Adverse Events and Measurement of Dissociation after the First Dose of Esketamine in Patients with TRD

Background: “Dissociation” comprises distinct phenomena, some of which are associated with esketamine treatment, and some may overlap with positive symptoms of psychosis. Relationships between dissociation and psychotic symptoms assessed by clinician report versus conventional rating scales were investigated in a post hoc analysis of data from the initial treatment session in an open-label, long-term safety, phase 3 study of esketamine plus a newly-initiated oral antidepressant in patients with treatment-resistant depression (TRD).Methods: Adverse events of dissociation or psychosis were examined via investigator report and the Clinician-Administered Dissociative States Scale (CADSS) and Brief Psychiatric Rating Scale-Plus (BPRS+), respectively, 40 minutes post-first esketamine dose. Range of CADSS total scores associated with investigator-reported severity of dissociation was determined by equipercentile linking. Logistic regression models and receiver operating curve analysis explored the CADSS cutoff point for determining the presence/absence of dissociation. The frequency of response to specific CADSS items was examined to investigate qualitative differences in the pattern of symptoms reported across investigator-reported levels of adverse event severity.Results: Dissociation was reported as an adverse event in 14.3% (109/764) of patients. The severity of most CADSS items increased with the severity of investigator-reported dissociation. No CADSS cutoff point discriminated well between the presence and absence of dissociation events. Hallucinations were reported as adverse events in 5 patients; none reported delusions.Conclusions: CADSS scores and severity of dissociation adverse events generally move in the same direction; however, there is substantial variability in this relationship. No signature profile of dissociative experiences was revealed, and psychotic symptoms were uncommon.