responders. Patients with a history of electroconvulsive therapy non-response usually have been excluded from participation in the TRANSFORM-1 and TRANSFORM-2 studies [6, 7], which assessed the acute efficacy of esketamine intranasal spray. In the ESCAPE-TRD trial comparing esketamine vs. quetiapine in patients receiving an SSRI or SNRI, ECT non-response was also an exclusion criterion [13]. Thus, there is lack of data regarding the efficacy of esketamine in ECT non-responders. Martinolli et al. included only one patient with a history of ECT [14]. In a French real-world sample, about 42% of the patients have been treated with ECT prior to esketamine, about 39% were resistant to ECT [19]. However, the authors did not report on the impact of ECT resistance on esketamine treatment outcome [19]. In a small case series, 6 out of 16 patients had a history of ECT [20]. In that study, history of ECT did not affect the outcome of esketamine nasal spray treatment, which is in line with our results. However, the authors did not report on the impact of ECT response status on esketamine treatment outcome [20]. Our results indicate that, in a naturalistic design, esketamine nasal spray can provide clinical improvement in individuals who previously did not respond to ECT in their current depressive episode. We observed that treatment effects tended to be smaller in previous ECT non-responders. However, since the results were not statistically significant, our results do not confirm the assumption that previous ECT non-response has a negative impact on esketamine treatment outcome. Additionally, the study may have been underpowered to detect between-group effects and a possible negative impact of ECT non-response on esketamine treatment outcome. Therefore, whether ECT non-response has a negative impact on esketamin treatment outcome or not should be investigated in future prospective, randomized controlled trials.

Since ECT non-responders benefited from esketamine treatment, our results support the approach to offer esketamine to those individuals with a history of ECT non-response in the current episode, particularly given that the array of treatment alternatives is limited after an unsuccessful course of ECT. Intermittent theta burst (iTBS) transcranial magnetic stimulation could also be a treatment option in patients after an unsuccessful series of ECT. Data on the outcome of ITBS in ECT non-responders are sparse. We recently reported that the probability of response to iTBS decreases dramatically to 10% in case of ECT non-response in the current episode [21]. Keeping in mind the limitations of the retrospective, non-randomized, naturalistic and unblinded study design, our results do no allow any comparison on the superiority of either esketamine or iTBS in previous ECT non-responders. Future head-to-head comparisons may answer this question, which would be a useful contribution to existing literature, when establishing a treatment algorithm for neuromodulatory treatments in major depression.

Overall, no life-threatening adverse events occurred during esketamine treatment. We observed one suicide attempt, which did not result in death. The number of treatment discontinuations (9.4%) was similar to other reports [7, 14]. Thus, esketamine treatment can be considered as a safe procedure.

In summary, we observed significant improvement of depression symptoms as well as suicidal ideations in highly affected inpatients with treatment-resistant depression and a history of ECT non-response in a real-world setting. No safety concerns became apparent, confirming the safety of esketamine intranasal treatment for real-world use.

This study is the largest study to report on the efficacy of esketamine in patients with a history of ECT non-response in the current episode, which has been an exclusion criterion in previous esketamine trials. It is also one of the largest single center real-world reports confirming the efficacy and safety of intranasal esketamine in real-world clinical practice. However, the study may have been underpowered to detected between-group effects of ECT pretreatment on treatment outcomes with esketamine.

Our results also demonstrate the safety and efficacy in a setting of patients with high prevalent psychiatric comorbidities. However, the main limitation of the study is the naturalistic and retrospective design with no randomization and no control group. Furthermore, patients also received standard of care treatment (psychotherapy, oral medication) in addition to esketamine. The ratings took place in routine clinical practice, thus the raters were not blinded. Furthermore, we did not use a dedicated suicidality scale. Instead, the suicidality item (item 10) of the MADRS was used to rate suicidality. The use of the suicidality item of the depression rating scale may have caused a parallelization in the rating of depression severity and suicidality. Another limitation of our study is that we did not collect data on the course of the previous ECT series. More detailed information on the course of ECT and the ECT technique, including electrode placement and number of sessions, would have been helpful.

Future studies should focus on patients with psychiatric comorbidities as well as patients with history of non-response to other neuromodulatory techniques. The management of esketamine non-response may be a focus of future clinical research.