Discussion
TRD, ideation, psychiatric, depressive symptoms, MDD, depression, drug abuse
ADVERSE EVENTS, REMISSION, ADVERSE EVENT
Long-term safety as well as remission and response with weekly or biweekly esketamine nasal spray, combined with an oral antidepressant, is being evaluated in SUSTAIN-3, a global multicenter study of participants with TRD. The results of this study extend those of a 1-year open-label study of esketamine nasal spray for TRD [The safety profile of esketamine, with continuous intermittent dosing for up to 4.5 years in SUSTAIN-3 (2,769 cumulative patient-years), is consistent with its established safety profile in participants with TRD treated for up to 1 year [While ketamine abuse could not have been detected if participants in SUSTAIN-3 surreptitiously obtained drug from illicit sources (the urine drug screen we used did not assay for the r-enantiomer of ketamine or its metabolites), the protocol represents a rigorous approach to estimating the abuse liability in a clinical population. In this regard, adverse events related to abuse of esketamine (or ketamine) were not reported by the site clinicians. Moreover, diversion or excess use was putatively prevented in the clinical trial setting as only one dose could be dispensed during each dosing session and each administration of esketamine occurred under clinical supervision. Additionally, a study drug reconciliation process was implemented.A minority of study participants discontinued esketamine treatment due to an adverse event. Likewise, few (1.5%, 4/259) serious adverse events were attributed to esketamine by the site investigators. Long-term exposure to esketamine yielded no additional concerns or trends related to suicidal ideation and/or behavior, drug abuse, or drug dependence.While up to 20% of patients with MDD attempt suicide over their lifetime [Cognition was assessed across multiple cognitive domains and remained stable, without changes over time, for the total sample and for the subgroup of participants <65 years of age. In participants ≥65 years, performance on all tests of higher cognitive function remained stable or slightly improved. However, among participants ≥65 years, slowing of simple and choice RT occurred during the optimization/maintenance period; mean change from baseline for z-score calculations indicated that the changes were in a range that would be characterized as a small effect. Slowing increased through approximately week 100, after which RT performance appeared to stabilize through week 160. The clinical relevance of the observed slowing of RT is unclear. Overall, attentional ability was not affected, and in the absence of a placebo group it is difficult to determine to what extent the slowing of RT reflects an effect of study drug. Slowing of RT/processing speed, possibly associated with increasing IIV of RT performance over time, has been observed in multiple longitudinal studies in older individuals, including patients with MDD [On average, the participants showed improvement in measures of depressive symptoms and other efficacy assessments during the induction phase (first 4 weeks of exposure), which appeared to be sustained during the optimization/maintenance phase. At the interim data cutoff, the majority of participants were receiving the 84 mg or 56 mg esketamine dose, either weekly or every other week, to maintain clinical stability. In the remainder, the every-4-week dosing interval was used only by about 14% of participants at the 1 year mark and close to 17% of participants at the 2 year mark, as shown in Table The generalizability of our findings is limited by the potential bias related to which participants chose to continue (or not continue) from the parent study into this study, the exclusion of participants with significant psychiatric or medical co-morbidities or substance dependence, and the relative lack of racial heterogeneity (86.8% white). Furthermore, sample size decreases at later study time points may have implications for representativeness and/or generalizability of findings. Notably, the data set includes current, interim data, which continues to be updated.In summary, no new safety signal was identified and improvement of depression appeared to be sustained with long-term, intermittently-dosed esketamine in this study of participants with TRD.