Rapid infusion of esketamine for unipolar and bipolar depression: a retrospective chart review

Major depressive disorder causes substantial clinical and socioeconomic burden, and about one third of patients do not achieve remission with available treatments; these individuals are commonly described as having treatment-resistant depression (TRD). Previous trials have shown that subanesthetic doses of ketamine, an NMDA receptor antagonist, can produce rapid antidepressant effects in TRD. Most published clinical work has used the racemic formulation RS-(±)-ketamine and infusion protocols of around 40 minutes; by contrast, clinical experience in anaesthesiology supports faster intravenous administration for higher doses, and relatively little evidence exists on the S-(+)-enantiomer (esketamine), its tolerability, and optimal infusion schedules. S Correia-Melo and colleagues set out to examine the efficacy, safety, and tolerability of a rapid intravenous infusion of esketamine (0.25 mg/kg administered over 10 minutes) in patients with TRD and bipolar depression. Depressive symptoms were assessed with the Montgomery–Åsberg Depression Rating Scale (MADRS) at baseline and at 24 hours, 72 hours, and 7 days after infusion; the Clinical Global Impression (CGI) was also recorded before and 7 days after treatment. The investigation used a retrospective chart-review approach to report clinical outcomes and adverse events associated with this faster infusion rate of esketamine.

This study used a retrospective chart review of patients treated with off-label intravenous esketamine. Treatment-resistant depression was defined as failure to respond to two or more adequate antidepressant trials (each at least 6 weeks). The clinical protocol excluded patients with psychotic disorder, prior dissociative disorders, dementia, substance use disorders, or uncontrolled hypertension. All participants continued naturalistic treatments for depression and comorbidities according to clinical need. Esketamine (Ketamin Dextrocetamine hydrochloride 50 mg/mL) was given at a standard dose of 0.25 mg/kg IV infused over 10 minutes. Primary endpoints were therapeutic response, defined as at least 50% reduction in MADRS from baseline, and remission, defined as MADRS <7. Adverse effects during infusion and follow-up were recorded. The local institutional review board approved the review and waived individual consent because data were anonymised. For analysis, descriptive statistics (mean, SD, median, IQR, min, max) for MADRS at each time point were reported. Temporal differences were tested using a linear mixed-effects model with Time and Presence of Clinical Comorbidity as fixed effects, a random intercept for each patient, and restricted maximum likelihood estimation. Model assumptions (normality of residuals, homogeneity of variance) were checked graphically. Mean differences were estimated via Tukey contrasts. Absolute and relative frequencies of response and remission were reported. Analyses were performed in R using the lme4 package.

MADRS data were available for 27 patients (from an initial 30), comprising 23 patients with unipolar TRD and 4 with bipolar depression. Before infusion the group had a high mean MADRS of 36.2±7.6. Median age at onset of the current major depressive episode was 38 years (IQR 26.0–50.0), and the lifetime median number of major depressive episodes was 4.0 (IQR 2.8–6.0). Psychiatric comorbidities included obsessive–compulsive disorder and social phobia (each 11.1%). Concomitant treatments were common: all patients were on antidepressants, 20 (74.1%) on atypical antipsychotics, 13 (48.1%) on benzodiazepines, and 5 (18.5%) on lithium. Most patients (17; 63.0%) had no medical comorbidity; among those with medical problems, cardiovascular conditions were most frequent (33.3%), followed by endocrine disease (18.5%) and cancer (7.4%). MADRS scores declined substantially after esketamine. Within 24 hours post-infusion, 16 patients (59.3%) met criteria for therapeutic response and 11 (40.7%) met remission criteria. By 7 days, 13 patients (48.1%) had shown therapeutic response and 10 (37.0%) were in remission. The linear mixed-effects model showed a significant effect of Time (Type II Wald χ2 = 66.846; df = 3; P < 0.001). Estimated mean differences versus baseline were large and statistically significant at 24 hours (mean change −18.73 ± 2.31), 72 hours (−17.51 ± 2.34), and 7 days (−17.16 ± 2.34), all P < 0.001. Presence of medical comorbidity had a positive but non-significant fixed-effect estimate (estimate = 3.397; SE = 4.929; Wald χ2 = 0.475; df = 1; P = 0.491). The most prominent adverse effect was dissociative symptoms of varying severity. Three patients (11.1%) experienced psychomimetic effects manifested as severe dissociation during infusion; two of these cases resolved within 3 weeks. The extracted text notes that 11.1% of patients reported the dissociative experience as very disturbing.

S Correia-Melo and colleagues interpret their findings as indicating rapid antidepressant effects after a single, fast (10-minute) infusion of esketamine in a naturalistic sample of TRD and bipolar depression patients. The magnitude and rapidity of MADRS score reductions were consistent with prior reports of ketamine’s rapid action. However, the authors emphasise that the rapid infusion rate appeared to be associated with distressing dissociative and psychomimetic effects in a subset of patients, which challenges suggestions from earlier studies that esketamine is uniformly better tolerated than racemic ketamine. The investigators note that the presence of dissociative symptoms did not consistently map onto clinical improvement; in four patients, severe side effects contrasted with symptomatic benefit. They discuss prior literature suggesting that dissociation may predict antidepressant response to ketamine but underline that this evidence is limited and methodologically constrained. Several important limitations are acknowledged: the retrospective, uncontrolled design; small sample size; lack of randomisation; concomitant psychotropic medications that could confound efficacy or pharmacokinetics; and absence of standardised instruments to quantify psychomimetic adverse effects. Given these constraints, the authors call for prospective, controlled trials that vary dose and infusion duration to more clearly define efficacy, safety, and tolerability of esketamine compared with racemic ketamine.

The case series suggests that a rapid 10-minute infusion of esketamine yields antidepressant effects broadly comparable to published data on RS-(±)-ketamine, but tolerability may be poorer, potentially related to the faster infusion rate. The authors recommend randomized, controlled studies directly comparing S-(+)-esketamine and RS-(±)-ketamine, with attention to dose and infusion time, to confirm these preliminary observations.